U.S. patent application number 10/373515 was filed with the patent office on 2003-09-04 for stable pharmaceutical budesonide preparation for producing propellant-free aerosols.
This patent application is currently assigned to Boehringer Ingelheim KG. Invention is credited to Freund, Bernhard, Krueger, Michael, Zierenberg, Bernd.
Application Number | 20030165435 10/373515 |
Document ID | / |
Family ID | 7765285 |
Filed Date | 2003-09-04 |
United States Patent
Application |
20030165435 |
Kind Code |
A1 |
Freund, Bernhard ; et
al. |
September 4, 2003 |
Stable pharmaceutical budesonide preparation for producing
propellant-free aerosols
Abstract
The invention relates to ethanol-containing pharmaceutical
preparations for the production of propellant-free aerosols.
Inventors: |
Freund, Bernhard;
(Gau-Algesheim, DE) ; Krueger, Michael;
(Ingelheim, DE) ; Zierenberg, Bernd; (Bingen,
DE) |
Correspondence
Address: |
BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P. O. BOX 368
RIDGEFIELD
CT
06877
US
|
Assignee: |
Boehringer Ingelheim KG
Ingelheim
DE
|
Family ID: |
7765285 |
Appl. No.: |
10/373515 |
Filed: |
February 25, 2003 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10373515 |
Feb 25, 2003 |
|
|
|
10102495 |
Mar 20, 2002 |
|
|
|
10102495 |
Mar 20, 2002 |
|
|
|
09396673 |
Sep 9, 1999 |
|
|
|
6491897 |
|
|
|
|
09396673 |
Sep 9, 1999 |
|
|
|
08973921 |
Feb 3, 1998 |
|
|
|
08973921 |
Feb 3, 1998 |
|
|
|
PCT/EP96/02700 |
Jun 21, 1996 |
|
|
|
Current U.S.
Class: |
424/45 |
Current CPC
Class: |
A61K 31/40 20130101;
A61P 11/06 20180101; A61P 11/00 20180101; A61K 31/58 20130101; A61K
9/08 20130101; A61K 9/0078 20130101; A61K 9/008 20130101 |
Class at
Publication: |
424/45 |
International
Class: |
A61L 009/04 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 27, 1995 |
DE |
19523207.0 |
Claims
1. A pharmaceutical preparation for use in producing
propellant-free aerosols which comprises a pharmacologically active
substance, and if necessary, pharmacologically-harmless adjuvants
and/or flavourings, characterised in that the pharmaceutical
preparation contains at least 70% (v/v) ethanol as a solvent.
2. A pharmaceutical preparation according to claim 1, characterised
in that it contains 96% (v/v) ethanol as a solvent.
3. A pharmaceutical preparation according to claim 1 or 2,
characterised in that the active substance is suitable for
administration by inhalation and is selected from the group
comprising betamimetics, anticholinergics, antiallergics and/or
PAF-antagonists.
4. A pharmaceutical preparation according to claims 1 to 3,
characterised in that the proportion of dissolved pharmaceutical
product in the pharmaceutical preparation is between 0.001 and 5.0
percent by volume.
5. A pharmaceutical preparation for the production of
propellant-free aerosols, comprising a steroid and, if necessary,
pharmacologically-harml- ess adjuvants and/or flavourings,
characterised in that the pharmaceutical preparation contains at
least 85% (v/v) ethanol as a solvent, and if necessary, a complex
forming agent.
6. A pharmaceutical preparation according to claim 5, characterised
in that the solvent is 96% (v/v) ethanol.
7. A pharmaceutical preparation according to claim 6, characterised
in that the complex forming agent is EDTA or a salt thereof.
8. A pharmaceutical preparation according to claim 5 or claim 7,
characterised in that the quantity of complex forming agent is
between 0.1 and 5 mg/100 ml of solution.
9. A pharmaceutical preparation according to one of claims 5 to 8,
characterised in that the pH value of the preparation is adjusted
to a level between 3.2 and 4.5.
10. A pharmaceutical preparation according to one of claims 5 to 9,
characterised in that the active substance is Flunisolide or
Budesonide.
11. A pharmaceutical preparation according to one of claims 1 to 6,
characterised in that the active substance is Tiotropium or an acid
addition salt thereof.
12. A pharmaceutical preparation according to one of claims 1 to 6,
characterised in that the active substance is
3-[(hydroxyl-2-thienylacety-
l)oxy]-8,8-dimethyl-8-azoniabicyclo[3,2,1]oct-6-ene or an acid
addition salt thereof.
13. A pharmaceutical preparation for use in producing a
propellant-free metering aerosol containing, per 100 ml of 96%
(v/v) ethanol, 1.667 g of Flunisolide hemihydrate and 1 mg of
disodium EDTA, the pH value of the pharmaceutical preparation being
adjusted to 4.0.
14. A pharmaceutical preparation for use in producing a
propellant-free metering aerosol containing, per 100 ml of 90%
(v/v) ethanol, 1.667 g of Flunisolide hemihydrate and 1 mg of
disodium EDTA, the pH value of the pharmaceutical preparation being
adjusted to 4.0.
15. A pharmaceutical preparation for use in producing a
propellant-free metering aerosol containing, per 100 ml of 96%
(v/v) ethanol, 1.333 g of Budesonide and 1 mg of disodium EDTA, the
pH value of the pharmaceutical preparation being adjusted to
4.0.
16. A pharmaceutical preparation for use in producing a
propellant-free metering aerosol containing, per 100 ml of 90%
(v/v) ethanol, 1.333 g of Budesonide and 1 mg of disodium EDTA, the
pH value of the pharmaceutical preparation being adjusted to
4.0.
17. Use of a pharmaceutical preparation comprising a
pharmacologically active substance in a solution containing at
least 79% ethanol by volume in the preparation of a propellant-free
composition for administration by inhalation.
18. Use of a pharmaceutical preparation as defined in one of claims
1 to 16 as a propellant-free composition for administration by
inhalation.
19. A process for preparing a pharmaceutical preparation as defined
in claim 1 which comprises dissolution of a pharmacologically
active substance in at least 70% v/v.
20. A delivery system for a pharmacologically active substance
which comprises a preparation as defined in any one of claims 1 to
16 in combination with a propellant-free nebuliser.
Description
[0001] The present invention relates to pharmaceutical preparations
in the form of stable ethanolic solutions of active substances for
producing propellant-free aerosols.
[0002] 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.
[0003] Some nebulisers are described, for example, in PCT Patent
Application WO91/14468, 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 micrometers.
[0004] 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 using ethanolic active substance
solutions in combination with, for example, the above-mentioned
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.
[0005] Suitable solvents for the pharmaceutical preparation within
the scope of the present inventions are solutions containing at
least 70% (v/v) of ethanol; solutions containing at least 85% (v/v)
are preferred whilst solutions having an ethanol content of more
than 95% (v/v) are particularly preferred. The concentration is
given in percent by volume (v/v), 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.
[0006] 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, polypropylene 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.
[0007] The proportion of dissolved pharmaceutical substance in the
finished pharmaceutical preparation is between 0.001 and 5%,
preferably between 0.05 and 3%, most particularly 0.01 to 2%, where
the figures refer to the percentage by weight. The maximum
concentration of pharmaceutical substance depends on the solubility
in the solvent and on the dosage required to achieve the desired
therapeutic effect.
[0008] 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, PAF-antagonists and particularly
steroids and combinations of active substances thereof.
[0009] The following are mentioned specifically by way of
example:
[0010] Tiotropium bromide,
3-[(hydroxyl-2-thienylacetyl)oxy]-8,8-dimethyl--
8-azoniabicyclo[3,2,1]oct-6-en-bromide
1 As betamimetics: Bambuterol Bitolterol Carbuterol Formoterol
Clenbuterol Fenoterol Hexoprenaline Procaterol Ibuterol Pirbuterol
Salmeterol Tulobuterol Reproterol Salbutamol Sulfonterol
Terbutaline
[0011]
1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-but-
ylamino]ethanol,
[0012]
erythro-5'-hydroxy-8'-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benz-
oxazin-3-(4H)-one,
[0013]
1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butyl-amino)et-
hanol,
[0014]
1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamin-
o)ethanol.
[0015] As anticholinergics:
[0016] Ipratropium bromide
[0017] Oxitropium bromide
[0018] Trospium chloride
[0019] N-.beta.-fluorethylnortropine benzilate methobromide
[0020] As steroids:
[0021] Budesonide
[0022] Beclomethasone (or the 17,21-dipropionate)
[0023] Dexamethasone-21-isonicotinate
[0024] Flunisolide
[0025] As antiallergics:
[0026] Disodium cromoglycate
[0027] Nedocromil
[0028] Epinastin
[0029] As PAF-antagonists:
[0030] WEB 2086
(4-(2-chlorophenyl)-9-methyl-2-[3-(4-morpholinyl)-3-propan-
on-1-yl]-6H-thieno-[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepine)
[0031] WEB 2170
(6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl-
)carbonyl]-4H,7H-cyclopenta[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]d-
iazepine)
[0032] The pharmaceutical preparations according to the invention
may contain other excipients such as soya lecithin or
surface-active substances.
[0033] 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 steroid-containing 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.
[0034] 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 acid, fumaric acid, acetic
acid, formic acid, propionic acid, etc.
[0035] 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 3.0 and
4.0.
[0036] 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.
[0037] 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% Flunisolide in the ethanol (96%
v/v) as solvent, which contains 0.01% (v/v) EDTA as complex forming
agent and is adjusted by the addition of acid to a pH of between
3.0 and 4.0.
[0038] Examples of steroids which may be used as an active
substance in the pharmaceutical preparation according to the
invention are:
2 Seratrodast Mycophenolate mofetil Pranlukast Zileuton Butixocort
Budesonide Deflazacort Fluticasone Promedrol Mometasone furoate
Tipredane Beclomethasone, Douglas Icomethasone enbutate
Ciclometasone Cloprednol Fluocortin butyl Halometasone Deflazacort
Alclometasone Ciclometasone Alisactide Prednicarbate Hydrocortisone
butyrate Tixocortol pivalate Alclometasone dipropionate Lotrisone
Canesten-HC Deprodone Fluticasone propionate Methylprednisolone-
Halopredone acetate Aceponate Mometasone Mometasone furoate
Hydrocortisone aceponate Mometasone Ulobetasol propionate
Aminoglutethimide Triamcinolone Hydrocortisone Meprednisone
Fluorometholone Dexamethasone Betamethasone Medrysone Fluclorolofle
acetonide Fluocinolone acetonide paramethasone acetate Deprodone
Propionate Aristocort diacetate Fluocinonide Mazipredone
Difluprednate Betamethasone valerate Dexamethasonisonicotinate
Beclomethasone dipropionate Fluocortoloncapronate Formocortal
Triamcinolon hexacetonide Cloprednol Formebolone Clobetason
Endrisone Flunisolide Halcinonide Fluazacort Clobetasol
Hydrocortisome-17-butyrate Diflorasone Flucortin Amcinonide
Betamethasone dipropionate Cortivazol Betamethasone adamantoate
Fluodexan Triiostane Budesonide Clobetasone Demetex Trimacinolon
Benetonide
[0039]
9.alpha.-chloro-6.alpha.-fluoro-11.beta.,17.alpha.-dihydroxy-16.alp-
ha.-methyl-3-oxo-1,4-androstadiene-17.beta.-carboxylic acid
methylester-17-propionate.
[0040] Table 1 shows a comparison of a deposition study which was
carried out on the one hand with a standard commercial metering
aerosol Inhacort.RTM. (Flunisolide, dichloromethane,
trichlorofluoromethane, cryofluoran, sorbitane triolate)=MDI, and
on the other hand with the pharmaceutical preparation according to
the invention containing Flunisolide in 96% (v/v) ethanol, which
was carried out with a nebuliser as in the above-mentioned PCT
Application WO 91/14468 (BINEB.RTM.; technical data: volume of drug
preparation administered 15 .mu.l, pressure approx. 300 bar, 2 jets
squeezed out of two nozzle openings measuring 5.times.8 .mu.m).
3TABLE 1 Table 1: Deposition study BINEB .RTM. MDI Lung (%) 39.7
(9.9) 15.3 (5.1) Mouthpiece (%) 39.9 (9.4) 66.9 (7.1) Exhaled part
(%) 10.4 (4.9) 1.4 (1.3) Central lung region (%) 10.7 (2.5) 4.5
(1.8) Middle lung region (%) 14.9 (3.6) 5.4 (1.9) Peripheral lung
region (%) 14.1 (4.3) 5.4 (1.4) Peripheral zone/central 1.3 (0.2)
1.3 (0.2) zone ratio
[0041] The Table clearly shows the advantage of the pharmaceutical
preparation according to the invention which was administered with
the nebuliser described.
EXAMPLES
[0042] Flunisolide
hemihydrate-6.alpha.-fluoro-11.beta.,16.alpha.,17.alpha-
.,21-tetrahydropregna-1,4-diene-3,20-16 acetonide hemihydrate has a
molecular weight of 442.5. When used in BINEB, 250 .mu.g of
Flunisolide are dissolved, per dose, in 15 .mu.l of solution so as
to give a concentration of 1.667% (g/100 ml).
[0043] 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 HCl.
[0044] Analogously to the above experiment, formulations were
prepared containing Budesonide as active substance.
[0045] The following mixtures of pharmaceutical preparations were
made up, containing Flunisolide-hemihydrate as active
substance.
4TABLE II Quantity of Ethanol disodium Experiment content EDTA in
No. Combination (v/v) % pH 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 5 C 85 3.6 1 6 AC 96 3.6 1 7 BC 85 7.0 1 8
ABC 96 7.0 1
[0046] The Flunisolide-hemihydrate content was 1,666.7 mg/100 ml.
The pH of the solution was adjusted using 1N HCl and was determined
using a pH meter, pH 1162 Radiometer Copenhagen. The samples were
transferred into 5 ml glass ampoules and stored at 80.degree. C.
away from light. The combination AC showed the lowest amount of
decomposition product after 30 days' storage.
[0047] Further examples of formulations which additionally contain
disodium EDTA as complex forming agent are shown in Table III.
5TABLE III I II III IV Amount in Amount in Amount in Amount in
Ingredients 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 HCl 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
[0048] The adjuvant menthol was added in order to mask the bitter
flavour of the steroid where necessary.
[0049] The formulations described above were packaged in 5 ml glass
ampoules and stored at 80.degree. C. The preferred preparation, on
account of the small amount of decomposition product, is
preparation III.
[0050] Table IV shows some examples of formulations for
Budenoside.
6TABLE IV I II III IV V Amount in Amount in Amount in Amount in
Amount in Ingredients mg/100 ml mg/100 ml mg/100 ml mg/100 ml
mg/100 ml Budesonide 1333 1333 1333 1333 1333 Disodium 1 -- 1 1 --
EDTA 0.1 N HCl 3.2 3.2 3.6 4.0 4.0 ad pH Ethanol 96% 100 100 100
100 100 ad
[0051] After 3 months' storage at 80.degree. 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.
* * * * *