DE202005004660U1 - Medicinal product useful for treating airway diseases comprises a unit dose of a dry powder mixture of tiotropium and a carrier in a moisture-impermeable container suitable for use in an inhaler - Google Patents

Abstract

Medicinal product comprises a unit dose of a dry powder mixture of tiotropium and a carrier with a mean particle diameter of at 10 mu m in a moisture-impermeable container suitable for use in an inhaler. ACTIVITY : Antiasthmatic. No biological data given. MECHANISM OF ACTION : None given.

Description

Territory of invention

The The present invention relates to a medical product comprising at least one inhalable, predosed dry powder dose Tiotropium with at least one excipient, preferably in a moisture-proof, dry container brought in. The invention further relates to a method for Optimization and maintenance of the delivered particulate matter dosage (FSD) of a medical dose of the tiotropium substance during the Time of use and over the period of use of the product.

additional Advantages and other features of the present invention will become Part set forth in the following description and become Part for the experts in the field will be apparent upon review of the following or can learned from the practical application of the present invention become. The advantages of the present invention can be realized and to be obtained as specifically shown in the appended claims is. As will be appreciated, the present invention is in the Able to encompass other and different embodiments, and their various details may be modifications in various Obviously, without departing from the present invention departing. The description is to be considered as illustrative and not restrictive become.

background the invention

asthma and chronic obstructive pulmonary disease (COPD) more than 30 million people in the US. More than 100,000 deaths each Year become these states attributed. A hindrance to the airflow through the lungs is the main feature of each of these tracheal diseases, and the one used Medication in the treatment is often similar.

The Chronic Obstructive Pulmonary Disease (COPD) is a common one chronic lung disease, which includes chronic bronchitis and Includes emphysema. The reasons the COPD are not complete known. Experience shows that the most important cause of chronic Bronchitis and emphysema is cigarette smoking. air pollution and occupational burdens can also play a role, especially in connection with cigarette smoking. Inheritance caused also some emphysema cases, due to an alpha-antitrypsin deficiency.

The Administration of asthma medications through an oral inhalation route is now very much in the center, because of the advantages offered how fast and predictable start of operation, cost effectiveness and higher Degree of comfort for the user. Dry powder inhalers (DPI) and in particular pre-dosed DPIs are considered as an administration tool compared to other inhalers interesting, because of the flexibility they have in terms of provide nominal dose range, i. H. the amount of active substance, which can be administered in a single inhalation.

tiotropium, and especially the bromide salts thereof, is an effective bronchodilator Active ingredient. Tiotropium has a relatively rapid onset effect and a long duration of action lasting up to 24 hours or more can. Tiotropium reduces the cholinergic affecting the vagus Tonus of the smooth muscle, which is the most reversible component at COPD is. Tiotropium has shown that it is relatively insignificant Side effects in clinical investigations causes dry mouth and constipation are perhaps the most common Symptoms. As it is common It is very difficult to properly diagnose and diagnose asthma and COPD there both disturbances can be present together It is beneficial to patients who have a temporary or permanent bronchial Narrowing that causes shortness of breath suffer with a low but effective dose of a long-acting Tiotropium, preferably tiotropium bromide, because of its fast-acting effect, the long duration of action and the low side effects. Nowadays a bronchial dilatation is going on Drug such as Tiotropium often in combination with prescribed other asthma medication and administered to a combined To provide therapy, for. B. Combination of a bronchodilator and an anti-inflammatory Treatment.

The efficiency of a dose depends largely on the delivery of a stable and high particulate matter dosage (FSD) from the dry powder inhaler. The FSD is the inhalable dose level from the dry powder inhaler with an aerodynamic particle size below 5 microns. Thus, when inhaling a dose of any type of dry drug powder, it is important to obtain in the mass a high level of fine particle fraction (FPF) of particles having an aerodynamic size preferably below 5 μm in the inhaled air. The majority of the larger particles (> 5 μm) do not follow the air flow in the many branches of the But remains stuck in the throat and the upper respiratory tract, where the drug can not unfold its intended effect, but instead can be harmful to the user. It is also important to keep the dosage as accurate as possible for the user and to maintain stable efficiency over time, and that the dosage of the drug during normal storage does not deteriorate. For example, Boehringer Ingelheim KG (BI) tiotropium bromide sells under the brand name Spiriva ^®. Surprisingly, we have found in a recent study of inhalability of Spiriva ^®, that the Spiriva ^® / HandiHaler ^® system from BI for administration of doses contained in gelatin capsules comprising, by inhalation poor performance and a short in-use stability.

Consequently there is a need for an improvement in tiotropium in general, and in particular regarding medical products with inhalable, predose Dry powder cans of z. B. tiotropium in terms of reaching a high and stable FSD performance from a dry powder inhaler over the Lifespan and the period of use of the product.

It There are several prior art methods based on tiotropium are applicable for the preparation of drug formulations, the suitable for inhalation with a dry powder inhaler. In such a process tiotropium and a drug carrier are in a liquid disbanded and then stirred and after obtaining a mixture, the liquid is evaporated. The mixing of substances with different particle sizes is another method which teaches how to make a uniform powder mixture by means of a special Mixing method is produced. Yet another method teaches like a permanent one Dosing in a mixer is performed to a uniform To obtain powder recipe. Other methods that are used can, to a uniform powder formulation of the drug carrier or the drug carrier and the tiotropium substance include use of air or another pharmaceutically acceptable gas a suspension medium in a load or a continuous mixing operation; a uniform mixture of the particles of the excipient or the drug carrier and Tiotropium and optionally one or more additional pharmacologically active Ingredients (API).

The Preparation of a formulation of tiotropium and a drug carrier, at which the amount of tiotropium very low, d. H. <1: 100, is the quality of the excipient from the utmost Importance for the FSD. Various prior art methods are aimed at one improved production of excipients to the FSD of the active Component to improve, for. B. coating the excipient to represent a fluorine-added particle surface. Other surface changes and surface treatment methods can be applied to the FSD performance to improve the recipe.

It is not uncommon in the art, a desiccant in the material of the container or in the device or in the outer packaging for the device to integrate. The amount of desiccant is usually at This type of construction is very small and the requirements for the container seal to to protect the drug powder, stay the same if the desiccant does not open before opening Destroyed product shall be.

Methods for forming cans of tiotropium formulations include conventional bulk, gravimetric or volumetric dimensions and apparatus and machinery used in the pharmaceutical industry for filling e.g. B. blister packs are well known. See also WO 03/27617 A1, WO 03/66437 A1, WO 03/66436 A1, WO 03/26965 A1, WO 02/44669 A1 and DE 100 46 127 A1 . DE 202 09 156 U1 for examples of the prior art for volumetric and / or mass processes and devices for producing drug doses in powder form. Electrostatic production methods can also be used, for example as in US 6,007,630 and US 5,699,649 disclosed.

A highly suitable process for depositing amounts of microgram and milligram dry powder uses electro-field technology (ELFID) as disclosed in our US Pat. No. 6,592,930 B2, which is incorporated herein by reference in its entirety. In this method, the flowability of the powder is unimportant because the powder particles are transported from a bulk source to a dose bed in a dose forming step without relying on gravity, but only by applying the technology of electrical and electrostatic force to a measured amount from powder, ie one dose, to a dose bed which may be a blister pack, a capsule or a high density container as disclosed in the present invention. An advantage of this electric field dose generation method is that it is not necessary to add large drug carrier particles to the drug powder because good powder flowability is not an issue. Drug carrier who to the active agent, in particular tiotropium, to dilute the drug to obtain a predosed dose in the inhaler greater than 100 μg. Preferably, the drug carrier is finely divided so that the mass median aerodynamic diameter (MMAD) is less than 10 μm. Tests confirm that particulate matter dosage (FSD) from a dose formed by the electric field method is significantly better than FSD from a similar dose formed by other methods commonly used in the art. The electric field method is also very well suited for combined doses such as tiotropium mixed with APIs or separately forming and depositing measured amounts of the active drugs in the same container.

dry powder inhalers, Use the peelable films to protect the dose in use are known in the art. The peelable lid foil is from a laminate with heat-sealed sealant (HSL) made on the PVC layer of the base layer after the powder was filled in a shaped cavity in the base layer. The process of filling is very important because every powder that's hot, too sealing surfaces remains, the quality the seal negatively affected. A removable HSL is always much more sensitive and difficult to seal compared to usual Sealing films. It is common necessary, to have an external, high-density packaging to the inhaler for his To obtain life and thus the peelable HSL the powder only during of the period of use protects. This type of prior art inhaler opens the dose of powder before the inhaler is ready to be inhaled and the dose will be reduced exposed to the environment and the possible exhalation of moist air by the user. An ideal inhaler for very sensitive to moisture Medication opens the Dose during inhalation and prevents exhalation into the device.

Summary the invention

The The present invention describes tiotropium-containing medicinal Products for use in the treatment of respiratory diseases and comprises a pre-dosed dose of tiotropium in a dry powder formulation, which comprises at least one excipient and optionally at least another active pharmaceutical ingredient (API). The dose Can be used directly in a moisture-proof, dry container a dry maximum protection seal filled against moisture and be sealed in it.

One Aim, which is achieved by the present invention, is the Generation and maintenance of a high fine dust dosage (FSD) of a medical product containing a measured dose of tiotropium for inhalation. The dose is filled and the medical product gets into a dry and tight container in a controlled environment Packed with low humidity, so the FSD when the Dose is dispensed while the life of the medical product due to normal fluctuations in the environmental conditions during Handling, storage and dispensing using a DPI not impaired is. Recipes are described, which are the selection of suitable, qualified drug carriers, have the good moisture properties, and the development to enable a recipe, a high FSD both by an electric field metering technology and by conventional volumetric filling process to achieve if a dose from a pre-dosed dry powder inhaler (DPI) is delivered.

at In another aspect of the invention, one or more excipients are in selected proportions with tiotropium in the dry powder recipe, so that the Effects of the excipient or the drug carrier are to dilute the potent active ingredient and the fluidity the dry powder recipe for make the dose-forming process acceptable and the FSD of the metered dose to optimize.

In Another aspect of the invention is one type of inhaler discloses at least one sealed, moisture-proof, dry container Take tiotropium with one dose of medicine and this dose with a stable high FSD over can give the expected life of the product.

In In another aspect of the invention, tiotropium may include at least one or more additional ones pharmaceutically active ingredient are mixed or formulated, with one goal, the tiotropium drug with other drugs to combine, which used in the treatment of respiratory diseases become. The present invention includes such an application of one or more additional ones Drugs besides tiotropium in a combined dose of medication in stable formulas that go straight into a sealed, moisture-proof, dry container, which is inserted into a DPI, are filled, the combined Dose is suitable for inhalation by the user.

Further For example, the invention discloses a method for preventing moistened Air from a user or from the ambient air the powder in reaches the dose before inhalation and still further a procedure around the dose for a misting available in connection with the breaking of the seal on the container, the the dose encloses.

Short description the drawings

The Invention, together with further objects and advantages thereof, is best understood by reference to the following detailed Description in conjunction with the attached drawings, in which

1 is a plot of the results of tests S1 to S5 and HBS1 to HBS3;

2 represents the sorption properties of the pharmaceutical excipients;

3 in plan view and side views, a first embodiment of a dose that is stored on a dose bed, and represents a maximum protection seal; and

4 in plan view and side views represents a second embodiment of a dose on a dose bed and a maximum protection seal.

Detailed description of preferred embodiments

Tiotropium has great potential as a bronchodilator drug, as its action starts quickly and lasts for a long time, even longer than 24 hours, making it ideal for many asthma conditions. It is a strong drug and inhalation once a day is enough to cope with asthma. If the user suffers from an acute asthma attack, extra tiotropium administration restores the asthma attack. But tiotropium is very sensitive to moisture. This fact is also documented in the report "College Ter Beoordeling Van Geneesmiddelen's Medicines Evaluation Board; Public Assessment Report; Spiriva ^® 18 μg, inhalation powder in hard capsules; RVG 26191 '(2002-05-21) on page 6/28 under "Product Development and Finished Product", which states a very short stability in the use of the product Spiriva ^® (9 days) and a fragility of the capsule in the blister packaging and a very low FSD: "about 3 μg." The capsules are packaged in a blister pack made of polyvinyl chloride and a protective aluminum layer A blister card consists of two blisters with 5 cavities connected along a perforated line The blister pack makes it possible to remove one capsule at a time so that the other capsules remain protected against moist air.This polyvinyl chloride film is obviously not sufficient to keep the Spiriva ^® capsules in use for more than 9 days to protect.

Details of inhaled powder inhalation of tiotropium and the use of an inhaler for the administration of tiotropium according to the prior art can also be studied in International Publication WO 03/84502 A1. Details of tiotropium compounds, medicaments based on such compounds, the use of compounds and methods of preparing compounds can be found in the European patent application 0 418 716 B1.

In view of the above information that was given in the quoted report a program of product Spiriva ^® was created in accordance with the guidelines of the Food and Drug Administration (FDA) for a stability test.

Spiriva ^® is a formulation with a finely divided excipient and a larger excipient for volumetric filling in a gelatin capsule, which is dried after filling and then packaged in a blister pack of PVC film. The blister pack is then covered with an aluminum foil. During the period of use after opening the first capsule, only the PVC foil protects the remaining 4 capsules in the blister pack.

A three-week test program under accelerated conditions (40 ± 2 ° C / 75 ± 5 RH) for the container packaging of the product Spiriva ^® , in this case the capsule and the blister pack, and the effect of the capsule and blister pack on the FSD was created and tested ,

The The present invention relates to tiotropium and as a high FSD value can be maintained and how tiotropium protects from moisture protected can be, from the moment when the cans are formed and sealed be, until the moment when a user selects a selected dose inhaled, over all phases of storage, transport, distribution, renewal Storage and finally the use of a dose. Furthermore become pharmacological compounds and suitable dry powder inhalers disclosed.

Carrying out of Testing

Spiriva ^® powder formulation in bulk form and Spiriva ^® capsules from the local pharmacy were added to the laboratory together with the HandiHaler ^® . The laboratory was set up to perform in vitro tests according to European Pharmacopoeia (EP) and US Pharmacopoeia (USP) using two Andersen cascade impactors. All analytical work was then performed according to the normalized procedures for physical tests and determinations for aerosols, metered dose inhalers and dry powder inhalers described in Pharmacopoeias (e.g., USP 2002 <601>) using a high performance liquid chromatograph system (HPLC ) of the prior art.

Spiriva ^® tests

Test S1

Aerodynamic fine particle fraction of metered and delivered dose out of Handihaler ^® using Spiriva ^® a -Formulation of loose powder filled into originator capsules during relative humidity below 10%. The test was performed with 4 kPa pressure drop over the HandiHaler ^® at room temperature and laboratory ambient conditions.

Test S2

Aerodynamic fine particle fraction of metered and delivered dose from the HandiHaler ^® using commercially available Spiriva capsules purchased from our local pharmacy. The test was performed with 4 kPa pressure drop over the HandiHaler ^® at room temperature and laboratory ambient conditions.

Test S3

A stability test in the use of the aerodynamic fine particle fraction of metered and delivered dose from the HandiHaler ^® using commercially available Spiriva capsules purchased from our local pharmacy. From the blister pack with 5 capsules one capsule was removed and the remaining 4 capsules were stored for 4 days at 40 ° C and 75% relative humidity. The blister pack containing the 4 capsules was then placed in an exicator for 2 hours before the tests were performed. The test was performed with 4 kPa pressure drop over the HandiHaler ^® at room temperature and laboratory ambient conditions.

Test S4

A stability test in the use of the aerodynamic fine particle fraction of metered and delivered dose from the HandiHaler ^® using commercially available Spiriva ^® capsules purchased from our local pharmacy. From the blister pack with 5 capsules one capsule was removed and the remaining 4 capsules were stored for 13 days at 40 ° C and 75% relative humidity. The blister pack containing the 4 capsules was then placed in an exicator for 2 hours before the tests were performed. The test was performed with 4 KPA pressure drop over the HandiHaler ^® at room temperature and laboratory ambient conditions.

Test S5

A stability test in the use of the aerodynamic fine particle fraction of metered and delivered dose from the HandiHaler ^® using commercially available Spiriva ^® capsules purchased from our local pharmacy. From the blister pack with 5 capsules, one capsule was removed and the remaining 4 capsules were stored for 21 days at 40 ° C and 75% relative humidity. The blister pack containing the 4 capsules was then placed in an exicator for 2 hours before the tests were performed. Of the Test was performed with 4 kPa pressure drop over the HandiHaler ^® at room temperature and laboratory ambient conditions.

Tests of maximum protection sealing

Test HBS1

A stability test in use of the aerodynamic fine particle fraction introduced of metered and delivered dose out of Handihaler ^® using Spiriva ^® -Rezeptur of loose powder, at a relative humidity below 10% into containers, which act as a high barrier seal, in this case aluminum foils from Alcan Singen , Germany, and then sealed absolutely tight. The aluminum containers were put in an exicator for 2 hours before the Spiriva ^® powder formulation was loaded from the containers into the originator capsules at a relative humidity below 10%. The test was performed with 4 kPa pressure drop over the HandiHaler ^® at room temperature and laboratory ambient conditions.

Test HBS2

A stability test in use of the aerodynamic fine particle fraction introduced of metered and delivered dose out of Handihaler ^® using Spiriva ^® -Rezeptur of loose powder, at a relative humidity below 10% into containers, which act as a high barrier seal, in this case aluminum foils from Alcan Singen , Germany, and then sealed absolutely tight. The sealed aluminum containers were stored for 7 days at 40 ° C and 75% relative humidity in climatic chambers. The aluminum containers were put in an exicator for 2 hours before the Spiriva ^® powder formulation was loaded from the aluminum containers into the originator capsules at a relative humidity below 10%. The test was performed with 4 kPa pressure drop over the HandiHaler ^® at room temperature and laboratory ambient conditions.

Test HBS3

A stability test in use of the aerodynamic fine particle fraction introduced of metered and delivered dose out of Handihaler ^® using Spiriva ^® -Rezeptur of loose powder, at a relative humidity below 10% into containers, which act as a high barrier seal, in this case aluminum foils from Alcan Singen , Germany, and then sealed absolutely tight. The sealed aluminum containers were stored for 14 days at 40 ° C and 75% relative humidity in climatic chambers. The aluminum containers were put in an exicator for 2 hours before the Spiriva ^® powder formulation was loaded from the aluminum containers into the originator capsules at a relative humidity below 10%. The test was performed with 4 kPa pressure drop over the HandiHaler ^® at room temperature and laboratory ambient conditions.

Tests for dry powder inhaler C-haler

A test was also performed outside of the stability test program to evaluate our own inhaler, the C-haler from Microdrug described in US Pat. US 6,422,236 B1 to evaluate in comparison to HandiHaler ^® . The C-haler cartridge used high barrier seal container made of aluminum foils from Alcan Singen, Germany, and the containers were volumetrically with 5 mg of the Spiriva ^® powder formulation filled in loose form. The test was carried out using a 4 kPa pressure drop across the C-haler at room temperature and laboratory ambient conditions. The Anderseninger's test results were calculated on the basis of a fraction of fine particles based on the delivered dose as well as the metered dose and converted into FSD values. The results are shown in Table 1 below.

The results of tests S1-5 and HBS1-3 are in 1 shown graphically. The Y-axis is designated '% of the FSD of the Spiriva ^® commercially available. "This relates to the FPD out of the HandiHaler ^®, where 100% is the FPD from a fresh sample from the pharmacy.

Table 1. Inhaled particulate matter (FSD) <5 μm in%

Conclusion from the tests performed with Spiriva ^®

We have found in our tests that tiotropium is extremely sensitive to moisture and that conventional packaging in gelatin capsules used for a majority of respiratory products seriously affects the original FSD present at bottling. We conclude that gelatin is not suitable as a drug carrier or material with the Spiriva ^® formulation. We have also found that the tiotropium formulation must also be properly protected during the period of use if a further reduction in FSD is to be avoided. The results indicate that there is a need for a dry, moisture-proof, top-seal-seal container that surrounds the tiotropium formulation to preserve the original level of fines and FSD.

The tests carried out show that the gelatin capsule, the FPD out of the HandiHaler ^® with approximately 50% from the time of loading the dose into a capsule until the point in time when the product reaches the market, is reduced. Most likely, this is an effect of the moisture content of the gelatin. When loading Spiriva ^® cans into dry containers made of materials that have high sealing properties and then storing the filled containers at 40 ° C and 75% relative humidity before filling the Spiriva ^® cans into the manufacturer capsules and using the same tests of the HandiHaler ^® as before, no change in PMD was recorded, even after long periods of time. However, the Spiriva ^® FSD in gelatin capsules continues to decrease during the product 's period of use and FSD has been shown to decrease by a further 20% after 5 days' storage at 40 ° C and 75% RH in use in the Stability Test Moisture barrier in the opened blister pack. Table 1 shows that the C-haler, the high barrier container used has an improved by 2.6 times performance than HandiHaler ^® with respect to FPD based on metered dose.

Measured doses of the Spiriva ^® powder formulation are today filled into gelatin capsules at the manufacturer's site. A gelatin capsule typically contains 13 to 14% by weight of water in the dosage forming step, and after the capsules have been filled, they are dried in a special process to minimize the water content. A number of dried capsules are then placed in a standard blister pack. Details of suitable capsule materials and prior art manufacturing methods can be found in the German patent application DE 101 26 924 A1 to be studied. The remaining amount of water in the capsule material after drying is thus trapped in the blister pack. The balance between the trapped air in the package and the gelatin capsule creates a relative humidity within the blister pack that adversely affects the FSD of the tiotropium powder from the dry powder inhaler.

It is interesting to note that the vast majority of dry powder formulations of many types of medicaments are not severely affected by the trapped moisture in the capsule material or by normal variations in the relative humidity of the ambient air. Examples of substances that are much more stable with respect to moisture are inhaled steroids, e.g. B. budesonide and fluticasone. Surprisingly, our research has shown that tiotropium is very different. Some mechanisms, not yet known, tend to reduce FSD over time when affected by very small amounts of water. Since the capsules ^® only as a practical, mechanical carriers of Spiriva doses to be used, the invention solves the problem by are not used at that capsules, but the cans rather directly in containers made from a dry packaging material with high barrier seal properties, during dry ambient conditions, preferably below 15% relative humidity.

The The present invention thus discloses a dry, moisture-proof, directly filled and sealed containers, comprising a measured, finely divided dose of tiotropium in a dry powder formulation with at least one excipient. Special embodiments include tiotropium in pure form, or a pharmaceutically acceptable one Salt, enantiomer, racemate, hydrate, or solvate, including mixtures same, and in particular bromide. In a particular embodiment is a dry powder tiotropium dose a mixture of powders with large particles of a drug carrier. Other special embodiments of dry powder tiotropium formulations include inhalable particles with tiotropium, where the particles are crystalline, hollow, porous or amorphous can be in the structure with an aerodynamic behavior equal to the small particles in a range of 1 to 5 μm. The term "tiotropium" in this document is a generic term for all active forms thereof, including pharmaceutically acceptable Salts, enantiomers, racemates, hydrates, solvates or mixtures thereof, and a metered dose usually includes excipients for various Purposes. The container uses dry maximum protection seals, the impermeable across from Moisture and other contaminants are, and may be in a dry powder inhaler can be used or the container can be designed to be part of a predosed inhaler device is.

By "dry" it is meant that the walls of the container are formed of selected materials so that the walls, particularly the inner wall surface of the container, can not release water which could interfere with the anticholinergic drug (eg tiotropium powder) in the dose As a logical consequence, the construction and materials of the container should not require the procedures described in the German publication DE 101 26 924 A1 were proposed. For example, gelatin is not a dry material and even after a special drying process gelatin still contains water. In general, "dry" means that the FSD of the drug is not affected by the material in question for the expected life of the product.

"Highest protection seal" means a dry one Packaging design or material or combinations of materials. A maximum protection seal is characterized in that it has a high barrier to moisture and that the seal itself is "dry", i.e. it can not produce measurable quantities at the expense of the powder. A maximum protection seal can be used for Example of one or more layers of materials, i. technical polymers, aluminum or other metals, glass, silicon oxide, etc., which together constitute the maximum protection seal. If the maximum protection seal a foil is a 50 μm thick pharmaceutical film made of PCTFE / PVC the minimum for the required high-density film, if a stability in use for two weeks should be achieved. For longer stability in use Metal foils, such as aluminum foils from Alcan Singen, are selected.

A "high sealing Container "is a mechanical Construction to receive and encapsulate a dose of tiotropium. Of the high sealing containers is using the maximum protection seals, which the walls of the container represent, built.

"Directly filled "means that the metered dose is filled directly into the high-sealing container, d. H. without the dose first z. B. to fill in a gelatin capsule, and then enclose from one or more main containers (Capsules) in a secondary packaging made of one material with maximum protection seal.

The high sealing containers to be filled with tiotropium drug doses should preferably be made of aluminum foil approved for direct contact with pharmaceutical products. Aluminum foils, which work well in this context, are usually made of engineering polymers coated with aluminum foil to give the film the proper mechanical properties to prevent tearing of the aluminum foil during molding. The sealing of the molded containers is normally carried out using a thinner cover sheet of pure aluminum or coated aluminum and polymer. The container and cover sheets are then sealed together using at least one of several possible methods, for example:
Use of a heat sealing lacquer, by pressure and heat;
Using heat and pressure to fuse the materials;
Ultrasonic welding of contacting materials.

• einheitliche Pulverrezeptur
• Pulverfließeigenschaften
• Menge des Pulvers für eine Dosis

fest.Tiotropium is a very powerful drug and is therefore normally used prior to the step of making the dose with physiologically acceptable excipients, e.g. Lactose, in a selected ver or selected ratios to suit a preferred method of forming or filling a dose. The step of forming the dose could include volumetric filling and relates to specific requirements for the physical properties of the formulation

• uniform powder formula
• Powder flow properties
• Amount of powder for one dose

firmly.

The Making a recipe with a very small amount of tiotropium and a much larger amount a drug carrier requires special precautions that need to be taken to a final, to obtain stable and robust manufacturing process.

A emitted fine dust dosage (FSD) from pure tiotropium, which by Inhalation is administered, is not limited and may generally be in the range 1 to 25 μg, including 5, 10, 15 and 20 μg. The selected Dose size is Usually prescribed by a doctor and depends on age, weight and Gender of the patient and the severity of the medical condition from. However, tiotropium dry powder usually exists as a chemical compound, a salt for example. Depending on the preferred chemical composition of the tiotropium substance the dose mass becomes common changed to the corresponding effect of the intended dose of pure To achieve tiotropium. If z. B. tiotropium bromide monohydrate is to be used as an active ingredient, the typical FSD falls into one Range from 1.25 to 31.25 μg. Furthermore The correct metered dose to be used in an inhaler for Use is filled for the purpose of administration, to be discontinued due to predicted losses such as retention or one or more less efficient distribution of the inhaled dose.

Powder flow properties

• Teilchengröße
• Teilchenoberfläche

The powder flow property of a formulation is important in building a robust manufacturing process using volumetric or gravimetric filling processes. Two properties are of particular importance:

• particle size
• particle

Drug carrier with a physical average particle size greater than 25 microns and a very narrow particle size distribution with generally less than 5% of the particles in the mass below 10 μm, wise generally good flow properties and are particularly suitable for use in mixtures together with tiotropium. Size Particles of excipients or APIs can as a carrier of small particles, in this case no particles of Tiotropium. For Inhalation purposes will typically be carrier particles with a medium Mass particle size in one Range from 10 to 250 μm selected, including 30, 50, 70, 100, 130, 160, 190 and 220 μm. The best average particle size, the chosen from this area will hang from many factors, eg. B. Type of vehicle, degree of reach Powder flowability, Type of inhaler and ease the distribution during the inhalation of the resulting drug. commercial varieties from Respitos are available (Lactose monohydrate of DMV with several defined particle size distributions up to 400 μm), suitable as special excipients used in recipes with Tiotropium should be used, for. B. Variety SV003. Standardized homogeneous tiotropium powder formulations with a physical middle Particle size up to 10 μm can also good flow properties provide when the particles have been changed so that they have a have a very smooth surface, which causes the flow properties improve the recipe.

A practical lower limit for volumetric dose formation is in a range of 0.5 to 1 mg. Smaller cans are very difficult to make and always have still a small relative standard deviation between doses in of the order of magnitude of 10 %. Typically, however, the dosage masses are in one Range from 1 to 10 mg.

Suitable excipients for inclusion in a tiotropium formulation can be found among the groups of monosaccharides, disaccharides, polyactides, oligosaccharides and polysaccharides, polyalcohols, polymers, salts or mixtures of these groups, e.g. Glucose, arabinose, lactose, lactose monohydrate, non-hydrous lactose (ie no crystalline water present in the lactose molecule), sucrose, maltose, dextran, sorbitol, mannitol, xylitol, sodium chloride, calcium carbonate. A special excipient is Lactose.

To concerning our findings of sensitivity Moisture in tiotropium powders, must have the moisture properties every proposed drug carrier should be suitable before it selected for inclusion in a tiotropium formulation, regardless of the function of the proposed drug carrier. One Excipient the after the formation of the dose a lot of water inside the container, which The dose that surrounds with mixed powders may be contained Active powder adversely affect, so the resulting FSD rapidly deteriorating after making the dose. Therefore, drug carriers, the to be used with tiotropium, primarily from acceptable Excipients selected which have good moisture qualities, in the sense that that the substance is the FSD of the active drug during the Life of the product will not adversely affect regardless of the normal changes in the environmental conditions while storage. Suitable "dry" excipients may be used in the above groups are found. In a special embodiment Lactose is selected as the dry excipient and is particularly preferred should use lactose monohydrate in a recipe with tiotropium become. A reason for the selection of lactose as an excipient is its inherent property a low and constant water-sorption isotherm. Drug carrier with a similar one or lower sorption isotherms may also be considered for use provided that other required quality requirements Fulfills are.

Environmental conditions while formation of a dose, filling and sealing the container should be closely monitored. The temperature should preferably below 25 ° C lie and the relative humidity should preferably be below 15% lie. The powder formulation should also be during the dose-forming process as dry as possible being held. Adhering to these precautions ensures that only a very small, acceptable amount of water in containers together Being trapped with the dose and not enough to be a danger for the stability Tiotropsubstance and FSD. The original one Fine particle fraction (FPF) of the tiotropium drug, clearly visible in a high particulate matter dosage (FSD) of the measured dose of medical product during the packaging, is in the container with maximum protection seal maintained. Thus, if the predosed dose by means of a DPI is administered while she is the life of the medical product through normal changes the environmental conditions during handling, storage and dispensing.

In In another aspect of the invention, tiotropium may be with one or more mixed with several pharmacologically active ingredients (API) or be formulated, in addition to the selected excipients, with a Aim to combine tiotropium with other medications that are in a treatment of z. As airway diseases are used. The present invention comprises such an application of tiotropium, Taking a combination of tiotropium with other medicines Formulation from which then measured doses are produced, filled in a dry, moisture-proof, high-sealing container and be sealed, the container for insertion into a DPI for administration according to a particular dosage instruction or as required by the user. In one particular embodiment At least one API may replace one or more selected excipients, so that the sum of the tiotropium dose and the added API (s) all requirements regarding Compatibility, Moisture properties, FSD stability, potencies and total dosage mass fulfill. Examples of interesting Combinations of substances together with tiotropium include:

inhalable Steroids: z. Budenoside, fluticasone, rofleponide, mometasone, ciclesonide.

Antihistamines: z. Epinastine, cetirizine, azelastine, fexofenadine, levocabastine, Loratadine, Mizolastine, Ketotifen, Emedastine, Dirnetinden, Clemastine, Bamipin, Cexchlorpheniramine, Pheniramine, Doxylamine, Chlorphenoxamine, Dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and Meclozin.

Beta-mimetics: z. Formoterol, salmeterol, salbutamol, terbutaline sulphate.

PDE4 inhibitors: z. B. 3 ', 5' - cyclic nucleotides phosphodiesterase and derivatives.

Adenosine A2A receptor agonists: z. B. ribofuranosylvanamide derivatives, Substances described in WO 02/94273.

• – Innenvolumen des Behälters: 100 mm³
• – Wirksamer Diffusionsbereich: 46 mm²
• – Diffusionskonstante: 0,044 g/m² für 24 Stunden bei 23 °C und unterschiedlicher relativer Luftfeuchtigkeit = 50

The sealed, dry, high-sealing container of the invention directly filled with a formulation of tiotropium may be in the form of a blister pack or may be e.g. B. a flat dose bed or comprise a molded cavity in an aluminum foil or a molded cavity of a polymeric material which utilize a high barrier film against ingress of moisture, e.g. As aluminum or a combination of aluminum and polymer materials. The sealed, dry, high-sealing container may form part of an inhaler device or it may be a separate part intended for insertion into an inhaler device for administering pre-dosed doses. The sealed, high-density container used in the previously described C-Haler test has the following data:

• - Inner volume of the container: 100 mm ³
• - Effective diffusion area: 46 mm ²
• - Diffusion constant: 0.044 g / m ² for 24 hours at 23 ° C and different relative humidity = 50

In other words, the diffusion of water into the container in this case was at a rate of 20 g / m ³ for 24 hours at 23 ° C with a presumed difference in humidity of 50%. The results from the C-Haler test indicate that the container used was adequate to protect the dose for 14 days. Thus, the present invention teaches that, for. For example, a sealed, highly-sealed container of the above size, which stores a dose of tiotropium, should not have a water transfer rate of greater than 20 g / m ³ for 24 hours at 23 ° C and different relative humidity = 50, for a maximum usage period of 2 Weeks to be suitable. The results from the C-Haler test may address a number of requirements for a different type of container, e.g. B. a blister pack transferred. Be a blister pack similar size to the C-haler cartridge would have to using a typical high quality material like 50 microns PCTFE / PVC prepared which just satisfies the diffusion constant of the C-haler container (= 0.118 g / m ² when on 38 ° C and 90% relative humidity extrapolated). If a device with a tiotropium container is to be used for a period longer than 2 weeks, then a moisture-proof container must be used to protect the FSD.

Our Tests indicate that compositions of tiotropium and at least a drug carrier, developed according to the in described in this application, have exceptionally good FSD data and that metered doses of such compositions over their Lifetime and during of the period of use, when stored in containers with High barrier seal filled are.

• – geringer absoluter Wassergehalt
• – geringe Änderung des absoluten Wassergehalts nach einer Veränderung der relativen Luftfeuchtigkeit
• – sehr stabil in der Temperatursituationen während Gebrauchssituationen

To develop a recipe with tiotropium with controlled moisture properties, a study must first be conducted on the chemical and physical properties of the selected excipient. The sorption isotherm properties provide information on how a formulation will react to different temperatures and relative humidity in its environment. A very important issue is also the "memory" of some excipients, which is branded by the fact that it takes a very long time to reach a stable state for the drug carrier after a disturbance of the environment A suitable excipient for a formulation with tiotropium is an excipient such as lactose monohydrate.The isotherm of lactose monohydrate has two important properties:

• - low absolute water content
• - slight change in the absolute water content after a change in the relative humidity
• - very stable in temperature situations during use situations

Of the low absolute water content ensures a disruption of stable conditions no big Influence on a tiotropium dose will have if the total amount of water in the excipient is present, is low. The small change in the absolute water content at different relative humidity ensures that the drug carrier has no "memory" and that he simply in a stable state at a given relative Humidity can be added before filling in a high sealing container. The temperature stability Ensures that adsorption and desorption within the highest protection seal the API as little as possible affected.

2 shows the isotherms of gelatine today used in the Spiriva ^® product and lactose monohydrate as examples of a bad and a good choice of excipient or materials for a moisture sensitive tiotropium powder formulation. The effect of the excipient is usually very large when the amount of API is small. When using a volumetric dosing method, the formulation must have certain physical flow properties, making it necessary to add larger excipient particles to the formulation. For tiotropium in the form of the Spiriva ^® -Rezeptur a relation between the API and the excipient or excipients is more than 1: 250, which indicated that a small change in the qualities of the excipient, z. B. its moisture properties, has an extremely large impact on the API and the performance of the recipe. When using the Electrofield Dosing Technology (ELFID) dose-forming technique, the ratio of API to excipient (s) can be limited to less than 1:10, making the effect of altering the drug carrier much less dangerous than volumetric dose formation.

One good understanding the considerations described above in selecting suitable Excipient is necessary, to make sure that the recipe of tiotropium does not affect the FSD change when a dose of the formulation is filled into a high-density container, even if the container strong changes is subjected in the ambient environment.

• 1. In einem ersten Schritt wird die minimale volumetrische Dosismasse der Tiotropiumrezeptur bestimmt. Normalerweise liegt die minimale Dosismasse in der Praxis in einem Bereich von 1000 bis 5000 μg, auch wenn kürzlich verbesserte Dosisbildungsverfahren eine minimale Dosismasse unter 500 μg sicher festlegen kann. Das Verdünnungsverhältnis folgt als ein Ergebnis der festgelegten Masse der Tiotropiumverbindung und der festgelegten minimalen Dosismasse.
• 2. Alternative A; einheitliche Mischungen und Zusammenstellungen der Tiotropium-Pulverrezeptur: In einem zweiten Schritt wird das Tiotropiumpulver verdünnt, um eine korrekte minimale Dosismasse zu erhalten, wie festgelegt, vorzugsweise unter Verwendung eines trockenen Arzneistoffträgers mit einer physikalischen Teilchengröße > 25 μm unter Verwendung eines Verfahrens, das eine einheitliche Mischung herstellt. Vorzugsweise wird dies durch Trockenmischung des Arzneistoffträgers und des Tiotropiumpulvers durchgeführt, entweder in einem ununterbrochenen Vorgang oder einem Vorgang nach Chargen.
• 3. Alternative B; einheitliche homogene Tiotropium-Pulverrezeptur: In einem zweiten Schritt wird das Tiotropiumpulver verdünnt, um eine korrekte minimale Dosismasse zu erhalten, wie festgelegt, unter Verwendung eines trockenen Arzneistoffträgers und Zuführen des Arzneistoffträgers in passender Weise in den Vorgang, der homogene Tiotropiumteilchen herstellt. Dieser Vorgang kann z. B. ein Sprühtrocknen oder ein Gefriertrocknen sein.

In order to develop a formulation with tiotropium which provides the best possible FSD, it is therefore necessary to consider a method for making an optimal formulation of the API with the excipient. Since tiotropium is a very strong drug, a dilution must first be made. The following procedure can be used:

• 1. In a first step, the minimum volumetric dose mass of the tiotropium formulation is determined. Normally, the minimum dose level in practice is in the range of 1000 to 5000 μg, although recently improved dose-forming methods can safely set a minimum dose level below 500 μg. The dilution ratio follows as a result of the fixed mass of the tiotropium compound and the specified minimum dose mass.
• 2. Alternative A; uniform mixtures and compositions of the tiotropium powder formulation: In a second step, the tiotropium powder is diluted to obtain a correct minimum dose mass, as determined, preferably using a dry excipient with a physical particle size> 25 μm using a uniform method Mixture produces. Preferably, this is done by dry blending the excipient and the tiotropium powder, either in a continuous process or batch process.
• 3rd alternative B; uniform homogeneous tiotropium powder formulation: In a second step, the tiotropium powder is diluted to obtain a correct minimum dose mass, as determined, using a dry excipient and feeding the excipient in an appropriate manner into the process producing homogenous tiotropium particles. This process can, for. As a spray drying or freeze drying.

To protect the FSD to the actual point of nebulization of the dose, a method of opening the dose container is presented a fraction of a second before nebulization of the dose is started and can be studied in detail in our publication WO 02/24266 A1, which hereby incorporated by reference in its entirety into this document. In this context, it is also important to prevent a voluntary or involuntary exhalation of a user of a DPI intending to inhale a dose from reaching the selected dose because of the high moisture content in the exhaled air. In our publication US Pat. No. 6,439,227 B1 , which is hereby incorporated in its entirety by reference in this document, discloses a device which closes the DPI if the user exhales, so that the exhaled air does not reach the dose container and the selected dose in the DPI. The apparatus also controls the release of a cutting tool and a suction nozzle so that the cutting tool can not open the container and the inhaled air can not begin to atomize the dose until there is a certain selected pressure drop due to the aspiration effort by the user.

The The present invention teaches the importance of preventing humid air from a user or from the ambient air the powder in the dose before inhalation reaches and emphasizes the importance of one Dose for the fogging available to do, preferably in direct connection with the breaking of the Sealing of the container, which includes the dose. Preferably, the period during which the dose should break after the container seal exposed to ambient air, do not exceed 2 minutes, or the FSD may otherwise fall off when the dose is finally delivered Tiotropium is negatively affected by moisture in the ambient air is affected, even if the powder exposed to only a few minutes is.

An inhaler for prolonged delivery of a dose during the course of a single inhalation of a high barrier container made of aluminum foil is a particular embodiment of an inhaler for the delivery of the tiotropium powder formulation. An air razor method as disclosed in our publication US 2003/0192539 A1, is preferably used in the inhaler to effectively and gradually nebulize the dose as it is delivered to the user. Amazing enough, the application performs an inhaler for a prolonged delivery and using the Air-razor method on a dose of tiotropium in Spiriva ^® -Rezeptur to an FSD which is at least twice as large as that of the HandiHaler ^® of the prior art. See examples of doses in 4 and 5 ,

In 3 and 4 , Reference number 11 to 32 In the drawings, like reference numerals designate like parts in both views of the two different embodiments of doses of a dry powdered medicament with a tiotropium powder formulation deposited on a dose bed of a container as illustrated, set forth herein as non-limiting examples.

3 shows a side view and a top view of a dose 21 on a dose bed 11 a high-sealing container is stored, the dose being moisture-proof with a maximum protection seal 31 is sealed.

4 shows a side view and a top view of a dose 21 on a dose bed 11 a high-sealing container is stored, the dose being moisture-proof with maximum protection seals 31 and 32 is sealed.

As As used herein, the formulations "comprise selected from a group off "," selected off "and the like Mixtures of specified materials.

All References, patents, applications, tests, standards, documents, publications, Brochures, Texts, articles, instructions, etc. mentioned herein are hereby incorporated by reference Reference added. If a numeric limit or a numeric Range, the endpoints are included. Also are all values and sub-ranges within a numeric limit or a numerical range, in particular, as if they were explicitly advertised.

The The above description of the invention provides a manner and a Process of preparation and use available, so that every expert in this field is able to carry it out and to use, with this enabling especially for the subject of the attached claims provided that form part of the original description, and include the following inventive concepts: a medical Product comprising a dry powder medicament dose of tiotropium and optionally an additional one API, filled in a container for use in a dry powder inhaler, wherein the first Component of the dry powder medicament from a fine dust dosage Tiotropium exists; at least one excipient is present in the drug; The dry powder medicament comprises particles of tiotropium and Particles having an average mass diameter of 10 μm or more at least one dry excipient; the container forms a dry maximum protection seal, the maximum protection seal of the container prevents the entry of moisture, causing the original Fine particle content of the dry powder dose is maintained; and the dry powder drug dose in the container is for either volumetric or gravimetric dose-forming methods.

As can be seen from the above description, another particular embodiment of the invention is a medical product having a dry powder medicament dose filled into a container for use in a dry powder inhaler, the dry powder medicament dose comprising a fine dust dosage of tiotropium and at least one dry excipient; and wherein the container comprises a dry peak protection seal, and the dry powder medicament dose in the container is suitable for either volumetric or gravimetric dose-forming procedures. Another particular embodiment of the invention is a medical product comprising a dry powder medicament dose filled into a container suitable for use in a dry powder inhaler, the dry powder medicament dose comprising: particles of tiotropium; and particles of at least one dry drug carrier; and wherein the container is a dry maximum protection seal to prevent ingress of moisture and to obtain the dry powder medicament dosage. In a particular embodiment, the drug dose is kept dry from the container, so that z. B. the original FSD is maintained during filling, for example, at 40 ° C and 75% relative humidity over 14 days. Alternatively, or additionally, the sealed container of the invention comprising a maximum protection seal preferably has no water transfer rate above 20 g / m ³ for 24 hours at 23 ° C and different relative humidity = 50%. Alternatively, or additionally, the sealed container of the invention comprising a maximum protection seal does not interfere with the tiotropium's FSD, e.g. For example, a consistent FSD is maintained during the expected life of the product.

The above description is presented to enable one skilled in the art, who Invention and is set forth in the context of a particular application and its requirements. Various modifications to the particular embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments and applications without departing from the spirit and scope of the invention. Thus, this invention should not be limited by the embodiments shown, but it should be accorded the widest scope consistent with the principles and features disclosed herein.

Summarized the invention discloses a medical product for treatment of airway diseases can be used.

Claims (35)

A medical product comprising a dry powder medicament dose and a container suitable for use in a dry powder inhaler, characterized in that the dry powder medicament dose is filled into the container; the dry powder medicament dose comprises particles of tiotropium and particles having an average mass diameter of 10 μm or more of at least one dry excipient; and the container is a dry high barrier seal which prevents moisture ingress and preserves the dry powder medicament dosage. Medical product according to claim 1, characterized that the at least one dry excipient comprises a drug carrier selected from the group consisting of monosaccharides, disaccharides, polyactides, Oligo- and polysaccharides, polyalcohols, polymers, salts and Mixtures thereof. Medical product according to claim 1, characterized that the at least one dry excipient has finely divided particles with a diameter of 25 microns and more in an amount of more than 80 mass% based the total mass of the excipient comprises; and that at least a dry excipient a drug carrier, selected from the group consisting of monosaccharides, disaccharides, polyactides, Oligo- and polysaccharides, polyalcohols, polymers, salts and Mixtures thereof. Medical product according to claim 1, characterized that the dry maximum protection seal a material selected from the group consisting of metals, thermoplastics, glass, silicon, Silicon oxides and combinations thereof. Medical product according to claim 1, characterized that the dry powder drug dose in the container using either a volumetric, gravimetric or electro-field dose-forming method is formed. Medical product according to claim 1, characterized that the at least one dry excipient comprises a drug carrier, selected from the group consisting of lactose, non-hydrous lactose, Lactose monohydrate and mixtures thereof. Medical product according to claim 1, characterized that the dry maximum protection seal a molded or flat aluminum foil, optionally with at least coated with a polymer. Medical product according to claim 1, characterized that the container forms a cavity made of a polymer with maximum protection sealing properties is shaped. Medical product according to claim 1, characterized that the container forms a cavity formed of a polymeric material and further comprising an aluminum foil. Medical product according to claim 1, characterized that the container is part of a dry powder inhaler. Medical product according to claim 1, characterized that the container a separate part for insertion into a dry powder inhaler suitable is. Medical product according to claim 1, characterized that the container a separate part, which is a main part, suitable for insertion in a Trockenpulverinhalator, and a secondary part, which the Main body in a moisture-tight packaging encloses includes. A medical product according to claim 1, adapted that the fine dust dosage of tiotropium, that of a dry powder inhaler more than 20% of the pre-dosed dose and 40% of the delivered Represents dose. Medical product according to claim 1, characterized that the medical product is for use in the treatment an airway disease, especially the chronic obstructive Pulmonary disease and asthma, is appropriate. Medical product according to claim 1, characterized that the dry powder drug dose tiotropium and at least a second active pharmaceutical ingredient selected from the group consisting of inhaled steroids, nicotinamide derivatives, beta-agonists, Beta-mimetics, antihistamines, adenosine A2A receptors, PDE4 inhibitors, dopamine D2 Receptor agonists and mixtures thereof. Medical product according to claim 1, characterized that the at least one second pharmaceutical ingredient from the Group consisting of Budenoside, Fluticasone, Rofleponide, Mometasone, Ciclesonide-Epinastine, Cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, Ketotifen, emedastine, dirnetindene, clemastine, bamipine, cexchlorpheniramine, Pheniramine, doxylamine, chlorphenoxamine, dimenhydrinate, diphenhydramine, Promethazine, ebastine, desloratidine, meclozin, formoterol, salmeterol, Salbutamol, terbutaline sulphate, 3 ', 5'-cyclic nucleotide phosphodiesterase, 3 ', 5'-cyclic nucleotide phosphodiesterase derivatives, Ribofuranosylvanamide, ribofuranosylvanamide derivatives and mixtures selected from it becomes. Medical product according to claim 15, characterized characterized in that the at least one dry excipient Excipient selected from the group consisting of monosaccharides, disaccharides, polyactides, Oligo- and polysaccharides, polyalcohols, polymers, salts and Mixtures thereof. Medical product according to claim 15, characterized characterized in that the at least one dry excipient is fine distributed particles with a diameter of 25 microns and more in an amount of more than 80% by weight based on the total mass of the excipient; and the at least one dry excipient comprises a drug carrier selected from the group consisting of monosaccharides, disaccharides, polyactides, Oligo- and polysaccharides, polyalcohols, polymers, salts and Mixtures thereof. Medical product according to claim 15, characterized characterized in that the dry maximum protection seal a material includes, selected from the group consisting of metals, thermoplastics, glass, silicon, Silicon oxides and mixtures thereof. Medical product according to claim 15, characterized characterized in that the dry powder medicament dose in the container below Use of either a volumetric, gravimetric or electro-field dose-forming method is formed. Medical product according to claim 15, characterized characterized in that the at least one dry excipient Excipient includes, selected from the group consisting of lactose, non-hydrous lactose, Lactose monohydrate and mixtures thereof. Medical product according to claim 15, characterized characterized in that the dry maximum protection seal is a molded or flat aluminum foil, optionally with at least one polymer coated, comprises. Medical product according to claim 15, characterized characterized in that the container forms a cavity made of a polymer with maximum protection sealing properties is shaped. Medical product according to claim 15, characterized characterized in that the container forms a cavity formed of a polymeric material and further comprising an aluminum foil. Medical product according to claim 15, characterized characterized in that the container is part of a dry powder inhaler. Medical product according to claim 15, characterized characterized in that the container a separate part for insertion into a dry powder inhaler suitable is. Medical product according to claim 15, characterized characterized in that the container a separate part, which is a main part, suitable for insertion in a Trockenpulverinhalator, and a secondary part, which the Main body in a moisture-tight packaging encloses includes. Medical product according to claim 15, characterized characterized in that the delivered by a dry powder inhaler Tiotropium particles more than 20% of the predosed dose and 40% represent the delivered dose. Medical product according to claim 15, characterized in that the medicinal product is to be used with the treatment of an airway disease, especially chronic obstructive pulmonary disease and asthma, is appropriate. Medical product according to claim 1, characterized that the at least one dry excipient and the tiotropium together in each of at least a portion of all particles containing the dry powder medicament dosage represent exist. Medical product according to claim 1, characterized that the at least one dry excipient and the tiotropium as separate particles, but together in a homogeneous mixture of all Particles representing the dry powder medicament dose, available. Medical product according to claim 1, characterized that the predosed drug dose of ambient air in a Dry powder inhaler device is exposed for a maximum of 2 minutes, after the maximum protection seal of the dose container was broken up until the inhaler delivers the dose. Medical product according to claim 15, characterized characterized in that the at least one dry excipient, the Tiotropium and the at least one second active pharmaceutical Component together in each of at least part of all particles, which is the dry powder medicament dose represent exist. Medical product according to claim 15, characterized characterized in that the at least one dry excipient, the Tiotropium and the at least one second active pharmaceutical Component as separate particles, but together in a homogeneous Mixture of all particles containing the dry powder drug dose represent exist. Medical product according to claim 15, characterized in that the predosed dose of medicament is the ambient air in a dry powder inhaler device for a maximum of 2 minutes is exposed after the maximum protection seal of the dose container was broken up until the inhaler delivers the dose.