Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M15/00—Inhalators
  • A61M15/0001—Details of inhalators; Constructional features thereof
  • A61M15/0003—Details of inhalators; Constructional features thereof with means for dispensing more than one drug
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M15/00—Inhalators
  • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
  • A61M15/0045—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters
  • A61M15/0046—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier
  • A61M15/0051—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier the dosages being arranged on a tape, e.g. strips
• • 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
  • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
• • 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
  • 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
• • 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
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M15/00—Inhalators
  • A61M15/0001—Details of inhalators; Constructional features thereof
  • A61M15/002—Details of inhalators; Constructional features thereof with air flow regulating means
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M15/00—Inhalators
  • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
  • A61M15/0045—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters
  • A61M15/0046—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier
  • A61M15/0048—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier the dosages being arranged in a plane, e.g. on diskettes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M15/00—Inhalators
  • A61M15/0065—Inhalators with dosage or measuring devices
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M15/00—Inhalators
  • A61M15/0065—Inhalators with dosage or measuring devices
  • A61M15/0066—Inhalators with dosage or measuring devices with means for varying the dose size
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M15/00—Inhalators
  • A61M15/06—Inhaling appliances shaped like cigars, cigarettes or pipes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
  • A61M11/06—Sprayers or atomisers specially adapted for therapeutic purposes of the injector type
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M15/00—Inhalators
  • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
  • A61M15/0045—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M2202/00—Special media to be introduced, removed or treated
  • A61M2202/06—Solids
  • A61M2202/064—Powder

Definitions

• the present invention relates to combined doses of medicaments for administration by an oral inhalation.
• combined doses of tiotropium and fluticasone are packaged to fit a new method of aerosolizing selected combined doses into air and more particularly, the invention relates to combinations of separate dry powder entities of medicaments constituting the combined doses intended for delivery in a single inhalation by a user.
• COPD chronic obstructive pulmonary disease
• asthma a respiratory condition characterized by airway inflammation, airway obstruction (at least partially reversible), and airway hyperresponsiveness to such stimuli as environmental allergens, viral respiratory-tract infections, irritants, drugs, food additives, exercise, and cold air.
• the major underlying pathology in asthma is airway inflammation.
• Inflammatory cell eosinophils, CD4+ lymphocytes, macrophages, and mast cells -- release a broad range of mediators, including interleukins, leukotrienes, histamine, granulocyte- colony-stimulating factor, and platelet aggregating factor. These mediators are responsible for the bronchial hyperreactivity, bronchoconstriction, mucus secretion, and sloughing of endothelial cells.
• COPD chronic obstructive pulmonary disease
• Chronic bronchitis is caused by excess mucus production in the lungs causing infection, which in turn causes inflammation and swelling, thus narrowing the bronchial tubes. This narrowing impedes airflow in and out of the lungs, causing shortness of breath.
• the condition usually begins with intermittent tracheobronchitis; however, repeated attacks occur until the disease and its symptoms persist continuously. If left untreated or if the patient continues to smoke, chronic bronchitis can lead to emphysema.
• DPI Dry powder inhalers
• an inhaler such that the efficacy becomes much higher than 10 - 20 %, thereby reducing the required amount of drug in the dose.
• corticosteroids are osteoporosis, growth retardation, candidiasis and muscle injuries and serious adverse effects of beta2-agonists, first choice among bronchodilators, are tremor, palpitations, headache, dizziness and oropharyngeal irritation.
• the Respimat produces a slow-moving cloud of medicament droplets with a high fine particle fraction in a prolonged dose delivery taking in the order of one second, which reduces the deposition in the oropharynx and raises the topical delivery to the correct site of action in the lung.
• the challenge of developing inhalers capable of producing a delivered dose with a high fine particle fraction in a prolonged dose delivery is discussed in another article in Journal of Aerosol Medicine, Volume 12, Supplement 1, 1999, Pp. S-3 - S-8 by the author Ganderton.
• a further document WO 01/78735, Sanders et al. claims a method of treating a respiratory disorder by administering an effective amount of the active ingredients formoterol and fluticasone separately, sequentially or simultaneously, provided that the ingredients comprise separate compositions.
• a dry powder inhaler containing formoterol and fluticasone in separate compositions is also claimed.
• Sanders et al. fail to teach how the skilled person should perform the method.
• Sanders goes on to teach that each of the active ingredients should be administered as separate compositions preferably once or twice daily.
• the claimed method may comprise an improvement of from 35 - 50 % (in glucocorticoid receptor translocation into the nucleus) over known combination therapies, but no relevant information is given as to why the claimed method is superior and novel in relation to prior art, e.g. as exemplified in the previously mentioned documents. Further, no distinctive characteristics of the dry powder inhaler are disclosed, separating the inhaler from prior art inhalers.
• a common denominator for the quoted documents is that they have as their first objective to simplify and improve asthma therapy for the user.
• a simple, once or twice daily administration by inhalation of well-known, well- documented medicaments, one of which selected to address symptoms of broncho-constriction and the other to address an underlying inflammation of the bronchi, has proved in clinical testing to result in high user acceptance and compliance with a prescribed dosing regimen.
• the results of this therapy are in many reports compared with therapy using only the one or the other medicament, sometimes with increased dosages, or compared to separate prescriptions of said medicaments, but without specific instructions to the user on how to combine the administration of the two medicaments to achieve the best effect.
• compositions of a bronchodilating drug preferably long-acting with fast onset like formoterol or tiotropium, and a corticosteroid, i.e. an anti-inflammatory drug e.g. budesonide or fluitcasone propionate, in mixtures using effective amounts of the drugs and varying ratios between drugs depending on the condition, age, sex etc of the patient.
• the disclosed inventions in the quoted documents rely on existing MDI or DPI inhalers to do the job of delivering the medicament mixtures using a single inhaler.
• the documents also teach various techniques of combining two drugs in order to simplify self- therapy for asthmatics.
• the disclosed techniques range from mixing the drugs in various ways into an indivisable medicament to supplying medical kits composed of separately packaged doses for insertion in separate inhalers for separate, sequential delivery of the selected drugs. In the latter case it is difficult to see where the improvement for the user is lying.
• the preferred embodiment of the inventions of the quoted documents is a mixture of the active drugs involving preferred prior art methods of preparing combined doses by mixing the ingredients. It is, however, difficult to mix dry medicament powders and optional excipients in a certain proportion consistently. The proportions in such a metered combined dose cannot easily be controlled, because the ratio of medicaments in an individual, combined dose depends significantly on the particle forces existing in each medicament powder, between particles of different medicaments and between medicament powders and dose packaging materials. Hence, actual variations in the ratio between active ingredients from combined dose to combined dose may be too large, causing serious problems if a potent ingredient is delivered in a higher or lower amount than expected.
• Bronchodilating medicaments such as short-acting beta2-agonists have been used for many years in control of asthma and particularly as rescue medicines, administered as needed.
• Salbutamol for instance, has very fast onset but short duration and may be administered, preferably by inhalation, several times per day in order to control attacks of dyspnoea, such that a puff of the drug provides immediate relief.
• Salmeterol and formoterol both long-acting beta2-agonists, are bronchodilators, which have been used with great success for more than 20 years in the treatment of asthma.
• Formoterol but not salmeterol, may be used as a rescue medicine for a quick relief of symptoms during an asthma attack.
• beta2-agonists have any significant effect on underlying inflammation of the bronchi.
• LABAs long-acting beta2-agonists
• a recent study in the US reports statistically positive evidence that salmeterol may be at the root of premature deaths caused by an acute asthma attack among salmeterol users with respiratory disorders. This is especially pronounced in the afro-american population, which has induced FDA to issue warning messages to users of salmeterol. It is too early to say if other LABAs are afflicted with this problem. Apparently, at this point no evidence points in this very disturbing direction for short-acting beta2-agonists.
• Anticholinergic agents e.g. ipratropium, oxitropium and tiotropium, particularly ipratropium bromide and tiotropium bromide, are also effective bronchodilators, but act in a different way to beta2-agonists, with relatively fast onset and long duration of action, especially ipratropium and tiotropium, of which the latter may be active for up to 24 hours.
• Adverse side effects for inhaled anticholinergic agents are insignificant, dryness of mouth and constipation are most common.
• fluticasone propionate like other anti-inflammatory steroids, does not have an immediate relief for a person suffering an asthma attack, but the drug will help to manage the inflammation and reduce the severity and number of exacerbations, if taken regularly.
• the present invention discloses a method for the administration by inhalation of co-ordinated, metered, combined doses of finely divided dry powders of (A) tiotropium and (B) fluticasone by means of an adapted inhaler designed for prolonged delivery of the combined doses.
• Metered dry powder medicinal combined doses are prepared comprising separately metered deposits of tiotropium, including pharmaceutically acceptable salts, enantiomers, racemates, hydrates, solvates or mixtures thereof, and fluticasone, including pharmaceutically acceptable salts, enantiomers, racemates, hydrates, solvates or mixtures thereof, in suitable quantities and ratios, optionally including diluents or other excipients.
• Tiotropium refers hereinafter to all the various chemical forms of the active substance, which are suitable for an intended therapeutic effect and particularly to tiotropium bromide.
• Flucasone refers hereinafter to all the various chemical forms of the active substance, which are suitable for an intended therapeutic effect and in particular to fluticasone propionate. Because of the potency of the respective drugs it may be necessary to dilute the active substances, tiotropium and fluticasone, separately using a pharmacologically acceptable diluent or excipient in order to secure the correct amounts as well as the ratio between the active substances in the formed combined doses.
• a user introduces the medicinal combined doses comprising the separated powder entities of tiotropium and fluticasone into an adapted inhaler device for a prolonged delivery of the combined doses during the course of a single inhalation.
• Delivery of the separated entities of powder deposits of tiotropium and fluticasone is preferably arranged to be sequential and more preferably such that tiotropium is delivered first and fluticasone shortly after, so that tiotropium may reach deeper into the lung for topical action and fast onset, while fluticasone may be topically deposited in the lung for best effect with as little systemic effect as possible.
• the delivered doses are composed of a high proportion of de-aggregated fine particles of the selected medicaments respectively, although the particle flows are preferably separated in time, whereby an intended prophylactic, therapeutic and psychologic effect on the user is achieved.
• pharmaceutical dry powder combined doses of tiotropium and fluticasone are disclosed.
• the doses are adapted for inhalation, for the prophylaxis or treatment of a respiratory disorder in a user.
• the pharmaceutical dry powder combined doses are prepared comprising separate entities of metered deposits of medicinally effective quantities of tiotropium and fluticasone respectively, optionally including diluents or excipients, where the sum of the entities constitutes the metered quantities of powder in the pharmaceutical, combined doses suitable for being introduced into an adapted inhaler device.
• the present method is set forth by the independent claim 1 and the dependent claims 2 to 8, and pharmaceutical combined doses are set forth by the independent claim 9 and the dependent claims 10 to 15 and the use of differently acting dry powder medicaments is set forth by the independent claim 16.
• FIG. 1 illustrates in top and side views a first embodiment of combined doses comprising two medicament entities deposited in separate compartments onto a dose bed
• FIG. 2 illustrates in top and side views a second embodiment of combined doses comprising three medicament entities deposited in separate compartments onto a dose bed
• FIG. 3 illustrates in top and side views a third embodiment of combined doses comprising two parallel medicament entities deposited onto a dose bed;
• FIG. 4 illustrates in top and side views a fourth embodiment of combined doses comprising several medicament entities and separating excipient entities deposited onto a dose bed;
• FIG. 5 illustrates in top and side views a fifth embodiment of combined doses comprising four medicament entities and separating excipient entities deposited onto a dose bed;
• FIG. 6 illustrates in top and side views a sixth embodiment of combined doses comprising two parallel medicament entities deposited on top of one another onto a dose bed;
• FIG. 7 illustrates in top and side views a seventh embodiment of combined doses comprising two medicament entities deposited on top of one another onto a dose bed, but separated by a deposited excipient entity;
• FIG. 8 illustrates in top and side views another embodiment of combined doses comprising two medicament entities separately deposited onto a dose bed
• FIG. 9 illustrates in top and side views yet another embodiment of combined doses comprising two medicament entities separately deposited onto a dose bed, but with some degree of overlap
• FIG. 10a illustrates in a sectional view an example of combined doses comprising two medicament entities deposited on top of one another but separated by a deposited excipient entity onto a dose bed and adjacent to the combined doses a nozzle in a starting position before the combined doses are released;
• FIG. 10b illustrates in a sectional view an example of combined doses comprising two medicament entities deposited on top of one another but separated by a deposited excipient entity onto a dose bed and adjacent to the combined doses a nozzle in a relative motion sucking up the powder particles to be dispersed into the air stream;
• the present invention discloses a new combination of active asthma drugs comprising two co-ordinated, metered, combined doses of the medicaments tiotropium, particularly tiotropium bromide, and fluticasone, in particular fluticasone propionate.
• the invention discloses a new therapeutic method of treating respiratory diseases like asthma by delivering such co-ordinated combined doses by an inhalation route to a user of a dry powder inhaler (DPI).
• DPI dry powder inhaler
• a medicament is defined as a pharmacologic substance, which comprises at least one chemically or biologically active agent.
• a medicament may exist in a pure form of one or more pure active agents, or a medicament may be a compound comprising one or more active agents, optionally formulated together with other substances, e.g. enhancers, carriers, diluents or exipients.
• excipient is used to describe any chemical or biologic substance mixed in with a pure active agent for whatever purpose. In this document, only medicaments in dry powder form are discussed.
• Tiotropium and fluticasone respectively are in this document generic terms for the respective active chemical substances including pharmaceutically acceptable salts, enantiomers, racemates, hydrates, solvates or mixtures thereof, which have a desired, specific, pharmacologic and therapeutic effect.
• a "dose bed” is henceforth defined as a member capable of harboring metered combined doses comprising one or more entities of dry powders, where the combined doses are intended for delivery to a user of a DPI in a single inhalation performed by the user.
• dose bed Different types of pharmaceutical blister packs or capsules are included in the term "dose bed".
• combined doses for treating asthma comprise metered, deposited entities of tiotropium and fluticasone respectively, optionally including excipients.
• the dose bed may be divided in two areas or incorporate two compartments, i.e. cavities of suitable volume, intended for deposited entities of dry powders of tiotropium and fluticasone respectively.
• the combined doses are packaged for a prolonged delivery, i.e.
• the delivery period for the combined doses is in a range from 0,01 to 6 s, usually in a range from 0, 1 to 2 seconds, delivery taking place sometime during the course of an inhalation as controlled by a purposefully designed DPI, adapted for combined doses.
• a DPI adopts an Air-razor method of gradual aerosolization of the combined doses by introducing a relative motion between an air-sucking nozzle and the powder doses.
• a preferred embodiment of metered combined doses use a dose bed split up in two separate compartments, where each compartment is intended for a metered deposition of a particular asthma medicament, in this case tiotropium and fluticasone respectively and more particularly tiotropium bromide and fluticasone propionate.
• Each compartment containing a metered entity of a medicament powder may then be sealed, e.g. by foiling, such that the different medicaments in the different compartments of the dose bed cannot interact in any way and cannot be contaminated by foreign substances or moisture.
• a common foil may enclose both compartments, and sealing between compartments may be excluded if individual sealing is not a GMP or medicinal requirement.
• a dose carrier is normally engaged to carry at least one dose bed loaded with combined doses, whereby the dose carrier may be inserted into a DPI for administering the combined doses, e.g. sequentially, to a user in need of treatment.
• a suitable carrier of combined doses is disclosed in our US Patent No. 6,622,723 Bl (WO 01 /34233 Al), which is hereby incorporated in this document in its entirety as a reference.
• a dose bed may be designed to act as a carrier, intended for direct insertion into a DPI.
• a suitable DPI for a continuous, prolonged dose delivery is disclosed in our US Patent No. 6,422,236 Bl, which is hereby incorporated in this document in its entirety as a reference.
• the dose bed may use separate indentations where different powders should be deposited, but flat target areas for separate deposits in a single plane on the dose bed are equally possible.
• the two medicaments are deposited sequentially dot- wise or string- wise onto two target areas of the dose bed.
• an isolating, biologically acceptable, inert substance like carbohydrates e.g. glucose or lactose
• inert substance e.g. glucose or lactose
• Forming combined doses comprising two medicaments in separate dry powder formulations may be done in different ways, known in prior art.
• the invention discloses that the finely divided powders to be included in the combined doses, i.e. tiotropium and fluticasone respectively, need not be mixed or processed together prior to dose forming and, indeed, should be kept separated during dose forming as well as after the respective entities of the combined doses are formed and sealed.
• the medicament entities of the combined doses are thus kept separated on the dose bed by suitable methods, as described in the foregoing, until the combined doses are about to be delivered by an inhalation route to a user and thereby preferably delivered in sequence, separated in time and therefore not mixed in the inhaled air leaving the mouthpiece of the DPI.
• the present invention offers inherent manufacturing advantages in comparison with prior art methods, which are based on mixing the active ingredients in bulk quantities, generally including diluents and/ or carriers before forming doses.
• the consequence of this mixing step in the manufacturing process apart from the regulatory problem of proving the mixture as such, is that many different blends of mixture must be made and verified to provide the correct ratios between the active ingredients in order to correspond to given therapeutic requirements, since different patients need different ratios, besides correct quantities.
• Disregarding the problem of verifying a mixture in bulk quantity, besides the problem of verifying the actual ratio between ingredients in each individual dose, a further consequence of the mixing step is the extra time required for producing, storing and verifying the mixture before and during the dose forming process. Also to be considered is the circumstance that it is not uncommon for active substances to have a limited period of stability, which is often even shorter when mixed with other active ingredients.
• the present invention avoids all of these problems, since the active ingredients are kept separate, optionally in a mixture with excipient(s), all the way through the dose manufacturing process, and, in fact, during packaging, distribution and storing until the moment when the user has introduced the combined doses into an inhaler and starts to inhale.
• the ratio between the active ingredients represents no problem, since it is a result of the metered quantities of the respective active ingredients constituting the combined doses.
• the powder entities of the combined doses of tiotropium and fluticasone may be sucked up simultaneously, partly or completely.
• the degree of mixing of the delivered powders leaving the DPI mouthpiece may vary between 0 and 100 % depending partly on the design of the DPI and its suction system, partly on the physical relative positions between deposited powder entities on the dose bed and partly on the relation between the dose bed and the suction system. For instance, if fluticasone is deposited first onto a dose bed and tiotropium is then deposited on top of the fluticasone, the powders will be mixed practically to 100 % when sucked up.
• the powder entities of the combined doses may be sucked up sequentially, e.g. if the powder entities are accessed one at a time by the suction system of the DPI in the course of a single inhalation.
• the suction system of the DPI in the course of a single inhalation.
• a pattern of physical positions and extensions in space of the deposited powder entities when forming the doses it will be possible to tailor the delivery of the powders in the doses such that the medicament powders get mixed into inspiration air to a selected degree between 0 and 100 %.
• Methods of dose forming include conventional mass or volumetric metering and devices and machine equipment well known to the pharmaceutical industry for filling blister packs, for example. Also see European Patent No. EP 0 319 131 Bl and US Patent No. 5, 187,921 for examples of prior art in volumetric and/ or mass methods and devices for producing doses of medicaments in powder form. Electrostatic forming methods may also be used, for example as disclosed in US Patent Nos. 6,007,630 and 5,699,649. Any suitable method capable of producing metered microgram and milligram quantities of dry powder medicaments may be used. Even completely different methods may be applied to suit the different medicaments selected to be part of the combined doses to be produced. A dose may hold together in a more or less porous entity by action of van der Waals forces, electrostatic forces, electric forces, capillary forces etc interacting between particles and particle aggregates and the dose bed material.
• Total mass in combined doses according to the present invention is typically in a range from 5 ⁇ g to 5 mg, but may extend to 50 mg. Regardless of which forming and filling method is being used for a particular medicament, it is important during dose forming to make sure that selected medicaments are individually metered and deposited onto their respective target areas or compartments of the dose bed.
• the target areas or compartments of the dose bed which aggregate to hold combined doses, may be of a same size or different sizes.
• the shape of compartments is governed by physical constraints defined by the type of dose bed used.
• a preferred type of dose bed is an elongated strip of a biologically acceptable, inert material, e.g. plastic or metal, between 5 and 50 mm long and between 1 and 10 mm wide.
• the strip is further divided into separate target areas or compartments arranged along the length of the elongated strip.
• the dose bed or, if necessary each compartment, receives an individual seal, for instance in the form of a foil, in a step immediately subsequent to the dose forming.
• An advantage of the present invention is that tiotropium and fluticasone are selected on merits of their own for inclusion in combined doses, in disregard of whether or not the respective formulations are compatible with one another.
• the regulatory process before introducing combined doses of e.g. tiotropium bromide and fluticasone propionate on the market may be drastically simplified.
• Another aspect of the invention is the use of the long- acting anticholinergic bronchodilator tiotropium instead of a long-acting beta2 -agonist, thereby eliminating the adverse side effects of the latter including possibly the risk of death in an asthma attack, the only trade-off being the minor side effects of tiotropium.
• a dose of tiotropium and a dose of fluticasone which are both long-acting, will permit a once daily administration by inhalation, in order to control asthma, thereby improving the quality of life for many users.
• Yet another advantage of the invention is the possibility of using pure, potent tiotropium and fluticasone substances for inclusion in the combined doses, without any included excipients.
• Combined doses are intended for administration in a single inhalation, either irregularly when need arises, or more typically as part of a daily management regime.
• the number of combined doses administered regularly may vary considerably depending on the type of disorder.
• Optimal dosages of tiotropium and fluticasone respectively for prevention or treatment of respiratory disorders may be determined by those skilled in the art, and will vary with their respective potency and the advancement of the disease condition. Furthermore, factors associated with the individual undergoing treatment determine correct dosages, such as age, weight, sex etc.
• the correct deposits by mass for the prepared medicaments may be calculated, such that metered deposits of each medicament entity to be included in the metered combined doses may be produced in a dose-forming step.
• the fine particle fraction i.e. particles having a mass median aerodynamic diameter (MMAD) less than 5 ⁇ m, per entity of the actual delivered doses must be taken into consideration.
• MMAD mass median aerodynamic diameter
• the inhaled tiotropium mass e.g. in the form of tiotropium bromide
• inhaled fluticasone e.g. in the form of fluticasone propionate
• the present invention makes it possible to deliver the combined doses, thus formulated, to the targeted sites of action.
• AD aerodynamic diameter
• AD for fluticasone in the delivered dose should be in a range from 2 to 8 ⁇ m
• AD for tiotropium in the delivered dose should be in a range from 1 to 5 ⁇ m.
• a dose of tiotropium should be the first to be sucked in followed by a dose of fluticasone.
• the present invention refutes prior art and claims that sequential delivery of combined doses, i.e. a dose of tiotropium first followed by a dose of fluticasone thereafter, is to be preferred compared to simultaneous delivery, e.g. combined doses in the form of a mixture.
• sequential delivery of combined doses i.e. a dose of tiotropium first followed by a dose of fluticasone thereafter, is to be preferred compared to simultaneous delivery, e.g. combined doses in the form of a mixture.
• the present invention presents a definite advantage regarding delivered dose efficacy and benefits for the user.
• the present invention makes use of proven dry powder formulations of tiotropium and fluticasone, particularly tiotropium bromide and fluticasone propionate, finely divided and adapted for separate deposition onto a common dose bed, normally with no mixing of the two active substances.
• Combined doses thus formed may be introduced into an adapted dry powder inhaler (DPI) such that the medicament entities constituting the combined doses may be aerosolized and delivered in the inspiration air during the course of a single inhalation through a DPI by a user.
• DPI dry powder inhaler
• Keeping the different medicament entities separated according to the invention may reduce the investment in time and resource necessary for getting the combined doses approved by the relevant regulatory bodies and released to the respective markets. For instance, no added substance to stabilize the combined doses will be needed and no testing to prove that an added substance is harmless needs to be performed.
• the present invention differs from prior art inhalers and related combined dose delivery methods by providing combined doses comprising two coordinated, individually proven asthma medicaments in form of separately deposited entities onto a dose bed.
• the combined doses are therefore not a single composition of asthma medicaments constituting a single physical entity.
• the invention discloses combined doses comprising at least two coordinated physical medicament entities loaded onto a common dose carrier with an objective of providing more efficient treatment of asthma. Inserted into an adapted DPI, the combined doses will be aerosolized during a single inhalation by a user.
• the entities of the combined doses of tiotropium and fluticasone will be delivered sequentially or optionally more or less simultaneously into the inspiration air. Whether the combined doses of medicaments are aerosolized sequentially or simultaneously depends on the physical form of the combined doses, i.e. how the deposited medicament entities are interrelated, and on the type of inhaler used to administer the combined doses.
• an inhaler which instantaneously subjects all powders of the combined doses to a jet-stream of air will aerosolize the aggregated deposits more or less simultaneously, whereby the medicament powders, still more or less agglomerated, become mixed into the air leaving the mouthpiece.
• an inhaler subjecting the combined doses to a jet stream gradually like a moving tornado attacking adjacent corn fields, one after the other, thereby not attacking all of the powder entities of the combined doses instantly, may aerosolize the entities of the combined doses gradually and efficiently over time.
• An object of the invention is to offer better control of dose release and to facilitate a prolonging of dose delivery in order to produce a high fine particle fraction (FPF) in the delivered, combined doses.
• FPF fine particle fraction
• Another object of the invention is to achieve a high ratio of delivered, combined doses relative metered, combined doses.
• it is possible to successfully apply the invention to prior art inhalers they tend to deliver the combined doses more or less mixed in too short a time, resulting in a poor FPF figure and low efficacy.
• a gradual, well-timed, sequential delivery of combined doses is possible using a new inhaler design where a relative movement is introduced between the combined doses and a suction nozzle through which the inspiration airflow is channeled.
• This arrangement utilizes the inhalation effort of the user to aerosolize the combined doses gradually for a prolonged period of dose delivery, thus using the power of the suction more efficiently and eliminating in most cases a need for external power to aerosolize the combined doses.
• a novel device for aerosolizing a dry powder dose is disclosed in our US Application No. US 2003/0192538 Al and a method of de-aggregating and dispersing dry medicament powder into air is disclosed in our US Application No. US 2003/0192539 Al . Both documents are hereby incorporated in this document in their entirety as references.
• a powder Air-razor method is advantageously used for aerosolizing the medicament powder entities of the combined doses, the Air-razor providing de-aggregation and dispersal into air of the finely divided medication powders.
• the particles of the deposited medicament powders By utilizing an effort of sucking air through a mouthpiece of an inhaler, said mouthpiece connected to a nozzle, the particles of the deposited medicament powders, made available to the nozzle inlet, are gradually de- aggregated and dispersed into a stream of air entering the nozzle.
• the gradual de-aggregation and dispersal is produced by the high shearing forces of the streaming air in connection with a relative motion introduced between the nozzle and the powder entities of the combined doses.
• the medicament powders are deposited onto a dose bed, such that the powder deposits occupy an area of similar or larger size than the area of the nozzle inlet.
• the nozzle is preferably positioned outside the area of deposits, not accessing the powder by the relative motion until the air stream into the nozzle, created by an applied suction, has passed a threshold flow velocity. Coincidental with the application of the suction or shortly afterwards the relative motion will begin such that the nozzle traverses the powder entities constituting the combined doses gradually.
• the high velocity air going into the nozzle inlet provides plenty of shearing stress and inertia energy as the flowing air hits the leading point of the border of the contour of the medicament entities, one after the other.
• This powder Air- razor method created by the shearing stress and inertia of the air stream, is so powerful that the particles in the particle aggregates in the powder adjacent to the inlet of the moving nozzle are released, de-aggregated to a very high degree as well as dispersed and subsequently entrained in the created air stream going through the nozzle. If the medicament deposits have been made in separate compartments of the dose bed and individually sealed, then obviously the compartments must be opened up first so that the nozzle can access the deposited powder entities in each compartment when suction is applied. Naturally, this is also true if the deposits share a common seal without an individual seal for each deposited entity.
• the present invention improves the efficacy of tiotropium/ fluticasone dose delivery, compared to the best selling inhalers on the market today, by at least a factor of two and typically 2.5. This is accomplished by raising the
• FPF ⁇ 5 ⁇ m in the delivered dose to more than 40 %, preferably to more than 50 %, by mass, compared to typically less than 30 % for prior art inhalers.
• asthma medicament delivery is dramatically improved compared to prior art performance, leading to important advances in delivering a majority of fine particles of the asthma medicaments of the combined doses to the intended target area or areas in the user's airways and lungs with very little loss of particles settling in the throat and upper airways.
• Administering asthma medicament combinations according to the present invention has a very positive therapeutic effect from a medical, psychological and social point of view on a host in need of asthma treatment with a co-ordinated combination of tiotropium and fluticasone.
• Figure 1 illustrates combined doses 100 comprising two different medicament entities deposited, 1 and 2, in separate compartments 21 and 22 onto a dose bed 20, said compartments may be capsules or blisters or moldings in the dose bed.
• An individual seal 13 for each compartment guarantees that the medicament doses cannot be contaminated by foreign matter or by one another.
• the illustrated doses are intended for a sequential delivery taking place during a single inhalation.
• Figure 2 illustrates combined doses 100 comprising three different medicament entities, 1, 2 and 3 in separate compartments 21, 22 and 23 similar to Figure 1, but arranged underneath the dose bed 20.
• entity 3 consists of the medicament of entity 2. It is thus possible not only to administer two medicaments, but also to compose combined doses of two medicaments with a very high ratio of mass between them.
• the illustrated deposited entities are intended for a sequential delivery taking place during a single inhalation.
• Figure 3 illustrates combined doses 100 comprising two different medicament entities, 1 and 2, laid out in parallel strips onto separate target areas 11 and 12 respectively onto the dose bed 20.
• a common protective foil 13 protects the medicaments of the combined doses from being contaminated by foreign matters.
• the illustrated entities are intended for a fully simultaneous delivery of the two medicaments taking place during a single inhalation.
• Figure 4 illustrates combined doses 100 comprising two different medicaments, 1 and 2, each comprising several deposited entities separated by deposited entities of an inert excipient 3.
• the deposited entities are laid out in a string of spots onto a target area 11 on a dose bed 20.
• the entities share a common seal 13.
• the combined doses are intended for a sequential delivery of incorporated medicament and excipient entities, said delivery taking place during an inhalation.
• the excipient deposits help to minimize unintentional mixing of the medicaments. If some mixing of medicaments can be accepted, then the excipient entities may be left out altogether.
• Combined doses composed of spot entities may of course comprise more medicaments than two.
• the mass ratio between medicament doses may be easily set by controlling the ratio between the number of spot entities per medicament in combination with the size of the respective spot entities in terms of deposited mass.
• the spot entities need not necessarily be circular in shape, they may take an elongated or elliptical form, depending on which types of combined dose forming methods are used.
• Figure 5 illustrates combined doses 100 comprising deposited entities representing up to four different medicaments, 1, 2, 4 and 5, separated by deposited entities of an inert excipient 3.
• the deposited entities are laid out in two parallel groups of two entities per group lined up in strips onto a common target area 11 on a dose bed 20.
• the deposited entities share a common seal 13.
• the excipient deposited entities help to minimize unintentional interaction of the medicament doses.
• the combined doses are intended for a combined parallel/ simultaneous and sequential delivery of incorporated medicament doses, said delivery taking place during a single inhalation.
• Figure 6 illustrates combined doses 100 comprising two different medicament entities, 1 and 2, each comprising a strip of deposited powder, medicament 1 deposited onto a target area 11 of a dose bed 20 and medicament 2 deposited on top of the entity of medicament 1.
• This method of forming combined doses is an alternative to the ones previously disclosed and may be used when a certain level of interaction or mixing of the medicaments may be tolerated.
• Figure 7 illustrates combined doses 100 comprising two different medicament entities, 1 and 2, and an excipient entity 3, each comprising a strip of deposited powder.
• Medicament 1 is deposited onto a target area 11 of a dose bed 20 and excipient 3 is deposited onto medicament 1 to insulate medicament 1 from a deposit of medicament 2 on top of the deposited entity of excipient 3.
• Figure 8 illustrates combined doses 100 comprising two different medicament entities, 1 and 2, of somewhat irregular shapes but separately laid out onto a common target area 11 of the dose bed 20.
• the illustrated entities are intended for a sequential delivery of the two medicament doses taking place during an inhalation.
• Figure 9 illustrates combined doses 100 comprising two different medicament entities, 1 and 2, of somewhat irregular shapes but generally separately laid out onto a common target area 11 of the dose bed 20.
• the illustrated deposited entities overlap slightly, resulting in an arbitrary mixture 9.
• the deposits are intended for a mostly sequential delivery of the two medicament doses taking place during a single inhalation.
• Figure 10a and 10b illustrate a delivery of combined doses 100 comprising two different medicament entities, 1 and 2, and an excipient entity 3, each comprising a strip of powder sequentially deposited in three different layers.
• a nozzle 25 with an established flow of air 26 going into the inlet is put in a relative motion, parallel to the dose bed 20, such that the nozzle passes over the combined doses beginning at the right side R and ending at the left side L of the dose bed.
• This Air-razor method results in a simultaneous, gradual delivery of medicament entities 1 and 2 together with the excipient entity 3.
• the powders of the entities are mixed into an aerosol 27 by the air flowing into the nozzle leading to simultaneous delivery of the two medicament doses and the excipient.
• This Air-razor method may be applied to all embodiments of the present invention and results in a simultaneous or sequential or a combined simultaneous/ sequential delivery of all included medicament doses and optional excipients.

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• 2003
  • 2003-11-18 SE SE0303091A patent/SE527191C2/sv not_active IP Right Cessation
• 2004
  • 2004-06-15 EP EP04749003A patent/EP1696882A1/de not_active Withdrawn
  • 2004-06-15 CA CA002529127A patent/CA2529127A1/en not_active Abandoned
  • 2004-06-15 AU AU2004246990A patent/AU2004246990A1/en not_active Abandoned
  • 2004-06-15 WO PCT/SE2004/000954 patent/WO2004110404A1/en active Application Filing

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