Proliposome powders for inhalation

 

(57) Abstract:

The invention relates to medicine. Proliposome powder contains monophasic discrete particles of the biologically active component and a lipid or mixture of lipids, as well as crystalline hydrophilic pharmacologically acceptable carrier. Lipids have a transition temperature below 37°C. the Lipids selected from natural and synthetic phosphoglycerolipids, sphingolipids and digalactosyldiacylglycerols. Proliposome powders are used for inhalation, are stable in the conditions of long-term storage and provide high bioavailability of the active component. 5 S. and 36 C.p. f-crystals.

The technical field to which the invention relates

The invention relates to proliposome the powders used, in particular for inhalation, to a method for proliposome powders, to compositions containing proliposome powders, and methods of use thereof.

Technical background of the invention

Liposomes are to membranophones the vesicles consisting of lipid bilayers alternating with hydrophilic areas. They can be constructed from a variety of natural and synthetic l is. One of the major applications of liposomes is their use as carriers for various types of pharmaceutically active components to improve drug delivery and to minimize the side effects of some treatments. Pharmaceutically active ingredients can be incorporated into liposomes or by encapsulating them in the hydrophilic areas of the liposomes (in the case when the active ingredient is water-soluble), or by encapsulating them of lipid bilayers, when the active component is lipophilic.

One of the main problems associated with pharmaceutical liposomal drugs is stability in long-term storage. Aqueous liposomal dispersions have limited stability associated with aggregation, loss of the active component in the external phase, the chemical degradation of the active component or lipid material, etc.

These problems can be largely overcome in the case of solid compositions. Such solid compositions may include liposomal powder, i.e., dried liposomal dispersion system, or proliposome powder.

The process of drying the liposomal Dschibuti in the presence of protecting sugars, as described, for example, in the publication WO 86/01103.

In U.S. patent 4906476 disclosed liposomal preparations for delivery of steroids inhaled. It also opens the possibility of delivery of dried liposomes in the form of powder aerosol using a suitable device. In addition, this document discloses shipping by spraying from a spray bottle containing the solvent gas propellant with suspended therein particles of a dry powder of liposomes, as well as the spray dried particles into the lungs using a propellant.

While liposomes as such are not present in proliposome powders, and are formed in the hydration process at a temperature exceeding the transition temperature of lipids. Proliposome powders have the advantage in comparison with dried preparations of liposomes, as in this case eliminates the risk of damage to liposomal membranes during dehydration.

Proliposome powders have already been described earlier.

For example, in U.S. patent 4311712 revealed liofilizovannye potentially liposomal mixture (having the ability to generate liposomes), which was obtained by dissolving forms of Oia in an organic solvent, which remains solid during lyophilization, followed by lyophilization of the resulting solution. Potentially liposomal mixture can be stored and then if desired to recover in the form of an aqueous liposomal drug. This biologically active compound may be any compound having the properties of a biological nature.

In the publication WO 90/00389 revealed liofilizovannye potentially liposomal mixture containing the amphipatic lipid and cyclosporine or its derivative, for use in the delivery process in cells of cyclosporine using the formed liposomes. Liofilizovannye mixture is recovered in the wave environment with the formation of liposomes, in which the encapsulated almost all of cyclosporine available in liofilizovannyh mixture.

In the publication WO 92/11842 disclosed proliposome powder, which when restoring water or saline solution to form a suspension of liposomes incorporating polyene drug, such as nystatin.

All of the above patents and applications had to proliposome compositions, which before the introduction of the subject of hydration.

In EP 309464 disclosed by proliposome the Ute solid particles, in which the biologically active component is contained in the form of a dispersion of lipid.

The purpose of the invention

The inventors have found that, if the preferred delivery of drugs by inhalation, it is advantageous to provide proliposome powders that include only one phase. Therefore, one of the purposes of the present invention is the provision of such proliposome powder.

Disclosure of the invention

The above objective of the present invention is achieved by the development proliposome powder, which contains only one phase consisting of discrete particles of biologically active agent in combination with a lipid or mixture of lipids having a transition temperature (Tcbelow 37oC.

Consider powder is the most convenient for administration via inhalation.

Single phase powder can also be described as including a homogeneous molecular mixture of the biologically active component and a lipid or mixture of lipids having a transition temperature (Tcbelow 37oC.

The terms "one, or a single phase and homogeneous molecular mixture" should be understood thus, CIDA.

Single phase powder can be inhaled directly, as well as in situ, for example, in the upper or lower part of the respiratory system, forming liposomes, which are fully incorporated biologically active component.

In General, it should be noted that the present invention can use any amphipatic lipid or mixture of lipids, which are known that they are suitable for the preparation of liposomes using existing known methods. Such a lipid or lipid mixture should have a transition temperature below body temperature (37oC) to ensure that the product is in the form proliposome powder could be subjected to hydration in physiological conditions (i.e. in order for this product to be able to form liposomes in the respiratory system). The phase transition temperature for different lipid mixtures can be readily determined using well known methods such as differential scanning calorimetry (DSC) (see, for example, J. Suurkuusk et al., Biochemistry, 1976, 15, no. 7, p. 1393). In General, the present invention can be any natural or synthetic lipid or mixture of lipids having a transition temperature below 37o

Lipids of particular interest in the context of the present invention are DPPC and/or DMPH. The preferred mixture of DPPC and DMPG containing at least 10 wt. % DMPG, for example, 10 to 50% DMPG. Most preferred is a mixture of DPPC and DMPG containing in addition at least one charged lipid, such as DMPG, DPPG, DMPC or SA, for example, in an amount up to 5 wt.%. Other preferred mixtures include DPSM and ACTS, not necessarily containing at least one charged lipid, as well as mixtures of cholesterol with I-lecithin or with lecithin, not necessarily containing at least one charged lipid, and with Twithless than 37oC. Other mixtures can be easily selected any specialist with the average level of skill in the art when referring to the relevant guidelines (e.g., Gregor Cevc, Phospholipids Handbook, Marcel Dekker, New York (1993), pp 427 - 435).

The active ingredient preferably has a molecular structure that can be included in of lipid bilayers to facilitate encapsulation in liposomes upon hydration. As examples, the ester of a fatty acid with a long hydrocarbon chain, sufficient to act as the an individual with the average level of knowledge in this area, these components may include, for example, anti-inflammatories and bronchomalacia, as well as antihistamines, cyclo-oxygenase inhibitors, inhibitors of the synthesis of leukotriene, leukotriene antagonists, inhibitors of phospholipase-A2 (PLA2), antagonists factor platelet aggregation (FOP) and prevention of asthma. In this context it may be of interest also antiarrhythmic agent, tranquilizers, cardiac glycosides, hormones, antihypertensives, antidiabetic, antiparasitic and anticancer funds selalunya tools, analgesics, antibiotics, Antirheumatic agents, drugs used for immunotherapy, anti-fungal drugs, hypertensive tools, vaccines, antiviral drugs, proteins, peptides and vitamins.

Specifically in this invention can be used glucocorticosteroids such as budesonide, dexamethasone, betamethasone, fluotsinolon, flumetazon, triamcinolone acetonide, flunisolide, beclomethasone and 16,17-acetals pregnanvy derivatives and derived compounds; and -2 agonists, such as terbutaline, salmeterol, salbutamol, formoterol, fenoterol, clenbuterol, procaterol, bitolterol and brosamer, a mixture of glucocorticosteroid with bronhodilatator, such as formoterol, salmeterol, terbutaline or salbutamol. In order to avoid ambiguity in cases of links to active components should indicate that these links cover a pharmaceutically acceptable esters, salts and hydrates of active components.

When the active ingredient is a steroid, it is preferable steroid ether.

The active component is a preferable steroid and preferably a steroid, esterified in the 21st position fatty acid comprising at least 8, for example, at least 10 or at least 12 carbon atoms. The fatty acid may contain up to 24 carbon atoms, in particular up to 20 or up to 18 carbon atoms. More preferably, the active component was a steroid-21-palmitate, myristate, laurate, capret, kaprilat or stearate. The most preferred active ingredient of the present invention is the compound (22R) -16 , 17 butylidenedioxy-6, 9-debtor-11-hydroxy-21-palmitoleate-pregna-4-ene-3,20-dione, rofleponide palmitate.

In the case where the active ingredient is ether, it must be hydrolyzed to the active agent. B is the required in situ hydrolysis, while the esters found in the crystalline state, is not hydrolyzed.

When the desirability of delivery by inhalation, as much as possible, proliposome powder of the present invention should consist of particles having diameter less than 10 microns, for example, 0.01 to 10 microns, or 0.1 to 6 μm, for example, 0.1 to 5 microns, or agglomerates of such particles. Preferably, at least 50% of the powder consisted of particles falling on the size in the specified range. So, for example, at least 60%, preferably at least 70%, more preferably at least 80% and most preferably at least 90% of the powder consisted either of particles with a size corresponding to the desired range, or of agglomerates of such particles.

In proliposome powder of the present invention do not need to enter other ingredients. However, pharmaceutical compositions containing powders of the present invention may also include other pharmaceutically acceptable additives, in particular adjuvants, diluents and carriers. They can be added to proliposome composition after conducting any type of micronisation or before it, provided that the solvent was Phnom substance. A preferred carrier is a crystalline monohydrate lactose. Other preferred carriers include glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, ▫ maltitol, melezitose, stachyose, lactic, palatinit, starch, xylitol, mannitol, monoset and others, including their hydrates, as well as amino acids, e.g. alanine and betaine.

The number of available drug additives may vary within a wide range. Under some circumstances may require that you make a very small amount of additives, or the need for them may not even be present, and often preferably using diluents for reconstitution of the powder with the aim of improving its properties, essential for inhalation. In the latter case, for example, at least 50%, in particular at least 70% or at least 80% of the drug may consist of additives, and only the remaining part is to present proliposome powder. The percentage of additives may also depend on the effectiveness of biologically active compounds and the optimal amount of powder used for inhalation.

When there is additive, in particular a carrier, the composition may be presented in the form of Ducati coarse particles with a mean diameter of more than 20 microns, or it may include agglomerates of smaller particles or agglomerates with an average diameter of, for example more than 20 microns, but in any case a given mixture proliposome and media.

Another object of the present invention is the provision of method of preparation proliposome powder of the present invention, i.e. the method which leads to obtaining monophasic proliposome powder.

In this regard, the present invention relates also to a method for preparing proliposome powder for inhalation, which involves the dissolution of the lipid or mixture of lipids and lipophilic biologically active component in a solvent, these lipid or mixture of lipids should have a transition temperature below 37oC; obtaining crystalline matrix solvent includes only the lipid phase, followed by freezing in the vitreous state, but such freezing is carried out at a temperature below the phase transition temperature of the lipid phase; and then evaporation of the frozen solvent at a temperature below the phase transition temperature of the lipid phase.

The freezing solution and the conventional lyophilization. So, for example, a solution of lipids and biologically active component can pour on the shelves in the chamber for freeze-drying and to reduce the temperature of the freezing solution. Evaporate the solvent can then, for example, by reducing the pressure in the chamber for freeze-drying, the powder soskrebajut with shelves camera with subsequent optional by passing it through a sieve. Liofilizovannye powder, if necessary, subjected to further processing in order to obtain particles having a size in the range acceptable for inhalation; for example, liofilizovannye powder can be crushed with obtaining suitable for inhalation of particles, and this can be by using, for example, vostokstrojj mill.

Freezing of a solution of the biologically active component and lipids is carried out in such a way to get only the lipid phase in the matrix of the frozen solvent. The formation of monophasic lipid system is governed by the final temperature and the rate of freezing of a solution; the optimal rate of freezing of any of the used solution must be a cross between a time required for crystallization of the existing solvent, and time, with the average level of knowledge in this area is simply by trial and error. The optimal value of the final temperature should be 10-20oC below the transition temperature of the lipid phase from the glassy state. In this assessment the crystalline state can be used powder x-ray diffraction method, and to monitor the degree of incorporation of the biologically active component in the liposomes hydrated you can use a differential scanning calorimeter.

The solvent should have a solubility sufficient to completely dissolve the lipids and biologically active component, because it is very important that all components are switched into the solution before freezing in order to avoid the deposition of particles or phase separation, which can lead to the formation of a powder comprising more than one phase. In addition, the solvent should have an acceptable Toxicological profile, to have a suitable freezing point and preferably high pressure steam. The solvent may constitute, for example, an organic solvent, particularly an alcohol, or a mixture of water and organic solvents. Preferred for use in the present invention the solvent is Treteiskie particles, in order to adjust the cohesive properties of the powder. The size of the spherical particles is preferably not more than 1 mm in diameter; larger spherical particles are removed, for example, during sifting. While any such agglomerate must have friability, which means its ability to be easily split into separate particles under appropriate conditions, for example in powder inhaler.

Proliposome powder of the present invention is used for local or systemic treatment of diseases and may for this purpose be placed through the upper and lower respiratory tract, including nasal path. As such, the present invention also relates to the use of the above proliposome powder in therapy; to use proliposome powder in the manufacture of medicaments used for the treatment of diseases through the respiratory tract, and to a method of treating a patient in need of such therapy which comprises introducing said patient a therapeutically effective amount proliposome powder of the present invention.

For example, proliposome powder of the present invention can be used for the treatment of inflammatory diseases dehai can be carried out, in particular, using an inhaler containing either dry powder or compressed aerosol.

Suitable powder inhalers include metered dose inhalers, for example inhaler single dose, known gender trademark Monohalerand inhalers with multiple dose, such as metered dose inhalers dry powder with a multiple-dose, breath-activated, in particular inhalers brand Turbuhaler.

In the case where proliposome powder of the present invention is best suited for administration by inhalation, it can be included in compositions used for other forms of delivery. For example, for use in the treatment, for example of inflammatory joint diseases such as arthritis, skin diseases and diseases of the bowel, can be made in oral form, forms for local application and forms for injection.

The following examples are given only to illustrate the present invention and in no way limit its scope.

Example 1

Rofleponide palmitate (10 parts), DPPC (63 parts), DMPG (24 parts) and Na (3 parts) was dissolved in tertiary butanol (1300 parts) when the temperature of the Solution purchased this temperature for 30 minutes; then to induce sublimation of the solvent reduced the pressure in the chamber for freeze-drying. While sublimation is regulated by the pressure decrease and temperature increase in the process temperature should not exceed -10oC. the Lyophilization continued until complete solvent removal. The obtained powder was scraped off the shelves camera for lyophilization and passed through a sieve.

The powder was crushed in vostokstrojj mill to obtain particles with a size less than 5 microns. Micronized powder was then mixed with lactose monohydrate (20 parts powder: 80 parts of lactose monohydrate) when screening and further homogenizing the mixture by grinding it in vostokstrojj mill under reduced pressure.

Conducted by agglomerating the powder mixture in a spherical particle size of not more than 1 mm using standard techniques. Larger spherical particles were removed by sieving. The agglomerated powder was filled with powder inhalers Turbuhaler.

Example 2

Repeating the procedure of Example 1 while using time freeze, equal to 6 hours, 17 hours and 24 hours.

Comparative example

Lipids and active asnow system, comprising individual particles of the active component and lipids.

Example 3

Repeat the procedure of Example 1, using the following mixture of lipids having a transition temperature below 37oC.

DPSM/DPSM

I-lecithin/cholesterol

with the lecithin/cholesterol

Example 4

Repeat the procedure of Example 1, using the following active ingredients:

rofleponide-21-monistat

rofleponide-21-laurate

rofleponide-21-kapat

rofleponide-21-kaprilat

rofleponide-21-stearate

Analysis of the powder

Analysis by powder x-ray diffraction carried out on the powder mixtures of Examples 1 and 2 showed that in these powders were no components in the crystalline state. While the powder of comparative example contained the active component in the crystalline state.

The inclusion of the active component in the liposomes

Conducted hydration proliposome powders from Examples 1 and 2 and measure the degree of inclusion of the active component using the methods of differential scanning calorimetry (DSC). The results of studies using DSC showed that the active component has been fully incorporated into liposomes. Then the NTA in liposomes.

Hydrolysis of the ester

We examined the level of hydrolysis proliposome powder from Example 1 and comparative example to the active agent. Proliposome powders of Examples 1 and 2 and comparative example (in each case taken 50 μm steroid ether) was hydrational the addition of water and was heated to a temperature of 50oC for 15 minutes. After that, the samples were incubated at temperature 37oC in the presence of lipase from the pancreas of pigs (2 mg/ml) in buffer (1 mm EDTA, 80 mm KCl, 10 mm HEPES, pH 7,4) and periodically destroyed the mixture with ultrasound sessions with different durations up to 120 minutes. Next, the samples were analyzed by HPLC to determine the level of hydrolysis of the ester to an active start.

94% proliposome powder of Example 1 was hydrational to the active agent, whereas in the powder of the comparative example, this value was only 2%.

Pharmacological studies

Antitumor efficacy was investigated in rats in the model using Sephadex (Kallskrom L. et al., Agents and Actions, 1985, 17 (3/4), 355).

Samples of the powders of Example 1 and comparative example suspended in cold saline and held intratracheal injected intratracheal instillation of granules Sephadex (5 mg/kg) and in the left and right lung. After 20 hours spent quantitative assessment developed interstitial edema by weighing the right and left lungs. Reducing the weight of the lung was considered as an indicator of pharmacological action powders. The weight of the lung in animals that were injected proliposome powder from Example 1 was 40 times less than the weight of the lung in rats, which were treated powder of the comparative example, and this means that the efficiency proliposome powder of the present invention 40 times higher than the efficiency of the powder of the comparative example.

Studies inhalation powder

Dogs Beagle was anestesiology, was intubated and treated aerosol powder having the composition of Example 1 or comparative example. The aerosol formed from powdered tablets with apparatus Wright Dust Feed, running with a speed of 1800 Rev/min In the process of inhalation recorded concentration of aerosol (Casella 950 AMS), tidal volume, the volume of the breath and the breathing frequency. Inhalation was used rofleponide palmitate dose of 25 µg/kg body weight. After inhalation were regularly collected plasma samples. Bioavailability was calculated by comparing plasma concentrations of rofleponide with those after him vnutr%, while the bioavailability of rofleponide determined in plasma after injection of the powder of comparative example 1 not measurable.

1. Pharmaceutical composition comprising proliposome powder, which contains monophasic discrete particles of the biologically active component and a lipid or mixture of lipids having a transition temperature below 37oC and crystalline hydrophilic pharmaceutically acceptable carrier.

2. The pharmaceutical composition under item 1, characterized in that the powder comprises one or more lipids selected from natural and synthetic phosphoglycerolipids, sphingolipids and digalactosyldiacylglycerols.

3. The pharmaceutical composition under item 1 or 2, characterized in that the powder comprises a mixture of lipids, selected from mixtures of sphingomyelin/phosphatidylcholine, sphingomyelin/cholesterol, egg yolk phosphatidylcholine/cholesterol, soy phosphatidylcholine/cholesterol, phosphatidylcholine/phosphatidylserine/cholesterol, dimyristoyl phosphatidylcholine/dipalmitoyl phosphatidylcholine, dimyristoyl phosphatidylcholine/dipalmitoyl phosphatidylcholine/cholesterol, dimyristoyl fosfate the Lina/dioleoyl phosphatidylcholine/cholesterol, dilauryl phosphatidylcholine/dipalmitoyl phosphatidylcholine, dilauryl phosphatidylcholine/dipalmitoyl phosphatidylcholine/cholesterol, dilauryl phosphatidylcholine/dimyristoyl phosphatidylcholine, dilauryl phosphatidylcholine/dimyristoyl phosphatidylcholine/cholesterol, and dioleoyl phosphatidylcholine/distearoyl phosphatidylcholine.

4. The pharmaceutical composition according to any one of paragraphs.1 to 3, characterized in that the said powder includes dipalmitoyl phosphatidylcholine, dimyristoyl phosphatidylcholine or a mixture of dipalmitoyl phosphatidylcholine and dimyristoyl phosphatidylcholine.

5. The pharmaceutical composition according to p. 4, characterized in that the said mixture comprises at least 10% dimyristoyl phosphatidylcholine.

6. The pharmaceutical composition according to any one of paragraphs.1 to 5, characterized in that the said powder further includes a charged lipid.

7. The pharmaceutical composition according to p. 6, characterized in that the said charged lipid selected from dimyristoyl of phosphatidylglycerol, dipalmitoyl of phosphatidylglycerol, dimyristoyl fosfatidinozitol acid and stearylamine.

8. The pharmaceutical composition according to any one of the preceding paragraphs, characterized in that paingivers Cox, the leukotriene antagonists, inhibitors of phospholipase-A2 (PLA2), antagonists factor platelet aggregation (FOP) and prophylaxis of asthma.

9. The pharmaceutical composition according to any one of the preceding paragraphs, characterized in that the said active component includes a glucocorticosteroid.

10. The pharmaceutical composition according to any one of the preceding paragraphs, characterized in that the said active component comprises -2 agonist.

11. The pharmaceutical composition according to any one of the preceding paragraphs, characterized in that the said active component comprises a steroid, esterified at the 21-position of fatty acids containing at least 8 carbon atoms.

12. The pharmaceutical composition according to any one of the preceding paragraphs, characterized in that the said active component comprises a steroid, esterified at the 21-position of fatty acids containing at least 10 carbon atoms.

13. The pharmaceutical composition according to any one of the preceding paragraphs, characterized in that the said active component comprises a steroid, esterified at the 21-position of fatty acids containing at least 12 carbon atoms.

15. The pharmaceutical composition according to any one of the preceding paragraphs, characterized in that the said active component comprises rofleponide palmitate.

16. The pharmaceutical composition according to any one of the preceding paragraphs, characterized in that at least 50% of the powder includes particles with a diameter less than 10 microns.

17. The pharmaceutical composition according to any one of the preceding paragraphs, characterized in that at least 60% of the powder includes particles with a diameter less than 10 microns.

18. The pharmaceutical composition according to any one of the preceding paragraphs, characterized in that at least 70% of the powder includes particles with a diameter less than 10 microns.

19. The pharmaceutical composition according to any one of the preceding paragraphs, characterized in that at least 80% of the powder includes particles with a diameter less than 10 microns.

20. The pharmaceutical composition according to any one of the preceding paragraphs, characterized in that at least 90% of the powder includes particles with a diameter less than 10 microns.

21. The pharmaceutical composition according to any one of paragraphs.16 to 20, in which the particles proliposome powder have a diameter of 0.01 - 10 μm.

22. The pharmaceutical composition according to any one of the position according to any one of paragraphs.16 - 20, in which the particles proliposome powder have a diameter of 0.1 - 5 μm.

24. The pharmaceutical composition according to any one of the preceding paragraphs which includes agglomerated particles proliposome powder.

25. The pharmaceutical composition according to any one of the preceding paragraphs, characterized in that the said carrier is a crystalline monohydrate lactose.

26. The pharmaceutical composition according to any one of paragraphs.1 to 24, characterized in that said media is chosen from glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maldita, melezitose, stachyose, lactate, Palatinate, starch, xylitol, mannitol, myoinositol and their hydrates and amino acids.

27. The pharmaceutical composition according to any one of the preceding paragraphs, wherein said media comprises particles with an average diameter greater than 20 microns.

28. The pharmaceutical composition according to any one of paragraphs.1 to 26, wherein said media comprises particles with an average diameter of less than 10 microns.

29. The method of obtaining proliposome powder according to any one of paragraphs.1 - 23, including the dissolution of the lipid or mixture of lipids and lipophilic biologically active to the same 37oC, obtaining the crystalline matrix of the solvent included lipid monopati in the vitreous state by freezing the solution, but such freezing is carried out at a temperature below the phase transition temperature of the lipid phase, and then evaporation of the frozen solvent at a temperature below the phase transition temperature of the lipid phase.

30. The method according to p. 29, characterized in that it further includes a step of micronization of liofilizirovannogo powder with obtaining particles corresponding to the size range of particle sizes suitable for inhalation.

31. The method according to p. 29 or 30, characterized in that the above-mentioned processes of freezing and evaporation of the solvent is carried out at a camera for lyophilization.

32. The method according to any of paragraphs.29 to 31, characterized in that said solvent comprises an organic solvent.

33. The method according to p. 32, characterized in that said solvent comprises alcohol.

34. The method according to 33, characterized in that said solvent comprises a tertiary butanol.

35. A method of obtaining a pharmaceutical composition according to any one of paragraphs.1 to 28, characterized in that the method includes p is ku, obtained in this way, crystalline hydrophilic pharmaceutically acceptable carrier and, optionally, the stage micronisation of the mixture of powder and carrier with obtaining particles corresponding to the size range of particle sizes suitable for inhalation.

36. The method according to any of paragraphs.29 to 35, characterized in that it comprises the additional step of agglomerating particles in spherical structures with a diameter of 1 mm or less.

37. The pharmaceutical composition according to any one of paragraphs.1 - 28 for use in the treatment of patients in need of inhalation.

38. A method of treating patients in need of inhalation, comprising introducing said patient a therapeutically effective amount of the pharmaceutical composition according to any one of paragraphs.1 - 28.

39. Powder inhaler containing a pharmaceutical composition according to any one of paragraphs.1 - 28.

40. Powder inhaler according to p. 39, characterized in that the inhaler is a inhaler with a single dose.

41. Powder inhaler according to p. 39, characterized in that the inhaler is a inhaler with multiple dose.

Priority signs and items:

22.12.1994 - PP.1, 29 (except Dinkov "50-80%"), 20-23, 26, 27 and the characteristic transition temperature below 37oC" PP.1 and 29).

20.12.1995 - p. 28 and the sign "50-80%" PP.16-19.

 

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