HK1104000B - Pre-metered dry powder inhaler for moisture-sensitive medicaments - Google Patents

Description

Pre-metered dry powder inhaler for moisture sensitive medicaments

Technical Field

The present invention relates to a Dry Powder Inhaler (DPI) that delivers a high and stable fine particle dose. Such an inhaler uses a highly impermeable sealed container containing at least one metered dose of a formulation comprising at least one excipient and a tiotropium drug.

Additional advantages and other features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention. The advantages of the invention may be realized and attained as particularly pointed out in the appended claims. It will be appreciated that the invention is capable of other and different embodiments, and that several embodiments thereof are capable of modification in various, obvious respects, all without departing from the invention. This description is to be considered as illustrative and not restrictive in character.

Background

Dry Powder Inhalers (DPIs) are becoming more and more popular because of their ease of use and therapeutic effectiveness. DPI can be divided into two main categories: reservoir (bulk) and pre-dosing devices. Pre-dosing devices have gained increasing market share due to their ability to control the production and process of dosing precise doses to users. Because of this, DPIs with a predetermined dose are more reliable than reservoir inhalers (bulk inhaalers) which dose powder doses in an inhaler. Pre-metered DPIs take the critical step of dosing pharmaceutical product processing.

Asthma and Chronic Obstructive Pulmonary Disease (COPD) affect more than 3 million americans. More than 10 million people die each year from these diseases. In each of these respiratory diseases, obstruction of airflow through the lungs is a typical feature, and the drugs used in treatment are often similar.

Chronic Obstructive Pulmonary Disease (COPD) is a widespread chronic lung disease that includes chronic bronchitis and emphysema. The cause of COPD is not yet fully understood. Experience has shown that the most important cause of chronic bronchitis and emphysema is smoking. Air pollution and occupational exposure also play a role, especially in combination with smoking. Some emphysema cases are also caused by inheritance of alpha 1 anti-trypsin (trypsin) deficiency.

The administration of asthma drugs via the oral inhalation route is of great interest today because of the advantages offered, such as rapid and predictable onset of action, cost effectiveness, and high level of comfort to the user. Dry Powder Inhalers (DPIs) are of particular interest as a means of administration compared to other inhalers because of the flexibility they offer in indicating the dose range, i.e. the amount of active substance that can be administered in a single inhalation.

Tiotropium, and in particular its bromide salt, is an effective bronchodilator. Tiotropium has a relatively rapid and long-lasting onset of action, which may last for 24 hours or more. Tiotropium reduces smooth muscle vagal cholinergic tone, a major reversible component of COPD. Tiotropium shows considerably less side effects in clinical trials, dry mouth and constipation being probably the most common symptoms. Because it is often difficult to correctly diagnose asthma and emphysema, and because both diseases can coexist, the use of a small but effective dose of long-acting tiotropium, preferably tiotropium bromide, is beneficial for treating patients with dyspnea due to temporary or persistent bronchial obstruction, due to its rapid onset, long-lasting action and low side effects. Currently, in order to provide combination therapy, for example combining bronchodilation with anti-inflammatory therapy, bronchodilators such as tiotropium are often prescribed and administered in combination with other asthma medications.

The effectiveness of medication depends largely on the release of a stable and high Fine Particle Dose (FPD) from a dry powder inhaler. The FPD is the mass of a respirable dose delivered from a dry powder inhaler with an aerodynamic particle size of less than 5 μm. Thus, when inhaling a dose of any one of the dry powders of the drug, it is important to obtain a high mass percent of Fine Particles (FPF) in the inhaled air with particles having an aerodynamic particle size preferably less than 5 μm. The majority of the larger particles (> 5 μm) do not follow the air flow into the many branches of the respiratory tract, but rather stick to themThe throat and upper respiratory tract where the medicament does not exert its intended effect, but may instead be harmful to the user. It is also important to keep the dosage as accurate as possible to the user in order to maintain a stable efficacy over time and that the drug dose does not deteriorate during normal storage (deteriorations). For example, Boehringer Ingelheim KG (BI) is in SpirivaThe name of the property right of (a) is to bring tiotropium bromide to the market. Surprisingly, in the recent SpirivaIn a survey of the products, we found BI Spiriva administered by inhalation of doses contained in gelatin capsules/HandiHalerThe system showed poor performance and was short in stability in use.

There are several prior art methods applicable to tiotropium for the production of pharmaceutical formulations suitable for inhalation with a dry powder inhaler device. In one such method, tiotropium is suspended with excipients in a liquid, followed by stirring and evaporation of the liquid after the mixture is obtained. Mixing materials of different particle size is another method that teaches how to produce a homogeneous powder mixture using a particular mixing method. Yet another method teaches how to perform continuous dosing into a mixer to obtain a uniform powder formulation. Still further methods may be used to produce a homogeneous powder formulation of one or more excipients with a tiotropium substance, comprising preparing homogeneously mixed particles of the excipient with tiotropium and optionally one or more additional pharmacologically active ingredients (API) in a batch or continuous mixing step using air or some other pharmaceutically acceptable gas as the suspending medium.

A formulation of tiotropium with excipients is prepared where the amount of tiotropium is very small (e.g. < 1: 100 amount of excipients) is of greatest importance for FPD. Several prior art approaches are directed to improved formulations containing excipients to improve the active ingredient FPD, e.g. coating excipients to produce fluorinated particle surfaces. Other surface modification and surface treatment methods may be used to improve the FPD performance of the formulation.

In the prior art, it is not common to incorporate a desiccant in the material of the container or in the device or in the outer packaging of the device. The amount of desiccant is usually small in this type of composition and the requirement for the container to be sealed to protect the drug powder remains unchanged if the desiccant is not destroyed prior to opening the product.

Methods of forming tiotropium formulations include, for example, conventional mass, weight or volume dosing, and apparatus and machinery for filling blister packs well known in the pharmaceutical industry. Examples of prior art for producing doses of powdered medicament by volume and/or mass methods and devices are also found in WO 03/27617A 1, WO 03/66437A 1, WO 03/66436A 1, WO 03/26965A 1, WO 02/44669A 1, and DE 10046127A 1, DE 20209156U 1. Electrostatic forming methods may also be used, for example as disclosed in US 6,007,630 and US 5,699,649.

One most suitable method for depositing microgram and milligram quantities of dry powder uses electric field technology (ELFID) as disclosed in our U.S. patent No. 6,592,930B 2, which is hereby incorporated by reference in its entirety. Powder flowability is not important in this method because during the dose forming step, the transport of the powder particles from the reservoir source to the dose bed does not rely on gravity but uses mainly electrical and electrostatic force techniques to deposit a metered amount of powder, i.e. a dose is placed on the dose bed, which may be a blister, capsule or a highly impermeable container as disclosed in the present invention. The advantage of this electric field dose forming process is that it is not necessary to add large excipient particles to the drug powder, since good powder flow is not an issue. Excipients are added to the active substance, in particular tiotropium, in order to dilute the drug so that it has a predetermined dose of over 100 μ g in the inhaler. Advantageously, the excipients are finely dispersed so that the Mass Median Aerodynamic Diameter (MMAD) is less than 10 μm. Attempts have been made to verify that the Fine Particle Dose (FPD) in one dose formed using the electric field method is significantly better than the FPD in a similar dose formed using other methods common in the art. The electric field method is also well suited for co-dosing, e.g. a metered amount of the active drug in the same container, in the form of tiotropium mixed with the API or formed and deposited separately.

The use of peelable foils to protect medium dose dry powder inhalers is known in the art. The peelable lidding foil is made from a PVC layer sealed to a base sheet by heat-seal painting after the powder is filled into the cavities formed in the base sheet. This filling step is important because any powder left on the heat seal surface will adversely affect the seal quality. Peelable HSLs are always more sensitive and difficult than conventional sealing foils. It is often desirable to maintain the shelf life of the inhaler with an external high barrier package, with the peelable HSL protecting the powder only during use. Such prior art inhalers open a dose of powder before the inhaler is ready for inhalation, and this dose is thus exposed to the ambient environment and to humid air that the user may exhale.

The object of the present invention is to preserve and release a high Fine Particle Dose (FPD) of tiotropium with a DPI product comprising a metered dose of tiotropium drug, suitable for inhalation, packaged in a dry, closed container, such that when released, the FPD is not affected by normal variations in the surrounding environment during processing, storage and release of the DPI product, during its pharmaceutical product's use. It will be seen that the inventors have achieved and exceeded this object by the following description.

Summary of The Invention

A DPI product, preferably suitable for use in the treatment of respiratory diseases, comprises a pre-measured amount of a dry powder medicament comprising at least one excipient and optionally at least one further Active Pharmaceutical Ingredient (API). Furthermore, the dose in the DPI is directly dosed and sealed in a moisture-proof dry container as a dry high barrier seal against moisture. Tiotropium is the preferred dry powder drug and is hereinafter referred to as a representative substance.

The DPI of the present invention contains a pre-metered dry powder dose with a high FPD and enables the selection of suitable high quality excipients to obtain good water content and form doses up to high FPD (e.g. using electric field split dosing techniques and conventional volume dispensing methods).

In a different aspect of the invention, one or more excipients are contained in the dry powder formulation with tiotropium in a ratio chosen so that the function of the excipients is, inter alia, to dilute the potent tiotropium component and/or to render the flowability of the dry powder formulation acceptable for the dose forming step and/or to optimize the FPD of the metered dose.

In another aspect of the invention, an inhaler of the type that can hold at least one sealed moisture-tight dry container containing a metered dose of tiotropium over the expected period of product life and can release the dose with a constant FPD is disclosed.

In another aspect of the invention, tiotropium is mixed or formulated with one or more additional pharmacologically active ingredients (APIs), thus combining tiotropium drugs with other drugs for the treatment of respiratory diseases. The present invention includes the use of tiotropium in a stable formulation as a combined dose of a drug directly metered into a sealed moisture-tight dry container for insertion into a DPI, the combined dose being suitable for inhalation by a user.

Furthermore, the invention discloses a method of preventing moist air from the user from reaching the powder in the dose before inhalation when the seal of the container containing the dose is broken, and yet another method of enabling the dose to be aerosolized at the same time.

Brief Description of Drawings

The invention, together with further objects and advantages thereof, may best be understood by reference to the following detailed description taken in conjunction with the accompanying drawings in which:

FIG.1 illustrates the results of tests S1 to S5 and HBS1 to HBS 3;

fig.2 illustrates the adsorption properties of pharmaceutical excipients;

fig.3 illustrates in a flow chart a method of developing a pharmaceutical composition with high FPD;

FIG.4 illustrates, from a top view and a side view, a first dose embodiment deposited on a dose bed and a high barrier seal, and

fig.5 illustrates a second dosage embodiment on a dosage bed and a high barrier seal from a top view and a side view.

Detailed description of the preferred embodiments

The present invention relates to moisture sensitive drug loaded DPIs, preferably comprising tiotropium, and describes dose delivery to achieve high levels of released FPD. Preferably, the DPI is a predetermined amount. In addition, the present invention solves the problem of how to protect such sensitive medicaments from moisture during all phases of storage, transport, distribution, restoration and final administration, from the moment of dose formation and sealing to the moment of inhalation of a selected dose by the user. Suitable dry powder inhalers for moisture sensitive medicaments are also disclosed.

A dry moisture-proof, direct-load and sealed container containing a measured amount of tiotropium in a high FPD formulation containing at least one excipient is disclosed. The term "tiotropium" is a generic term for all active forms thereof, including pharmaceutically acceptable salts (especially bromides), derivatives, enantiomers, racemates, hydrates, solvates or mixtures thereof. A metered dose will typically include at least one excipient. The container uses a dry, highly impervious seal that is impervious to moisture and other foreign matter and is adapted to be inserted into a dry powder inhaler device or the container may be adapted to be part of an inhaler device.

By "dry" is meant that the walls of the container are constructed of a material selected so that the walls, and particularly the inner wall surfaces of the container, are not able to release moisture which could affect the anticholinergic drug powder in the formulation in order to avoid FPD reduction. As a reasonable result, the construction and materials of the container do not require the method shown in german patent publication DE 10126924 a 1. As an example, gelatin is not a dry material and gelatin still contains moisture even after a particular drying step.

By "high barrier seal" is meant a dry packaging construction or material or combination of materials. A high barrier seal is one in which it represents a high barrier against moisture and the seal itself is "dry", i.e. it cannot release measurable moisture to the loaded powder. The high barrier seal may be, for example, composed of one or more layers of materials, i.e., industrial polymers, aluminum or other metals, glass, silicon oxide, etc., together forming a high barrier seal. If the high barrier seal is a foil, a 50 μm PCTFE/PVC pharmaceutical foil would be the least desirable high barrier foil if stability in use for two weeks would be achieved. For longer in-use stability, metal foils such as aluminum foil from Alcan Singen may be used.

A "high barrier container" is a mechanical construction prepared for the purpose of containing a dose of, for example, tiotropium. The high barrier container is made with a high barrier seal layer constituting the container wall.

By "direct loading" is meant that the metered dose is loaded directly into a highly impermeable container, i.e. without first loading the dose into, for example, a gelatin capsule, and then loading one or more of the basic containers (capsules) into a second package made of a highly impermeable sealing layer material.

Tiotropium is an excellent bronchodilator because it takes effect quickly and has a long-lasting effect even longer than 24 hours, which makes it an ideal drug for many asthmatics. It is a potent drug administered by inhalation once a day sufficient for treatmentAsthma is caused. If the user has an asthma attack, additional administration of tiotropium medication allows the asthma attack to be controlled again. Tiotropium is extremely sensitive to moisture. This fact is described, for example, in the report "COLLEGE TER BEOORDELINGVAN GENEESMIDDELEN MEDICINES EVALUATION BOARD; PUBLIC AS SESSMENT REPORT; spiriva 18 μ g, incubation powder unhardened capsules; at page 6/28 "Product development and finished Product" of RVG 26191 "(2002-05-21), Spiriva is reportedThe stability of the product in use is very short (9 days), the capsules in blister packs are brittle and the FPD is very low: 'about 3. mu.g'. The capsules are packaged in a blister made of polyvinyl chloride and a layer of protective aluminum foil. One plate of blister cards consists of two 5-compartment blisters connected along a perforation line. A layer of peelable aluminum foil surrounds the chamber. The blister allows one capsule to be taken at a time so the other capsules remain protected from moist air. In the case of use, this polyvinyl chloride film is clearly insufficient to protect SPIRIVAThe capsule is used for more than 9 days.

Details regarding the prior art inhalation kit (inhalation kit) comprising inhalable tiotropium powder and the administration of tiotropium using an inhaler can also be investigated in international patent publication WO03/084502 a 1. Details regarding tiotropium compounds, medicaments based on such compounds, the use of compounds and methods for preparing compounds can be investigated in european patent application 0418716B 1.

Based on the above information given in the cited report, a Spiriva was established according to the Food and Drug Administration (FDA) recommendationsAnd (5) planning product stability test.

SpirivaBy HandihalerDPI administration. SpirivaAre formulations containing tiotropium with finely divided excipients and with larger excipients for volumetric dispensing into gelatin capsules which, after filling, are dried and then packed into thermoplastic blisters made of PVC foil. The blister was then wrapped with aluminum foil. During use after opening the first capsule, only the PVC foil protects the remaining 4 capsules in the blister.

3 week trial plan under accelerated conditions for the determination of SpirivaProduct container tightness, in this case, the capsule and blister package, and the effect of the capsule and blister package on the FPD, were set and measured.

Implementation of the test

Bulk Spiriva from our local pharmacyPowder preparation and SpirivaCapsules and HandiHalerUsed together in a laboratory. A laboratory was set up to perform in vitro tests using two Andersen cascade impactors in accordance with the European Pharmacopoeia (EP) and the United States Pharmacopoeia (USP). All analytical work was followed by standard methods for physical testing and determination of aerosols, metered dose inhalers and dry powder inhalers as described in the pharmacopoeia (e.g. USP 2002)<601>) By means of existing heightA liquid chromatography (HPLC) system.

Test S1

With Spiriva from bulk powder filled into inventor's capsules at a relative humidity of less than 10%The formulation is from HandiHalerThe percentage of aerodynamically fine particles of the dose is dosed and released. The test was used in a HandiHaler at room temperature and ambient laboratory conditionsA pressure drop of 4kPa above.

Test S2

With the commercial product Spiriva purchased from the local pharmaciesCapsules from HandiHalerThe percentage of aerodynamically fine particles of the dose is dosed and released. The test was used in a HandiHaler at room temperature and ambient laboratory conditionsA pressure drop of 4kPa above.

Test S3

With the commercial product Spiriva purchased from the local pharmaciesCapsules from HandiHalerStability test in use of percentage of aerodynamically fine particles of the dosed and released dose. One capsule was removed from the blister with 5 capsules and the remaining 4 capsules were placed at 40 ℃ with 75% Rh for 4 days. The blisters containing 4 capsules were then placed in a desiccator for 2 hours before testing was performed. The test was used in a HandiHaler at room temperature and ambient laboratory conditionsA pressure drop of 4kPa above.

Test S4

With the commercial product Spiriva purchased from the local pharmaciesCapsules from HandiHalerStability test in use of percentage of aerodynamically fine particles of the dosed and released dose. One capsule was removed from the blister with 5 capsules and the remaining 4 capsules were placed at 40 ℃ with 75% Rh for 13 days. The blisters containing 4 capsules were then placed in a desiccator for 2 hours before testing was performed. The test was used in a HandiHaler at room temperature and ambient laboratory conditionsA pressure drop of 4kPa above.

Test S5

With the commercial product Spiriva purchased from the local pharmaciesCapsules from HandiHalerStability test in use of percentage of aerodynamically fine particles of the dosed and released dose. One capsule was removed from the blister with 5 capsules and the remaining 4 capsules were placed at 40 ℃ with 75% Rh for 21 days. The blisters containing 4 capsules were then placed in a desiccator for 2 hours before testing was performed. The test was used in a HandiHaler at room temperature and ambient laboratory conditionsA pressure drop of 4kPa above.

High barrier seal test

Test HBS1

With Spiriva from bulk powder filled into a container made as a high barrier seal at a relative humidity of less than 10%The formulation is from HandiHalerThe in-use stability test of the percentage of aerodynamic fine particles of the dosed and released dose was in this case sealed subsequently with aluminium foil of Alcan Singen, germany, to achieve complete tightness. Said aluminum container is at SpirivaThe powder formulation was placed in a desiccator for 2 hours before being loaded from an aluminum container into the inventor's capsule at a relative humidity of less than 10%. The test was used in a HandiHaler at room temperature and ambient laboratory conditionsA pressure drop of 4kPa above.

Test HBS2

With Spiriva from bulk powder filled into a container made as a high barrier seal at a relative humidity of less than 10%The formulation is from HandiHalerThe in-use stability test of the percentage of aerodynamic fine particles of the dosed and released dose was in this case sealed subsequently with aluminium foil of Alcan Singen, germany, to achieve complete tightness. The sealed aluminum container was placed in an atmosphere chamber of 40 ℃ and 75% Rh for 7 days. Said aluminum container is at SpirivaThe powder formulation was placed in a desiccator for 2 hours before being loaded from an aluminum container into the inventor's capsule at a relative humidity of less than 10%. The test was used in a HandiHaler at room temperature and ambient laboratory conditionsA pressure drop of 4kPa above.

Test HBS3

With Spiriva from bulk powder filled into a container made as a high barrier seal at a relative humidity of less than 10%The formulation is from HandiHalerThe in-use stability test of the percentage of aerodynamic fine particles of the dosed and released dose was in this case sealed subsequently with aluminium foil of Alcan Singen, germany, to achieve complete tightness. The sealed aluminum container was placed in an atmosphere chamber of 75% Rh at 40 ℃ for 14 days. Said aluminum container is at SpirivaThe powder formulation was placed in a desiccator for 2 hours before being loaded from an aluminum container into the inventor's capsule at a relative humidity of less than 10%. The test was used in a HandiHaler at room temperature and ambient laboratory conditionsA pressure drop of 4kPa above.

C-haler DPI test

Tests outside the stability test program were also performed, with HandiHalerIn contrast to the proprietary pre-metered dry powder inhaler known as C-haler. The C-haler cartridge used a high barrier seal made from aluminum foil from Alcan Singen, Germany and was filled with 5mg Spiriva by volumeA container of bulk powder formulation. The test was conducted at room temperature and ambient laboratory conditions with a 4kPa pressure drop over C-haler. The results obtained with the Andersen impactor are calculated as the percentage of fine particles based on the released and dosed dose and converted to FPD. The results are shown in table 1 below.

The results of tests S1-5 and HBS1-3 are shown graphically in FIG. 1. The Y axis is defined as SpirivaFPD% of (1). This involves proceeding from HandiHalerReleased FPD, 100% of which was measured from fresh samples obtained from pharmacy.

TABLE 1 inhaled Fine Particle Dose (FPD) < 5 μm%

Surprisingly, we found and concluded from our experiments that a predetermined amount of Spiriva was presentExtremely sensitive to moisture, the conventional packaging of gelatin capsules, which are now widely used for inhalation products, especially respiratory products, will seriously affect FPD. The results show that a predetermined dose of tiotropium formulation requires a dry moisture resistant high barrier seal to maintain the initial fine particle percentage and that gelatin is not a high barrier seal with Spiriva in a containerSuitable excipients or materials for formulation together. Based on these findings, it was not so surprising that we also found that tiotropium formulations must be properly protected during use if further reduction of FPD is to be avoided.

The tests carried out show that the water content of gelatin capsules decreases by Hahdihaler from the moment of loading the dose in the capsule to the moment of the product on the marketThe released FPD reaches about 50%. At the moment of SpirivaThe doses were transferred to the inventor's capsules and used as before with HandiHalerBefore carrying out the same experiment, SpirivaThe dose is loaded into a dry container made of a material with high barrier properties and the loaded container is then stored at 40 ℃ with 75% Rh, even after a long period of time, with no change in the measured Fine Particle Dose (FPD). However, Spiriva in gelatin capsules due to breakage of the moisture barrier of the blister packThe FPD of (a) further gradually decreased during the use of the product, showing a decrease of up to 20% in FPD after storage at 40 c and 75% Rh for 5 days in the shelf life stability test. Table 1 shows our C-haler with high barrier container is higher than the HandiHaler based on FPD dosing2.6 times the performance.

State of the art

Today, Spiriva quantified at the inventor's production siteThe powder formulation is loaded into a gelatin capsule. Gelatin capsules typically contain 13-14% by weight moisture during the dose forming stage and they are dried in a special step after the capsules are loaded with the drug to minimize moisture content. The plurality of dried capsules are then filled into a common blister pack. Details regarding suitable state-of-the-art capsule materials and production processes can be investigated in german patent application DE 10126924 a 1. The remaining moisture content of the dried capsule material is then enclosed in blister packs. The equilibrium between the air enclosed in the package and the gelatin capsule will create a relative humidity in the blister package which will adversely affect the FPD of the tiotropium powder released by the dry powder inhaler.

It is interesting to note that most dry powder formulations of many drugs are normally exposed to the relative humidity of the humidity and ambient air in the capsule materialThe effect of storage variations is not significant. Examples of substances which are very stable to moisture are inhaled steroids such as budesonide and fluticasone. Surprisingly, our investigations showed that tiotropium is very different. FPD becomes smaller by some unknown mechanism when affected by very small amounts of moisture. Since the capsule is used only as a speriva in particularA convenient mechanical carrier for the formulation, partly to solve the moisture problem, is to not use capsules at all, but to load the formulation directly into containers made of dry packaging material with high barrier properties, preferably with Rh below 15% under dry ambient conditions.

The moisture-tight, highly impermeable and sealed container containing a metered amount of tiotropium according to the invention should preferably be made of aluminium foil which allows direct contact with the pharmaceutical product. Aluminum foil that functions properly in these respects is typically composed of a commercial polymer laminated with the aluminum foil, which provides the resulting foil with suitable mechanical properties to avoid aluminum fracture during the forming process. The sealing of the formed container is usually performed using a thin pure aluminum or a sheet of aluminum and polymer clad foil. The container and the wrapping foil are then sealed together by at least one of several possible methods, for example:

applying heat-sealing paint by pressure and heat;

melting the materials together with heat and pressure;

the materials are ultrasonically welded together.

Tiotropium in pure form is a potent drug and is therefore diluted by mixing with acceptable excipients such as lactose in selected proportions prior to the dose forming step to conform to the preferred dose forming and loading method. For example, details regarding inhalation powders comprising tiotropium in admixture with excipients, methods for the production of powders, the use of powders and capsules containing powders can be studied in International patent publication WO 02/30389A 1 to Bechtold-Peters et al. The production of formulations containing very large amounts of excipients together with very small amounts of e.g. tiotropium requires special care to obtain a final stable and robust process.

The Fine Particle Dose (FPD) released by the pure tiotropium administered herein by inhalation is not limited according to the present invention and may typically be in the range of 1 to 25 μ g, including 5, 10, 15 and 20 μ g. The selected dose size is usually prescribed by a physician and is determined by the age, weight, sex and severity of the condition of the patient. However, the dried tiotropium powder is usually present as a compound, such as a salt. Depending on the preferred chemical composition of the substance, e.g. tiotropium in the examples, the formulation quality is often adjusted to obtain an effect corresponding to a predetermined dose of pure tiotropium. For example, if tiotropium bromide monohydrate is used as the active ingredient, typical FPD's fall in the range of 1.25 to 31.25 μ g, the correct metered dose loaded into the inhaler for administration purposes must be adjusted to prevent predictable losses, such as residues and more or less effective deaggregation of the inhaled dose.

Flowability of powder

Powder flowability of the formulation is important in establishing a robust manufacturing process using volumetric or gravimetric dispensing methods. Two properties are of major importance, they are:

particle size

Surface of the particles

Excipient particles having a physical median particle diameter of greater than 25 μm and a narrow particle size distribution, typically less than 5% by mass of the particles being less than 10 μm, generally exhibit good flowability and are particularly suitable for use in admixture with tiotropium. The large particles of excipient or API may act as a carrier for the small particles, in this case the small particles of tiotropium. For inhalation purposes, carrier particles having a mass median particle diameter in the range of from 10 to 250 μm are generally selected, including 30, 50, 70, 100, 130, 160, 190 and 220 μm. The optimum median particle size selected within this range will depend on a number of factors, such as the type of carrier material, the degree of powder flowability to be achieved, the type of inhaler and the ease of deagglomeration during inhalation of the resulting medicament. A variety of commercial grades of Respitos (lactose monohydrate with several defined particle size distributions of DMV up to 400 μm), e.g. the commercial grade of SV003, are available which are suitable as specific excipients for use in tiotropium-containing formulations. A homogeneous and homogeneous tiotropium powder formulation with a physical median particle size down to 10 μm may also provide good flowability when the particles are modified to have a very smooth surface, thus improving the flowability of the formulation. Laboratory tests have shown that up to 20% of the API fine particles (w/w), i.e. less than 10 μm, may be mixed with larger particles, i.e. more than 25 μm, and still maintain a stable formulation with very good FPD properties. Generally, when a volumetric dose forming method is used, large particles account for more than 80% (w/w) of the dose.

The lower limit of the capacity dose forming method is in the range of 0.5 to 1 mg. It is difficult to produce smaller doses and still maintain a low relative standard deviation between doses at the 10% level. Thus, the formulation mass is typically in the range of 1 to 10 mg.

Suitable excipients for inclusion in a tiotropium formulation include monosaccharides, disaccharides, polylactides, oligosaccharides and polysaccharides, polyols, polymers, salts or mixtures of these groups, for example glucose, arabinose, lactose monohydrate, lactose anhydrous (i.e. no crystal water is present in the lactose molecule), sucrose, maltose, dextran, sorbitol, mannitol, xylitol, sodium chloride, calcium carbonate. Lactose is a particular excipient.

In our findings, the aqueous character of any proposed excipient must be appropriate before selection for inclusion in a tiotropium containing formulation, regardless of the function of the proposed excipient, in view of the moisture sensitivity of the tiotropium powder. Excipients that release much moisture in the container enclosing the mixed powder formulation after dose formation can adversely affect the active powder contained so that the resulting FPD quickly deteriorates after dose formation. Thus, the excipients to be mixed with tiotropium should be chosen mainly from acceptable excipients which have good water-containing properties in so far as the active pharmaceutical FPD, in spite of normal variations in the ambient environment during storage, will not adversely affect the useful life of the product concerned. Suitable dry excipients include those of the classes described above. In a preferred embodiment, the excipient with lactose "dry" is chosen and most preferably lactose monohydrate is used in the mixture with tiotropium. One reason lactose was chosen as an excipient is that it has the inherent property of a low and constant moisture sorption isotherm. Excipients having similar or lower adsorption isotherms are also contemplated if other necessary properties are met.

The surrounding environment during dose formation, loading and container sealing should be closely controlled. The temperature should preferably be below 25 deg.c and the relative humidity should preferably be below 15% Rh. The powder formulation should also be kept as dry as possible during the dose forming step. Note that this will ensure that only a small acceptable amount of moisture is included with the dose in the container, which is insufficient to threaten the stability of the moisture sensitive substance and FPD. A fine particle dose high initial fine particle percentage (FPF) of a pharmaceutical formulation (e.g., tiotropium) showing a metered dose of a pharmaceutical product during the packaging stage is maintained in a highly barrier sealed container. Thus, if a predetermined dose is delivered by a DPI, the shelf life of the drug product is not affected by normal changes in the surrounding environment during processing, storage and delivery.

In another aspect of the invention, tiotropium may be mixed or formulated with one or more other pharmacologically active ingredients (API) in addition to the selected excipients for the purpose of combining the anticholinergic agent with other agents for the treatment of e.g. respiratory diseases. The present invention encompasses such use of tiotropium, wherein tiotropium is formulated with other drugs, and from this formulation a metered dose is subsequently produced, dispensed and sealed in a dry, moisture-tight, highly barrier sealed container intended to be inserted into a DPI according to a specific dosing regimen or the needs of the user. In a particular embodiment, at least one selected API may replace one or more selected excipients, so that the sum of the tiotropium dose and the added API meets all requirements regarding compatibility, aqueous properties, FPD stability, pharmaceutical efficacy and total dose quality. Examples of interesting combinations of substances with tiotropium include:

steroid medicine for inhalation: such as budesonide, fluticasone, rofleponide, mometasone, ciclesonide.

Antihistaminic agents: such as epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedasine, dirneteine, clemastine, myristine, cexchlorophen amine, pheniramine, doxylamine, chlorphenhydramine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratadine (desloratidine) and meclizine.

Beta-receptor mimetic agents: such as formoterol, salmeterol, salbutamol, terbutaline sulphate.

PDE IV inhibitors: such as 3 ', 5' -cyclic nucleotide phosphodiesterases and their derivatives.

Adenosine A2a receptor agonists: such as Ribofuranosylvanamide and its derivatives, the substance described in publication WO 02/94273.

The sealed dry high barrier container of the invention containing directly the tiotropium formulation may be in the form of a blister and it may for example comprise a flat dose bed or a cavity formed in aluminium foil or a cavity moulded in a polymeric material, using a high barrier seal foil, such as aluminium or a combination of aluminium and polymeric material, resistant to ingress of moisture. The sealed dry highly impermeable container may form part of the inhaler device or it may form part of a separate part intended to be inserted into the inhaler device for administration of the drug. The aforementioned sealed height impermeable containers used in the C-haler test had the following data:

internal volume of the container: 100mm³

Effective diffusion area: 46mm²

Diffusion constant: at 23 ℃ for 24 hours with differential (differential) Rh of 50%, 0.044g/mm²

Expressed in a different way, in this case the diffusion rate of water into the container is 20g/m per 24 hours at 23 ℃ with a set Rh driving difference of 50%³. The results of the C-haler test showed that the containers used were sufficient to protect the formulation for 14 days. Thus, the present invention recognizes that for a maximum lifetime of 2 weeks, for example, a sealed high barrier container of the above size containing a tiotropium formulation should not have a water transport rate of more than 20g/m for 24 hours at 23 ℃ and a differential Rh of 50%³. The results of the C-haler test can be transposed to a set of requirements placed on different types of containers, such as blisters. Blisters of similar size to the C-haler cartridges should be made using a typical high quality material such as 50 μm PCTFE/PVC which has just reached the diffusion constant of the C-haler container (e.g., recalculated as @38 ℃ C. and 90% Rh, ═ 0.118g/m³). If a device containing a container containing tiotropium is intended for use for longer than 2 weeks, a more moisture resistant container should be used to protect the FPD.

Our experiments show that compositions containing tiotropium and at least one excipient developed according to the method described in the present application have particularly good FPD data and that the compositions are stable over time and during use if filled into highly barrier sealed containers.

In order to develop tiotropium formulations with controlled aqueous properties, first a study of the physicochemical properties of the selected excipients should be carried out. The adsorption isotherm properties will give information about how the formulation will react to different temperatures and relative humidities of its surroundings. A very important problem is also the "memory" of some excipients, which is established by the fact that it takes a long time for the excipient to reach a steady state after being disturbed in the environment. Suitable excipients for formulations containing tiotropium are excipients like lactose monohydrate. The isotherm of lactose monohydrate has three important properties:

low absolute water content

Low absolute water content change after relative humidity change

Very stable under the conditions of the use temperature

The low absolute water content ensures that disturbances from a stable environment will not have a large effect on the tiotropium dose when the amount of moisture present in the excipient is low. The low absolute water content change at different relative humidities ensures that the excipient has no "memory" and that the excipient can easily enter a steady state at a given relative humidity before being filled into a highly impermeable container. Temperature stability ensures that adsorption and desorption within the high barrier seal will affect the API as little as possible.

FIG.2 shows the current application for SpirivaThe isotherms of gelatin and lactose monohydrate of the product serve as examples of choices for poor and good excipients or materials for the moisture sensitive tiotropium formulation. If the amount of API is low, the effect of the excipient is usually large. When volumetric dose forming methods are used, the formulation must have physical flowability such that it is necessary to incorporate larger excipient particles into the formulation. For SpirivaTiotropium in the form of a formulation, the relationship between API and excipient is over 1: 250, which means that small changes in the properties of the excipient, such as its aqueous character, can have a great influence on the API and formulation performance. If an electric field dose dispensing technique (ELFID) dose forming method is used, the relationship between API and excipient can be limited to less than 1: 10, making excipient changes much less important than the effect of a dose forming method of capacity.

A good understanding of the above considerations regarding the selection of suitable excipients is necessary to ensure that if a dose of formulation is loaded into a highly impermeable container, the FPD of the anticholinergic will not change even if the container is subjected to large changes in the surrounding climate.

Therefore, in order to develop a tiotropium formulation that provides the best possible FPD out of a pre-metered dry powder inhaler, a method of producing an optimized formulation containing API and excipients must also be considered. See the flow chart illustrated in fig. 4. Tiotropium was chosen as an example of a very potent drug, which first had to be diluted. The following methods may be used:

1. in a first step, the minimum volumetric dose mass of the tiotropium formulation is determined. Although the most recent improved dose-forming methods can safely specify minimum dose masses below 500 μ g, it is common practice for the minimum dose mass to be in the range 1000 to 5000 μ g. The dilution ratio follows the calculation of the specified mass of tiotropium compound with the specified minimum dose mass.

2. Alternative method a; homogeneous mixture of tiotropium powder formulations:

in a second step, the tiotropium powder is diluted, preferably with dry excipients having a physical particle size > 25 μm, using a method that results in a homogeneous mixture to obtain an accurate determined minimum dose mass. Preferably, this step is carried out by dry mixing together the excipient and the tiotropium powder in a continuous or batch process.

3. Alternative method B; homogeneous tiotropium powder formulation:

in a second step, the tiotropium powder is diluted with dry excipients to obtain the exact determined minimum dose mass, and excipients are appropriately added to this step to prepare uniform tiotropium particles. This step may be, for example, spray drying or freeze drying.

To protect the FPD from the point where the formulation is just aerosolized, a method of opening a small portion of the formulation container immediately prior to the onset of aerosolization of the formulation has been proposed, which can be specifically studied in our publication WO02/24266 a1, which is hereby incorporated by reference in its entirety in this specification. In this context, it is also important to prevent the spontaneous or involuntary exhalation of a user of a DPI, who is about to inhale a formulation, from reaching the selected formulation, because of the high water content in the exhaled air. In our publication US 6,439,227B 1, which is hereby incorporated by reference in its entirety, a device is disclosed which closes the DPI, such that exhaled air does not reach the formulation container and the selected formulation in the DPI, if the user exhales. The device also controls the release of the cutter from the mouthpiece so that the cutter cannot open the container and inhalation of air can not begin to aerosolize the formulation until a certain selected pressure drop is created due to the user's inhalation.

The present invention recognises the importance of preventing moist air from the user or ambient air from reaching the powder in the formulation prior to inhalation and stresses the importance of enabling the formulation to be atomised preferably upon direct contact with a breach in the seal of the container in which the formulation is contained. Preferably, the time the formulation is exposed to ambient air after the container seal is broken should not exceed 2 minutes, otherwise the FPD will decrease when the formulation is finally released, since tiotropium can be adversely affected by moisture in the ambient air, even if the powder is exposed for only 2 minutes.

The inhaler provides for extended release of the formulation from a highly impermeable sealed container during a single inhalation constitutes a preferred embodiment of the inhaler for the release of tiotropium powder formulations. Preferably in an inhaler application such as the air razor method described in our publication US 2003/0192539 a1, to effectively and gradually aerosolize the formulation when released to the user. It is surprising enough that in SpirivaProlonged release of tiotropium containing dose in formulations using inhaler and air razor method results in FPD from state of the art HandiHalerAt least twice as large. See the formulation examples illustrated in figures 4 and 5.

In fig.4 and 5, where the reference numerals 11-32 of the drawings indicate like elements in both figures of two different embodiments of dry powder pharmaceutical formulations comprising a tiotropium powder formulation loaded onto a dose bed in a container as shown in the figures, the embodiments being listed here by way of non-limiting example.

Fig.4 illustrates a side view and a top view of a dose 21 loaded on a dose bed 11 of a high barrier container, which is moisture-tight sealed with a high barrier seal 31.

Fig.5 illustrates a side view and a top view of a dose 21 loaded on a dose bed 11 of a high barrier container, which is moisture-tight sealed with high barrier seals 31 and 32.

As used herein, the phrase "selected from the group consisting of … …/selected from", "selected from" and the like includes mixtures of the specified materials. All references, patents, applications, tests, standards, patent specifications, publications, manuals, textbooks, articles, instructions for use, and the like, referred to herein are incorporated by reference. If a numerical limitation or range is specified, the endpoints thereof are inclusive. As expressly written, all numerical limitations or ranges and subranges are expressly included.

The above written description of the invention provides the means and methods of making and using it so that any person skilled in the art can make and use it as such, which allows for the provision of the subject matter specifically set forth in the appended claims, which form a part of the original description and include the following inventive concepts: a pre-metered dry powder inhaler comprising a dry powder drug formulation and a container, wherein the dry powder drug formulation is loaded into the container and comprises particles of tiotropium particles and at least one dry excipient, the container constitutes a dry high barrier seal, whereby the high barrier seal of the container prevents ingress of moisture, thereby protecting the dry powder drug formulation, and the dry powder drug formulation within the container is formed by a volumetric or electric field dose forming process; said at least one dry excipient is present in the pharmaceutical formulation as fine particles of 10 μm or more in diameter and said at least one dry excipient comprises an excipient selected from the group consisting of monosaccharides, disaccharides, polylactides, oligosaccharides and polysaccharides, polyols, polymers, salts and mixtures thereof; said at least one dry excipient is present in the pharmaceutical formulation in particles of 25 μm or more in diameter and in an amount exceeding 80% by weight, and said at least one dry excipient comprises an excipient selected from the group consisting of monosaccharides, disaccharides, polylactides, oligosaccharides and polysaccharides, polyols, polymers, salts and mixtures thereof; the dry high barrier seal is formed from a material selected from the group consisting of metal, thermoplastic, glass, silicon oxide, and mixtures thereof; modifying the inhaler to allow dry powder formulation administration by inhalation of a dry powder inhaler providing extended dose release; the excipient is selected from lactose, anhydrous lactose, lactose monohydrate and mixtures thereof; the dry high barrier seal layer comprises a flat aluminum foil, optionally pressed into a sheet with one or more polymers; the container forming a chamber formed of a polymeric material selected to impart a high degree of barrier sealing properties to the container; the container forming a chamber formed of a polymeric material together with a high barrier seal layer providing it with high barrier sealing properties; the container is part of a dry powder inhaler; the container is a separate part adapted to be inserted into a dry powder inhaler; the container is a separate part comprising a main portion adapted for insertion into a dry powder inhaler and a secondary portion enclosing the main portion in a moisture-proof package; the dry powder pharmaceutical formulation is used for the treatment of respiratory diseases; the high barrier seal layer is comprised of a peelable foil; the high barrier seal is a rigid integral reservoir comprising a plurality of integral reservoirs; said high barrier seal is a compartment having first and second surfaces sealed with a foil, said foil being rupturable prior to inhalation; the dose of drug released from the dry powder inhaler exhibits more than 20% of the predetermined dose and 40% of the released dose; said dry powder pharmaceutical formulation further comprising at least one additional active pharmaceutical ingredient selected from the group consisting of inhalable steroids, nicotinamide derivatives, beta-receptor agonists, beta-receptor-mimetic active drugs, antihistamines, adenosine A2A receptors, PDE4 inhibitors, dopamine D2 receptor agonists, and mixtures thereof; said at least one second additional pharmaceutical ingredient is selected from the group consisting of budesonide, fluticasone, rofleponide, mometasone, ciclesonide, epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emetine, dirninene, clemastine, pamirpine, cexchlorpheniramine, pheniramine, doxylamine, chlorphenxamine, dimenhydrimine, diphenhydramine, promethazine, ebastine, desloratadine, mezlozine, formoterol, salmeterol, terbutaline sulfate, 3 ', 5' -cyclic nucleotide phosphodiesterase and derivatives thereof, ribofuranosylnamide, and mixtures thereof; a dry powder pharmaceutical formulation formed by a volumetric or electric field dose forming process, said formulation comprising particles of tiotropium and particles of at least one dry excipient, contained in a container, wherein said container constitutes a dry high barrier seal against the ingress of moisture and thereby protects the dry powder pharmaceutical formulation.

As clearly illustrated by the above description, another particular embodiment of the present invention is a dry powder inhaler comprising a dry powder drug formulation loaded in a container suitable for use in a dry powder inhaler, wherein the dry powder drug formulation comprises: tiotropium particles; with at least one dry excipient particle; and wherein the container constitutes a dry high barrier seal against moisture ingress and protects the dry powder pharmaceutical formulation. In a particular embodiment, the pharmaceutical formulation is kept dry with the container, such as to maintain the initial FPD of the dispensing stage at, for example, 40 ℃ with 75% Rh for 14 days. Alternatively, or additionally, the container of the invention comprising a sealed high barrier preferably has a moisture transmission rate at 23 ℃ and differential Rh 50% for 24 hours of no more than 20g/m³. Alternatively, or in addition, the inclusion of a sealed, highly impermeable container according to the present invention does not affect the FPD of tiotropium — for example, the FPD remains consistent over the expected shelf life of the product.

The previous description is presented to enable any person skilled in the art to make and use the invention and is provided in the context of a particular application and its requirements. Various modifications to the specific 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, the present invention is not intended to be limited to the embodiments shown, but is to be accorded the widest scope consistent with the principles and features disclosed herein.

Claims (17)

1. A pre-metered dry powder inhaler comprising a dry powder drug formulation and a container, characterized in that

Said dry powder pharmaceutical formulation being loaded into said container and comprising particles of tiotropium and particles of at least one dry excipient;

said container constituting a dry high barrier seal comprising a flat aluminum foil whereby the high barrier seal of said container prevents moisture ingress and thereby protects said dry powder pharmaceutical formulation; and is

The dry powder drug formulation within the container is formed using a volumetric or electric field dose forming method.

2. The metered dose dry powder inhaler of claim 1, characterized in that

The at least one dry excipient is present in the pharmaceutical formulation as fine particles having a diameter of 10 μm or more; and is

The at least one dry excipient comprises an excipient selected from the group consisting of monosaccharides, oligosaccharides and polysaccharides, polyols, polylactides, salts and mixtures thereof.

3. The metered dose dry powder inhaler of claim 1, characterized in that

Said at least one dry excipient being present in the pharmaceutical formulation in the form of particles having a diameter of 25 μm or more and in an amount of more than 80% by weight; and is

The at least one dry excipient comprises an excipient selected from the group consisting of monosaccharides, oligosaccharides and polysaccharides, polyols, polylactides, salts and mixtures thereof.

4. The metered dose dry powder inhaler of claim 1, characterized in that

The dry high barrier seal is formed from a material selected from the group consisting of metal, thermoplastic, glass, silicon oxide, and mixtures thereof.

5. The metered dose dry powder inhaler of claim 1, characterized in that

The inhaler is adapted such that administration of the dry powder formulation is by inhalation of the dry powder inhaler which provides for prolonged dose release.

6. The metered dose dry powder inhaler of claim 1, characterized in that

The excipient is selected from lactose, anhydrous lactose, lactose monohydrate and mixtures thereof.

7. The metered dose dry powder inhaler of claim 1, characterized in that

The container forms a chamber formed of a polymeric material together with the aluminum-containing high barrier seal layer that provides it with high barrier sealing properties.

8. The metered dose dry powder inhaler of claim 1, characterized in that

The container is part of the dry powder inhaler.

9. The metered dose dry powder inhaler of claim 1, characterized in that

The container is a separate part adapted to be inserted into the dry powder inhaler.

10. The metered dose dry powder inhaler of claim 1, characterized in that

The high barrier seal is comprised of a peelable foil.

11. The metered dose dry powder inhaler of claim 1, characterized in that

The high barrier seal is a rigid unitary reservoir comprising a plurality of integral reservoirs.

12. The metered dose dry powder inhaler of claim 1, characterized in that

The high barrier seal is a compartment having first and second surfaces sealed with a foil which is rupturable prior to inhalation.

13. The metered dose dry powder inhaler of claim 1, characterized in that

The dose of medicament released from the dry powder inhaler is more than 20% of the predetermined dose and more than 40% of the released dose.

14. The metered dose dry powder inhaler of claim 1, characterized in that

The dry powder pharmaceutical formulation further comprises at least one additional active pharmaceutical ingredient selected from the group consisting of budesonide, fluticasone, rofleponide, mometasone, ciclesonide, beta-receptor agonists, beta-receptor-mimetic active agents, antihistamines, adenosine A2A receptor, PDE4 inhibitors, dopamine D2 receptor agonists, and mixtures thereof.

15. The metered dose dry powder inhaler of claim 14, characterized in that

The at least one additional active pharmaceutical ingredient is selected from the group consisting of budesonide, fluticasone, rofleponide, mometasone, ciclesonide, epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, clemastine, pamirine, pheniramine, doxylamine, chlorphenxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratadine, meclizine, formoterol, salmeterol, salbutamol, terbutaline sulfate, 3 ', 5' -cyclic nucleotide phosphodiesterase and derivatives and mixtures thereof.

16. A pre-metered dry powder inhaler according to claim 2 or 3, characterized in that the oligosaccharide is a disaccharide.

17. A dry powder pharmaceutical formulation in a container formed by a volumetric or electric field dose forming method, said formulation comprising particles of tiotropium and particles of at least one dry excipient, characterized in that

The container constitutes a dry high barrier seal to prevent moisture ingress and thus protect the dry powder pharmaceutical formulation, the dry high barrier seal comprising a flat aluminum foil.