AU3257000A - New, stable medicinal compositions for generating propellant-free aerosols - Google Patents

Description

-1-

AUSTRALIA

PATENTS ACT 1990 DIVISIONAL APPLICATION NAME OF APPLICANT: •Boehringer Ingelheim KG :ACTUAL INVENTORS: *9 FREUND Bemrnhard **KROGER Michael ZIERENBERG Bernd ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street Melbourne, 3000.

INVENTION TITLE: "New, stable medicinal compositions for generating propellant-free aerosols" The following statement is a full description of this invention, including the best method of performing it known to us: Q:\OPER\MKR\GENERAL\64144-96-div.doc 5/5/00 1A New stable pharmaceutical preparation for producing propellant-free aerosols The present invention relates to pharmaceutical preparations in the form of stable ethanolic solutions of active substances for producing propellant-free aerosols.

In the last 20 years, the use of metering aerosols has become an established component of the treatment of obstructive lung diseases, particularly asthma.

Usually, fluorochlorohydrocarbons have been used as propellant gases. Since the ozone-damaging potential of these propellant gases was recognised, more and more efforts have been made to develop alternatives. One alternative is the development of nebulisers in which aqueous solutions of pharmacologically-active substances are sprayed under high pressure so as to produce a mist of inhalable particles. The advantage of these nebulisers is that there is no need to use any propellant gases whatsoever.

Some nebulisers are described, for example, in PCT Patent Application W091/14468, the contents of which are referred to hereinafter. In the nebulisers described therein, solutions of defined volumes containing active substances are sprayed, using high pressures through small nozzles so as to produce inhalable aerosols with a preferred particle size of between 1 and 10, preferably between 2 and 5 micrometres.

Hitherto, it has been assumed that, with conventional metering aerosols containing propellant gas, the optimum level of lung-bound particles is obtained in the aerosol. It has now been found, surprisingly, that by I bbufjiod PWu OPER MKR SPEC; .1114- OC -2using ethanolic active substance solutions in combination with, for example, the abovementioned nebulisers it is possible to generate a significantly better spectrum of inhalable particles than is usually the case with metering aerosols which contain propellant gas.

According to one embodiment of the present invention there is provided a propellant-free pharmaceutical preparation which comprises a solution of a pharmacologically active substance other than nitroglycerine or beclomethasone, 17, 21-dipropionate dissolved in a solvent containing at least 70% ethanol, in the absence of undissolved solute.

10 According to another embodiment of the invention there is provided a propellant-free pharmaceutical preparation which contains, per 100ml of 96% ethanol, 1.667 g of Flunisolide hemihydrate, Img of disodium EDTA and acid to adjust the pH to 4.0, in the absence of undissolved solute.

15 According to another embodiment of the invention there is provided a propellant-free pharmaceutical preparation which contains, per 100ml of 90% ethanol, 1.667 g of Flunisolide hemihydrate, Img of disodium EDTA and acid to adjust pH to 4.0, in the absence of undissolved solute.

According to another embodiment of the invention there is provided a propellant-free pharmaceutical preparation which contains, per 100ml of 96% ethanol, 1.333g of Budesonide, Img of disodium EDTA and acid to adjust pH to 4.0, in the absence of undissolved solute.

According to another embodiment of the invention there is provided a propellant-free pharmaceutical preparation which contains, per 100ml of 90% ethanol, 1.333g Budesonide, Img of disodium EDTA and acid to adjust pH to 4.0, in the absence of undissolved solute.

According to another embodiment of the invention there is provided a process for the preparation of a propellant-free pharmaceutical preparation which comprises dissolving a Abbo-ord PmP-, OPER .%KR SPECI Jo4-c" "A" -2Apharmacologically active substance other than nitroglycerine or beclomethasone 17,21dipropionate in a solvent containing at least 70% ethanol, in the absence of an aerosol propellant and in the absence of undissolved solute.

According to another embodiment of the invention there is provided a system for delivery of a pharmacologically active substance to a subject by inhalation which comprises a preparation as outlined above in combination with a propellant-free nebuliser.

According to another embodiment of the invention there is provided a nebuliser ampoule 10 containing the propellant-free pharmaceutical preparation as outlined above.

According to another embodiment of the invention there is provided a method for the treatment of an obstructive lung disease including the step of administering by inhalation to a subject in need thereof an effective amount of a propellant-free pharmaceutical 15 preparation comprising a pharmaceutically active substance other than nitroglycerine dissolved in a solvent containing at least 70% ethanol.

Suitable solvents for the pharmaceutical preparation within the scope of the present inventions are solutions containing at least 70% of ethanol; solutions containing at 20 least 85% are preferred whilst solutions having an ethanol content of more than are particularly preferred. The concentration is given in percent by volume the remainder being water. Most particularly preferred is ethanol which already contains small amounts of water, e.g. 96% ethanol, so that it is no longer hygroscopic and evaporates azeotropically.

Apart from water, the solvent may include other cosolvents and the pharmaceutical preparation may also contain flavourings and other pharmacological excipients. Examples of cosolvents are those which contain hydroxyl groups or other polar groups, e.g. alcohols, especially isopropyl alcohol, glycols, particularly propylene glycol, polyethylene glycol, Abbomf.on1PaPc-, OPER MKR SPECNII4-4-1IJ6rl do. "4 -1) -2Bpolypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and esters of polyoxyethylene fatty acids. Cosolvents are suitable for increasing the solubility of the excipients and possibly the active substances.

The proportion of dissolved pharmaceutical substance in the finished pharmaceutical preparation is between 0.001 and preferably between 0.05 and most particularly 0.01 to where the figures refer to the percentage by weight. The maximum concentration of pharmaceutical substance depends on the solubility in

S.

-3the solvent and on the dosage required to achieve the desired therapeutic effect.

As pharmaceutically active agent in the new preparations, it is possible to use any substances which are suitable for administration by inhalation and which are soluble in the solvent specified. These may include, in particular, betamimetics, anticholinergics, antiallergics, PAP-antagonists and particularly steroids and combinations of active substances thereof.

The following are mentioned specifically by way of example: Tiotropium bromide, 3-f (hydroxydi-2-thienylacetyl)oxy 8,8-dimethyl-8-azoniabicyclo[3,2, loct-6-en-bromide As betamimetics: Barbuterol Bitolterol Carbuterol Formoterol Clenbuterol Fenoterol Hexoprenaline Procaterol Ibuterol Pirbuterol Salmeterol Tulobuterol Reproterol Salbutamol Sulfonterol Terbutaline 1-(2-fluoro-4-hydroxypnenyl l-benzimidazolyl)-2methyl-2-butylamino]ethanol, erythro-5'-hydroxy-8'-(l-hydroxy-2-isopropylaminobutyl)- 2H-l,4-benzoxazin-3-(4H)-one, 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.butyl-amino)ethanol, 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2- (tert.-butylamino)ethanol.

As anticholinergics: Ipratropium bromide 1 Oxitropium bromide Trospium chloride N-P-fluorethylnortropine benzilate methobromide 4 As steroids: Budesonide Beclomethasone (or the 17,21-dipropionate) Dexamethasone-21-isonicotinate Flunisolide As antiallergics: Disodium cromoglycate Nedocromil Epinastin As PAF-antagonists: WEB 2086 (4-(2-chlorophenyl)-9-methyl-2-[3-(4morpholinyl)-3-propanon-1-yl]-GH-thieno-[3,2-f] triazolo[4,3-a] [1,4]diazepine) WEB 2170 (6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4morpholinyl)carbonyl]-4H,7H-cyclopenta[4,5]thieno- .0 [1,2,4]triazolo[4,3-a] [1,4]diazepine) The pharmaceutical preparations according to the invention may contain other excipients such as soya lecithin or surface-active substances.

Surprisingly, it has also been found that the addition of an organic or inorganic acid, preferably in conjunction with a complex forming agent, leads to an improvement in the stability (shelf life) of steroidcontaining preparations. This has been found particularly useful for pharmaceutical preparations which contain as active substance Flunisolide or the hydrate or hemihydrate thereof or Budenoside, and which contain ethanol as solvent.

Examples of inorganic acids include, for example: hydrochloric acid, sulphuric acid or phosphoric acid; examples of organic acids include ascorbic acid, malic acid, citric acid, tartaric acid, maleic acid, succinic 5 acid, fumaric acid, acetic acid, formic acid, propionic acid, etc.

The amount of acid in the finished pharmaceutical preparation is in every case selected so that the pH of the solution is between 2.0 and 7.0, especially between and In a preferred embodiment, the pharmaceutical preparation also contains a complex forming agent.

Examples of complex forming agents include EDTA, citric acid, nitrilo triacetic acid and the salts thereof. The quantity of complex forming agent is between 0.1 and 3 mg/100 ml, preferably between 0.2 and 2 mg/100 ml, particularly between 0.9 and 1.1 mg/100 ml, based on the finished pharmaceutical preparation.

S. The preferred complex forming agent is EDTA (ethylene diamine tetraacetic acid or a salt thereof, such as the disodium salt). A preferred pharmaceutical preparation according to the present invention contains 1.667% S* Flunisolide in the ethanol (96% v/v) as solvent, which contains 0.01% EDTA as complex forming agent and is adjusted by the addition of acid to a pH of between and Examples of steroids which may be used as an active substance in the pharmaceutical preparation according to the invention are: Seratrodast Mycophenolate mofetil Pranlukast Zileuton Butixocort Budesonide Deflazacort Fluticasone Promedrol Mometasone furoate Tipredane Beclomethasone, Douglas Icomethasone enbutate -6 of*.

0 *fee Ciclometasone Fluocortin butyl Deflazacort Ciclometasone Prednicarbate Tixocortol pivalate Lotrisone Deprodone Methyiprednisolone- Aceponate Mometasone Hydrocortisone aceponate Ulobetasol propionate Triamcinolone Mepredni sone Dexame thas one Medrys one Fluocinolone acetonide Deprodone Propionate Fluocinonide Difluprednate Dexamethasonisonicotinate Fluocortoloncapronate Triamcinolon hexacetonide Formebo lone Endrisone Halcinonide Clobetasol Diflorasone Amc inonide Cart ivazol Fluodexan Budesonide Demetex Cloprednol Halometasone Alciometasone Alisactide Hydrocortisone butyrate Alciometasone dipropionate Canes ten-HC Fluticasone propionate Halopredone acetate Mometasone furoate Mometasone Ami nogi ute t himi de Hydrocortisone Fluorometholone Betamethasone Fluclorolone acetonide Paramethasone acetate Aristocort diacetate Mazipredone Betamethasone valerate Beclomethasone dipropionate Formocortal Cloprednol C lobe ta son Flunisolide Fluazacort Hydrocortisone -17 -butyrate Flucortin Betamnethasone dipropionate Betamethasone adamantoate Triiostane Clobetasone Trimacinolon Benetonide 9oa-chloro-6o(-fluoro-2p, 17o-dihydroxy-16oa-methyl-3-oxo- 1,4-androstadiene-17h-carboxylic acid methylester-17prop ionate.

7 Table 1 shows a comparison of a deposition study which was carried out on the one hand with a standard commercial metering aerosol Inhacort® (Flunisolide, dichloromethane, trichlorofluoromethane, cryofluoran, sorbitane triolate) MDI, and on the other hand with the pharmaceutical preparation according to the invention containing Flunisolide in 96% ethanol, which was carried out with a nebuliser as in the abovementioned PCT Application WO 91/14468 (BINEB®; technical data: volume of drug preparation administered 15 A1, pressure approx. 300 bar, 2 jets squeezed out of two nozzle openings measuring 5 x 8 im).

Table 1 Table 1: Deposition study S. *u 4 BINEB® MDI 9e Lung Mouthpiece Exhaled part Central lung region Middle lung region Peripheral lung region Peripheral zone/central zone ratio 39.7 (9.9) 39.9 (9.4) 10.4 (4.9) 10.7 (2.5) 14.9 (3.6) 14.1 (4.3) 1.3 (0.2) 15.3 (5.1) 66.9 (7.1) 1.4 (1.3) 4.5 (1.8) 5.4 (1.9) 5.4 (1.4) 1.3 (0.2) The Table clearly shows the advantage of the pharmaceutical preparation according to the invention which was administered with the nebuliser described.

8 Examples: Flunisolide hemihydrate-6a-fluoro-ll3,16a,17a,21tetrahydropregna-1,4-diene-3,20-16 acetonide hemihydrate has a molecular weight of 442.5. When used in BINEB, 250 pg of Flunisolide are dissolved, per dose, in 15 pl of solution so as to give a concentration of 1.667% (g/100 ml).

96% ethanol is used as solvent. In addition, the finished pharmaceutical preparation contains 1 mg/100 ml of disodium-EDTA. The pH value of the pharmaceutical preparation is adjusted to pH 4 using 0.1N HC1.

Analogously to the above experiment, formulations were prepared containing Budesonide as active substance.

The following mixtures of pharmaceutical preparations were made up, containing Flunisolide-hemihydrate as active substance.

Table II Experiment Combination Ethanol pH Quantity of No. content disodium EDTA in mg/100 ml 1 1 85 3.6 0 2 A 96 3.6 0 3 B 85 7.0 0 4 AB 96 7.0 0 C 85 3.6 1 6 AC 96 3.6 1 7 BC 85 7.0 1 8 ABC 96 7.0 1 9 The Flunisolide-hemihydrate content was 1,666.7 mg/100 ml. The pH of the solution was adjusted using IN HC1 and was determined using a pH meter, pH 1162 Radiometer Copenhagen. The samples were transferred into 5 ml glass ampoules and stored at away from light. The combination AC showed the lowest amount of decomposition product after 30 days' storage.

Further examples of formulations which additionally contain disodium EDTA as complex forming agent are shown in Table III.

Table III Ingredients I II III IV Amount in Amount in Amount in Amount in mg/100 ml mg/100 ml mg/100 ml mg/100 ml Flunisolide 1667 1667 1667 1667 hemihydrate Disodium 1 1 1 1

EDTA

0.1 N HCI ad pH 3.6 ad pH 3.2 ad pH 4.0 ad pH 3.6 Menthol -667 Ethanol 96% ad 100 ml ad 100 ml ad 100 ml ad 100 ml The adjuvant menthol was added in order to mask the bitter flavour of the steroid where necessary.

The formulations described above were packaged in 5 ml glass ampoules and stored at 80 0 C. The preferred preparation, on account of the small amount of decomposition product, is preparation III.

Table IV shows some examples of formulations for Budenoside.

Table IV I I T f lv Ingredients

I

Amount in mg/100 ml

II

Amount in mg/100 ml

III

Amount in mg/100 ml

IV

Amount in mg/100 ml

V

Amount in mg/100 ml oO *o* *o* *o *o Budesonide 1333 1333 1333 1333 1333 Disodium I 1

EDTA

0.IN HCI 3.2 3.2 3.6 4.0 ad pH Ethanol 96% ad 100 100 After 3 months' storage at 80 0 C in sealed glass ampoules the amount of decomposition product was determined by HPLC. Formulations IV and V showed the smallest amount of decomposition product.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Claims (40)

1. A propellant-free pharmaceutical preparation which comprises a solution of a pharmacologically active substance other than nitroglycerine or beclomethasone, 17, 21- dipropionate dissolved in a solvent containing at least 70% ethanol, in the absence of undissolved solute.

2. A propellant-free pharmaceutical preparation according to claim 1 in which the i' pharmacologically active substance is selected from the group comprising betamimetics, 10 anticholinergics and/or antiallergics.

3. A pharmaceutical preparation according to claim 1 or 2 in which the solvent contains at least 85% ethanol.

4. A pharmaceutical preparation according to any of claims 1 to 3 in which the 9 solvent contains at least 95% ethanol.

5. A pharmaceutical preparation according to any of claims 1 to 4 in which the proportion of dissolved pharmaceutical product in the pharmaceutical preparation is between 0.001 and 5.0 percent by weight.

6. A pharmaceutical preparation according to any of claims 1 to 5 which further contains one or more pharmacologically harmless adjuvants and/or flavourings.

7. A pharmaceutical preparation according to any of claims 1 to 6 in which the active substance is Tiotropium or an acid addition salt thereof.

8. A pharmaceutical preparation according to any of claims 1 to 6 in which the active substance is 3-[(hydroxydi-2-thienylacetyl)oxy]-8,8-dimethyl-8-azoniabicyclo[3,2,1]oct-6- ene or an acid addition salt thereof. Abboufard PatP-imGPER,\tKR SPEC I 611 1- Jo-l I'

12- 9. A pharmaceutical preparation according to any one of claims 1 to 6 in which the active substance is Ipratropium bromide. A pharmaceutical preparation according to any one of claims 1 to 6 in which the active substance is Tiotropium bromide. 11. A pharmaceutical preparation according to any one of claims 1 to 6 in which the active substance is Oxitropium bromide. 10 12. A pharmaceutical preparation according to any one of claims I to 6 in which the .o active substance is Trospium chloride.

13. A pharmaceutical preparation according to either claim 3 or claim 4 characterised in that the active substance is a steroid.

14. A pharmaceutical preparation according to claim 13 characterised in that the solvent contains 96% ethanol.

15. A pharmaceutical preparation according to claim 13 or claim 14 which further contains one or more pharmacologically harmless adjuvants and/or flavourings and/or a complex forming agent.

16. A pharmaceutical preparation according to claim 15 in which the complex forming agent when present is EDTA or a salt thereof.

17. A pharmaceutical preparation according to either of claims 15 or 16 in which the quantity of complex forming agent when present is between 0.1 and 5 mg/100ml of solution.

18. A pharmaceutical preparation according to any one of claims 13 to 17 in which the pH value of the preparation is adjusted to a level between 3.2 and Abboufrd P1nP~nt, OPER MKR SPECI (W44-- "A 13-

19. A pharmaceutical preparation according to any one of claims 13 to 18 in which the active substance is Flunisolide or Budesonide.

20. A propellant-free pharmaceutical preparation which contains, per 100ml of 96% ethanol, 1.667 g of Flunisolide hemihydrate, Img of disodium EDTA and acid to adjust the pH to 4.0, in the absence of undissolved solute. i 21. A propellant-free pharmaceutical preparation which contains, per 100ml of 10 ethanol, 1.667 g of Flunisolide hemihydrate, Img of disodium EDTA and acid to adjust pH to 4.0, in the absence of undissolved solute.

22. A propellant-free pharmaceutical preparation which contains, per 100ml of 96% ethanol, 1.333g of Budesonide, Img of disodium EDTA and acid to adjust pH to in the absence of undissolved solute.

23. A propellant-free pharmaceutical preparation which contains, per 100ml of ethanol, 1.333g Budesonide, Img of disodium EDTA and acid to adjust pH to 4.0, in the absence of undissolved solute.

24. Use of a propellant-free pharmaceutical preparation according to any of claims 1 to 23 in the preparation of a nebuliser ampoule containing the propellant-free pharmaceutical preparation for administration of the preparation by inhalation for treatment of obstructive lung disease. A process for the preparation of a propellant-free pharmaceutical preparation which comprises dissolving a pharmacologically active substance other than nitroglycerine or beclomethasone 17,21-dipropionate in a solvent containing at least 70% ethanol, in the absence of an aerosol propellant and in the absence of undissolved solute. Abbo-fod P.Pcm OPER MKR SPECI I.,lW- doc-0." 4 14-

26. A system for delivery of a pharmacologically active substance to a subject by inhalation which comprises a preparation as defined in any one of claims 1 to 23 in combination with a propellant-free nebuliser.

27. A nebuliser ampoule containing the propellant-free pharmaceutical preparation according to any of claims 1 to 23.

28. A method for the treatment of an obstructive lung disease including the step of Sadministering by inhalation to a subject in need thereof an effective amount of a 10 propellant-free pharmaceutical preparation comprising a pharmaceutically active substance other than nitroglycerine dissolved in a solvent containing at least 70% ethanol.

29. The method according to claim 28 in which the pharmacologically active substance is selected from the group comprising betamimetics, anticholinergics and/or antiallergics. The method according to claim 28 or 29 in which the solvent contains at least ethanol.

31. The method according to any of claims 28 to 30 in which the solvent contains at least 95% ethanol.

32. The method according to any of claims 28 to 31 in which the proportion of dissolved pharmaceutical product in the pharmaceutical preparation is between 0.001 and percent by weight.

33. The method according to any of claims 28 to 32 wherein the preparation further contains one or more pharmacologically harmless adjuvants and/or flavourings.

34. The method according to any of claims 28 to 33 in which the active substance is Tiotropium or an acid addition salt thereof. Abbolufr.d'P.,iP-n OPER NIER SPEC I6414 doW I r II The method according to any of claims 28 to 33 in which the active substance is 3- [(hydroxydi-2-thienylacetyl)oxy]-8,8-dimethyl-8-azoniabicyclo[ 3 ,2,1]oct-6-ene or an acid addition salt thereof.

36. The method according to any of claims 28 to 33 in which the active substance is Ipratropium bromide.

37. The method according to any of claims 28 to 33 in which the active substance is Tiotropium bromide.

38. The method according to any of claims 28 to 33 in which the active substance is Oxitropium bromide.

39. The method according to any of claims 28 to 33 in which the active substance is 15 Trospium chloride. The method according to either claim 30 or claim 31 characterised in that the active substance is a steroid. e

41. The method according to claim 40 characterised in that the solvent contains 96% ethanol.

42. The method according to either claim 40 or claim 41 wherein the preparation further contains oiie or more pharmacologically harmless adjuvants and/or flavoulings and/or a complex forming agent.

43. The method according to claim 42 wherein the complex forming agent when present is EDTA or a salt thereof.

44. The method according to either claim 42 or claim 43 wherein the quantity of complex forming agent when present is between 0.1 and 5 mg/100ml of solution. Abbosford P.aPmn OPER MEIR SPECI64 I-4i'I9 doc-"' -16- The method according to any one of claims 40 to 44 wherein the pH value of the preparation is adjusted to a level between 3.2 and

46. The method according to any one of claims 40 to 45 wherein the active substance is Flunisolide or Budesonide.

47. The method according to any one of claims 28 to 46 wherein the pharmaceutical •preparation is administered as an aerosol of inhalable particles of 1 to 10 micrometers in 10 size.

48. A pharmaceutical preparation according to any one of claims 1 or 20 to 23 substantially as hereinbefore described with reference to the examples.

49. The process according to claim 25 or method according to claim 28, substantially S* as hereinbefore described with reference to the examples. DATED this 5th day of May, 2000 Boehringer Ingelheim KG By DAVIES COLLISON CAVE Patent Attorneys for the Applicant