AU2003206290A1 - Composition for inhalation - Google Patents
Composition for inhalationInfo
- Publication number
- AU2003206290A1 AU2003206290A1 AU2003206290A AU2003206290A AU2003206290A1 AU 2003206290 A1 AU2003206290 A1 AU 2003206290A1 AU 2003206290 A AU2003206290 A AU 2003206290A AU 2003206290 A AU2003206290 A AU 2003206290A AU 2003206290 A1 AU2003206290 A1 AU 2003206290A1
- Authority
- AU
- Australia
- Prior art keywords
- pharmaceutical composition
- composition according
- hfa
- peg
- pnp
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000000203 mixture Substances 0.000 title claims description 39
- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 claims description 12
- 229960002848 formoterol Drugs 0.000 claims description 12
- 229920001223 polyethylene glycol Polymers 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 claims description 8
- 230000014759 maintenance of location Effects 0.000 claims description 8
- 208000023504 respiratory system disease Diseases 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 4
- 239000002274 desiccant Substances 0.000 claims description 4
- 229920002523 polyethylene Glycol 1000 Polymers 0.000 claims description 4
- 238000011321 prophylaxis Methods 0.000 claims description 4
- 206010039083 rhinitis Diseases 0.000 claims description 4
- 239000011888 foil Substances 0.000 claims description 3
- NWLPAIVRIWBEIT-SEPHDYHBSA-N (e)-but-2-enedioic acid;dihydrate Chemical compound O.O.OC(=O)\C=C\C(O)=O NWLPAIVRIWBEIT-SEPHDYHBSA-N 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 20
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 20
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 14
- 238000009472 formulation Methods 0.000 description 9
- 239000003380 propellant Substances 0.000 description 9
- 239000002202 Polyethylene glycol Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 6
- 229920003080 Povidone K 25 Polymers 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- XRHGYUZYPHTUJZ-UHFFFAOYSA-M 4-chlorobenzoate Chemical compound [O-]C(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-M 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940112141 dry powder inhaler Drugs 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Description
Composition for inhalation
Field of the invention
The present invention relates to a pMDI formulation of formoterol in a blend of propellants for use in the treatment of inflammatory conditions/disorders, especially respiratory diseases such as asthma, COPD and rhinitis.
Background of the invention
Stability is one of the most important factors, which determines whether a compound or a mixture of compounds can be developed into a therapeutically useful pharmaceutical product.
Formoterol is known in the art, and is marketed as Oxis ™ in a dry powder inhaler. There are a variety of other inhalers by which a respiratory product can be administered, such as pressurised metered dose inhalers (pMDFs). Formulations for pMDFs may require certain excipients such as those disclosed in WO 93/05765. It is also known that drug deposition can be reduced by internally coating the cans of pMDFs.
It has now been found that certain HFA formulations comprising formoterol together with polyvinylpyrrolidone (PNP) and polyethylene glycol (PEG) exhibit excellent product stability, particularly when contained in pMDFs having internally coated cans and where the pMDFs are wrapped to exclude moisture. The formulations of the invention are stable at ambient temperature for at least 12 months and exhibit good levels of dose uniformity. This is in contrast to an alternative commercial CFC product, which has to be stored in refrigerated conditions prior to dispensing to the patient.
The excipients of the formulation are soluble in the propellant blend, thus overcoming the problems of solubility of PNP in certain propellants such as 134a. An important aspect of the invention is the use of propellant 227 as a solvating agent for PNP. A major aspect of the invention is the use of the blend to achieve the required levels of PVP K25 for this particular formulation. The result is a physically and chemically stable suspension formulation of superior quality.
Description of the invention
In accordance with the present invention, there is provided a pharmaceutical composition suitable for use in a pMDI having a coated can fitted with a retention valve comprising formoterol, HFA 227, HFA 134a, PNP and PEG.
Preferably the PNP is present from about 0.0001 to about 0.01 %w/w and the PEG is present from about 0.001 to about 0.15% w/w.
Preferably the PNP is present in an amount of 0.001 % w/w. Preferably the PVP is PNP K25.
Preferably the PEG is present in an amount of 0.1 % w/w. Preferably the PEG is PEG 1000.
The HFA 134a and HFA 227 can be present in any suitable ratio, depending on the level of PVP required. Preferably the HFA227 is present as at least 20% of the propellant mixture. More preferably HFA 134a and HFA 227 are present in a ratio of 75% to 25%.
Preferably the can is coated and fitted with a retention valve. Suitable coatings include PFA, PTFE and FEP polymers, known in the art, which can be applied using known techniques. Alternatively the cans may be coated using plasma techniques.
Suitable retention valves include retention valves such as Valois RCS valves
Preferably the pMDI is packaged in a moisture resistant wrapping such as a foil pouch optionally containing a desiccant.
The compositions of the invention can be inhaled from any suitable MDI device. Doses will be dependent on the severity of the disease and the type of patient, but are preferably below or within the range 2-12 microgram per dose ex actuator, more preferably 4.5 meg per actuation.
Preferably the concentration of formoterol is such that the formulation delivers formoterol at 4.5 meg per actuation ex-actuator.
The formoterol can be in the form of a mixture of enantiomers, or as a single enantiomer, e.g.the R,R, S, S, R,S or S,R enantiomer. The formoterol can be in the form of the free base, salt or solvate, or a solvate of a salt, preferably the formoterol is in the form of its fumarate dihydrate salt. Other suitable physiologically salts that can be used include chloride, bromide, sulphate, phosphate, maleate, tartrate, citrate, benzoate, 4- methoxybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, p-toluenesulphonate, benzenesulphonate, ascorbate, acetate, succinate, lactate, glutarate, gluconate, tricaballate, hydroxynapaphthalenecarboxylate or oleate.
The pharmaceutical compositions according to the invention can be used for the treatment or prophylaxis of a respiratory disorder, in particular the treatment or prophylaxis of asthma, rhinitis or COPD.
In a further aspect the invention provides a method of treating a respiratory disorder, in particular asthma, rhinitis or COPD, in a mammal, which comprises administering to a patient a pharmaceutical composition as herein defined.
In an additional aspect the invention provides a pMDI containing a composition as defined above. Preferably the pMDI is packaged in moisture resistant wrapping such as a foil wrap, optionally with desiccant such as silica gel.
Experimental section
The compositions may be produced by cold fill or pressure fill techniques, both techniques and methods well known in the art. In cold filling, the ingredients are placed in a cooled mixing vessel, cooled liquefied propellant added and a dispersion produced by vigorous stirring. Aliquots of the dispersed composition are then filled into cooled aerosol cans and sealed with a suitable valve, e.g. a metering valve.
In pressure filling, the ingredients are placed in a pressure vessel, liquefied propellant added under pressure through a valve and a dispersion of the ingredients in the liquefied dispersed composition are then filled, under pressure, through the valve into suitable cans provided with appropriate valves, e.g. metering valves.
The following example illustrates the invention:
Where x gives a dose of 2 - 12 micrograms ex actuator Where PVP = polyvinylpyrrolidone Where PEG = polyethylene glycol
In order to achieve the required level of 0.001%, the solubility of the PNP had to be determined in both HFA 227ea and HFA 134a.
The level of HFA227 necessary to dissolve the required %w/w of previously specified excipients in the HFA 227/HFA134a blend was determined by the following method:
Method for Solubility
0.005% PNP K25 Solutions
Stock solutions of 0.1% w/wPEGlOOO in HFA134a and PEGIOOO in HFA227 were prepared in aerosol cans. A series of mixtures containing PNP K25 0.005% w/w were prepared at room temperature, (20C), using the stock solutions above, resulting in 0.005%w/w PVP K25 in various blend mixtures of 227 and 134a. The PVP had previously been weighed into PET vials that had been crimped with a valve. The samples were left for 6 hrs to equilibrate.
The clarity of the resulting solution/suspensions was noted. (Results 1, 2, 4 and 5)
0.002% PVP K25
A mix of 0.002% PVP K25 in HFA 227/134a (60:40) was also prepared in the above manner. (Result 3)
For more dilute solutions
a) A mixture of θ.02% PVP K25, 0.1% PEG 1000 in HFA 227 was prepared. (Previous work had shown PVP to be soluble at this level in HFA 227 alone)
b) Cans of 0.1% w/w PEGIOOO in HFA134a and 0.1%w/w PEGIOOO in HFA 227ixtures) were made up. The temperature was ambient (approx 22° C).
c) Using the above solutions, mixtures of PVP in varying blends of HFA134a and HFA227 were prepared by pressure filling into pre-crimped PET vials. The blends ranged from 5- 20% HFA227 w/w. The resulting mixtures were overnight on rollers to equilibrate after which the clarity of the resulting mixture was observed. (Results 6 to 10 and 12)
A final "test" mix of a weighed amount of PVPK25 in a PET precrimped vial was mixed with 100% HFA134a, left for several hours and the clarity noted. (Result 11)
Another control solution of 0.1% PEGIOOO in HFA134a and HFA 227 remained clear throughout.
Data
Data is summarised in tables 1 - 3.
TABLE 1
A mixture of 0.025% PNP in HFA 227ea remained clear i.e. was soluble
A control is solution of 0.1% w/w PEG 1000 in HFA 134a remained clear i.e. was soluble
Solubility of PNP ( as % w/w) in varying propellant ratios
Product Performance (based on change in dose through can life ) of 227 alone or blended with HFA 134a can be demonstrated using the data below.
Method for determining change in dose is: % = mean value end dose/ mean value beginning dose* 100
TABLE 2
Change in dose through can life for HFA 227 alone and HFA 227/134a blend formoterol formulations
nd=not done
UW/W = unwrapped wrapped
WD = wrapped with desiccant
For comparison purposes the data at 30/60 is presented although for the blend product more storage points were used. The 227 only batches were not tested after 3M due to loss of prime problems and the worsening rise in dose through can life.
The data in table 2 indicates that the blend of propellants provides superior dose uniformity even when the cans are stored in an unwrapped state.
TABLE 3
The advantage of using an RCS retention valve, for example, a Nalois DF31, can clearly be seen in the data below, which shows the dose profile of the product using either RCS (retention) or ACT (rapid-fill, rapid-drain) valve types.
Valve ACT vs RCS
Claims (15)
1. A pharmaceutical composition for use in a pMDI having a coated can fitted with a retention valve comprising formoterol, HFA 227, HFA 134a, PNP and PEG.
2. A pharmaceutical composition according to claim 1 in which the PNP is present from about 0.0001 to about 0.01 %w/w and the PEG is present from about 0.001 to about 0.15% w/w
3 A pharmaceutical composition according to claim 1 or 2 in which the ratio of HFA 134a to HFA227 is 75% to 25%.
4. A pharmaceutical composition according to any one of claims 1 to 3 in which the PNP is PNP K25.
5. A pharmaceutical composition according to any one of claims 1 to 4 in which the PVP is present in an amount of 0.001% w/w.
6. A pharmaceutical composition according to any one of claims 1 to 5 in which the PEG is PEG 1000.
7. A pharmaceutical composition according to any one of claims 1 to 6 in which the PEG is present in an amount of 0.1% w/w.
8. A pharmaceutical composition according to any one of claims 1 to 7 in which formoterol is in the form of its fumarate dihydrate salt
9. A pharmaceutical composition according to any one of claims 1 to 8 for use for the treatment or prophylaxis of a respiratory disorder.
10. A pharmaceutical composition according to any one of claims 1 to 8 for use for the treatment or prophylaxis of asthma, rhinitis or COPD.
11. A pMDI containing a composition as defined in any one of claims 1 to 10.
12. A pMDI according to claim 11, which is fitted with a retention valve.
13. A pMDI according to claim 11 or 12, which is packaged in a moisture resistant wrapping.
14. A pMDI according to claim 13 in which the moisture resistant wrapping is a foil pouch, optionally with desiccant.
15. A method of treating a respiratory disorder in a mammal, which comprises administering to a patient a pharmaceutical composition according to any one of claims 1 to 9.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE0200412-5 | 2002-02-01 | ||
| SE0202138-4 | 2002-07-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2003206290A1 true AU2003206290A1 (en) | 2003-09-02 |
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7228726B2 (en) | Pharmaceutical composition | |
| CA2411047C (en) | Stable pharmaceutical solution formulations for pressurised metered dose inhalers | |
| SK286394B6 (en) | Medical aerosol formulations | |
| AU2017328908B2 (en) | Pharmaceutical composition | |
| EP1474118A1 (en) | Composition for inhalation | |
| AU2003206290A1 (en) | Composition for inhalation | |
| AU2005293328B2 (en) | Process for the preparation of suspension aerosol formulations, wherein the particles are formed by precipitation inside an aerosol canister | |
| ZA200406089B (en) | Composition for inhalation. | |
| NZ752430B2 (en) | Pharmaceutical composition |