Aerosol preparations of peptides and proteins

 

(57) Abstract:

Pharmaceutical aerosol drug contains hydrofluroalkane propellant, pharmaceutically active polypeptide with a molecular mass of 40 KD and a surfactant. The polypeptide is dispersed in the propellant. The surfactant is8-C16- fatty acid or its salt, a salt of bile acid, phospholipid, or alkyl-saccharide. The surfactant enhances the systemic absorption of the polypeptide in the lower respiratory tract and is present in a ratio of surfactant:the polypeptide from 1:10 - 1: 0,2. Polypeptide aerosol drug used for local or systemic treatment of respiratory diseases. These drugs are sustainable and provide a high bioavailability of the polypeptide with good reproducibility. 3 C. and 40 C.p. f-crystals, 2 tab.

The invention relates to medicinal preparations containing medical useful peptides and proteins, inhalation of an aerosol inhaler.

The background to the invention

The number of drugs administered in aerosol products through the throat or nose. A widely used method of dispensing such aerosol preparation includes the preparation of such suspension of the drug Lekarstva inhalers or pMDI''s usually used for delivery of such drugs to the patient. Surface-active substances or surfactants typically include to facilitate dispersion of the drug in the propellant and to prevent aggregation of micronized particles of the medication.

Until recently been adopted for use in all pharmaceutical aerosol products harpercollinscanada propellants (CFC's). Typical surface-active dispersing agents used in the CFC preparations are, for example, sarbatorile, oleic acid, lecithins and ethanol. Because CFC is involved in the destruction of the ozone layer, there is a new generation of propellants to take their place.

Hydrofluroalkane (HFA) propellants such as 1,1,1,2-Tetrafluoroethane (RA), 1,1,1,2,3,3,3-Heptafluoropropane (R) and 1,1-differetn (RA) are considered the most promising new propellants. They are not only environmentally, but also have low toxicity and vapor pressure suitable for use in aerosols. However, the surfactants commonly used in CFC-aerosol preparations, are not particularly suited for use with the new generation of propellants, and therefore, in recent years proposed some alternative surfactants for use tx2">

Drugs based on peptides traditionally not included in the number of medicines which type of aerosol products, although there have been proposed various aerosol products. For example, U.S. patent number 5284656 describes the preparation of colony-stimulating factor granulocyte (G-SCF) containing fine powder, including G-SCF, suspended in a propellant with the auxiliary additive surfactant, such as triolein sorbitan, soy lecithin or oleic acid. U.S. patent number 5364838 describes the preparation of insulin, in which the dry powder insulin suspended in a propellant with a low-boiling diluent, such as oleic acid.

Brief description of the invention

We unexpectedly found that the various substances that enhance the absorption of polypeptides in the respiratory tract, are also particularly suitable as surfactants for use with the HFA propellants.

The invention relates to a pharmaceutical aerosol formulation containing (a) HFA propellant with a molecular mass of 40 KD; (b) a pharmaceutically active polypeptide, dispersible in the propellant, and (C) surfactant, which is C8-16- fatty acid or its salt, the bile salt to the respiratory ways and is present in the ratio of sufactant: polypeptide from 1:10 to 1:0,2. The surfactants used in the present invention are surprisingly suitable for use with the HFA propellants; their ability to enhance the absorption of the polypeptide give them dual functionality, which makes them particularly useful for use in the present polypeptide aerosol preparations.

Of fatty acids and their salts, preferred salts of C8-16-fatty acids. 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, glycocholic acid, human beings need it to acid, glockengiesserwall acid, taurochenodeoxycholate acid, deoxycholic acid, glycometabolic acid, taurodeoxycholic acid, lithocholic acid and ursodeoxycholic acid.

Of bile salts is preferred salt trihydroxide who built their sodium and potassium salts. The most preferred salt of the bile acid 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 surfactants are the salts of bile acids.

The propellant may contain one or more of the following: 1,1,1,2-Tetrafluoroethane (RA), 1,1,1,2,3,3,3-Heptafluoropropane (R) and 1,1-differetn (RA), for example, possibly in a mixture with one or more other propellants. Preferably, the propellant contains RA or R or a mixture RA and R, for example, agreed on platnm or protein-small to medium size, for example, up to molecular weight (MW) of about 40 KD, for which it is desirable system introduction. Mechanisms for improved absorption of the polypeptide corresponding to the present invention, generally applicable and could be used for all such polypeptides, although the degree to which it improves their absorption may vary in accordance with the MW and physico-chemical properties of the polypeptide and used within a specific surfactant. It is assumed that the polypeptides having a molecular weight of up to 30 KD, should be the most useful in the present invention, such as polypeptides having a molecular weight of up to 25 KD or up to 20 KD, and especially up to 15 KD or up to 10 KD.

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 coactor (ANF), thyrotropin-releasing hormone (TRH), desoksiribonukleaza (DNaa), prolactin and follicle-stimulating hormone (FSH) and analogs of any of the foregoing.

Other possible polypeptides include growth factors, interleukins, polypeptide vaccines, enzymes, endorphins, glycoproteins, lipoproteins, and polypeptides involved in the pathway of blood coagulation, which exert their pharmacological effects systemically. It is assumed that most, if not all, of the polypeptides small to medium size can be effectively delivered by the methods of this invention.

A preferred polypeptide is insulin.

In addition to medication, the propellant and the surfactant a small amount of ethanol (usually up to 5%, but up to 20% by weight) may be included in the preparations of the present invention. Ethanol is usually included in the aerosol composition, as it can improve the function of the metering valve and, in some cases, also to improve the stability of the dispersion.

The composition may of course contain other additives, when necessary, including other pharmaceutical active substances, adjuvants, carriers, flavoring agents, buffers, antioxidants, highfructose, galactose, trehalose, sucrose, maltose, raffinose, ▫ maltitol, melezitose, stachyose, lactic, palatinit, starch, xylitol, mannitol, monoset, etc. and their hydrates, and amino acids such as alanine, glycine and betaine, and peptides, and proteins, such as albumin.

A preferred carrier is melezitose.

The drug of the present invention is particularly useful due to the dual functionality of that specific surfactants. Surfactants, proposed by the present invention are not only surprisingly capable of forming a thin dispersion in a new generation of propellants, but, importantly, also improve the absorption of the polypeptide. These drugs are sustainable and provide a high bioavailability of the polypeptide with good reproducibility.

The surfactants used in the present invention, can improve the absorption polypeptide by, for example:

(1) Improvements paracetomol permeability of the polypeptide by inducing structural changes in tight contacts between epithelial cells.

(2) Improvements translational permeability of the polypeptide by interacting with protein or lipid are icepay solubility of the polypeptide in aqueous solution. This can occur by preventing the formation of polypeptide aggregates (dimers, trimers, hexamers) or by solubilization of polypeptide molecules in the micelles of the amplifier.

(4) reduce the viscosity or dissolution of the mucosal barrier lining the alveoli and passages of the lungs, which opens access to the epithelial surface for direct absorption of the polypeptide.

(5) the reduction of the activity of protease inhibitors in the lungs and thereby increase the stability of the polypeptide and enhance its absorption.

Surfactants can operate only one of the above mechanisms or for two or more. Surfactant, acting through several mechanisms, is more favorable for increasing the effective absorption of the polypeptide than one that uses only one or two.

The phrase "enhances absorption" means that the amount of polypeptide that is absorbed into the systemic circulation in the presence of the surfactant is higher than in its absence.

The surfactant is present in the present invention in a ratio of surfactant: the polypeptide in the range from about 1:10 to 1:0,2, preferably from 1:4 to 1:1, b is placed from 0.1 to 25 mg/ml

To the extent possible, the polypeptide preferably comprises particles having a diameter of less than about 10 microns, for example from 0.01 to 10 microns, or 0.1 to 6 microns, such as 0.1-5 microns. Preferably at least 50% of the polypeptide consists of particles within the desired limits. For example, at least 60%, preferably at least 70%, more preferably at least 80% and most preferably at least 90% polypeptide consists of particles within the desired limits.

Therefore, the polypeptide for use in the present invention should be redesigned to include in the preparations, in order to obtain particles within the desired limits. For example, the polypeptide may be Micronesian, for example, in a suitable mill such as a jet mill. Alternatively, the particles in a desired dimension can be obtained, for example by drying methods when spraying or controlled crystallization, for example crystallization using supercritical fluids.

It is advisable that the surfactant for use in the present invention also consisted of particles in the desired size range. Accordingly, the polypeptide and a surfactant are mixed is zeerovannyy powder is added to the fraction of the propellant (and optional, ethanol) at a low temperature. After mixing medicines add the remaining surfactant and propellant and, optionally, ethanol and the suspension fill in appropriate containers.

Polypeptide aerosol preparation of the present invention is suitable for local or systemic treatment of diseases and can be entered, for example, through the upper and lower respiratory tract, including the introduction through the nose. Thus, the present invention also provides the specified polypeptide aerosol formulation for use in therapy; the use of the polypeptide of the aerosol preparation 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 polypeptide of the aerosol preparation 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, preparations containing insulin, corresponding to the present invention can be used, for example, in the treatment of diabetes; any; drugs, containing GnRH may be useful, for example, in the treatment of male infertility. Readings for all of the above polypeptides are well known. Polypeptide aerosol preparations of the present invention can also be used in prevention activities.

The following examples are provided to illustrate, but not limit the invention.

Insulin in RA and/or R prepared with different surfactants in order to evaluate the quality of the resulting suspensions. In the following examples suspensions are regarded as "acceptable" or "good". Acceptable suspension is characterized by one or more of these signs, as slow delamination or separation, ready for re-dispersion, weak occulation and no crystallization or morphological changes, so that the dispersion is stable enough to provide a uniform dosage. Good dispersion even more sustainable.

Example 1

Way

Insulin (25-35 parts, as described below) is added to the chemical glass of water and dissolve. Surfactant (65-75 parts, as described below) is added and dissolved and the pH adjusted to 7.4. The solution concentrate of ispar orosco loaded into a plastic-coated glass bubble. The bubble is cooled to approximately -40oC with a mixture of dry ice (solid carbon dioxide) and isopropanol and add 10 ml of chilled RA (approximately -40oC). The vial is closed with a metering valve and then vigorously shaken for about 30 seconds. Examples 1 through 1n further treated in an ultrasonic bath for about 10 minutes (see table. 1)

Example 2

Caprint sodium (25 parts) and insulin (75 parts) micronizing and then mixed in the dry state. 40 mg of this mixture in a plastic-coated glass bubble. The bubble is cooled to approximately -40oC with a mixture of dry ice and isopropanol and add 10 ml of chilled (approximately -40oC) RA. The vial is closed with a metering valve and then vigorously shaken for about 30 seconds. Get a good suspension.

Example 3

Way

Insulin (25-35 parts, as described below) is added to the chemical glass of water and dissolve. Surfactant (65-75 parts, as described below) is added and dissolved and the pH 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. 40 or 50 mg of powder loaded into a plastic-coated glass bubble. is th (approximately -40oC) R. The vial is closed with a metering valve and then vigorously shaken for about 30 seconds. Examples with 3g on 3n additionally in an ultrasonic bath for about 10 minutes process (see tab. 2).

Example 4

Micronized preparations containing DN, surfactant (taurocholate sodium or dictyochophyceae) and melezitose (DN: surfactant: melezitose - 1: 0,33: 98,67, total weight 50 mg), add a plastic-coated glass bottle is cooled to approximately -40oC. Chilled propellant 134a or propellant 227 (approximately -40oC approximately 10 ml) is added and the vials closed with a metering valve and treated in an ultrasonic bath for about 10 minutes.

Identical preparations prepared with the addition of 5% (wt./mass.) ethanol before processing in an ultrasonic bath.

The quality of the suspensions assessed immediately and after storage at room temperature for 20 hours. In all cases, see good suspension.

Example 5

Caprint sodium and insulin micronizer separately and then mixed in the dry state. Attitude caprinate sodium to insulin - 25:75. 80 mg of this mixture in an aerosol container.

And najdennogo (approximately -40oC) RA. An aerosol vessel is closed dispensing 50 ál of the valve and is then treated in a couple of minutes in an ultrasonic bath.

The particle size of insulin in the aerosol emitted from the container, measured with the inertial separator "Andersen" at 28.3 l/min Fraction of fine particles (less than 6 microns) is 41% of the allocated dose. Particle measurement is repeated after storage for two months at room temperature and no deterioration is not observed. The fraction of fine particles is 46%.

Example 6

50 aerosol samples containing insulin and taurocholate sodium (ratio 75:25, 8 mg/ml) prepared as follows. The substance is weighed in a beaker. Chemical glass is cooled to approximately -40oC with a mixture of carbon dioxide and isopropanol. Add propellant (RA, approximately -40oC) the mixture is stirred for several minutes with an ultraturrax, then pour into the process vessel and another type of propellant (RA, approximately -40oC). (Total volume 500 ml). The preparation is stirred with a ultraturrax and loaded into the metering inhalers, 10 ml each. The inhaler is closed with a metering valve.

Aerosols stored at different R> The quality of the suspensions assessed. In all cases, there are good suspension.

Additionally assess the stability of insulin measurement using standard chromatographic techniques the concentration of decomposition products of desamethasone and other related to insulin impurities. In all cases, the content of impurities is within the acceptable range (less than 5% of desamethasone and less than 3% other related to insulin impurities).

Example 7

Working under pressure dosing inhaler filled with product from example 5, will use the selected aerosol collected in the intermediate device. Air flow (8 l/min) is passed through an intermediate device in allocating system, the effect of which is subjected to within five minutes of each of the five dogs. Target Invalidovna dose is 1 unit of insulin/kg Bioavailability is determined by comparing the curve of its content in plasma after inhalation curve and content in plasma after intravenous infusion in the early stages. Bioavailability of 66% of the drug reaching the lungs.

Example 8

Working under pressure dosing inhalers filled with product from example 6 or respectively the nom device. Air flow (8 l/min) is passed through an intermediate device in allocating system, the effect of which is subjected to within two minutes of each of the five dogs. Target Invalidovna dose is 1 unit of insulin/kg of blood Samples collected dosed before and after various time intervals up to 245 minutes after the start of dosing. The concentration of insulin in plasma was measured by radioimmunoassay.

Drugs without amplifier insulin mainly absorbed relatively slowly with peak levels of insulin in plasma occurring between 50 and 100 minutes after the introduction of some of the animals. In other animals the peak levels of insulin in plasma are observed between 10 and 20 minutes after injection.

Upon absorption of drugs relevant to the invention, the peak insulin level in the plasma is achieved in all animals within 10 minutes after injection, followed by another peak about 25 minutes in all animals.

Usually more rapid absorption of insulin preparations, corresponding to the invention, is closer to the curve of natural insulin in plasma after ingestion in healthy people. Furthermore, no abnormalities in animals shows that the desired level is retene.

1. Pharmaceutical aerosol drug, characterized in that it contains (a) hydrofluroalkane (HFA) propellant; (b) a pharmaceutically active polypeptide, dispersible in the propellant, with a molecular mass of 40 KD, and (C) surfactant, which is8- C16- fatty acid or its salt, a salt of bile acid, phospholipid, or alkyl-saccharide, and surfactant increases systemic absorption of the polypeptide in the lower respiratory tract and is present in a ratio of surfactant : polypeptide= 1 : 10 - 1 : 0,2.

2. The drug under item 1, characterized in that the surfactant is a salt WITH8- C16fatty acid.

3. The drug under item 2, wherein the salt of a fatty acid selected from sodium, potassium and lysine salts kaprilat (C8), caprinate (C10), laurate (C12and myristate (C14).

4. The drug under item 1, characterized in that the surfactant is a salt of trihydroxy-bile acids.

5. The drug under item 4, characterized in that the salt of the bile acid is selected from salts holeva, glycocholic and human beings need it to acid.

6. The drug under item 5, characterized in that the salt of the bile acid is selected from sodium and potassium salts of holeva, glycocholic kolat sodium.

8. The drug under item 1, characterized in that the surfactant is a single-chain phospholipid.

9. The drug under item 8, wherein the surfactant is selected from lysophosphatidylcholine, lysophosphatidylserine, lysophosphatidylethanolamine, lysophosphatidylcholine and lysophosphatidylserine.

10. The drug under item 1, characterized in that the surfactant is a double-stranded phospholipid.

11. The drug under item 10, wherein the surfactant is selected from diarylphosphino, diazepaminjectionow, diazepampharmacyonline, decylphosphonic and diazepampremedication.

12. The drug under item 11, wherein the surfactant is selected from dictyochophyceae and dictyosphaeria.

13. The drug under item 1, wherein the surfactant is selected from Alkylglucoside or alkylation.

14. The drug under item 13, wherein the surfactant is selected from desillusioned and dodecylsulfonate.

15. The drug PCP. 1-14, characterized in that the propellant contains 1,1,1,2-Tetrafluoroethane (RA), 1,1,1,2,3,3,3-Heptafluoropropane (R) or 1,1-differetn (RA).

16. The drug under item 15, characterized in that the propellant contains 1,1,1, is repellent contains a consistent density mixture of 1,1,1,2-Tetrafluoroethane (RA) and 1,1,1,2,3,3,3-Heptafluoropropane (R).

18. The drug according to any one of the preceding paragraphs, wherein the polypeptide has a molecular mass of 30 KD.

19. The drug under item 18, wherein the polypeptide has a molecular weight of about 25 KD.

20. The drug according to any one of the preceding paragraphs, wherein the polypeptide has a molecular weight of about 20 KD.

21. The drug according to any one of the preceding paragraphs, wherein the polypeptide has a molecular weight of about 15 KD.

22. The drug according to any one of the preceding paragraphs, wherein the polypeptide has a molecular weight of about 10 KD.

23. The drug according to any one of the preceding paragraphs, wherein the polypeptide is a peptide hormone.

24. The drug according to any one of paragraphs.1-17, characterized in that the polypeptide is selected from insulin, glucagon, C-peptide of insulin, vasopressin, desmopressina, 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), soma is HRH), somatostatin, oxytocin, atrial natriuretic factor (ANF), thyrotropin-releasing hormone (TRH), deoxyribonuclease (DNase has), prolactin and follicle-stimulating hormone (FSH) and their analogues.

25. The drug under item 24, wherein the polypeptide is insulin.

26. The drug according to any one of the preceding paragraphs, characterized in that it further comprises ethanol in an amount up to 20% by weight of the propellant and a surfactant.

27. The drug according to any one of the preceding paragraphs, characterized in that it further comprises ethanol in an amount up to 5% by weight of the propellant and a surfactant.

28. The drug according to any one of the preceding paragraphs, characterized in that it further includes an additive selected from adjuvants, carriers, flavoring agents, buffers, antioxidants, and chemical stabilizers.

29. The drug under item 28, wherein the additives are selected from lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maldita, melezitose, stachyose, lactate, palatinite, starch, xylitol, mannitol, myoinositol, their hydrates, alanine, glycine and betaine, and albumin.

30. The drug under item 29, wherein naotoshi surfactant : polypeptide in the range of 1:4 - 1:1.

32. The drug according to any one of the preceding paragraphs, characterized in that the polypeptide contains particles having a diameter of 0.01-10 MCR.

33. The drug under item 32, wherein the polypeptide contains particles having a diameter of 0.1-6 MCR.

34. The drug under item 32, wherein the polypeptide contains particles having a diameter of 0.1-5 MCR.

35. The drug according to any one of paragraphs.32-34, wherein at least 50% of the polypeptide consists of particles within a specified size range.

36. The drug according to any one of paragraphs.32-34, wherein at least 60% of the polypeptide consists of particles within a specified size range.

37. The drug according to any one of paragraphs.32-34, wherein at least 70% of the polypeptide consists of particles within a specified size range.

38. The drug according to any one of paragraphs.32-34, wherein at least 80% of the polypeptide consists of particles within a specified size range.

39. The drug according to any one of paragraphs.32-34, wherein at least 90% of the polypeptide consists of particles within a specified size range.

40. The drug according to any one of the preceding paragraphs, characterized in that the concentration of the polypeptide is any one of paragraphs.1-40, characterized in that it comprises a stage of mixing the polypeptide and a surfactant in an aqueous buffer; drying to obtain a solid powder; add optional, micronized solid powder, part of the propellant and, optionally, ethanol into the vessel at a temperature of about -40oWith mixing and add the remainder of the propellant and, optionally, ethanol.

42. Polypeptide aerosol preparation according to any one of paragraphs.1-40 for the treatment of diseases through the respiratory tract.

43. A method of treating a patient in need of treatment, characterized in that it includes the introduction of the indicated patient a therapeutically effective amount of the polypeptide of the aerosol products, as claimed in any of paragraphs.1-40.

Priority points:

06.07.1995 - PP.1, 6, 9, 11, 13, 14, 26;

22.12.1994 - PP.2, 7, 8, 10, 15, 16, 18-23, 25, 27, 33, 40, 42, 43;

19.12.1995 - PP.3-5, 12, 17, 24, 28-32, 34-39, 41.

 

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