Title of Invention	EXCIPIENT FOR USE IN DRY POWDER INHALATION PREPARATIONS
Abstract	This invention relates to an excipient for dry powder inhalation preparations comprising granules made of primary carrier material, which granules break down during inhalation in such a manner that they give a concentration of primary carrier material at stage 2 kof the twin stage impinger of at least 5%, which excipient is obtainable by granulating a primary carrier material in a fluid binding agent and drying the granules thus obtained, wherein said primary carrier material is selected from monosaccharides, disaccharids, polyols derived from mono- and/or disaccharides and their monohydrates, and oligo- or polysaccharides. The invention also relates to a method for producing the excipient and to dry powder inhalation preparations.

Title of Invention

EXCIPIENT FOR USE IN DRY POWDER INHALATION PREPARATIONS

Abstract

This invention relates to an excipient for dry powder inhalation preparations comprising granules made of primary carrier material, which granules break down during inhalation in such a manner that they give a concentration of primary carrier material at stage 2 kof the twin stage impinger of at least 5%, which excipient is obtainable by granulating a primary carrier material in a fluid binding agent and drying the granules thus obtained, wherein said primary carrier material is selected from monosaccharides, disaccharids, polyols derived from mono- and/or disaccharides and their monohydrates, and oligo- or polysaccharides. The invention also relates to a method for producing the excipient and to dry powder inhalation preparations.

Full Text	The present invention relates to an excipient for dry powder inhalation preparations and a method for preparing the same. The invention furthermore relates to dry powder inhalation preparations containing the excipient, to a method for making the excipient and to an excipient made of lactose. The delivery of active molecules to the lungs can be achieved using metered dose inhalers However, this success has been blighted in recent times by the environmental concerns over chlorofluorocarbons (CFCs), which have been used as propellants. The Montreal protocol in 1989 detailed the need to replace CFC propellants, because of their contribution to ozone depletion. This has resulted in the development of propellants which do not deplete ozone and an increase in activity in the DPI field. There are a number of DPI products available on the market today, using many different technological approaches for delivering an active component to the lungs. To penetrate into the target areas of the lungs, active molecules must possess an aerodynamic particle size of less than 5um. This is achieved primarily by micronisation. The particles produced are, however, inherently cohesive/adhesive in nature due to an excess of surface free energy. The surface properties generated in manufacture can lead to adherence to the device and/or the formation of stable agglomerates, both of which can have a negative influence on the dose reproducibility as they are uncontrollable. Therefore, traditionally a DPI product consists of the device, the active component and an inert carrier (i.e. excipient) with the purpose to aid flow and encourage dispersion. The active particles adhere to the surface of the carrier, ideally preventing segregation but allowing detachment during inhalation. The preferred carrier material has always been ct-lactose monohydrate. The reasons for this include the fulfillment of the carrier functions by improving flow, the availability of toxicological information and its relatively low price. The manipulation of lactose to balance the requirements of high and constant deposition values and good flow properties has focused primarily on the particle size distribution. However, a number of other techniques have been investigated to improve the performance of lactose as a carrier. US patent 5,254,330 describes the use of smooth crystals produced by controlled crystallization, which have a rugosity of less than 1.75. An alternative to alpha-lactose monohydrate is described in the International patent WO98/50015, which makes use of roller dried anhydrous lactose with a size between 50 and 250 pnv and a rugosity between 1.9 and 2.4. The lactose described in the prior art is in a crystalline form. The particle size is relatively small. It was found that the deposition of these known particles can be further improved. It is known that decreasing the carrier particle size of a powder mixture, results in an increase in the fine particle fraction. As the particle size is reduced the relationship between the carrier lactose particle and micrcnised active component changes. For large carrier particles the active adheres to the surface of the carrier. As carrier size decreases and approaches that of the micronised active component the relationship is more of a weak agglomerate, which can be easily dispersed especially with the modern inhaler devices. However, as the carrier particle size is decreased, so are the flow properties which affects the distribution of the active component within the mix and the dose reproducibility. It is the object of the present invention to provide an excipient that can be used as a carrier in dry powder inhalation preparations and that consists of particles large enough to have suitable flow properties and a structure to promote dispersion. This object is achieved by an excipient for dry powder inhalation preparations comprising granules made of primary carrier material, which granules break up during inhalation in such a manner that they give a concentration of primary carrier material on stage 2 of the twin stage impinger (e.g. by Erweka, OK) determined by the antrone reaction of at least 5%. Preferably, the concentration of primary carrier material at stage 2 of the twin stage impinger determined by the antrone reaction is at least 10%, more preferably at least 20%. Such an excipient is obtainable by granulating a primary carrier material in a fluid binding agent, for example in a fluid bed dryer or a shear mixer, and drying the granules thus obtained. The fluid binding agent is preferably an aqueous solution of the primary carrier material. Alternatively, the fluid binding agent is a solvent, in particular ethanol. The fluid binding agent may be water also. The properties of the excipient granules may be varied by choosing the fluid binding agent. A solvent will usually evaporate more quickly thus resulting in weaker granules that lead to a higher percentage at stage 2 of the twin stage impinger. The strength of the granules can be manipulated by varying the process parameters such as the amount of fluid binding agent (granulation fluid). Weaker granules have the structure which promotes dispersion of the active component, as they will break down as they pass through an inhaler. Drying the granules can be performed in various manners. In general, it was found that the quicker the drying operation, the weaker the granules. Suitable drying means are for example formed by an oven. Especially preferred is drying while the granules are kept in motion, such as in a fluid bed dryer. The particle size of the granules that (alone or in combination with some other vehicle) form the excipient lies between 50-1000 pm. Preferably, the particle size of the granules lies between 200-500 pm. The primary particle median geometric size of the granules lies in the range 1-170 ym, preferably in the range 1-15 pm. The primary carrier material can be selected from a wide variety of materials which are preferably known to be suitable for DPI, including monosaccharides, such as glucose, fructose, mannose; polyols derived from these monosaccharides, such as sorbitol, mannitol or their monohydrates; disaccharides, such as lactose, maltose, sucrose, polyols derived from these disaccharides, such as lactitol, mannitol, or their monohydrates; oligo or polysaccharides, such as dextrins and starches. Preferably the primary carrier material is a crystalline sugar such as glucose, lactose, fructose, mannitol or sucrose because such sugars are both inactive and safe. Most preferably, lactose is used. The invention furthermore relates to a dry powder inhalation formulation which contains a pharmacologically active component and an excipient as claimed for delivery of the active component to the lungs. The active component is for example selected from the group consisting of steroids, bronchodilators, cromoglycate, proteins, peptides and mucolytics, or from the group consisting of hypnotics, sedatives, analgesics, anti¬inflammatory agents, anti-histamines, anti-convulscents, muscle relaxants, anti-spasmodics, anti-bacterials, antibiotics, cardiovascular agents, hypoglycaemic agents. According to a further aspect thereof, the invention relates to a method for producing an excipient as claimed, comprising granulating a primary carrier material in a fluid binding agent and drying the granules thus obtained. The same preferred process parameters apply as indicated above. The invention in a preferred embodiment thereof relates to lactose granules for use in dry powder inhalation preparations, which granules break down during inhalation in such a manner that they give a concentration of primary Carrier material at stage 2 of the twin stage impinger determined by the antrone reaction of at least 5%, preferably at least 10%, more preferably at least 20%. These granules are obtainable by granulating lactose in a lactose solution or a solvent, such as ethanol, and drying the granules thus obtained. The active component is added to the finished granules. The present invention is further illustrated in the example that follows. EXAMPLE To demonstrate the concept of the present invention, granules with a particle size distribution o£ 200-500vim were produced from tt-lactose monohydrate (DMV International, the Netherlands) with a particle size distribution of 2-16pro. A medium shear mixer (Kenwood) was used to granulate 450 g of lactose using an aqueous lactose solution, water or ethanol as the binding agent, added using a peristaltic pump (LKB). The mass was passed through a 1 mm screen (Erweka) and then dried in a fluid bed dryer (Aeromatic) or tray oven (HeraeusJ. The 200-500 pm fraction was prepared by screening with a sieve shaker (Retsch). The batches were as summarized in Table 1. Determining the quantity of lactose on stage 2 by means of the antrone test is performed as follows. The antrone solution is prepared by dissolving 200 mg antrone in 200 g sulphuric acid. 1 ml of sample deposited at stage 2 of the impinger is collected and added to 2 ml of antrone solution. This mixture is allowed to stand for one hour. Subsequently the UV absorbance at 625 nm is determined. The result is given in the following table.The fine particle fraction (FPF) is the active component {e.g. the drug) reaching stage 2 (Table 2), determined as described hereinbelow. The granules were blended with the drug sodium cromoglycate (1.8% (w/w)). On completion of the mixing process it was clearly evident that the granules had maintained their initial shape. The formulations were assessed in vitro using the twin stage impinger at 60 1/min which has a cut off diameter of 6.4 pm, using the Novolizer Inhaler (Sofotec) . The amount of active component on each stage was determined using OV spectroscopy. (Table 3). Table 3 shows the in vitro deposition values for the 8 batches of granules Granulation is determined fc listribution of liquid over the surface of particles, forming liquid bridges between particles. This is followed by the evaporation of the liquid resulting in the formation of solid bridges which binds particles together forming granules. From the results of this experiment it can de derived that decreasing the amount of liquid available for dispersion in granulation, reduces the amount of potential solid bridges producing weaker granules (batch nos. 5 and 2). Poor dispersion of liquid as a result of shorter mixing times does also produce weaker granules (batch nos. 2 and 3). Furthermore, it was found that the slower the drying rate the larger the crystals, formed during recrystallisation (batch nos. 1, 2 and 4) . Fluid bed drying is faster. Solids concentration in the liquid has no effect due to the relatively good solubility of lactose (batch nos. 3, 6 and 7). WE CLAIM: 1. An excipient for dry powder inhalation preparations comprising granules made of primary carrier material, which granules break down during inhalation in such a manner that they give a concentration of primary carrier material at stage 2 of the twin stage impinger of at least 5%, which excipient is obtainable by granulating a primary carrier material in a fluid binding agent and drying the granules thus obtained, wherein said primary carrier material is selected from monosaccharides, disaccharides, polyols derived from mono- and/or disaccharides and their monohydrates, and oligo- or polysaccharides. 2. The excipient as claimed in claim 1, wherein the concentration of primary carrier material at stage 2 of the twin stage impinger is at least 10%. 3. The excipient as claimed in claim 1 or 2, wherein the concentration of primary carrier material at stage 2 of the twin stage impinger is at least 20%. 4. The excipient as claimed in any one of claims 1 to 3, wherein the fluid binding agent is an aqueous solution of the primary carrier material. 5. The excipient as claimed in any one of the claims 1 to 3, wherein the fluid binding agent is a solvent, in particular ethanol. 6. The excipient as claimed in any one of the claims 1 to 3, wherein the fluid binding agent is water. 7. The excipient as claimed in any one of the claims 1 to 6, wherein the drying is performed in an oven. 8. The excipient as claimed in any one of the claims 1 to 6, wherein the drying is performed while the granules are kept in motion, such as in a fluid bed dryer. 9. The excipient as claimed in any one of the claims 1 to 8, wherein the particle size of the granules lies between 50 - 1000 urn. 10. The excipient as claimed in any one of the claims 1 to 9, wherein the particle size of the granules lies between 200 - 500 um. 11. The excipient as claimed in any one of the claims 1 to 10, wherein the primary particle median geometric size of the granules lies in the range 1 - 170 um. 12. The excipient as claimed in any one of the claims 1 to 11, wherein the primary particle size median geometric size of the granules lies in the range 1-15 \im. 13. The excipient as claimed in any one of the claims 1 to 12, wherein the primary carrier material is glucose, fructose, mannose, sorbitol, mannitol or their monohydrates, lactose, maltose, sucrose, lacitol, manitol, or their monohydrates, dextrins and/or starches. 14. The excipient as claimed in any one of the claims 1 to 13, wherein the primary carrier material is a crystalline sugar such as glucose, lactose, fructose, mannitol or sucrose. 15. The excipient as claimed in any one of the claims 1 to 14, wherein the primary carrier material of the granules is lactose. 16. A dry powder inhalation formulation which contains a pharmacologically active component and an excipient as claimed in any one of the claims 1 to 15, for delivery of the active component to the lungs. 17. The dry powder inhalation formulation as claimed in claim 16, in which the active component is selected from the group consisting of steroids, bronchodilators, cromoglycate, proteins, peptides and mucolytics. 18. The dry powder inhalation formulation as claimed in claim 16, in which the active component is selected from the group consisting of hypnotics, sedatives, analgesics, anti-inflammatory agents,anti-histamines, anti-convulscents, muscle relaxants, anti-spasmodics, anti-bacterials, antibiotics, cardiovascular agents, hypoglycaemic agents. 19. A method for producing an excipient as claimed in any one of the claims 1 to 15, comprising granulating a primary carrier material in a fluid binding agent and drying the granules thus obtained, 20. The method as claimed in claim 19, wherein the fluid binding agent is an aqueous solution of the primary carrier material. 21. The method as claimed in claim 19, wherein the fluid binding agent is a solvent, in particular ethanol. 22. The method as claimed in claim 19, wherein the fluid binding agent is water. 23. The method as claimed in any one of the claims 19 to 22, wherein the drying is performed in an oven. 24. The method as claimed in any one of the claims 19 to 22, wherein the drying is performed while the granules are kept in motion, such as in a fluid bed dryer. 25. Lactose granules for dry powder inhalation preparations, characterized in that the granules break down during inhalation in such a manner that they give a concentration of primary carrier material at stage 2 of the twin stage impinger of at least 5%, preferably at least 10%, more preferably at least 20%. 26. The dry powder inhalation formulation as claimed in any one of claims 16 to 18 for the treatment of diseases of the respiratory tract.

Full Text

The present invention relates to an excipient for dry powder inhalation preparations and a method for preparing the same. The invention
furthermore relates to dry powder inhalation preparations containing the excipient, to a method for making the excipient and to an excipient made of lactose.
The delivery of active molecules to the lungs can be achieved using metered dose inhalers However, this success has been blighted in recent times by the environmental concerns over chlorofluorocarbons (CFCs), which have been used as propellants. The Montreal protocol in 1989 detailed the need to replace CFC propellants, because of their contribution to ozone depletion. This has resulted in the development of propellants which do not deplete ozone and an increase in activity in the DPI field.
There are a number of DPI products available on the market today, using many different technological approaches for delivering an active component to the lungs. To penetrate into the target areas of the lungs, active molecules must possess an aerodynamic particle size of less than 5um. This is achieved primarily by micronisation. The particles produced are, however, inherently cohesive/adhesive in nature due to an excess of surface free energy. The surface properties generated in manufacture can lead to adherence to the device and/or the formation of stable agglomerates, both

of which can have a negative influence on the dose reproducibility as they are uncontrollable.
Therefore, traditionally a DPI product consists of the device, the active component and an inert carrier (i.e. excipient) with the purpose to aid flow and encourage dispersion. The active particles adhere to the surface of the carrier, ideally preventing segregation but allowing detachment during inhalation.
The preferred carrier material has always been ct-lactose monohydrate. The reasons for this include the fulfillment of the carrier functions by improving flow, the availability of toxicological information and its relatively low price. The manipulation of lactose to balance the requirements of high and constant deposition values and good flow properties has focused primarily on the particle size distribution. However, a number of other techniques have been investigated to improve the performance of lactose as a carrier.
US patent 5,254,330 describes the use of smooth crystals produced by controlled crystallization, which have a rugosity of less than 1.75.
An alternative to alpha-lactose monohydrate is described in the International patent WO98/50015, which makes use of roller dried anhydrous lactose with a size between 50 and 250 pnv and a rugosity between 1.9 and 2.4.
The lactose described in the prior art is in a crystalline form. The particle size is relatively small. It was found that the deposition of these known particles can be further improved.
It is known that decreasing the carrier particle size of a powder mixture, results in an increase in the fine particle fraction. As the particle size is reduced the relationship between the carrier lactose particle and

micrcnised active component changes. For large carrier particles the active adheres to the surface of the carrier. As carrier size decreases and approaches that of the micronised active component the relationship is more of a weak agglomerate, which can be easily dispersed especially with the modern inhaler devices.
However, as the carrier particle size is decreased, so are the flow properties which affects the distribution of the active component within the mix and the dose reproducibility.
It is the object of the present invention to provide an excipient that can be used as a carrier in dry powder inhalation preparations and that consists of particles large enough to have suitable flow properties and a structure to promote dispersion.
This object is achieved by an excipient for dry powder inhalation preparations comprising granules made of primary carrier material, which granules break up during inhalation in such a manner that they give a concentration of primary carrier material on stage 2 of the twin stage impinger (e.g. by Erweka, OK) determined by the antrone reaction of at least 5%.
Preferably, the concentration of primary carrier material at stage 2 of the twin stage impinger determined by the antrone reaction is at least 10%, more preferably at least 20%.
Such an excipient is obtainable by granulating a primary carrier material in a fluid binding agent, for example in a fluid bed dryer or a shear mixer, and drying the granules thus obtained. The fluid binding agent is preferably an aqueous solution of the primary carrier material. Alternatively, the fluid binding agent is a solvent, in particular ethanol. The fluid binding agent may be water also. The properties of the excipient granules

may be varied by choosing the fluid binding agent. A solvent will usually evaporate more quickly thus resulting in weaker granules that lead to a higher percentage at stage 2 of the twin stage impinger.
The strength of the granules can be manipulated by varying the process parameters such as the amount of fluid binding agent (granulation fluid).
Weaker granules have the structure which promotes dispersion of the active component, as they will break down as they pass through an inhaler.
Drying the granules can be performed in various manners. In general, it was found that the quicker the drying operation, the weaker the granules. Suitable drying means are for example formed by an oven. Especially preferred is drying while the granules are kept in motion, such as in a fluid bed dryer.
The particle size of the granules that (alone or in combination with some other vehicle) form the excipient lies between 50-1000 pm. Preferably, the particle size of the granules lies between 200-500 pm. The primary particle median geometric size of the granules lies in the range 1-170 ym, preferably in the range 1-15 pm.
The primary carrier material can be selected from a wide variety of materials which are preferably known to be suitable for DPI, including monosaccharides, such as glucose, fructose, mannose; polyols derived from these monosaccharides, such as sorbitol, mannitol or their monohydrates; disaccharides, such as lactose, maltose, sucrose, polyols derived from these disaccharides, such as lactitol, mannitol, or their monohydrates; oligo or polysaccharides, such as dextrins and starches.
Preferably the primary carrier material is a crystalline sugar such as glucose, lactose, fructose,

mannitol or sucrose because such sugars are both inactive and safe. Most preferably, lactose is used.
The invention furthermore relates to a dry powder inhalation formulation which contains a pharmacologically active component and an excipient as claimed for delivery of the active component to the lungs.
The active component is for example selected from the group consisting of steroids, bronchodilators, cromoglycate, proteins, peptides and mucolytics, or from the group consisting of hypnotics, sedatives, analgesics, anti¬inflammatory agents, anti-histamines, anti-convulscents, muscle relaxants, anti-spasmodics, anti-bacterials, antibiotics, cardiovascular agents, hypoglycaemic agents.
According to a further aspect thereof, the invention relates to a method for producing an excipient as claimed, comprising granulating a primary carrier material in a fluid binding agent and drying the granules thus obtained. The same preferred process parameters apply as indicated above.
The invention in a preferred embodiment thereof relates to lactose granules for use in dry powder inhalation preparations, which granules break down during inhalation in such a manner that they give a concentration of primary Carrier material at stage 2 of the twin stage impinger determined by the antrone reaction of at least 5%, preferably at least 10%, more preferably at least 20%. These granules are obtainable by granulating lactose in a lactose solution or a solvent, such as ethanol, and drying the granules thus obtained. The active component is added to the finished granules.
The present invention is further illustrated in the example that follows.

EXAMPLE
To demonstrate the concept of the present invention, granules with a particle size distribution o£ 200-500vim were produced from tt-lactose monohydrate (DMV International, the Netherlands) with a particle size distribution of 2-16pro. A medium shear mixer (Kenwood) was used to granulate 450 g of lactose using an aqueous lactose solution, water or ethanol as the binding agent, added using a peristaltic pump (LKB). The mass was passed through a 1 mm screen (Erweka) and then dried in a fluid bed dryer (Aeromatic) or tray oven (HeraeusJ. The 200-500 pm fraction was prepared by screening with a sieve shaker (Retsch).
The batches were as summarized in Table 1.

Determining the quantity of lactose on stage 2 by means of the antrone test is performed as follows. The antrone solution is prepared by dissolving 200 mg antrone in 200 g sulphuric acid. 1 ml of sample deposited at stage 2 of the impinger is collected and added to 2 ml of antrone solution. This mixture is allowed to stand for one hour. Subsequently the UV absorbance at 625 nm is determined. The result is given in the following table.The fine particle fraction (FPF) is the active component {e.g. the drug) reaching stage 2 (Table 2), determined as described hereinbelow.

The granules were blended with the drug sodium cromoglycate (1.8% (w/w)). On completion of the mixing process it was clearly evident that the granules had maintained their initial shape. The formulations were assessed in vitro using the twin stage impinger at 60 1/min which has a cut off diameter of 6.4 pm, using the Novolizer

Inhaler (Sofotec) . The amount of active component on each stage was determined using OV spectroscopy. (Table 3).

Table 3 shows the in vitro deposition values for the 8 batches of granules Granulation is determined fc listribution of liquid over the surface of particles, forming liquid bridges between particles. This is followed by the evaporation of the

liquid resulting in the formation of solid bridges which binds particles together forming granules.
From the results of this experiment it can de derived that decreasing the amount of liquid available for dispersion in granulation, reduces the amount of potential solid bridges producing weaker granules (batch nos. 5 and 2).
Poor dispersion of liquid as a result of shorter mixing times does also produce weaker granules (batch nos. 2 and 3).
Furthermore, it was found that the slower the drying rate the larger the crystals, formed during recrystallisation (batch nos. 1, 2 and 4) . Fluid bed drying is faster.
Solids concentration in the liquid has no effect due to the relatively good solubility of lactose (batch nos. 3, 6 and 7).

WE CLAIM:
1. An excipient for dry powder inhalation preparations comprising granules made of primary carrier material, which granules break down during inhalation in such a manner that they give a concentration of primary carrier material at stage 2 of the twin stage impinger of at least 5%, which excipient is obtainable by granulating a primary carrier material in a fluid binding agent and drying the granules thus obtained, wherein said primary carrier material is selected from monosaccharides, disaccharides, polyols derived from mono- and/or disaccharides and their monohydrates, and oligo- or polysaccharides.
2. The excipient as claimed in claim 1, wherein the concentration of primary carrier material at stage 2 of the twin stage impinger is at least 10%.
3. The excipient as claimed in claim 1 or 2, wherein the concentration of primary carrier material at stage 2 of the twin stage impinger is at least 20%.
4. The excipient as claimed in any one of claims 1 to 3, wherein the fluid binding agent is an aqueous solution of the primary carrier material.
5. The excipient as claimed in any one of the claims 1 to 3, wherein the fluid binding agent is a solvent, in particular ethanol.
6. The excipient as claimed in any one of the claims 1 to 3, wherein the fluid binding agent is water.
7. The excipient as claimed in any one of the claims 1 to 6, wherein the drying is performed in an oven.

8. The excipient as claimed in any one of the claims 1 to 6, wherein the drying is performed while the granules are kept in motion, such as in a fluid bed dryer.
9. The excipient as claimed in any one of the claims 1 to 8, wherein the particle size of the granules lies between 50 - 1000 urn.
10. The excipient as claimed in any one of the claims 1 to 9, wherein the particle size of the granules lies between 200 - 500 um.
11. The excipient as claimed in any one of the claims 1 to 10, wherein the primary particle median geometric size of the granules lies in the range 1 - 170 um.
12. The excipient as claimed in any one of the claims 1 to 11, wherein the primary particle size median geometric size of the granules lies in the range 1-15 \im.
13. The excipient as claimed in any one of the claims 1 to 12, wherein the primary carrier material is glucose, fructose, mannose, sorbitol, mannitol or their monohydrates, lactose, maltose, sucrose, lacitol, manitol, or their monohydrates, dextrins and/or starches.
14. The excipient as claimed in any one of the claims 1 to 13, wherein the primary carrier material is a crystalline sugar such as glucose, lactose, fructose, mannitol or sucrose.
15. The excipient as claimed in any one of the claims 1 to 14, wherein the primary carrier material of the granules is lactose.

16. A dry powder inhalation formulation which contains a pharmacologically active component and an excipient as claimed in any one of the claims 1 to 15, for delivery of the active component to the lungs.
17. The dry powder inhalation formulation as claimed in claim 16, in which the active component is selected from the group consisting of steroids, bronchodilators, cromoglycate, proteins, peptides and mucolytics.
18. The dry powder inhalation formulation as claimed in claim 16, in which the active component is selected from the group consisting of hypnotics, sedatives, analgesics, anti-inflammatory agents,anti-histamines, anti-convulscents, muscle relaxants, anti-spasmodics, anti-bacterials, antibiotics, cardiovascular agents, hypoglycaemic agents.
19. A method for producing an excipient as claimed in any one of the claims 1 to 15, comprising granulating a primary carrier material in a fluid binding agent and drying the granules thus obtained,
20. The method as claimed in claim 19, wherein the fluid binding agent is an aqueous solution of the primary carrier material.
21. The method as claimed in claim 19, wherein the fluid binding agent is a solvent, in particular ethanol.
22. The method as claimed in claim 19, wherein the fluid binding agent is water.
23. The method as claimed in any one of the claims 19 to 22, wherein the drying is performed in an oven.

24. The method as claimed in any one of the claims 19 to 22, wherein the drying is performed while the granules are kept in motion, such as in a fluid bed dryer.
25. Lactose granules for dry powder inhalation preparations, characterized in that the granules break down during inhalation in such a manner that they give a concentration of primary carrier material at stage 2 of the twin stage impinger of at least 5%, preferably at least 10%, more preferably at least 20%.
26. The dry powder inhalation formulation as claimed in any one of claims 16 to
18 for the treatment of diseases of the respiratory tract.

Documents:

2261-chenp-2004 abstract-duplicate.pdf

2261-chenp-2004 abstract.pdf

2261-chenp-2004 claims-duplicate.pdf

2261-chenp-2004 claims.pdf

2261-chenp-2004 correspondence-others.pdf

2261-chenp-2004 correspondence-po.pdf

2261-chenp-2004 description (complete)-duplicate.pdf

2261-chenp-2004 description (complete).pdf

2261-chenp-2004 form-1.pdf

2261-chenp-2004 form-18.pdf

2261-chenp-2004 form-26.pdf

2261-chenp-2004 form-3.pdf

2261-chenp-2004 form-5.pdf

2261-chenp-2004 pct search report.pdf

2261-chenp-2004 pct.pdf

2261-chenp-2004 petition.pdf

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Patent Number

228008

Indian Patent Application Number

2261/CHENP/2004

PG Journal Number

10/2009

Publication Date

06-Mar-2009

Grant Date

27-Jan-2009

Date of Filing

07-Oct-2004

Name of Patentee

CAMPINA NEDERLAND HOLDING B.V

Applicant Address

Hogeweg 9, NL-5301 LB Zaltbommel,

Inventors:

#	Inventor's Name	Inventor's Address
1	ELLISON, Mark, Jason, Heath	Jan Heinstraat 2a, NL-5211 TD 's Hertogenbosch,
2	LAMBREGTS-VAN DEN HURK, Theodora, Antonia, Maria	Generaal v. Vlijmenstraat 5, NL-5463 CH Veghel,

PCT International Classification Number

A61K 9/16

PCT International Application Number

PCT/EP2002/004207

PCT International Filing date

2002-04-12

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA