ES2371601T3 - COMPOSITION FOR INHALATION. - Google Patents

Abstract

A dry powder inhalation composition consisting of (a) formoterol medicament particles or a pharmaceutically acceptable salt thereof, and (b) a mixture of lactose particles with an average volume diameter of between 70 and 120 micrometers and a diameter smaller than 250 micrometers, said mixture is characterized in that up to 96% by weight of the lactose particles have a diameter less than 150 micrometers and in which up to 25% by weight of the lactose particles have a diameter less than 5 micrometers

Description

Composition for inhalation

Cross reference to related requests

The present application claims priority to United Kingdom Patent Application No. 0219513.7 filed on August 21, 2002 and to United Kingdom Patent Application No. 0219513.9 filed on August 21, 2002.

Technical Field of the Invention

The present invention relates to a composition for inhalation of dry powder. In particular, it aims at formulations of the drug formoterol or its pharmaceutically acceptable salt mixed with lactose particles.

10 Background of the invention

In order to have the ability to be inspired by the key target sites in patients' lungs, inhalation drugs are typically provided in micronized form with average particle sizes of up to 10 micrometers. A number of devices have been developed to assist in the administration of such medications to patients' lungs. In one type of device, a dry powder inhaler device (DPI), the medicament to be inhaled is dispensed in a stream of air produced by the inspiratory action of the patient. A large number of such devices have been developed. The device may be a single dose device (eg, in which the drug is dispensed from a premeditated dosage medium such as a capsule) or multiple dose (in which the drug is stored in a reservoir and it is then measured before dispersion in the air stream or in which the drug is rewarded and then stored in multiple dose packages such as blister packs). In a number of DPI devices, the particulate drug is mixed with an excipient powder with a larger average particle size and the drug particles are combined with the excipient to create a generally homogeneous mixture. The larger particle size of the excipient results in the fluidity of the powder mixture, and the homogeneity of the mixture that allows it to be measured in precisely measurable doses. This is of particular importance when only very large quantities are required.

25 small drugs in one dose. Excipient powders of this type and pharmaceutical powder compositions for inhalation in which such excipients are used are described, for example, in United States Patent No. 3,957,965.

The precise measurement of high potency inhalant drugs causes particular problems, since it is likely that the amount of medication in the composition relative to that of the vehicle is particularly small (less

30 than 1 part of drug in 50 parts of carrier). This is exemplified by the drug formoterol, which is often given to patients in a dose less than 60 micrograms (doses may contain amounts as small as 6 micrograms).

US Patent No. 6,199,607 to Trofast describes a multi-stage process for preparing a dry powder formoterol composition. The procedure described includes mixing the

35 components followed by the micronization of the combination. The micronized particles were subsequently treated to eliminate amorphous areas in their crystal structure. Then, the particles agglomerate, pass through sieve, and spheronize, followed by a second sieving, spheronization and sieving.

So, what is required are simple procedures to produce dry powder medications that maintain desirable flow and deposition characteristics after dispersion.

US2002 / 0106332 discloses a process for preparing an inhalable powder, in which portions substantially equal to N + m of an excipient having a distribution of a particle size larger and portions equal to N of active substance having a distribution of a smaller particle size they are mixed in alternative layers in an appropriate mixing vessel and in which once all the excipient and the active substance have been added the two 2N + m layers of the two components are mixed together by the use of a mixer

45, in which a portion of the excipient having the largest particle size is added first, and in which N is an integer> 0 and m denotes 0 or 1.

Document US2002 / 0110529 discloses a powder preparation containing tiotropium for inhalation, procedures for its preparation as well as its use in the preparation of a pharmaceutical composition for the treatment of respiratory ailments, in particular COPD (chronic obstructive pulmonary disease) and asthma .

WO01 / 78695 discloses powders for use in a dry powder inhaler comprising a fraction of fine particles consisting of a mixture of excipient and additives, a fraction of unrefined particles and an active ingredient. Compositions based on particles of lactose, magnesium stearate as additive and formoterol fumarate as active ingredient are disclosed in the examples.

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Summary of the invention

The invention provides compositions for inhaling dry medicament powder comprising a particulate medicament and a lactose carrier with defined particle sizes and proportions, wherein the medicament is formoterol or a pharmaceutically acceptable salt thereof. The compositions provide a precise, uniform and consistent dispersion when used with, for example, a multi-dose dry powder inhaler. Methods for the use of the compositions of the invention are also disclosed.

Therefore, compositions for inhaling dry powder of a particulate medicament (formoterol) and lactose with defined particle sizes and proportions that are easy to handle, and which can be easily filled in the reservoir of a dry powder inhaler are described. multiple doses (MDPI), (see, for example, WO 92/10229). In addition, these compositions are measured more precisely and provide more uniform and consistent dispersions when dispensed by MDPI devices. Certain compositions may also be more stable.

One aspect of the invention provides a dry powder inhalation composition consisting of formoterol medicament particles or a pharmaceutically acceptable salt thereof, and a mixture of lactose particles with a VMD (average volume diameter) between 70 and 120 micrometers and a diameter smaller than 250 micrometers, in which the mixture is characterized in that up to 96% by weight of the lactose particles have a diameter less than 150 micrometers and in which up to 25% by weight of the lactose particles They have a diameter smaller than 5 micrometers.

Another aspect of the invention provides a multi-dose dry powder inhaler comprising the compositions according to the invention.

Brief description of the drawings

Figure 1: Graphical representation of particle size distribution for lactose particles.

Figure 2: Graphical representation of the drug by action from a representative commercial product with an amount claimed on the 6 Ig label of formoterol (OXIS TURBUHALERT, Lot ZE226).

Figure 3: Graphical representation of drug administration by action from an IVAXT MDPI with an amount claimed on the 6 Ig label.

Detailed description of the invention

The invention provides compositions for inhaling dry medicament powder comprising a particulate medicament and a lactose carrier with defined particle sizes and proportions, wherein the medicament is formoterol or a pharmaceutically acceptable salt thereof. The compositions provide a more precise, uniform and consistent dispersion when used with, for example, a multi-dose dry powder inhaler. Methods for the use of the compositions of the invention are also disclosed.

Any conflict between any reference cited herein and the specific teachings of this application must be resolved in favor of the latter. Likewise, any conflict between a definition within the technique of a word or expression and a definition of the word or expression as specifically taught herein must be resolved in favor of the latter.

The technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which the present invention pertains, unless otherwise defined. Reference is made herein to various methodologies and materials known to those skilled in the art. Standard reference works that set out the general principles of pharmacology include The Pharmacological Basis of Therapeutics by Goodman and Gilman, 10th Ed., McGraw Hill Companies Inc., New York (2001).

Any suitable materials and / or procedures known to those skilled in the art can be used to carry out the present invention. However, preferred materials and procedures are described. The materials, reagents and the like referred to in the following description and examples are obtainable from commercial sources, unless otherwise indicated.

As used herein, either in a transitional phrase or in the body of the claim, the terms " comprises " and "which includes" they must be interpreted as carriers of open meaning. That is, the terms must be interpreted as synonymous with the expressions "which has at least" or "which includes at least". When used in the context of a procedure, the term "comprising" It means that the procedure includes at least the referred stages, but that it may include additional stages. When used in the context of a compound or composition, the term "comprising" means that the compound or composition includes the

55 E03751884 11-11-2011

less the characteristics or components referred to, but which may also include additional characteristics or components.

As used herein, the singular forms " a / a / or " and "the" specifically they also cover the plural forms of the terms to which they refer, unless the content clearly indicates otherwise.

The term "approximately" it is used herein to mean roughly, in the region of, broadly, or around. When the term "approximately" It is used together with a numerical interval, modifies the interval by the extension of the upper and lower limits of the numerical values exposed. In general, the term "approximately" it is used herein to modify a numerical value in a higher or lower form of the declared value by a difference of 5%.

As used herein, unless specifically stated otherwise, the word "or" it is used in the sense "inclusive" of " and / or " not in the sense "exclusive" of "none."

Hereinafter, reference is made in detail to specific embodiments of the invention. While the invention will be described in conjunction with these specific embodiments, it will be understood that it is not intended to limit the invention to such specific embodiments. In other cases, well-known procedure operations have not been described in detail, so as not to unnecessarily complicate the present invention.

One aspect of the invention provides a dry powder inhalation composition consisting of formoterol medicament particles or a pharmaceutically acceptable salt thereof and a mixture of lactose particles with an average volume diameter (VMD) of between 70 and 120 micrometers and a diameter smaller than 250 micrometers, in which the mixture is characterized in that up to 96% by weight of the lactose particles have a diameter less than 150 micrometers and in which up to 25% by weight of the lactose particles They have a diameter smaller than 5 micrometers.

In one embodiment, up to 85% by weight of the lactose particles have a diameter less than 90 micrometers, while in another embodiment up to 37% by weight of the lactose particles have a diameter less than 60 micrometers.

In yet another embodiment, up to 35% by weight of the lactose particles have a diameter of less than 30 micrometers, while in still other embodiments up to 31.5% by weight of the lactose particles have a diameter of less than 15 micrometers. .

In other embodiments of this aspect, up to 30% by weight of the lactose particles have a diameter of less than 10 micrometers, and in some embodiments between 6.5 and 24.5% by weight of the lactose particles have a smaller diameter. than 5 micrometers

In some embodiments of this aspect, the composition comprises up to 10% by weight of medicament. In some cases, the medicine is formoterol fumarate dihydrate.

As used herein, with the inclusion of a numerical range for a variable it is intended to express that the invention can be practiced with the variable equal to any one of the values within the range. Thus, for a variable that is inherently discrete, the variable can be equal to any one of the integer values of the numerical interval, which include the values of the extremes of the interval. Similarly, for a variable that is inherently continuous, the variable can be equal to any one of the real values of the numerical range, which include the values of the ends of the range. As an example, a variable that is described as a carrier of values between 0 and 2, can be 0, 1 or 2 for variables that are inherently discrete, and can be 0.0, 0.1, 0.01, 0.001, or any other real value for variables that are inherently continuous.

As used herein, "up to" when used in conjunction with a percentage of lactose particles of an expressed size, means the requirement of the presence of a non-zero amount of particles of the expressed size and that the percentage Numeric expressed is the upper limit for the presence of particles of the expressed size.

Another aspect of the invention provides a multi-dose dry powder inhaler comprising a composition according to the invention.

The compositions described are optionally formulated in a pharmaceutically acceptable carrier with any one of the following well known medicinally inert and pharmaceutically acceptable moieties such as carriers, including diluents, excipients, surfactants, and flavorings (see Remington's Pharmaceutical Sciences, 18th Ed., Gennaro , Mack Publishing Co., Easton, PA 1990 and Remington: The Science and Practice of Pharmacy, Lippincott, Williams & Wilkins, 1995). Although the type of pharmaceutically acceptable carrier / vehicle employed in the generation of the compositions will vary depending on the mode of administration of the composition to a mammal, generally pharmaceutically acceptable carriers are physiologically inert and non-toxic. See also Zeng, et al. Particulate Interactions in Dry Powder Formulations of Inhalation, Taylor & Francis, London, 2001.

55 E03751884 11-11-2011

As used herein, with terms such as "medication" or "active ingredient" It is intended to cover active pharmaceutical agents suitable for inhalation therapy in the form of dry powder. Non-limiting, representative examples include bronchodilators (e.g., epinephrine, metaproterenol, terbutaline, albuterol, and the like), anticholinergic agents (e.g., ipratropium bromide), xanthines (e.g., diphilin, aminophylline), corticosteroids inhalants (e.g., flunisolide, beclomethasone, budesonide, and the like), or �-2 adrenergic receptor agonists (e.g., salmeterol and formoterol).

The medicament may be in any isomeric form or mixture of isomeric forms, for example, a pure enantiomer, particularly R, R-enantiomer, a mixture of enantiomers, a racemate or a mixture thereof (eg, formoterol). Pharmaceutically acceptable formoterol derivatives include pharmaceutically acceptable salts, in particular salts with addition of acid with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. The salt can also be with an organic acid such as acetic, succinic, maleic, smoking, citric, tartaric, lactic or benzoic acid. The active ingredient and its pharmaceutically acceptable derivatives may exist in the form of a solvate, in particular a hydrate.

One form of active ingredient for use in the invention is formoterol fumarate, especially formoterol fumarate dihydrate, conveniently in its racemic form. Formoterol, its salts and hydrates and its salt hydrates described above can be prepared by known procedures, for example those described in United States Patent No. 3,994,974 or United States Patent No. 5,684,199.

In general, the medicament is present in the dry powder composition in an amount that is less than 10%, preferably less than 2% and more preferably less than 1% by weight of the composition. The actual amount of medication in the composition will depend largely on the nature of the dry powder inhaler and the amount of composition that is calculated for each individual dose. In the case where a large dose of composition is calculated, the proportion of the drug in the dose will be reduced. Particularly disclosed are compositions diluted in WO 01/39745, for example, 0.02% by weight.

In some embodiments, the average particle diameter of the medicament is up to 10 micrometers in diameter, while in other embodiments, the average particle size is up to 5 micrometers in diameter. In still other embodiments, the average particle size ranges from about 1 to about 5 micrometers in diameter. The particle size of the medicament can be reduced to the desired level by conventional means, for example, milling in a mill, for example, an air jet mill, a ball mill, or a vibrating mill, by meshing, by crystallization, by drying. by spraying or lyophilization. The particle size can be determined by the use of laser light scattering (Sympatec GmbH, Claasthal-Zellerfeld, Germany).

The distribution of the desired particle size of lactose can be prepared in a similar manner. However, it is preferable to prepare lactose by the combination of two or more portions of previously prepared and classified lactose, for example a fine combination of lactose, in which the average particle diameter is less than 10 micrometers in diameter and a portion in that the average particle diameter is relatively thick. A characteristic unrefined lactose is supplied as a classified lactose, which is collected on a mesh with a mesh size of 63 micrometers, after being passed through a mesh with a mesh size of 90 micrometers.

The formulations of the compositions of the invention may conveniently be presented in unit dosage forms and may be prepared by conventional pharmaceutical techniques. Such techniques include the step of associating the compound and pharmaceutically acceptable carriers, or an excipient. In general, the formulations are prepared by the uniform and close association of the active ingredient with finely divided solid carriers, and then, if necessary, the preparation of separate dosage units of the product.

The dry powder composition can be measured and filled into capsules, eg, gelatin or hydroxypropyl methylcellulose capsules, such that the capsule contains a unit dose of medication.

The doses of medication to be used can generally range from 1 to 60 micrograms. When the drug is formoterol fumarate dihydrate, the dose may range, for example, from 6 to 54 micrograms. Preferred doses are 6 to 24 micrograms, especially unit doses of 6 micrograms, 12 micrograms and 24 micrograms. These doses can be administered once or twice a day.

When the dry powder is in a capsule containing a unit dose of medication, the total amount of composition will depend on the size of the capsules and the characteristics of the inhalation device with which the capsules are used. However, representative total filling weights representative of dry powder per capsule are between 1 and 25 mg, e.g., 5, 10, 15 or 20 mg.

Alternatively, the dry powder composition according to the invention can be filled in the reservoir of a multi-dose dry powder inhaler (MDPI), for example, of the type illustrated in WO 92/10229 (hereinafter referred to as " MDPI IVAXT ").

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The compositions according to the invention can be easily prepared by combining the required amount of active ingredient with the required amount of lactose in particles of the desired particle size distribution. Preferably, the lactose is alpha lactose monohydrate.

A procedure for the administration of a therapeutically effective amount of compositions prepared by the procedures described herein, for the treatment of conditions responsive to the medications of choice is also disclosed. Non-limiting examples of conditions include chronic obstructive pulmonary disease, asthma, late phase allergic responses, or pulmonary inflammations.

The expression "therapeutically effective amount" It is used to denote treatments in effective doses to achieve the desired therapeutic result. In addition, those skilled in the art will appreciate that the therapeutically effective amount of the compositions of the invention can be reduced or increased by precise adjustments and / or by the administration of more than one composition of the invention, or by the administration of a composition of the invention. invention with another compound or composition. Therefore, the present disclosure provides a procedure to tailor the administration / treatment to the specific requirements specific to a given mammal.

The following examples are intended to further illustrate certain preferred embodiments of the invention and have no limiting nature. Those skilled in the art will recognize, or will be able to determine, by the use of no more than routine experimentation, numerous equivalents to the specific substances and procedures described herein.

Examples

Example 1

Particle size distribution, dose administration, and fine particle fractions for a combination of formoterol lactose

0.265 grams of formoterol (such as dihydrated fumarate salt) were combined with 99,735 grams of lactose that had a particle size distribution within the range shown in Table 1. The combination was conducted by the use of a drum mixing procedure. (TURBULAT, Glen Creston, Newersey, USA). The combination of formoterol lactose is filled in the reservoir of a MDPI IVAXT device.

Table 1

Distributions of lactose carrier particle size. The average value of the particle size distribution should be in the range of 70-120 Im.

Tamafo / Im

Cumulative Subdimension%

Diana

Interval

�10

11.0 8-13.5

�30

17.5 10-25

�60

31.0 20-42

�90

45.0 30-60

�174

> 90 -

250

100 -

Then, the inhalers containing the formulation were tested for pharmaceutical performance under conditions specified in the European Pharmacopoeia (2001) which include uniformity of administered dose and fine particle dose. The acting drug (DPA) was measured by the use of a unit dose sampling unit together with a critical flow controller model TP�, high capacity pump and flow meter (Copley Scientific, Nottingham, U.�.) While The fine particle dose (FPD) and fine particle fraction (FPF) were measured by the use of a 5-stage liquid impactor MSL also from Copley Scientific.

The compositions gave excellent dose uniformity with relative standard deviation (RSD) of administered doses ranging from 4-13% (Table 2) when used in association with the IVAXT MDPI device, with a good proportion of fine drug particles ( Table 3). The pharmaceutical performance of inhalers remains stable after unprotected exposure to elevated storage conditions.

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Table 2

Relative standard deviation (RSD) of 10 doses (3 at the beginning, 4 in the middle and 3 at the end of the device's shelf life) of each inhaler containing a formulation for the use of said lactose as the excipient before and after Unprotected storage at 25�C / 60% RH for one month.

Before storage

After storage

Device 1

Device 2 Device 3  Device 1 Device 2 Device 3

8.1%

7.9% 11.4% 12.8% 10.5% 4.7%

Table 3

Fraction of fine particles (FPF, recovered dose%) of formoterol from each inhaler device containing a formulation for the use of said lactose as an excipient before and after storage in the open state at 25 ° C / 60% RH for one month.

Parameters

Before storage After storage

Device 1

Device 2 Device 3  Device 1 Device 2 Device 3

At the beginning of the useful life of the device

38 40 40 41 39 39

At the end of the device's life

38 38 42 40 35 43

5 Example 2

Particle size distribution for a combination of formoterol lactose

0.265 grams of formoterol (as the dihydrate fumarate salt) were combined according to the procedures of Example 1, with 99,735 grams of lactose having a particle size distribution within the range shown in Table 4. Lactose was prepared by the combination of a lactose mixture from 90 to 150

10 micrometers (95%) with a lactose microfin that had a VMD of 7.5 micrometers (5%). The combination of formoterol lactose is filled in the reservoir of a MDPI IVAXT dry powder inhaler. A typical particle size distribution for a combination of lactose thus prepared is shown in Fig. 1.

Table 4

Particle size distribution for the combination of formoterol lactose

Parameters

Middle value Interval

VMD

97 Im 89-110 Im

GSD

4.4 2.2-4.9

�5 Im

13.1% 8.0% -24.0%

�10 Im

21.6% 14.2% -28.5%

�15 Im

24.5% 15.0% -31.0%

�30 Im

26.5% 16.0% -34.0%

�60 Im

29.6% 18.9% -36.1%

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(cont.)

Particle size distribution for the mixture of formoterol lactose

Parameters

Middle value Interval

�90 Im

44.5% 34.8% -50.8%

�150 Im

87.7% 83.9% -93.5%

�174 Im

96.0% 93.8% -98.9%

�250 Im

100% 100%

Example 3

Determinations of the formoterol deposition profile

5 In order to measure the performance of the product thus developed, a study was carried out that compared the administration and drug deposition profiles of the compositions of the invention from, for example, an MDPI device with a representative commercial product. , OXIS TURBUHALERT (AstraZeneca Pharmaceuticals, U.�, amount claimed on the label 6 mcg of formoterol per dose). IVAXT MDPI and TURBUHALERS OXIS were tested under the same conditions specified in the European Pharmacopoeia

10 (2001). The acting drug (DPA) was measured by the use of a unit dose sampling apparatus while the fine particle dose (FPD) and fine particle fraction (FPF) were measured by the use of a liquid impactor of 5 steps as for Example 1.

The commercial product (Fig. 2) showed a greater variation in the DPA than the compositions used with an IVAXT MDPI (Fig. 3). The average DPA of three commercial products (with an amount claimed on the 6 Ig label)

15 was 3.9 Ig, suggesting that a larger portion (greater than 30%) of the drug was not released from the device. The average DPA of the three IVAXT MDPIs was 5.3 Ig, (within 80-120% of the amount claimed on the 6 Ig label). The three commercial devices showed an RSD of 27.8% for DPA values that was more than double the value (11.9%) of the MDPI IVAXT, indicating a more consistent administration of the drug.

There was no significant difference in the dose of fine particles (FPD) of formoterol from MDPI IVAXT (2.37� 0.19 20 Ig) and the commercial representative (2.27 � 0.39 Ig) (See Table 5) .

Table 5

Formoterol deposition profiles from a representative commercial product (OXIS TURBUHALERT) and an IVAXTM MDPI (The amount claimed on the label of both devices was 6 Ig)

MDPI IVAXTM

OXIS TURBUHALERTM (Lot ZE 226)

Actions 7-26

Device 1 Device 2 Device 3 Device 1 Device 2 Device 3

PUERTO IND. (Ig)

1.07 1.12 0.98 1.00 1.00 1.10

STAGE 1 (Ig)

1.95 1.94 1.94 0.20 0.10 0.20

STAGE 2 (Ig)

0.39 0.24 0.29 0.10 0.10 0.20

STAGE 3 (Ig)

0.82 0.77 0.83 0.60 0.70 0.90

STAGE 4 (Ig)

0.83 0.90 0.82 0.90 0.90 1.10

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(cont.)

Formoterol deposition profiles from a representative commercial product (OXIS TURBUHALERT) and an IVAXTM MDPI (The amount claimed on the label of both devices was 6 Ig)

MDPI IVAXTM

OXIS TURBUHALERTM (Lot ZE 226)

Actions 7-26

Device 1 Device 2 Device 3 Device 1 Device 2 Device 3

STAGE 5 (Ig)

0.73 0.78 0.65 0.70 0.70 0.90

RD (Ig)

5.79 5.75 5.51 3.50 3.50 4.20

FPD (Ig)

2.60 2.50 2.40 2.30 2.30 2.80

FPF (RD%)

Four. Five 43 44 66 66 67

FPF (LC%)

43 42 40 38 38 47

Performances 37-56

PUERTO IND. (Ig)

0.93 0.83 0.85 1.10 0.90 0.70

STAGE 1 (Ig)

2.16 2.08 2.15 0.30 0.20 0.20

STAGE 2 (Ig)

0.25 0.27 0.26 0.10 0.10 0.20

STAGE 3 (Ig)

0.64 0.72 0.67 0.70 0.60 0.50

STAGE 4 (Ig)

0.71 0.84 0.76 0.90 0.80 0.60

STAGE 5 (Ig)

0.60 0.76 0.71 0.70 0.70 0.50

RD (Ig)

5.29 5.50 5.40 3.90 3.40 2.60

FPD (Ig)

2.10 2.40 2.20 2.40 2.20 1.60

FPF (RD%)

40 44 41 62 65 62

FPF (LC%)

35 40 37 40 37 27

Note: RD is the total dose recovered from the impactor� LC is the amount claimed on the label and IND Port. means Port of Induction.

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Example 4

Consistency of formoterol administration

A combination composed of 0.26% w / w micronized formoterol in lactose was prepared as previously described. It was found that the final products produced an average drug per actuation within 80-120% of the amount claimed on the label, an average dose of fine particles expressed as a percentage of the amount claimed on the label> 37%. All parameters meet the Pharmacopeia specifications set forth for dry powder inhalers, previously cited. The dose of fine particles for the composition when used in conjunction with an IVAXTM MDPI, which refers directly to the therapeutic equivalence of these inhalers, was comparable to that of the representative commercial product. It was shown that the administration of the

The composition of the invention with an IVAXTM MDPI was more consistent in the administration of formoterol than the commercial product. (Data not revealed).

Example 5

Preparation of drug combinations

A combination of micronized medication selected from a group consisting of, but not limited to,

15 bronchodilators (e.g., epinephrine, metaproterenol, terbutaline, albuterol, and the like), anticholinergic agents (e.g., ipratropium bromide), xanthines (e.g., aminophylline, diphilin, aminophylline), inhalant corticosteroids (e.g. , flunisolide, beclomethasone, budesonide, and the like), or �-2 adrenergic receptor agonists (e.g., salmeterol) is mixed with lactose according to the procedures described in Example 1. The resulting mixture is introduced into a IVAXTM MDPI then it was tested for its pharmaceutical performance under the conditions specified in the

20 European Pharmacopoeia. The acting drug (DPA) is measured by the use of a unit dose sampling unit while the fine particle dose (FPD) and fine particle fraction (FPF) are measured by the use of a liquid impactor of 5 stages described previously.

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Claims (12)

1. A composition for dry powder inhalation consisting of

(to)

 formoterol medication particles or a pharmaceutically acceptable salt thereof, and

(b)

 a mixture of lactose particles with an average volume diameter of between 70 and 120 micrometers and a diameter less than 250 micrometers, said mixture is characterized in that up to 96% by weight of the lactose particles have a diameter less than 150 micrometers and in which up to 25% by weight of the lactose particles have a diameter of less than 5 micrometers.

2.

A dry powder inhalation composition according to claim 1, wherein up to 85% by weight of the lactose particle mixture has a diameter of less than 90 micrometers.

3.

A dry powder inhalation composition according to claim 1, wherein up to 37% by weight of the lactose particle mixture has a diameter of less than 60 micrometers.

Four.

A dry powder inhalation composition according to claim 1, wherein up to 35% by weight of the lactose particle mixture has a diameter of less than 30 micrometers.

5.

A dry powder inhalation composition according to claim 1, wherein up to 31.5% by weight of the lactose particle mixture has a diameter of less than 15 micrometers.

6.

A dry powder inhalation composition according to claim 1, wherein up to 30% by weight of the lactose particle mixture has a diameter of less than 10 micrometers.

7.

A dry powder inhalation composition according to claim 1, wherein between 6.5 and 24.5% by weight of the lactose particle mixture has a diameter of less than 5 micrometers.

8.

A dry powder inhalation composition according to any one of claims 1 or 7, comprising up to 10% by weight of drug particles.

9.

A dry powder inhalation composition according to any one of the preceding claims, wherein the formoterol or its pharmaceutically acceptable salt is in the form of a solvate.

10.

A dry powder inhalation composition according to any one of the preceding claims, wherein the formoterol or its pharmaceutically acceptable salt is in the form of a hydrate.

eleven.

A dry powder inhalation composition according to any one of the preceding claims, wherein the medicament particles are formoterol fumarate dihydrate.

12.

A multi-dose dry powder inhaler comprising a composition for dry powder inhalation according to any one of the preceding claims.

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