SE527191C2 - Inhaler device and combined doses of tiotropium and fluticasone - Google Patents

Abstract

The present invention discloses a method and pharmaceutical dry powder combined doses for administration by inhalation of metered dry powder combined doses of finely divided dry medication doses. Tiotropium and fluticasone are selected medicaments for forming the combined doses. Metered dry powder medicinal combined doses comprising separately metered deposits of medicinally effective quantities of each of the selected medicaments are prepared, in which the sum of the metered deposits constitutes the metered quantities of powder of the combined doses and the medicinal combined doses are introduced into an adapted inhaler device for a generally simultaneous or sequential prolonged delivery of the medicinal combined doses during the course of a single inhalation by a user, such that each one of the administered medicinal combined doses is composed of a high proportion of de-aggregated fine particles of the selected medicament or medicaments and directed to a selected location in the lungs.

Description

o o a n u: to chronic bronchitis and pulmonary emphysema year cigarette smoking. Air pollution and occupational exposure can also play a role, especially when combined with cigarette smoking. Heredity also causes some cases of emphysema due to antitrypsin deficiency.

Chronic bronchitis is caused by excess mucus production in the lungs which causes infection, which in turn causes inhalation and swelling, ie narrowing of the bronchial tubes. This constriction inhibits the flow of air into and out of the lungs and causes shortness of breath. The condition usually begins with irregular tracheobronchitis, however, repeated attacks occur until the disorder and its symptoms persist continuously. If left untreated or if the patient continues to smoke, chronic bronchitis can lead to pulmonary emphysema.

Administration of astral drugs through an oral inhalation route is today much in focus, due to the benefits offered such as fast and predictable initiation of action, cost-effectiveness and high grain fortification level for the user. Dry powder inhalers (DPI) are particularly interesting as a delivery tool, compared to other inhalers, due to the fl flexibility they offer in terms of nominal dose range, ie. the amount of active substance that can be administered in a single inhalation. Development efforts have largely been directed towards producing effective medicines and formulations for specific abnormal conditions and not so much towards the development of measurement of combined doses and a suitable delivery device, ie. inhaler.

When inhaling a combined dose of dry drug powder, it is important to obtain per mass a large particle fraction (FPF) of particles with an aerodynamic size preferably less than 5 microns in the inhaled air.

The majority of larger particles do not follow the airflow into the many branched airways, but get stuck in the throat and the upper airways. It is not uncommon for inhalers according to the state of the art to have an efficiency of only 10 - 20%, ie. only 10 - 20% of the measured dose I a u c o J I o o o o o oo Lfà mass is actually delivered as particles with an aerodynamic size less than 5 pm. Because most drugs can have unwanted side effects, e.g. steroids delivered to the system, it is important to keep the dosage to the user as accurate as possible and to design the delivery system, e.g. an inhaler, such that the effectiveness is much higher than 10 - 20%, thus reducing the required amount of drug in the dose. Common serious adverse effects of widely used corticosteroids are osteoporosis, growth retardation, candidiasis and muscle damage, and common serious adverse effects of beta2 agonists, the first choice among bronchodilators, are tremor, palpitations, headache, dizziness and throat irritation.

In the search for methods and devices to improve dose efficacy and reduce the doses necessary for adequate control of symptoms and respiratory disorders, some developments should be noted. For example, in an article in the Journal of Aerosol Medicine, Volume 12, Supplement 1, 1999, p. 33 - 39, authors Pavia and Moonen report clinical trials comparing therapy efficacy for a "mild fog inhaler", Respimat from Boeringer Ingelheim KG, with that for an MDI. Studies show that Respimat provides at least the same therapeutic bronchodilator effect as the MDI device but uses only half or less of the dosage in the MDI device. This Respimat produces a slow moving cloud of droplets of drug with a high particle fraction in an extended dose delivery that is in the order of one second, which reduces the deposition in the oropharynx and increases the local delivery to the right place of action in the lung. The challenge of developing inhalers capable of generating a delivered dose with a high particle fraction in an extended dose delivery is discussed in another article in Joumal of Aerosol Medicine, Volume 12, Supplement 1, 1999, p. 3 - 8 by author Ganderton.

Over the past ten years, research on respiratory disorders, their prophylaxis and treatment, has interestingly shown conclusively that concomitant administration of combinations of different drugs can significantly improve the clinical condition of patients. See, for example, NIH, National II ca now a 527 191 ax L, III 'I' Heart, Lung, and Blood Institute "Guidelines for the Diagnosis and Management of Asthma" NIH Publication No. 97-4051, July 1997, where a combined use of drugs with a long-acting beta2-agonist and a corticosteroid are recommended, with formoterol and fl uticason being mentioned as good examples of substances from the two groups.

The document emphasizes the importance of reducing the adverse effects of drugs in general and inhaled corticosteroids in particular by reducing the dosage to a minimum, which still keeps the medication under control. At the time these instructions were compiled, there were no medical products available that offered comprehensive combination medication along with appropriate administration tools, at least not to the American public.

The only possibility at the time was to combine by two prescribed different drugs, suitable for inhalation, one from each group and separate inhalers for administration. This method of treatment was well known to practitioners at the time. Numerous studies in the mid-1990s have shown that by combining a combined treatment it has been possible to reduce the dose of steroid compared to using the steroid as a background treatment and a short-acting beta2 agonist which in addition to improving rescue medication, lung function and reducing difficulty and frequency of attacks of dyspnoea.

For example, in Switzerland, patients diagnosed with asthma have been prescribed FORADIL (formoterol, a bronchodilator) along with PULMICORT (budesonide, an anti-inflammatory steroid) since the 1980s to treat their asthma. Until recently, however, different asthma drugs have generally been administered separately, sequentially or by different routes, but not in compositions comprising more than one active ingredient. However, there are public number of published patent applications and granted patents showing methods for the treatment of respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD) fancological compositions of various biological and chemical lung diseases as well as substances for this purpose, where the combinations offer benefits is 2 7 19 1 f == :. :: § ==: 5 the treatment of these disorders. See for example EP 0 416 950 Bl "Medicaments", EP 0 416 951 Bl "Medicaments comprising salmeterol and fl uticasone", EP 0 613 337 Bl "New combination of formoterol and budesonide" WO98 / 15280 "New combination", WOOO / 48587 " Combinations of formoterol and fl uticasone propionate for asthma ", WO01 / 70198 Al" Stabilized dry powder formulations ", WO01 / 7 8737 Al" Medical combinations comprising formoterol and budesonide ", WO 01/78739 A1" Medical combinations comprising formoterol and fl uticasone propionate ", WO 01/78745 A1 "Medical combinations comprising formoterol and fl uticasone propionate", WO 02/28368 A1 "New combination for the treatment of asthma", WO 03/13547 Al "Pharmaceutical composition comprising salmeterol and budesonide for the treatment of respiratory disorders". US 5,603,9 18 "Aerosol composition of a salt of ipratropium and a salt of albuterol", US 6,433,027 "Medicament compositions based on tiotropium bromide and formoterol fumarate", US 2003/0096834 "Pharmaceutical compositions", WO 00/47200 "Compositions of formoterol and a tiotropium salt ". However, the cited documents relate to the purposes of formulation, processing, stabilization and use of mixtures of at least two ingredients. The mixing ratios of active ingredients and compositions thereof including suitable carriers, solutions and excipients are generally focused on, but not methods of administration or devices for this purpose.

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 fornoterol and fluticasone separately, sequentially or simultaneously, provided that the ingredients comprise separate compositions. A dry powder inhaler containing formoterol and fl uticasone in separate formulations is also claimed. Sanders et al., However, fail to teach how those skilled in the art should perform the method.

Sanders goes on to teach that each of the active ingredients should be administered as separate compositions once or twice daily. The document shows that the claimed method may include an increase in 35 - 50% (in glucocorticoid receptor translocation into the cell nucleus) over known combination therapies, but no relevant information is given why the claimed method is superior and new in relation to the state of the art, e.g. as exemplified in the previously mentioned documents. Furthermore, no distinctive features of the dry powder inhaler are shown which distinguish it from prior art inhalers.

A common denominator for the cited documents is that their first purpose is to simplify and improve asthma therapy for the user. A simple, once or twice daily administration, by inhalation of well-known, well-documented drugs, one of which has chosen to target the symptoms of bronchoconstriction and the other to target an underlying inhalation of the bronchi, has been shown in clinical trials to result in high user acceptance and accommodating of a prescribed dosing regimen.

The results of this therapy are compared in many reports with therapies using only one or the other drug, sometimes with increased dosages, or compared to separate prescriptions of the drugs, but without specific instructions to the user on how to combine the administration of the two drugs to obtain best effect.

It comes as no surprise to those skilled in the art that a combination of two well-documented drugs would be a good idea, one to provide rapid relief of symptoms and the other to treat the cause in the long run. Many of the cited documents teach compositions of a bronchodilator, preferably a long-acting one with rapid onset as well as formoterol or tiotropium, and a corticosteroid, i.e. an anti-inflammatory drug e.g. budesonide or fluticasone propionate, in mixtures that use effective amounts of the drugs and varying ratios of the drugs depending on the patient's condition, age, sex, etc. The findings in the cited documents rely on existing MDI or DPI inhalers to do the job of delivering the drug mixtures using a single inhaler. 5 7 i 1. f: fr:. 122: å The documents also teach different techniques for combining two drugs to simplify self-therapy for asthmatics. The techniques shown range from mixing the drugs in various ways into an indivisible drug to providing kits composed of separately packaged doses for insertion into 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 lies.

None of the cited documents indicate that the claimed drug composition offers a therapeutic benefit, or cite clinical studies that support such benefits in comparison with separate, sequential delivery of the equivalent active drugs. On the contrary, most documents teach that there is no therapeutic difference between the delivery of the active drugs substantially simultaneously, sequentially or separately.

Furthermore, none of the cited documents discuss in depth the importance of formulating dry powder drugs for inhalation, e.g. the claimed compositions, so as to arrive at an optimal distribution of aerodynamic particle diameters for optimal therapeutic effects of the selected drugs. There is also no general recommendation for a sequence according to which the different drug doses, if physically separated, should be delivered to an inhaling user, probably because a concept of single inhalation delivery, dose combinations composed of separate, individual doses of each drug is unusual if not completely unknown in the state of the art. Likewise, a concept is practically unknown in the prior art for reducing the quantities of active ingredients in the combined doses by implementing a huge increase in the efficiency of the unlearned dosage by introducing an extended dose slowdown.

The preferred embodiment of the inventions in the cited documents is a mixture of the active drugs including methods according to the prior art for the preparation of combined doses by 527 191 sf mixing of the ingredients. However, it is difficult to consistently mix dry drug powders and optional excipients in a certain proportion.

The proportions of such a measured combined dose cannot be easily controlled because the ratio of drugs in an individual, combined dose significantly depends on the particle forces existing in each drug powder, between particles in different drugs and between drug powder and dose packaging material. Consequently, actual variations in the ratio of active ingredients from combined dose to combined dose may be excessive, causing serious problems if a potent ingredient is unlearned in a higher or lower amount than expected.

Bronchodilators such as short-acting betaZ agonists have been used for many years in the control of asthma and especially as a rescue medicine, administered as needed. Salbutamol, for example, has a very rapid onset but short duration and can be administered, preferably by inhalation, several times a day to control attacks of dysponia, so that a puff of the drug provides immediate relief. Salmeterol and formoterol, both long-acting beta2 agonists, are bronchodilators that have been used with great success for more than 20 years in the treatment of asthma. Forrnoterol, but not salmeterol can be used as a rescue medicine for a quick relief of symptoms during an asthma attack. However, none of the beta2 agonists has a significant effect on the underlying inflammation of the bronchi. In addition to the already well-known adverse side effects of long-acting beta2-agonists (LABAs), a recent study in the US reports statistically positive evidence that salmeterol may be the root of premature death caused by an acute asthma attack among salmeterol users with respiratory disorders. This is particularly pronounced in the African American population, which has prompted the FDA to issue warning messages to salmeterol users. It is too early to say whether other LABAs are suffering from this problem. Obviously at this time no evidence points in this very disruptive direction for short-acting beta2 agonists. 5 2 7 1 1 É ": í": '°.: °: ": §.:": §: ":":: -' if) 3 ": '._:: __: _:' z: "': E' 'Anticholinergic agents, e.g. ipratropium, oxitropium and tiotropium, especially ipratropium bromide and tiotropium bromide, are also effective bronchodilators, but act differently against betaQ agonists, with relatively rapid initiation and long duration of action, especially ipratropium and tiotropium, of which the latter may be active during up to 24 hours.

Adverse side effects with inhaled anticholinergics are insignificant, dry mouth and constipation are most common.

Fluticasone, on the other hand, especially fl uticasone propionate, is an anti-inflammatory corticosteroid, which over the past two decades has proven to be very successful and potent drugs to reduce inflammation in the nasal passages and bronchial tissue to facilitate breathing.

However, fluticasone propionate, like other anti-inflammatory steroids, does not have immediate relief for a person suffering from an asthma attack, but the drug will help manage the injection and reduce the severity and number of aggravations, if taken regularly.

National palliative care institutions in the lest countries have been late in actively supporting the use of combination therapy in the previous days due to unfounded fears, as it turned out, of negative long-term side effects of the beta2 agonist, although in the last ten years combined treatment has been listed as an open opportunity for physicians in the treatment of asthma patients. Consequently, the full potential has not been realized for the obvious benefits that can be achieved with a laxative controlled therapy using a combination of a bronchodilator and an anti-inflammatory drug for the management of asthma and COPD.

One reason for the slowness has been a lack of understanding among researchers and scientists of the complex mechanisms of respiratory diseases. Today, although much remains to be learned about asthma and COPD, many trials have conclusively shown that combination therapy works and provides good therapeutic results for many asthmatics.

Accordingly, there is a need for improvements in methods of treating respiratory disorders using combined, consistently measured doses of tiotropium and fl uticason for coordinated administration using a new type of inhaler device.

SUMMARY The present invention provides a method of administration by inhalation of coordinated measured, combined doses of finely divided dry powders of (A) tiotropium and (B) fl uticasone by means of an adapted inhaler designed for a prolonged delivery of the dose combination. Measured combined doses of medicinal dry powders are prepared including separately measured deposits of tiotropium, including pharmaceutically acceptable salts, enantiometers, racemic isomers, hydrates, solutions or mixtures thereof, and fl uticasone including pharmaceutically acceptable salts, enantiometers, racemic isomers, hydromeric isomers, hydrates in appropriate quantities and conditions, optionally including diluents or other excipients.

"Tiotropium" hereinafter refers to all the various chemical forms of the active substance which are suitable for the intended therapeutic effect and in particular tiotropium bromide. "Fluticasone" hereinafter refers to all the various chemical forms of the active substance, which are suitable for the intended therapeutic effect, and in particular to a ason uticasone propionate. Due to the potency of the respective drug, it may be necessary to dilute the active substances tiotropium and fl uticasone using a separate pharmacologically acceptable diluent or excipient to ensure the correct amounts as well as the ratio of the active substances in the formulated dose combinations. Accurate measurement of the units of deposited powder constituting the dose combination A 'and B', respectively, can control the very small, individual narrow quantities of active substances. Accordingly, the sum of the measured units constitutes the measured powder quantities of the dose combination. 527 191 are; r 'ß! I I I II II I I A user introduces the medical dose combination comprising the separated powder units of tiotropium and anpass uticasone into an adapted inhaler device for prolonged delivery of the dose combination during a single inhalation. Delivery of the separated units of powder deposits of tiotropium and fl uticason is arranged to be Sequential and preferably so that tiotropium is delivered first and fl uticason shortly thereafter, so that tiotropium can reach deeper into the peripheral lung for local absorption and rapid initiation, while fl uticason can locally deposited in the lung for best effect with as little systemic effect as possible. The delivered doses are composed of a high proportion of deaggregated particles of the selected respective drugs, even if the particles are separated in time, whereby an intended prophylactic, therapeutic and psychological effect is achieved in the user.

Furthermore, combined doses of pharmaceutically dry powder of tiotropium and fl uticasone are shown. The doses are adapted for inhalation, for prophylaxis or treatment of a user's respiratory disorders. The combined pharmaceutical doses of dry powder are prepared comprising separate units of measured deposits of medically effective quantities of tiotropium and fl uticasone, optionally including diluents, or the powder quantities in the pharmaceutical dosage combination are subject to excipients, where the sum of the units measured is introduced into an adapted device.

The present method is determined by the independent claim 1, and the dependent claims 2 to 8, and the combined pharmaceutical doses are determined by the independent claim 9 and the dependent claims 10 to 15, and the use of various active dry powdered drugs is determined by the independent claim 16. 527 191 ¿..__ ..: .___. n, fl BRIEF DESCRIPTION OF THE DRAWINGS The invention together with further objects and advantages thereof can best be understood by reference to the following detailed description read in conjunction with the accompanying drawings, in which: FIG. 1 illustrates from above and from the side a first embodiment of combined doses comprising two drug units deposited in separate compartments on a dose bed, FIG. 2 illustrates a top and side view of a second embodiment of combined doses comprising three drug units deposited in separate compartments on a dose bed, FIG. 3 illustrates a top and side view of a third embodiment of combined doses comprising two parallel drug units deposited on a dose bed, FIG. 4 is a top and side view illustrating a fourth embodiment of combined doses comprising multiple drug units and separating excipient units deposited on a dose bed; FIG. 5 illustrates from above and from the side a fifth embodiment of combined doses comprising four drug units and separating excipient units deposited on a dose bed, FIG. 6 illustrates, seen from above and from the side, a sixth embodiment of combined doses comprising two parallel drug units deposited on top of each other on a dose bed, FIG. 7 illustrates from above and from the side a seventh embodiment of combined doses comprising two drug units deposited on top of each other on a dose bed, but separated by a deposited excipient unit, o O nu lol l I 000000 no en 00 I on 00 n I 0 o 00 I 27 f: '191 FIG. 8 illustrates from above and from the side another embodiment of combined doses comprising two drug units separately deposited on a dose bed, FIG. 9 illustrates, seen from above and from the side, yet another embodiment of combined doses comprising two drug units separately deposited on a dose bed, but with some degree of overlap, FIG. 10a illustrates in a cross-sectional view an example combined doses comprising two drug units deposited on top of each other, but separated by a deposited excipient unit, on a dose bath and adjacent to the combined doses a suction tube in an initial position before the combined doses are released, FIG. 10b illustrates in a cross-sectional view an example of combined doses comprising two drug units deposited on top of each other but separated by a deposited excipient unit, on a dose bed and adjacent the combined doses a suction tube in relative motion which sucks up the powder particles to be dispersed in the air stream.

DETAILED DESCRIPTION The present invention discloses a novel combination of active asthma drugs comprising two coordinated measured combined doses of the drugs tiotropium, especially tiotropium bromide, and fl uticasone, especially fl uticasone propionate. In a further object, the invention discloses a novel therapeutic method for treating respiratory disorders such as asthma by delivering such coordinated dose combinations via an inhalation route to a user of a dry powder inhaler (DPI).

"Asthma" is used in this document as a generic term for the various respiratory disorders known in the medical field.

| Q o Q n Q u o no 527q 191 In the context of this application, the word "medicinal product" is defined as a pharmacological substance comprising at least one chemically or biologically active ingredient. Furthermore, a drug may exist in a pure form of one or ren your pure active ingredients, or a drug may be a composition comprising one or fl your active ingredients, optionally formulated together with other substances, e.g. amplifiers, carriers, diluents or excipients. Hereinafter, "excipient" is used to describe any chemical or biological substance mixed with a pure active ingredient for any reason. In this document, only drugs in dry powder form are discussed. Tiotropium and fl uticasone, respectively, are in this document generic terms for the respective active chemical substances including pharmaceutically acceptable salts, enantiomers, racemic isomers, solutions or mixtures thereof, which have a desired, specific, pharmacological and therapeutic effect.

A "dose bed" is hereinafter referred to as an element capable of accommodating measured combined doses comprising one or two units of dry powder, the dose combination being intended for delivery to a user of a DPI in a single inhalation by the user. Various types of pharmaceutical blister packs or capsules are included in the term "dose bed". In the present invention, a dose combination for the treatment of asthma comprises measured deposited units of tiotropium and fl uticasone, optionally including excipients. The dose bed can be divided into several areas or include two sections, ie. cavities of suitable volume, intended for deposited units of dry powder of tiotropium and fl uticason, respectively. In a preferred embodiment, the combined doses are packed for a continuous prolonged release, i.e. the delivery period for the combined doses is in the range of 0.01 to 6 seconds, usually in the range of 0.1 to 2 seconds, the delivery occurring at some point during the course of an inhalation, controlled by an appropriately designed DPI, adapted for administration of combined doses. Advantageously, such a DPI adopts an air planer method with gradual aerosolization of the combined doses by introducing a relative movement between an air suction tube and the powder doses. Advantages of prolonged release of a dose for inhalation are disclosed in U.S. Patent No. 6,571,1793 B1 (WO02 / 24264 A1), which is hereby incorporated by reference in its entirety.

A preferred embodiment of metered combined doses uses a dose bed divided into at least two separate compartments, each compartment being intended for a metered deposition of a specific asthma drug, in this case tiotropium and fl uticasone, respectively, and more particularly thioptropium bromide and fl uticasone propionate. Each compartment containing a measured unit of a drug powder can then be sealed, e.g. through foil, so that the different drugs in the different compartments of the dosing bed can not interact in any way and can not be contaminated by foreign substances or moisture. Alternatively, a common foil may enclose both compartments, and sealing between compartments may be omitted if individual sealing is not a GMP or medical requirement. A dose carrier is normally employed to carry at least one dose bed loaded with a dose combination, whereby the dose carrier can be inserted into a DPI for administration of the combined doses, e.g. sequentially, to a user in need of treatment. A suitable carrier of combined doses is disclosed in our U.S. Patent 6,622,723 B1 (WO100 / 34233 A1) which is hereby incorporated by reference in its entirety. However, a dosing bed can be designed to act as a carrier intended for direct insertion into a DPI. A suitable DPI for continuous, prolonged dose delivery is disclosed in our U.S. Patent 6,422,236 B1, which is hereby incorporated by reference in its entirety.

If complete physical separation of the deposited units of the two drugs forming the dose combination is not required, but some degree of overlap or mixing is acceptable from a physical, chemical and medical point of view, then other methods of separating the deposited units may be implemented. Depending on the degree of mixing allowed or in some cases even desired, different methods of separating drug units 527 191 must be allowed to be introduced. For example, the dosing bed can use separate depressions where different powders are to be deposited, but flat target areas for separate deposits in a single plane on the dosing bed are also possible. In another embodiment, the two drugs are deposited sequentially pointwise or sternly on two target areas on the dose bed. If necessary, in order to stop chemical or biological interaction or dissolution caused by, for example, the incompatibility of nearby medicinal powders, a biologically acceptable neutral substance such as carbohydrates, e.g. glucose or lactose is deposited between the nearby drug units. Once the combined dosage units have been fully formed, they are usually sealed from the ingress of dirt and moisture through a foil covering the entire dosage bath. A method for depositing micrograms and milligram quantities of dry powder using electric field technology is disclosed in our U.S. Patent 6,592,930 B2 which is hereby incorporated by reference in its entirety.

The formation of a dosage combination comprising two drugs in separate dry powder formulations can be done in various ways known in the art. The invention shows that the finely divided powders to be included in the dose combination, e.g. tiotropium and fluticasone, respectively, do not need to be mixed or processed together prior to dosing and should indeed be kept separate during dosing as well as after the respective units in the dosing combination have been designed and sealed.

The drug units in the dose combination are thus kept separated on the dose bed by suitable methods as described above, until the dose combination is to be delivered via an inhalation route to a user, and thus suitably delivered sequentially, separated in time and therefore not mixed in the inhaled air leaving the mouthpiece. in this DPI.

The present invention inherently offers manufacturing advantages over prior art methods, which are based on mixing the active ingredients in bulk quantities, generally o n o c co 527 191 i? including diluents and / or carriers before dosing.

The consequence of this mixing step in the manufacturing process, in addition to the regulatory problems of determining the mixture as such, is that many different mixtures of mixtures must be made and verified to provide the right ratios of the active ingredients to meet given therapeutic requirements, as different patients need different conditions, in addition to correct quantities. Apart from the problem of verifying a mixture in bulk quantity, in addition to the problem of verifying the actual ratio of the ingredients in each individual dose, an additional consequence of the mixing step is the extra time required for production, storage and verification of the mixture before and during the dose processing process. Also to be taken into account is the fact 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 because the active ingredients are kept separate, optionally in a mixture with excipient (s), all the way through the dose manufacturing process, and de facto, during packaging, distribution and storage until the moment the user has introduced the dose combination into an inhaler and begins to inhale. Furthermore, the ratio between the active ingredients does not represent a problem, since it is a result of the measured dose quantities of each active ingredient that constitutes the dose combination. Although the drug units in the combined doses are separated on the dose bed until the doses are to be delivered by a DPI, it is perfectly possible in accordance with alternative embodiments of the invention to aspirate the doses more or less mixed into the inhaled air during inhalation. For one purpose, the powder units in the combined doses of tiotropium and fluticasone may be aspirated simultaneously, partially or completely. The degree of mixing of the delivered powders leaving the nozzle in this DPI can vary between 0 and 100% depending in part on the construction of this DPI and 5 2 7 191. . . . . . . . .. fi! its suction system, partly on the physical relative positions between powder units deposited on the dosing bed and partly on the ratio between the dosing bed and the suction system. If, for example, fl uticason is first deposited on a dose bed and tiotropium has been deposited on top of fl uticason, the powders will be practically 100% mixed in the air when absorbed.

For another purpose, the powder units in the combination of doses can be sucked up sequentially. for example if the powder units are accessed one at a time by the suction system of this DPI during the course of a single inhalation. Of course, in that case, no mixing of the powders will take place, since the delivery of the doses in the inhaled air will be sequentially separated in time.

For a third purpose, by selecting a pattern of physical positions and extensions in the space of the deposited powder units when designing the doses, it will be possible to tailor the delivery of the powders in the doses so that the drug powders are mixed in the inhaled air to a selected degree between 0 and 100%.

Dosage design methods include conventional mass or volumetric measurement and devices and machinery well known in the pharmaceutical industry for filling, for example, blister packs.

See also European Patent EP 0 319 131 B1 and US Patent US 5,187,921 for examples of prior art in volumetric and / or mass methods as well as devices for producing doses of powdered drugs. Electrostatic design methods can also be used. for example as disclosed in U.S. Patents 6,007, 630 and 5,699,649. Any suitable method capable of producing saturated micrograms and milligram quantities of dry powder drugs can be used. Completely different methods can also be applied to suit the different drugs chosen to be part of the dose combination to be produced.

A dose can be poured together in a more or less porous unit by the action of van der Waals forces, electrostatic forces, electric forces, capillaries 5 2 7 191 lf? forces etc. that interact between particles and particle aggregates and the dose bed material.

Total mass in combined doses in accordance with the present invention is typically in the range of 5 pg to Smg, but may range to 50 mg. Regardless of the design and filling method used for a particular drug, it is important during dose design to ensure that selected drugs are individually measured and deposited in their respective target areas or compartments on the dosing bed. The target areas or compartments of the dose bed, which are combined to hold combined doses, may be of the same size or different sizes. The form of the wards is governed by physical limitations defined by the type of dose bed used. As an example, a preferred type of dose bed is an elongated strip of a biologically acceptable, neutral 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 extended strip. The dose bed or, if necessary, each compartment, receives an individual seal, for example in the form of a foil, in one step immediately following the dose design.

An advantage of the present invention is that tiotropium and fl uticasone are selected on their own merits for: reduction in a dose combination, regardless of whether the respective formulations are compatible with each other.

Consequently, the regulatory process prior to the introduction of a dose combination of e.g. tiotropium bromide and fl uticasone propionate on the market are drastically simplified. Another object of the invention is the use of the long-acting anticholinergic bronchodilator tiotropium instead of a long-acting beta2 agonist thereby eliminating the adverse effects of the latter, including the possible risk of death in an asthma attack, the only compromise being the minimal side effects of tiotropium. For a further purpose, the combination of a dose of tiotropium and a dose of fl uticasone, both of which are long-acting, will allow administration once daily, to control asthma, thereby improving the quality of life for many users. Yet another advantage of the invention is the ability to use pure substances of potent tiotropium and fl uticasone for inclusion in the combined doses, without any included excipients.

Table 1. Typical dosages of tiotropium and fl uticason in asthma therapy Active drug- Dosage delivered- Dosage ingredient delivered area per dose (pg) area per day for adults (us) tiotropium 1 -50 1- 1 00 fl uticason 40-2000 50-5000 u Combined doses are intended for administration in a single inhalation, either irregularly when the need arises, or more typically as part of a daily handling regimen. The number of combined doses administered regularly can vary considerably depending on the type of disorder. Optimal dosages of tiotropium and fl uticasone, respectively, for the prevention or treatment of respiratory disorders can be determined by those skilled in the art, and will vary with their respective potency and the progression of the disease state. Furthermore, factors associated with the individual undergoing treatment determine correct doses, such as age, weight, sex, etc.

Depending on what constitutes the correct doses per day and the number of planned administrations per day, the correct mass deposits for the selected drugs can be calculated, so that metered deposits of each drug unit to be included in the metered dose combination can be produced in a dose design step. When calculating a correct nominal mass deposition for each drug unit, the particle fraction must be taken into account, ie. particles having an aerodynamic mass median diameter (MMAD) of less than 5 μm, per unit of the actual delivered dose. As discussed above, the efficiency of inhalers differs significantly and it is therefore important to include the expected efficiency of the selected inhaler in the calculation of a suitable 5:47 191: 11 nominal mass in the deposited unit or units.

What constitutes appropriate amounts of the two drugs and the respective optimal masses of tiotropium and fl uticasone, respectively, depend on factors described above, but in general the inhaled tiotropium mass, e.g. in the form of tiotropium bromide, per dose be in a range from 1 to 50 pg, suitably between 2 to 40 pg and inhaled fluticasone, e.g. in the form of fl uticasone propionate per dose in a range from 40 to 2000 pg, preferably between 50 to 500 pg.

There is generally a medical need to direct the delivery, ie. the deposition, of inhaled doses of a drug to the optimal site of action, where the therapeutic effect is the best possible in the lung, including the deep lung, either for a topical effect or for a systemic effect. Returning to the case in question, it is of course desirable to control the deposition of the combined doses of tiotropium and fl uticasone to their preferred sites of action in the lung in order to obtain the highest possible overall efficacy for each dose with a minimum of adverse side effects. Aerodynamic particle size is a major factor that greatly affects where particle deposition is likely to occur in the lung. From the target area point of view, it is therefore desirable to tailor the physical formulations of the respective drug powder in the dose combination in such a way that they result in a favorable aerodynamic particle size distribution per mass in the delivered dose. The present invention makes it possible to deliver the combined doses, thus formulated, to the target areas of action. Available data indicate that for best performance, the ((aerodynamic diameter) of fl uticasone in the delivered dose should be in the range of 2 to 8 μm while the AD of tiotropium should be in the range of 1 to 5 μm.

Another circumstance to consider is the order of delivery for the combined doses of the present invention. The first air sucked in by a person inhaling reaches deep into the peripheral lung and air that is then sucked in gradually fills the lungs. What this 0 ø u I J o I I I o! I aff I: II .O t. U: ooz I ooo k .. va: nov ooun: nun aouonooo co uunoopoooo oc r ao n .. 5 2 7 ii generally means that powders intended for a peripheral lung deposition should be inhaled early in the inhalation cycle to maximize deposition in this area while powder intended for, for example, a central lung deposition should be inhaled slightly later in the cycle to maximize deposition in the central lung. Since available data suggest that a bronchodilator, e.g. tiotropium should be suitably deposited in the peripheral lung region and an anti-inflammatory steroid, e.g. fl uticasone, in the central lung area a dose of tiotropium should be the first to be absorbed followed by a dose of fluticasone. Provided that an adapted DPI is available for sequential delivery of the combined dose in the course of a single inhalation, the present invention refutes the state of the art and claims that Sequential delivery of combined doses, i.e. a dose of tiotropium first followed by a dose of fl uticason thereafter, is preferable to co-administration, e.g. dose combination in the form of a mixture.

Compared to the prior art invention, a definite advantage in terms of dose efficiency and benefits standpoint presents the present to the user.

The present invention uses proven powder formulations of tiotropium and fl uticasone, especially tiotropium bromide and fl uticasone propionate, finely divided and adapted for separate deposition on a common dose carrier, normally with no mixture of the two active substances. Combined doses thus designed can be introduced into a custom dry powder (DPI) inhaler so that the drug units constituting the combined doses can be aerosolized and delivered into the inhaled air during a user's single inhalation through a DPI. Keeping the various deposited drug units separate in accordance with the invention can reduce the investment in time and resources necessary to have the combined doses approved by the relevant regulatory authorities and released to the respective markets. For example, no added substance will be needed and no test to prove that an added substance is harmless will need to be performed.

The present invention differs from prior art inhalers and related combined dose delivery methods by providing dose combinations comprising two coordinated, individually tested asthma drugs in the form of separately deposited units on a dose bed. The combined doses are therefore not a single combination of asthma drugs that form a single physical unit. The invention discloses combined doses comprising at least two coordinated physical drug units loaded on a common dose bed for the purpose of providing more effective treatment for asthma. Inserted into a custom DPI, the combined doses will be aerosolized during a single inhalation by a user. Conveniently, the units in the dose combination of tiotropium and fl uticasone will be sequentially or optionally delivered more or less simultaneously into the inhaled air. Whether the combined doses of drugs are aerosolized sequentially or simultaneously depends on the physical form of the dose combination, i.e. how the deposited drugs are related to each other, and the type of inhaler used to administer the combined doses.

It is obvious that an inhaler, which instantly exposes all the powder in the dose combination to an air jet stream, will aerosolize the aggregated deposits more or less simultaneously, while the drug powders, still more or less agglomerated, are mixed into the air leaving the nozzle. In contrast, an inhaler that exposes the combined doses to a jet stream gradually, like a moving tornado attacking a corn field piece by piece, does not attack all the units in the combined doses instantly, but can aerosolize the units in the combined doses gradually over time. An object of the invention is to offer better control of dose release and enable an extension of the dose delivery to produce a high particle fraction (FPF) in the delivered combined doses. Another object of the invention is to achieve a high ratio in delivered combined doses relative to measured combined doses. Although it is possible to successfully apply the invention to prior art inhalers, these tend to: 1H deliver the combined doses more or less mixed for too short a time, resulting in poor FPF number and low efficiency. On the other hand, a gradual, well-timed, sequential delivery of the dose combination is possible using a new inhaler design in which a relative movement is introduced between the combined doses and a suction tube through which the inhaled air is channeled. This arrangement utilizes the user's inhalation attempts to aerosolize the combined doses gradually over an extended period, thus using the force of suction more efficiently and in most cases eliminating the need for external force to aerosolize the combined doses. A new device for aerosolizing a dry powder dose is disclosed in our U.S. application US 2003/0192538 A1 and a method for deaggregating and dispersing dry drug powder in air is disclosed in our U.S. application US 2003/0192539 A1. Both documents are hereby incorporated by reference into this document in their entirety.

A powder air planer method is advantageously used to aerosolize the drug powder units in the combined doses, the air planer providing deaggregation and dispersion into air of the divided medicated powders. When attempting to suck air through a nozzle in an inhaler, the nozzle being connected to a suction tube, the particles in the deposited drug powders, which are locally available for the suction tube inlet, are gradually deaggregated and spread into an air stream entering the suction tube. The gradual deaggregation and dispersion is generated by the high shear forces in the flowing air in connection with a relative movement introduced between the suction tube and the powder units in the combined doses. In a preferred embodiment, the drug powders are deposited on a dose bed, so that the powder deposits occupy an area of equal or larger size than the area of the suction tube inlet. The suction tube is suitably located outside the deposition area, and does not access the powder through the relative movement until the air flow into the suction tube, created by an applied suction, has passed a threshold fl speed of fate. Simultaneously with the application of the suction or shortly thereafter, the relative movement will begin so that the suction tube gradually passes over the powder units constituting the combined doses. Air 527 191 QS,. ... o oo o o o o o o o o o oo which enters the suction tube inlet at high speed offers a lot of cutting stress and inertial energy when the fl destructive air hits the leading edge of the drug contours' boundary contour, one after the other.

This powder air planer method created by the cutting stress and inertia of the air stream is so powerful that the particles in the particle aggregates in the powder near the inlet of the movable suction tube are released, deaggregated to a very high degree as spread and then trapped in the created air stream passing through the suction tube. If the drug deposits have been placed in separate compartments on the dosing bath and individually sealed, then obviously the compartments must first be opened up so that the suction tube can enter the deposited powder units in each compartment when suction is applied. Of course, this is also true if the deposits share a common seal but individual seal for each deposit. An arrangement for cutting foil is shown in our Swedish patent publication SE 517 227 C2 (WOO2 / 24266 A1), which is hereby incorporated into this document in its entirety for reference. Depending on how the units are laid out on the dosing boat, the suction tube will either suck up the powder units sequentially or in parallel or in some series / parallel combination.

The present invention improves the efficacy of tiotropium / fl uticason dose delivery compared to the best selling inhalers on the market today by at least a factor of 2 and typically 2.5. This is accomplished by increasing the FPF <5 μm in the delivered dose to more than 40%, preferably more than 50% per mass, compared to typically less than 30% for prior art inhalers. The implication of this extensive improvement and the use of an anticholinergic with a beta2 agonist is significantly less adverse reactions in users, even in eliminating the risk of death, due to high doses of beta2 agonists or corticosteroids systemically or in the wrong parts. of the airways.

Thus, the quality of delivered asthma drugs improves dramatically compared to prior art performance, leading to significant advances in the delivery of a majority of the particles of asthma drugs in the combined the doses to the intended target area or areas of the user's airways and lungs with very little loss of particles remaining in the throat and upper airways. Administration of asthma drug combinations in accordance with the present invention has a very positive therapeutic effect from a medical, psychological and social point of view in a user in need of asthma treatment with a coordinated combination of tiotropium and fl uticasone.

DETAILED DESCRIPTION OF THE DRAWINGS Referring to reference numerals 1 to 100 in the drawings in which like numerals indicate like elements throughout the numerical views of ten different embodiments of combined doses comprising at least two deposited units of two drugs on a dose bath illustrated in Figures 1-10 are shown. here as a non-limiting example.

Figure 1 illustrates combined doses 100 comprising two different deposited drug units, 1 and 2, in separate compartments 21 and 22 on a dose bed 20, the compartments may be capsules or blister packs or orifices in the dose bed. An individual seal 13 of each compartment guarantees that the drugs cannot be contaminated by foreign matter or by each other. The illustrated deposits are intended for a sequential delivery that takes place during a single inhalation.

Figure 2 illustrates combined doses 100 comprising three different drug units, 1, 2 and 3, in separate compartments 21, 22 and 23 similar to Figure 1, but arranged below the dose bed 20. In addition to a separate arrangement with compartments on the dose bed 20 and the respective prescriptions. 13, the main difference between Figure 1 and Figure 2 is that unit 3 consists of the drug from unit 2. It is thus possible not only to administer two drugs, but also to combine dose combinations of two drugs with a very large mass ratio between them. De. . . . ..

Q? The illustrated deposits are intended for a sequential delivery that takes place through a single inhalation.

Figure 3 illustrates combined doses 100 comprising two different drug units, 1 and 2, laid out in parallel strips on separate target areas 11 and 12, respectively, on the dose bed 20. A common protective foil 13 protects the drugs in the dose combination from being contaminated by foreign matter. The illustrated units are intended for a fully simultaneous delivery of the two drugs that occur during a single inhalation.

Figure 4 illustrates combined doses 100 comprising two different drugs, 1 and 2, each comprising the number of deposited units separated by deposited units of an inactive excipient 3. The deposited units are laid out in a string of dots on a target area 11 on a dose bed 20. The units share a common seal 13.

The dose combination is intended for a sequential delivery of included drug and excipient units, the delivery taking place during an inhalation. The deposits of excipient help to minimize unintentional mixing of the drugs. If a certain mixture of the drugs can be accepted, then the excipient units can be completely omitted. Dosage combinations composed of dot units may, of course, comprise more than two drugs.

The mass ratio of drug doses can be easily determined by controlling the ratio of the number of points per drug in combination with the size of the respective dot units in terms of deposited mass.

Of course, the dot units do not necessarily have to be circular in shape, they can have an elongated or elliptical shape depending on the types of method for combining doses used.

Figure 5 illustrates combined doses 100 comprising deposited units of up to four different drugs, 1, 2, 4, and 5, separated by deposited units of an inactive excipient 3. The deposited units are laid out in two parallel groups of two units per group in lined strips on a common target area 11 on a dose bed 20. They deposited 527 191 .... u 2% 'no oo uaon. a u Q oo units share a common seal 13. Excipient deposited units help minimize unintended drug-drug interactions. The combined doses are intended for a combined parallel / simultaneous and Sequential delivery of included drug doses, the delivery taking place during a single inhalation.

Figure 6 illustrates combined doses 100 comprising two different drug units, 1 and 2, each comprising a strip of deposited powder, drug 1 deposited on a target area 11 on a dose bed 20 and drug 2 deposited on top of the drug 1 unit. design of a combination of doses is an alternative to those previously shown and can be used when a certain level of interaction between the drugs can be tolerated.

Figure 7 illustrates combined doses 100 comprising two different drug units, 1 and 2, and an excipient unit 3, each comprising a strip of deposited powder. Drug 1 is deposited on a target area 11 on a dose bed 20 and excipient 3 is deposited on top of drug 1 to isolate drug 1 from a deposition of drug 2 on top of the deposited unit of excipient 3.

Figure 8 illustrates combined doses 100 comprising two different drug units, 1 and 2, of somewhat irregular shapes but laid out separately on a common target area 11 on the dose bed 20. The illustrated units are intended for a sequential delivery of the two drugs that occur during an inhalation .

Figure 9 illustrates combined doses 100 comprising two different drug units, 1 and 2, of somewhat irregular shapes but generally laid out separately on a common target area 11 on the dose bed 20. The illustrated deposited units overlap easily, resulting in an arbitrary mixture 9. The deposit is intended for a largely sequential delivery of the two drugs that take place during a single inhalation. 527 191 M. .. _ ........ ...

Figures 10a and 10b illustrate a delivery of combined doses 100 comprising two different drug units, 1 and 2, and an excipient unit 3, each comprising a strip of powder sequentially deposited in three different layers. A suction tube 25 with an established air gap 26 entering the inlet is set in a relative motion, parallel to the dose bath 20, so that the suction tube passes over the combined doses starting on the right side R and ending at the left side L of the dose bed. This air planer method results in simultaneous, gradual delivery of the drug units 1 and 2 together with the excipient unit 3. The powders in the units are mixed into an aerosol 27 through the air which flows into the suction tube, which leads to simultaneous delivery of the two drug doses and the excipient. This planing method can be applied to all embodiments of the present invention and results in simultaneous or Sequential or a combined simultaneous / Sequential delivery of all included drug doses and optional excipients.

Claims (15)

527 191 30 PATENT REQUIREMENTS A dry powder inhaler device comprising metered combined dry doses of powdered substances intended for delivery through the inhaler device, characterized by substances A and B selected for the formulation of pharmaceutical combined doses, where A represents tiotropium or a pharmaceutically acceptable salt, an enantiomeric, racemic isomer , hydrate, or solution including mixtures thereof, and B represents fl uticasone or a pharmaceutically acceptable salt, an enantiomer, racemic isomer, hydrate, or solution including mixtures thereof, and wherein substances A and B may optionally further include excipients, to measure medicinal combined dry powder doses in preparation comprise separately deposited units of medically effective quantities of each of the substances in selected target areas on a common dose bed, the sum of the deposited units constituting the measured quantities of powder in the combined doses, and the combined doses being introduced. in the inhaler device adapted for prolonged powder delivery of the combined doses during a single aspiration, the powders in the combined doses being aerosolized and divided, and generally having a particle fraction of at least 30-50% of the delivered powder mass, and the particles in the combined doses either simultaneously or separately in sequence or in a combination thereof. An inhaler device according to claim 1, characterized in that the deposited powders in the combined doses are aerosolized gradually over a time period of 0.01 - 6 seconds, but within the time of a single powder delivery. An inhaler device according to claim 1, characterized in that tiotropium bromide and fl uticasone propionate are selected as substances, optionally including excipients to form the combined doses. P401 SE00l0303091-3 5 2 7 19 1 'Zl An inhaler device according to any one of claims 1 or 3, characterized in that the combined doses are coordinated so that when the combined doses are introduced for delivery into the adapted inhaler device, the measured units of the tiotropium dose are first sucked up and then the measured units of the fluticasone dose are sucked up. whereby tiotropium powder and fl uticasone powder will be delivered separately. An inhaler device according to any one of claims 1 or 3, characterized in that the combined doses are coordinated so that when the combined doses are introduced for inhalation in the adapted inhaler device, the measured units of the tiotropium dose are sucked up together with the measured units of the fl uticasone dose, the powdered substances emitted as a mixed aerosol. An inhaler device according to any one of claims 1 or 3, characterized in! of measuring dry medicinal combined powder doses were prepared comprising separately deposited units of substances, where aerodynamic particle size for tiotropium is generally in a range 1 to 5 μm and for fl uticason generally in a range 2 to 8 μm, and the combined doses are coordinated so that the units in the tiotropium dose is aspirated first and the units in the fl uticasone dose are aspirated thereafter. An inhaler device according to claim 1 or 3, characterized in that the combined doses of dry medicinal powder are prepared to a total mass in a range from 5 pg to 50 mg. Inhaler device according to claim 1 or 3, characterized in that deposited units of the included substances are separated from each other on a dose bed, intended for introduction into the adapted P401SE00l0303091-3 5 2 7 1 fi * "in 3.2 inhaler device, so that the substances are not harmful can be mixed with each other after the creation of the combined doses. Combined doses of dry pharmaceutical powders, adapted for delivery from a dry powder inhaler device, characterized in that substances A and B are selected to form pharmaceutical combined doses, wherein A represents tiotropium or a pharmaceutically acceptable salt, an enantiomer, racemic isomer , hydrate, or solution including mixtures thereof, and B represents fl uticasone or a pharmaceutically acceptable salt, enantiomer, racemic isomer, hydrate, or solution including mixtures thereof, and wherein substances A and B may optionally further include excipients, the combined doses of pharmaceutical dry powders are prepared to comprise separate, deposited units of medically effective quantities of the respective selected substances on a common dose bed, intended for introduction into the dry powder inhaler device, a sum of the deposited units constituting the combined doses of pharmaceutical dry powders, when the combined doses have int reduced in an inhaler device adapted for prolonged delivery of the combined doses and a single suction is applied to the inhaler device, the powders are aerosolized in the combined doses, the units of the combined doses being delivered either simultaneously or separately in sequence or in a combination thereof. Combined doses according to Claim 9, characterized in that the deposited powders in the combined doses are aerosolized gradually over a period of 0.01 to 6 seconds, but within the time of a single suction. Combined doses according to claim 9, characterized in that tiotropium bromide and fl uticasone propionate are selected as substances, optionally including excipients to form the combined doses. P401 SE0010303091 -3 5527 191 33 Combined doses according to one of Claims 9 or 1, characterized in that the units in the combined doses are coordinated so that when the combined doses are introduced into the adapted inhaler device, the measured units are first sucked up by the tiotropium dose and then the measured units are sucked up. of the fl uticasone dose, with tiotropium powder and fl uticasone powder being delivered separately. Combined doses according to any one of claims 9, or 11, characterized in that the units in the combined doses are coordinated so that when the combined doses are introduced into the adapted inhaler device, the measured units of thiotropium are sucked up together with the measured units by a fl utica dose. wherein the powders will be delivered as a mixed aerosol. Combined doses according to claim 9, characterized in that the combined doses are prepared to provide a total mass in a range from 5 pg to 50 mg. Combined doses according to Claim 9 or 11, characterized in that deposited measured units of powder are separated from one another on a dosing bath, so that the substances cannot be adversely mixed with one another after the creation of the combined doses. P401 8500 / 0303091-3