Powdered preparations containing melezitose as diluent

 

(57) Abstract:

Powdery preparation for the introduction of health of useful polypeptides containing useful medical polypeptide with melezitose as a diluent. The invention relates to pharmaceutical industry and relates to a powdery product containing medical useful polypeptides. The invention consists in that a powder preparation containing the polypeptide with melezitose as a diluent, is administered by inhalation. Also the invention is the production method of powder preparation. The invention provides for the use of a good solvent, compared with other solvent-based nereguliruemyi sugars, protein powder, because when inhaled it gives unexpectedly high respirable fraction of the powder. 3 S. and 49 C.p. f-crystals, 2 tab.

The invention relates to powdered preparations containing medical useful polypeptides.

Prior art

Polypeptide powders containing medical useful polypeptides and pharmaceutically acceptable carriers or diluents, can be prigotovleyny in WO 95/00197 and WO 95/00128. They are used for the stabilization of the different medications in the production process and storage and to bring the number prepared from the powder of uniform doses mostly powder inhalers are able to select medicinal substance with good metering accuracy only at a specific size doses, while different drugs have different activity and therefore they have to be allocated in varying amounts. Since these quantities are often too small to ensure proper dosage accuracy, add the diluent to obtain the desired size of the dose.

Earlier in the polypeptide powdered preparations as diluents used reducing sugars, such as lactose and glucose. They, however, tend to react with polypeptides and are therefore unsatisfactory.

In WO 95/00127 and WO 95/00128-related polypeptide powders for inhalation, indicates that nereguliruemyi sugar, such as raffinose, melezitose, lactic, ▫ maltitol, trehalose, sucrose, mannitol and starch, may be preferred additives to the polypeptide powders.

Currently, it is found that melezitose is the claim of akharov, for polypeptide powder products because when inhaled it gives unexpectedly high respirable fraction of the powder.

The invention

Accordingly, the present invention relates to powdery preparations for the introduction of health of useful polypeptides containing useful medical polypeptide with melezitose as a diluent.

Preferably the introduction by inhalation.

Melezitose may contain, for example, D-melezitose (-D - melezitose)- D - glucopyranosid O--D - glucopyranosid-1,3 _-D - fructofuranosyl (-D - melezitose) or sollecito. Melezitose may be, for example, in the form of a monohydrate or a dihydrate.

It is revealed that the powdered drug of the present invention is very effective for oral inhalation, as it gives excellent fraction of inhaled particles in comparison with the powdered drugs with other diluents, as described here. As a result of higher fraction of the inhaled powder can reach the lungs and a higher fraction of the polypeptide is utilized.

Powdered drug of the present invention is also suitable for use by inhalation through the nose.

Preferred enhancers include C8-16fatty acids and their salts, salts of bile acids, phospholipids and alkyl-saccharides.

Of fatty acids and their salts, preferred salts of C8-16fatty acid. Examples of preferred salts of fatty acids are sodium, potassium and lysine salts kaprilat (C8), caprinate (C10), laurate (C12and myristate (C14). As the nature of the counterion is not important, potentially suitable, any of the salts of fatty acids. Particularly preferred salt of fatty acid is caprint sodium.

Suitable salts of bile acids can be, for example, salts holeva acid, chenodesoxycholic acid, deoxycholic acid, glycometabolic acid, taurodeoxycholic acid, lithocholic acid and ursodeoxycholic acid.

Of bile salts is preferred salt trihydroxychalcone acids. The preferred salts are salts holeva, glycocholic and human beings need it to acid. The most preferred salt of bile acids is taurocholate sodium.

Suitable phospholipids can be, for example, single-chain phospholipids, for example, lysophosphatidylcholine, lysophosphatidylserine, lysophosphatidylethanolamine, lysophosphatidylcholine and lysophosphatidylserine, or double-stranded phospholipids, for example, diazepamwithdrawlay, diazepammedicine, dieselpartikelfilter, diarylheptanoid and diarylphosphides.

From phospholipids preferred diazepammedicine and diazepamwithdrawlay, for example, dictyochophyceae and dictyochophyceae.

Suitable alkyl-saccharides can be, for example, Alkylglucoside or alkylsulfonate, such as disillusioned and dodecylsulfate.

The most preferred enhancers are bile salts.

The polypeptide is preferably a peptide hormone, such as insulin, glucagon, C-peptide of insulin, vasopressin, desmopressin, corticotropin (ACTH), corticotropin-releasing hormone (CRH), gonadotropin releasing hormone (GnRH) agonists and antagonists of gonadotropin-releasing hormone, gonadotropin (luteinizing hormone, or LHRH), calcitonin, parathyroid hormone (PTH), bioactive fragments of PTH, such as PTH(34) and PTH(38), growth hormone (GH) (for example, somatotropic hormone, human (hGH), somatotropin-releasing hormone (GHRH), somatostatin, oxytocin, atrial naturethese factor (ANF), thyrotropin-releasing hormone (TRH), desoxyribonuclease (DN), prolactin and follicle-stimulating hormone (FSH) and analogs of any of the foregoing.

Other possible polypeptides include growth factors, interleukins, polypeptide vaccine, fer> A preferred polypeptide is insulin.

In the powdered drug of the present invention of melezitose may be present in amounts up to almost 100% of the total mass of the powder. For example, melezitose may be present in amounts of between 20% and almost 100%, for example, between 30% and almost 100%, or between 40% and almost 100%, or between 50% and almost 100%, for example, between 60% and about 100% or between 65% and almost 100%, such as between 65% and 99%, or between about 70% and about 99%, such as between 80% and 98% by weight of the total weight of the powder.

As with all pharmaceutical drugs, some additives, for example, for pH control, for example, organic or inorganic salt, for flavor or to increase stability, for example, preservatives, carbohydrates, amino acids, peptides or proteins, can also be included in the drug.

When powdered drug of the present invention is intended for oral inhalation, the polypeptide must consist of (a) primary particles having a diameter of less than about 10 microns, for example between 0.01 and 10 microns and preferably between 0.1 and 6 microns, for example between 0.01 and 5 microns, or (b) agglomerates of these particles. Preferably at least 50%, at least 70%, more preferably at least 80% and most preferably at least 90% of the polypeptide consists of particles within the desired limits, when the desired oral inhalation.

Melezitose in preparation for oral inhalation can mainly be composed of particles having a diameter of less than about 10 microns, so that the resulting powder consists of optional agglomerated primary particles having a diameter of less than about 10 microns; alternatively, melezitose can mainly be composed of larger particles ("coarse particles"), so "ordered mixture" may be formed between the active compounds and melezitose. In an ordered mixture, alternatively known as interactive or adhesive mixture, polypeptide particles can be fairly randomly distributed on the surface rough melezitose. It is preferable in this case that the active compounds were not in the form of agglomerates before the formation of an ordered mixture. Coarse particles can have a diameter greater than 20 microns, for example, more than 60 microns. Above these lower limits of the diameter of the coarse particles is not critical, so that various sizes of coarse particles can be ispolzovanie coarse particles in ordered mixtures were the same size, but the coarse particles are mainly to be of similar size within an ordered mixture. Preferably the coarse particles have a diameter of 60-800 microns.

The particle size is less important when inhaled through the nose, although desirable small particles. An ordered mixture generally should not be used for inhalation through the nose.

A useful mechanism for delivering powder into the respiratory tract of a patient is provided through portable nebulizer, suitable for inhalation as a dry powder. There are many such devices are usually designed to deliver anti-asthma and anti-inflammatory drugs in the respiratory system.

Described powdered drug can be prepared in a variety of ways using conventional technologies. Particles of the desired size range can be obtained by any known method, for example, by means of freeze-drying or controlled crystallization, for example, by crystallization using supercritical fluids; or ways micronisation. For example, you can mix the dry powders of the polypeptide and melezitose (and optional improver), and then ekranizirovat substances together; alternatively, the have different physical properties such as hardness and fragility, their resistance micronisation is different, and they may require different pressures for destruction to a suitable particle size. Therefore, when the joint micronisation the size of the resulting particles of one component may be unsatisfactory. In this case, it would be preferable to ekranizirovat different components separately and then mix them.

It is also possible, when not intend to prepare an ordered mixture, initially dissolving the components in a suitable solvent, e.g. in water, in order to achieve mixing at the molecular level. This procedure also allows you to bring the pH to the desired level. To obtain a powder, the solvent is removed in a way that retains the biological activity of the polypeptide. Suitable drying methods include concentration in vacuum, open air drying, drying by spraying and drying by freezing. You should avoid exposure to temperatures above 40oC for more than a few minutes, as it may be some degradation of the polypeptide.

After the stage of drying of the solid material, if necessary, pulverized to obtain a rough prednaznachennoe inhalation, process for improving the rheological properties, for example, a dry granulation prior to the formation of spherical agglomerates with excellent properties for dealing with them. In this case, the device must have a configuration to provide significant deagglomeration agglomerates before leaving their device in order to included in the respiratory tract of the patient, were mostly in the desired size range.

When the desired ordered mixture, the active connection process, for example, by micronisation, to obtain, if desired, the particles in a certain range of sizes. Melezitose also processed, for example, to get the desired size and the desired surface properties, such as a certain ratio of surface to mass or a certain roughness, and to ensure optimal adhesion forces in an ordered mixture. Such physical requirements of an ordered mixture is well-known as various means for obtaining an ordered mixture that meets specified requirements, and can be easily determined by the expert according to the specific circumstances.

The powders of the present invention aspirate path, including the introduction through the nose. Thus, the present invention also provides a powder for use in therapy; application of powder in the manufacture of medicaments for the treatment of diseases through the respiratory tract and a method of treating a patient who needs treatment, including the introduction of the indicated patient a therapeutically effective amount of the powder of the present invention.

Diseases that can be treated powder of the present invention, are some of those that can be treated powder-like polypeptide in each case; for example, powders, containing insulin, corresponding to the present invention can be used, for example, in the treatment of diabetes; powders containing corticotropin, can be used, for example, in the treatment of inflammatory diseases; powders containing GnRH may be useful, for example, in the treatment of male infertility. Readings for all of the above polypeptides are well known. The powders of the present invention can also be used in prevention activities.

Although the powders of the present invention include, in particular, to a polypeptide powder inhalation device for the Oia, for example, injectable solutions and aerosol preparations.

Respirable fraction by oral inhalation powders of the present invention is determined by the method described herein in the examples.

Some embodiments of the invention are illustrated in the following examples, which should not be considered a limitation:

Example 1

Insulin (0.6 g) dissolved in distilled water (50 ml). The diluent (14.4 g) is added and dissolved and the pH was adjusted to 7.4. The obtained solid residue is crushed, sieved and micronizer in the jet mill. Micronized powders aglomerated and loaded into a spray dry powder Turbuhaler(registered trademark) and the dose produced when the air flow rate 60 l/min under varying conditions.

Sprayed dose collected using multi-stage impinger; insulin at each stage of impinger determined using liquid chromatography with detection at 235 nm. The results are presented in table. 1.

It is clear that melezitose gives the greatest fraction of inhaled particles in all cases. Moreover, respirable fraction does not depend on external factors, when melezitose is razbunarea (amplifier, 4). Add different diluents (84 parts) and dissolved and pH was adjusted to 7.4. The solution is concentrated by evaporation of water. The obtained solid residue is crushed, sieved and micronizer in the jet mill. Micronized powder aglomerated and loaded into a spray dry powder Turbuhalerand dose produced when the air flow rate 60 l/min under varying conditions.

Sprayed dose collected using multi-stage impinger; insulin at each stage of impinger determined using liquid chromatography with detection at 235 nm. The results are presented in table. 2.

The results show that the drug melezitose significantly less exposed to high humidity.

Example 3

Micronized preparations containing DN, surfactant (taurocholate sodium or dictyochophyceae) and melezitose (DN: surfactant: melezitose - 1:0,33:98,67, total weight 50 mg) add to propellant (gas vehicle) 134a or propellant 227 (approximately 10 ml) coated glass bubble. Drugs mixed with ultra turrax priblizitel is approximately 10 minutes using an ultraturrax apparatus.

The quality of the resulting suspensions assessed immediately or after 20 hours. In all cases, there are good suspension.

This shows that containing melezitose preparations of the present invention is suitable for use in preparations other than for inhalation of a dry powder, in this case in aerosol preparations.

1. Powdery preparation for the introduction of health of useful polypeptides by inhalation, characterized in that it contains useful medical polypeptide with melezitose as a diluent.

2. Powdered drug under item 1, characterized in that melezitose contains D-melezitose (-D-melezitose)- D-glucopyranosid, 0--D-glyukopiranozil-1,3-D-fructofuranosyl (-D-melezitose) or sollecito.

3. Powdered drug under item 1 or 2, characterized in that melezitose is in the form of a monohydrate or a dihydrate.

4. Powder preparation by PP.1 to 3, characterized in that the preparation contains the amplifier, which increases the absorption of useful medical polypeptide in the lower respiratory tract.

5. The powdered drug on p. 4, characterized in that the amplifier are selected from C8-16fatty acids and their salts, sa fact, the amplifier selected from sodium, potassium and lysine salts kaprilat (C8), caprinate (C10), laurate (C12and myristate (C14).

7. The powdered drug on p. 4, characterized in that the amplifier is selected from salts of bile acids selected from salts holeva acid, chenodesoxycholic acid, glycocholic acid, human beings need it to acid, glockengiesserwall acid, taurochenodeoxycholate acid, deoxycholic acid, glycometabolic acid, taurodeoxycholic acid, lithocholic acid and ursodeoxycholic acid.

8. The powdered drug on p. 4, characterized in that the amplifier selected from salts trihydroxychalcone acids.

9. The powdered drug on p. 4, characterized in that the amplifier selected from salts holeva, glycocholic and human beings need it to acid.

10. The powdered drug on p. 4, characterized in that the amplifier is selected from sodium and potassium salts of holeva, glycocholic and human beings need it to acid.

11. The powdered drug on p. 4, characterized in that the amplifier is taurocholate sodium.

12. The powdered drug on p. 4, characterized in that the amplifier selected from tnotebook is fosfatidilkholina, lysophosphatidylserine, lysophosphatidylethanolamine, lysophosphatidylcholine and lysophosphatidylserine.

14. The powdered drug on p. 4, characterized in that the amplifier selected from double-stranded phospholipids.

15. The powdered drug on p. 4, characterized in that the amplifier selected from diarylphosphino, diazepaminjectionow, diazepampharmacyonline, decylphosphonic and diazepampremedication.

16. The powdered drug on p. 4, characterized in that the amplifier selected from dictyochophyceae and dictyosphaeria.

17. The powdered drug on p. 4, characterized in that the amplifier selected from Alkylglucoside or alkylhalides, such as disillusioned and dodecylsulfate.

18. Powder preparation according to any one of paragraphs.1 to 17, characterized in that the polypeptide is selected from insulin, glucagon, C-peptide of insulin, vasopressin, desmopressina, corticotropin (ACTH), corticotropinreleasing hormone (CRH), gonadotropinreleasing hormone (GnRH) agonists and antagonists gonadotropinreleasing hormone, gonadotropin (luteinizing hormone, or LHRH), calcitonin, parathyroidectomies hormone, human (hGH)), somatotropinomas hormone (GHRH), somatostatin, oxytocin, atrial natriuretic factor (ANF), thyrotropinreleasing hormone (TRH), deoxyribonuclease (DNaSa), prolactin and follicle-stimulating hormone (FSH) and their analogues.

19. Powder preparation according to any one of paragraphs.1 to 18, characterized in that the polypeptide has a molecular weight (MW) up to about 40 KD.

20. Powdered drug under item 19, wherein the polypeptide has a molecular mass of up to 30 KD.

21. Powdered drug under item 19, wherein the polypeptide has a molecular mass of up to 25 KD.

22. Powdered drug under item 19, wherein the polypeptide has a molecular mass of up to 20 KD.

23. Powdered drug under item 19, wherein the polypeptide has a molecular mass of up to 15 KD.

24. Powdered drug under item 19, wherein the polypeptide has a molecular mass of up to 10 KD.

25. Powdered drug under item 19, wherein the polypeptide has a molecular mass of up to 5 KD.

26. Powdered drug under item 18, characterized in that the polypeptide is what melezitose is present in the amount of 20 - 100% by weight of the powder.

28. The powdered drug on p. 27, characterized in that melezitose is present in the amount of 30 to 100% by weight of the powder.

29. The powdered drug on p. 28, characterized in that melezitose is present in the amount of 40 to 100% by weight of the powder.

30. The powdered drug on p. 29, characterized in that melezitose is present in the amount of 50 to 100% by weight of the powder.

31. The powdered drug on p. 30, characterized in that melezitose is present in the amount of 60 to 100% by weight of the powder.

32. The powdered drug on p. 31, characterized in that melezitose is present in the amount of 65 to 100% by weight of the powder.

33. The powdered drug by p. 32, characterized in that melezitose is present in the amount of 65 to 99% by weight of the powder.

34. The powdered drug by p. 33, characterized in that melezitose is present in the amount of 70 to 99% by weight of the powder.

35. The powdered drug on p. 34, characterized in that melezitose is present in the amount of 80 to 98% by weight of the powder.

36. Powder preparation according to any one of the preceding paragraphs, characterized in that the polypeptide contains (a) primary particles, and is from the preceding paragraphs, characterized in that the polypeptide contains (a) primary particles having a diameter of 1 to 6 microns, or (b) agglomerates of these particles.

38. The powdered drug by p. 35 or 36, characterized in that at least 50% of the polypeptide consists of particles within the desired size.

39. The powdered drug on p. 38, characterized in that at least 60% of the polypeptide consists of particles within the desired size.

40. The powdered drug on p. 39, characterized in that at least 70% of the polypeptide consists of particles within the desired size.

41. The powdered drug by p. 40, characterized in that at least 80% of the polypeptide consists of particles within the desired size.

42. The powdered drug on p. 41, characterized in that at least 90% of the polypeptide consists of particles within the desired size.

43. Powder preparation according to any one of the preceding paragraphs, characterized in that melezitose consists of particles having a diameter of less than about 10 microns.

44. Powder preparation according to any one of paragraphs.1 - 43, characterized in that melezitose consists of coarse particles of diameter greater than 20 microns.

46. Powder preparation according to any one of paragraphs.1 to 3 and 18 to 45, characterized in that the preparation does not contain an amplifier.

47. The production method of powder preparation according to any one of paragraphs.1 - 43 and 46, characterized in that it contains stage dry mixing of powders polypeptide and melezitose and, optionally, amplifier and joint micronisation substances.

48. The production method of powder preparation according to any one of paragraphs.1 - 43 and 46, characterized in that it contains stage micronisation polypeptide and micronisation of powders melezitose and, optionally, the amplifier separately and mixing micronized powders.

49. The production method of powder preparation according to any one of paragraphs.1 - 43 and 46, characterized in that it contains the stage of dissolution of the components in a solvent, optionally adjusting the pH to the desired level, solvent removal, drying and optional micronisation obtained solid substance.

50. Method for the production of powdered drug on p. 44 or 45, characterized in that it comprises dry mixing of powders melezitose and micronized polypeptide.

51. The powder according to any one of paragraphs.1 - 50 for use in therapy.


 

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