NZ719346B2 - Method for preparing dry powder inhalation compositions - Google Patents
Method for preparing dry powder inhalation compositions Download PDFInfo
- Publication number
- NZ719346B2 NZ719346B2 NZ719346A NZ71934614A NZ719346B2 NZ 719346 B2 NZ719346 B2 NZ 719346B2 NZ 719346 A NZ719346 A NZ 719346A NZ 71934614 A NZ71934614 A NZ 71934614A NZ 719346 B2 NZ719346 B2 NZ 719346B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- excipient
- active ingredient
- mixing
- particulate
- vmd
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 66
- 239000000843 powder Substances 0.000 title claims abstract description 41
- 239000004480 active ingredient Substances 0.000 claims abstract description 85
- 238000002156 mixing Methods 0.000 claims abstract description 47
- 239000002245 particle Substances 0.000 claims abstract description 29
- 239000004615 ingredient Substances 0.000 claims abstract 3
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 claims description 46
- 239000008101 lactose Substances 0.000 claims description 46
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 claims description 15
- 229960004017 salmeterol Drugs 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 14
- 239000011780 sodium chloride Substances 0.000 claims description 14
- 229960004436 Budesonide Drugs 0.000 claims description 9
- VOVIALXJUBGFJZ-VXKMTNQYSA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3O[C@@H](CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-VXKMTNQYSA-N 0.000 claims description 9
- BPZSYCZIITTYBL-YJYMSZOUSA-N Formoterol Chemical group C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-YJYMSZOUSA-N 0.000 claims description 8
- 230000003182 bronchodilatating Effects 0.000 claims description 7
- 229960002848 formoterol Drugs 0.000 claims description 7
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 4
- -1 asone Chemical compound 0.000 claims description 4
- 150000003431 steroids Chemical class 0.000 claims description 4
- 229940092705 Beclomethasone Drugs 0.000 claims description 3
- 230000003110 anti-inflammatory Effects 0.000 claims description 3
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 claims description 3
- 239000000168 bronchodilator agent Substances 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 45
- XTZNCVSCVHTPAI-UHFFFAOYSA-N 2-carboxynaphthalen-1-olate;[2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]-[6-(4-phenylbutoxy)hexyl]azanium Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CC=C21.C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 XTZNCVSCVHTPAI-UHFFFAOYSA-N 0.000 description 9
- MGNNYOODZCAHBA-GQKYHHCASA-N Fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 description 9
- 229960005018 Salmeterol xinafoate Drugs 0.000 description 9
- 229960002714 fluticasone Drugs 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 239000010419 fine particle Substances 0.000 description 7
- ZDUPYZMAPCZGJO-NSCGSSGESA-N (E)-but-2-enedioic acid;N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(2R)-1-(4-methoxyphenyl)propan-2-yl]amino]ethyl]phenyl]formamide Chemical compound OC(=O)\C=C\C(O)=O.C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(NC=O)=C1 ZDUPYZMAPCZGJO-NSCGSSGESA-N 0.000 description 6
- 229940079593 drugs Drugs 0.000 description 6
- 229960003610 formoterol fumarate dihydrate Drugs 0.000 description 6
- 229940112141 Dry Powder Inhaler Drugs 0.000 description 4
- 230000003247 decreasing Effects 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- WMWTYOKRWGGJOA-CENSZEJFSA-N Fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229960000289 fluticasone propionate Drugs 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000007873 sieving Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 208000006673 Asthma Diseases 0.000 description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 2
- 210000004072 Lung Anatomy 0.000 description 2
- 206010038683 Respiratory disease Diseases 0.000 description 2
- 230000001419 dependent Effects 0.000 description 2
- BPXZSHHCUKRDHD-HTLUESNNSA-N (E)-but-2-enedioic acid;N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(2R)-1-(4-methoxyphenyl)propan-2-yl]amino]ethyl]phenyl]formamide;hydrate Chemical compound O.OC(=O)\C=C\C(O)=O.C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(NC=O)=C1.C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(NC=O)=C1 BPXZSHHCUKRDHD-HTLUESNNSA-N 0.000 description 1
- 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 description 1
- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-N 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- LSLYOANBFKQKPT-UHFFFAOYSA-N Fenoterol Chemical compound C=1C(O)=CC(O)=CC=1C(O)CNC(C)CC1=CC=C(O)C=C1 LSLYOANBFKQKPT-UHFFFAOYSA-N 0.000 description 1
- VPNYRYCIDCJBOM-UHFFFAOYSA-M Glycopyrronium bromide Chemical compound [Br-].C1[N+](C)(C)CCC1OC(=O)C(O)(C=1C=CC=CC=1)C1CCCC1 VPNYRYCIDCJBOM-UHFFFAOYSA-M 0.000 description 1
- QZZUEBNBZAPZLX-QFIPXVFZSA-N Indacaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)CNC1CC(C=C(C(=C2)CC)CC)=C2C1 QZZUEBNBZAPZLX-QFIPXVFZSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229960001664 Mometasone Drugs 0.000 description 1
- 239000008896 Opium Substances 0.000 description 1
- 210000003800 Pharynx Anatomy 0.000 description 1
- NDAUXUAQIAJITI-UHFFFAOYSA-N Salbutamol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 1
- DQHNAVOVODVIMG-UHFFFAOYSA-M Tiotropium bromide Chemical compound [Br-].C1C(C2C3O2)[N+](C)(C)C3CC1OC(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 DQHNAVOVODVIMG-UHFFFAOYSA-M 0.000 description 1
- DAFYYTQWSAWIGS-DEOSSOPVSA-N Vilanterol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCCCCCOCCOCC=2C(=CC=CC=2Cl)Cl)=C1 DAFYYTQWSAWIGS-DEOSSOPVSA-N 0.000 description 1
- 229950000339 Xinafoate Drugs 0.000 description 1
- 229960001692 arformoterol Drugs 0.000 description 1
- 229960003728 ciclesonide Drugs 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229960001022 fenoterol Drugs 0.000 description 1
- 229960000193 formoterol fumarate Drugs 0.000 description 1
- 229940005644 glycopyrronium Drugs 0.000 description 1
- 229960002462 glycopyrronium bromide Drugs 0.000 description 1
- 229960004078 indacaterol Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229960004286 olodaterol Drugs 0.000 description 1
- COUYJEVMBVSIHV-SFHVURJKSA-N olodaterol Chemical compound C1=CC(OC)=CC=C1CC(C)(C)NC[C@H](O)C1=CC(O)=CC2=C1OCC(=O)N2 COUYJEVMBVSIHV-SFHVURJKSA-N 0.000 description 1
- 229960001027 opium Drugs 0.000 description 1
- 239000011236 particulate material Substances 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- 229940110309 tiotropium Drugs 0.000 description 1
- 229960004258 umeclidinium Drugs 0.000 description 1
- FVTWTVQXNAJTQP-KRKINAOUSA-N umeclidinium Chemical compound C=1C=CC=CC=1C([C@@]12CC[N@@+](CCOCC=3C=CC=CC=3)(CC1)CC2)(O)C1=CC=CC=C1 FVTWTVQXNAJTQP-KRKINAOUSA-N 0.000 description 1
- 229960004026 vilanterol Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
Abstract
method for preparing dry powder inhalation compositions which comprise two or more active ingredients and inert particulate excipient, and a method for adjusting the performance of such compositions is described. The method comprises mixing the first active ingredient and a portion of the second active ingredient with a first excipient to provide a first preblend, mixing the remaining portion of the second active ingredient with a second excipient to provide a second preblend, and finally mixing the first and the second preblends together, wherein the two excipient grades differ in their median particle size. The FPD level of second active ingredient can be adjusted simply by changing the ratio how it is divided between the first and the second excipient. ctive ingredient with a first excipient to provide a first preblend, mixing the remaining portion of the second active ingredient with a second excipient to provide a second preblend, and finally mixing the first and the second preblends together, wherein the two excipient grades differ in their median particle size. The FPD level of second active ingredient can be adjusted simply by changing the ratio how it is divided between the first and the second excipient.
Description
METHOD FOR PREPARING DRY POWDER INHALATION COMPOSITIONS
Field of the ion
The invention relates to a method for preparing dry powder inhalation itions
which comprise two or more active ingredients and inert particulate ent, and to
a method for adjusting the performance of such compositions.
Background of the Invention
Inhaled ments for the treatment of respiratory diseases such as asthma and
COPD are often formulated as dry powders and are red using a dry-powder
inhaler (DPI). The medicaments are micronized such as to have a respirable
aerodynamic diameter which is typically in the region of 0.5 to 10 µm. Such
micronized particles tend to be cohesive and have poor flow properties. To se
flowability and dosing accuracy the fine drug particles of respirable size are typically
mixed with coarser excipient particles to form an ordered mixture, wherein fine drug
les are ed to the coarser excipient particles. This technique necessitates
the break-up of the drug/excipient agglomerates before they enter the patient's mouth
and throat, where individual large particles and agglomerated large and small
particles tend to deposit. Effective aerosolization and omeration of the powder
requires that forces exerted on particles (e. g. forces between particles and surfaces of
the device, between drug particles and excipient particles or between drug particles
themselves) must be overcome such that high fine particle dose (FPD) of
medicament particles in the respirable size is obtained. Improvements in FPD and
dose uniformity have been reported by suitably adjusting the size range of the
excipient particles.
The interaction between the drug and the excipient is further complicated when the
inhalation powder includes particles of two or more different active ingredients. In
the pment of such combination products it is often desirable to adjust the FPD
level of each active ingredient independently. However, this often proves to be
ult as attempts to affect the FPD level of one active ingredient affect the FPD of
the other active ingredient(s) of the combination as well.
Efforts to control the performance of dry powder inhalation products having two or
more active ingredients have been recently reported. EP 2221048 discloses a method
of first preblending each different active ingredient with different excipient (differing
in their particle size) and, thereafter, blending the obtained nds er in a
main blending procedure to obtain the final composition. The method allegedly
enables adhesion of each of the active ingredient to one excipient, but not to other.
The FPD of one active substance could be then tuned independently from the other
active substance by suitably adjusting the particle size of each excipient.
The method of EP 2221048 suffers from the drawback that various lactose grades
with different particle size distribution are required for each tuning step. cial
lactose grades may differ also in other teristics than particle size and
unexpected effects in the FPD may occur. Thus, there is a need for simplified
methods for adjusting the FPD level of each active substance ndently in
inhaled dry powder combination products. It is an object of the t invention to
go some way towards meeting this need, and/or to at least provide the public with a
useful choice.
Summary of the Invention
It has been found that FPD level of each active ingredient of the combination can be
adjusted independently t the need to change the excipient grades used in the
composition. This is achieved by providing two excipient grades which differ in their
median le size, mixing the first active ingredient and a portion of the second
active ingredient with a first excipient to e a first preblend, mixing the
remaining portion of the second active ingredient with a second excipient to provide
a second preblend, and finally mixing the first and the second preblends together.
The FPD level of second active ingredient can be adjusted simply by changing the
ratio how it is divided between the first and the second excipient. Preblending with
coarser excipient is found to be associated with a lower FPD level. Thus, the FPD
value of the second active ingredient can be adjusted to the desired level by changing
the portion of second active ingredient which is preblended with coarser excipient.
At the same time, the FPD level of the first active ingredient is only minimally
affected.
Brief Description of the Drawings
Figure 1a shows the ed changes in the fine particle dose (FPD) of salmeterol
xinafoate by adjusting preblend parameters (percent of fine e and proportion of
salmeterol xinafoate preblended with coarser excipient).
Figure 1b shows the observed changes in the FPD of fluticasone propionate in vitro
using s preblend parameters (percent of fine lactose and proportion of
salmeterol xinafoate preblended with coarser excipient).
Detailed Description of the Invention
In one aspect, the present invention provides a method of preparing a dry powder
inhalation ition comprising a first and a second active ingredient in
micronized form comprising the steps of:
(a) mixing the first active ient and a portion of the second active
ingredient with a first particulate excipient to provide a first preblend;
(b) mixing the remaining portion of the second active ingredient with a
second particulate excipient to provide a second preblend; and
(c) mixing the first and the second preblends together;
wherein the first particulate excipient and the second particulate ent
differ in their median particle size, such that VMD (volume median er)
of the finer ulate excipient is less than 90 % of the VMD of the coarser
particulate excipient.
The term “about” refers to a variation of 5 % from the indicated numeric value.
The term “finer particulate excipient”, as used herein, means the excipient selected
from the first and the second particulate excipients which has the lowest VMD value.
The term “coarser particulate excipient”, as used herein, means the excipient selected
from the first and the second particulate excipients which has the highest VMD
value.
The term “micronized form” means particle size lower than about 10 µm, for
example in the range between 0.5 to 10 µm, ularly in the range between 1 and 6
The particle size, for example volume median diameter (VMD), of the particulate
material can be determined by a laser diffractometer (e.g. n Instruments Ltd,
UK) using dry dispersion method and Fraunhofer approximation.
The term “comprising” as used in this ication and claims means sting at
least in part of”. When interpreting statements in this specification and claims which
include the term “comprising”, other es besides the features prefaced by this
term in each statement can also be t. Related terms such as “comprise” and
“comprises” are to be interpreted in similar manner.
In another , the present ion provides a method of preparing a dry powder
inhalation composition comprising a first and a second active ingredient in
micronized form comprising the steps of:
(a) mixing the first active ingredient and a portion of the second active
ingredient with a first particulate excipient having VMD within the range
of from about 30 to about 70 µm to provide a first preblend;
(b) mixing the remaining portion of the second active ingredient with a
second ulate excipient having VMD within the range of from about
80 to about 150 µm to provide a second preblend; and
(c) mixing the first and the second preblends, optionally with additional first
or second particulate excipient, together and
(d) optionally mixing the obtained blend with additional first or second
particulate excipient.
The first and second active ingredients, which are understood herein to be different,
can be generally any two active ingredients which are suitable for administration by
inhalation in dry powders as a combination. In particular, the active ingredients may
be selected from those that are useful in the treatment of respiratory diseases such as
asthma and COPD. The present method can be used also in the preparation of dry
powder inhalation compositions which incorporate more than two different active
ingredients, for example in the preparation of a combination of three active
ingredients.
According to one embodiment of the invention, the first and second active
ingredients are selected from anti-inflammatory steroids and bronchodilators.
es of anti-inflammatory steroids include, but are not limited to, budesonide,
fluticasone, beclomethasone, ciclesonide, fluticasone, mometasone and
ceutically acceptable salts thereof. Examples of odilators include, but
are not limited to, formoterol, salmeterol, nium, arformoterol, erol,
fenoterol, glycopyrronium, indacaterol, opium, olodaterol, salbutamol,
tiotropium, umeclidinium, vilanterol and pharmaceutically acceptable salts thereof.
According to one particular ment of the invention, the first active ingredient
is an anti-inflammatory steroid and the second active ingredient is a bronchodilator.
According to another ular embodiment of the invention, the first active
ingredient is a bronchodilator and the second active ient is an flammatory
steroid. According to another particular embodiment of the invention,
the first active ingredient is budesonide or a pharmaceutically acceptable salt thereof
and the second active ingredient is formoterol or a pharmaceutically acceptable salt
thereof. According to still another particular embodiment of the invention, the first
active ingredient is fluticasone or a pharmaceutically acceptable salt thereof and the
second active ient is salmeterol or a pharmaceutically acceptable salt thereof.
The active ingredients should be in micronized form, i.e. having particle size lower
than about 10 µm, for example in the range from about 0.5 to about 10 µm,
particularly in the range from about 1 to about 6 µm, such as to be able to deposit
target areas in the lungs. tional methods, such as milling, can be used to
provide the active ingredients in micronized form.
The amount of the active ingredient in the dry powder inhalation composition can
vary depending e.g. on the active ingredient and the type of dry powder inhaler used.
Generally, the amount of the active ingredient in the dry powder tion
composition is within the range of 0.02 to 30 %, typically from 0.05 to 10 %, more
typically from 0.1 to 5 %, per weight of the composition.
According to one embodiment of the invention, the excipient used in the dry powder
inhalation ition is a mono- or disaccharide, particularly lactose or mannitol,
for example alpha e monohydrate. In general, the particle size of the excipient
is preferably such that it can be entrained in the air stream but not enter deeply into
the lung. However, a small proportion of particles with respirable size (< 10 µm) can
be present in the excipient as such fine particles of the excipient may help in
attaining higher FPD . The VMD of the excipient, such as lactose, to be used
in the composition is suitably in the range of, for example, from about 30 to about
150 µm. The excipient of desired VMD can be obtained from commercial sources or
can be prepared using methods known in the art such as by blending together
excipient powders of known le size or by sieving.
In the present method two particulate excipients are used which differ in their median
particle size such that the VMD of the finer particulate excipient is less than 90 % of
the VMD of the r particulate excipient. According to one embodiment of the
invention, the VMD of the finer particulate excipient is less than 85 % of the VMD
of the coarser particulate excipients. According to another embodiment of the
invention, the VMD of the finer ulate ent is within the range of from
about 30 to about 70 µm, for example from about 35 to about 65 µm, and the VMD
of the coarser particulate excipient is within the range of from about 80 to about 150
µm, for example from about 90 to about 120 µm.
The weight ratio of the finer particulate ent to coarser particulate excipient in
the dry powder inhalation composition may vary within a wide range, but is typically
within the range of 0.2 to 5, more typically from 0.25 to 3, for example from 0.5 to
1.5.
Preferably, the first and the second particulate excipient is e.
In the first step of the mixing process, the entirety of the first active ingredient and a
portion of the second active ingredient are mixed with a first particulate excipient
(e.g. the finer particulate excipient) to provide a first nd. In this step the
entirety or only a portion of the total first excipient may be used. If only a proportion
of the first ent is used in this step, the proportion is typically 5 – 80 %, for
example 10-75 %, of the total amount used in the composition. The rest of the first
particulate excipient may then be used in subsequent blending steps. The components
of the first preblend are mixed in a suitable ng device, for example a low shear
powder mixer or high shear powder mixer. The mixing speed and mixing time may
vary within a broad range depending on the ng device used but are in general
selected such as to produce homogenous powder composition. The mixing speed
may be for example in the range of 10 – 50 rpm, for e 20 - 40 rpm. The
mixing time may be for example in the range of 1 to 60 min, for example 3 to 15
min.
The second nd is prepared by mixing the remaining portion of the second
active ingredient with a second particulate excipient (e.g. the coarser particulate
ent) to provide a second preblend. In this step the entirety or only a portion of
the total second excipient may be used. If only a proportion of the second excipient is
used in this step, the proportion is typically 1-50 %, for example 1-30 %, of the total
amount used in the composition. The rest of the second particulate excipient may
then be used in the final ng step. The same blending conditions as above can
be utilized.
Next the first and the second preblends are suitably sieved and then mixed together.
If only a portion of the first excipient was used in the preparation of the first
preblend, the rest of the first excipient (e.g. the rest of the finer particulate excipient)
is mixed in this step with the first and the second preblends to obtain a blend
containing the first and the second active ingredient. The blend is then preferably
sieved. The same blending conditions as above can be utilized.
If only a n of the second excipient was used in the ation of the second
preblend, the rest of the second excipient (e.g. the rest of the coarser particulate
excipient) can now be mixed with the previously obtained blend containing the first
and the second active ingredient such as to obtain the final dry powder inhalation
composition. The same blending conditions as above can be utilized. The final
ition can be filled in a suitable dry powder inhaler.
If desired, further excipients or active ingredients can be added to the composition
during above mentioned mixing steps or during r mixing steps.
In the pment of dry powder inhalation compositions incorporating a
combination of active ingredients there often occurs a desire to adjust the fine
particle dose (FPD) of one active ingredient ndently of the other active
ingredient. According to the present method, the FPD of the second active ingredient
of the composition can be independently adjusted by simply changing the tion
of the second active ingredient which is mixed with a first particulate excipient.
Preblending the active ingredient with coarser excipient is found to be ated
with lower FPD level. Thus, in case the first particulate excipient is the finer
particulate excipient, the FPD of the second active ingredient can be increased by
increasing the proportion of the second active ingredient which is mixed with a first
particulate excipient. Inversely, the FPD of the second active ingredient can be
decreased by decreasing the proportion of the second active ingredient which is
mixed with the first particulate excipient.
The invention is illustrated further with the following Examples.
Example 1.
A dry powder formulation for inhalation according to Table 1 was prepared.
Table 1. Dry powder formulation for inhalation
erol fumarate dihydrate 1.71 g
Budesonide 60.9 g
Lactose A (VMD = 55 µm) 862 g
Lactose B (VMD = 105 µm) 575 g
A first preblend was ed by mixing 0.855 g of micronized formoterol fumarate
dihydrate, 60.9 g of micronized budesonide and 287 g of lactose A in a swing-mix
type powder mixer followed by sieving the mixture and blending it with the rest (575
g) of lactose A in a swing- mix type powder mixer. A second preblend was prepared
by mixing 0.855 g of micronized formoterol fumarate dihydrate and 192 g of lactose
B in a swing-mix type powder mixer followed by sieving the mixture and blending it
with 192 g of lactose B in a swing-mix type powder mixer. The two preblends were
ed by g and then mixed with the rest (191 g) of lactose B in a swing-
mix type powder mixer to obtain the final formulation. The mixing time of each step
was 5 min at 35 rpm.
Example 2. ence example)
A dry powder formulation for inhalation according to Example 1 was prepared with
the ion that all formoterol fumarate ate was incorporated in the second
preblend (with lactose B).
Example 3. (Reference example)
A dry powder formulation for inhalation according to Example 1 was ed with
the exception that all formoterol fumarate dihydrate was incorporated in the first
preblend (with lactose A).
Example 4.
The formulations of Examples 1, 2 and 3 were filled in Easyhaler® powder inhaler
device and the FPD values for the active ingredients (formoterol fumarate dihydrate
and budesonide) were determined in vitro using methods well known in the art. The
results are shown in Table 2.
Table 2. Fine particle dose (FPD) values of formulations of Examples 1-3.
Example No. FPD of formoterol (µg/dose) FPD of budesonide (µg/dose)
2 2.8 137
1 3.1 139
3 3.6 133
It can be seen that FPD of formoterol fumarate dihydrate can be adjusted by blending
part of formoterol fumarate dihydrate with lactose B (coarser e) while the FPD
of budesonide is only minimally affected. The change in FPD is dependent on the
proportion of formoterol which is blended with e B (coarser lactose).
Example 5.
A dry powder formulation for inhalation ing to Table 3 was prepared.
Table 3. Dry powder ation for inhalation
Salmeterol xinafoate 1.9g
Fluticasone propionate 13.0g
Lactose A (VMD = 55 µm) 145.5g
Lactose B (VMD = 105 µm) 339.6g
A first preblend was prepared by mixing 0.95 g of micronized salmeterol xinafoate,
13.0 g of micronized fluticasone propionate and 107.3 g of lactose A in a swing- mix
type powder mixer. A second preblend was prepared by mixing 0.95 g of micronized
salmeterol xinafoate and 7.3 g of lactose B in a swing- mix type powder mixer. The
two preblends were ed by g and then mixed with 38.2 g of lactose A in
a swing- mix type powder mixer. The resulting mixture was sieved and finally mixed
with 332.3 g of lactose B in a swing- mix type powder mixer to obtain the final
formulation. The mixing time of each step was 5 min at 35 rpm.
Example 6. Effect of salmeterol/lactose ratio of the second nd on fine particle
dose (FPD)
It was studied how s in the ratio of salmeterol/lactose B in the second
preblend affects the fine particle dose (FPD) of the final erol/fluticasone
formulation. A series of salmeterol/fluticasone formulations were prepared as in the
previous example with the exception that the proportion of salmeterol used in the
second preblend was varied as well as the proportion of lactose A (of the total
lactose) used in the ation. The formulations were filled in ler® powder
inhaler device and the FPD values for the active ingredients were determined in vitro
using methods well known in the art. The results were fitted in a mathematical model
which demonstrates the effect of the variables on the FPD of the active ingredients.
The observed s in the FPD of salmeterol xinafoate and fluticasone nate
are presented in Figure 1a and 1b, respectively. In the Figures the tion (% of
total) of salmeterol xinafoate (SX) mixed with lactose A (finer lactose) in the first
preblend is shown in x-axis. The proportion of lactose A (% of total lactose) used in
the ition is shown in y-axis. The resulting FPD value of erol xinafoate
is shown in Figure 1a as zones ranging from about 4 µg/dose to about 10 µg/dose.
The resulting FPD value of fluticasone nate is shown similarly in Figure 1b.
The Figures demonstrate that the FPD value (shown in a box) for each active
ingredient of the composition can be increased by increasing the proportion of
lactose A (finer lactose) in the composition. For example, the FPD of salmeterol can
be increased from about 4 µg/dose to about 10 µg/dose by sing the proportion
of lactose A (finer lactose) from 0 % to 30 % (Figure 1a). At the same time, the FPD
of fluticasone increases from about 60 µg/dose to about 100 µg/dose (Figure 1b).
On the other hand, when part of salmeterol of the composition is blended with
lactose B (coarser lactose), the FPD value of salmeterol is decreased. The decrease is
dependent on the proportion of salmeterol which is blended with lactose B (coarser
lactose). For example, when the ratio of lactose A to lactose B is fixed to 10:90 (i.e.
proportion of lactose A is 10 %) in the composition, the FPD of salmeterol can be
linearly decreased from about 7.2 µg/dose down to about 5.5 µg/dose by increasing
the part of salmeterol which is blended with lactose B (coarser lactose) from 0 % to
100 %. This corresponds to a decrease of 24 % in the FPD of salmeterol.
Importantly, at the same time the FPD value of fluticasone drops only 5 % (from
about 74 µg/dose to about 70 µg/dose). Thus, blending part of the second active
ient of the combination with a second lactose grade differing in the particle
size from the first lactose grade provides a method of adjusting the FPD of the
second active ingredient while only minimally affecting the FPD of the first active
ingredient of the composition.
In this specification where reference has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose
of providing a t for discussing the features of the ion. Unless ically
stated otherwise, reference to such external documents is not to be construed as an
admission that such documents, or such sources of information, in any jurisdiction,
are prior art, or form part of the common general knowledge in the art.
Claims (14)
1. A method of preparing a dry powder inhalation composition comprising a first and a second active ingredient in micronized form comprising the steps of: 5 (a) mixing the first active ingredient and a portion of the second active ingredient with a first particulate excipient to e a first preblend; (b) mixing the remaining portion of the second active ingredient with a second particulate excipient to provide a second preblend; and (c) mixing the first and the second preblends together; 10 wherein the first particulate excipient and the second particulate excipient differ in their median particle size, such that VMD e median diameter) of the finer ulate excipient is less than 90 % of the VMD of the r ulate excipient.
2. A method according to claim 1, wherein the VMD of the finer particulate 15 excipient is less than 85 % of the VMD of the coarser particulate excipient.
3. A method according to claim 1 or 2, wherein the VMD of the finer particulate excipient is within the range of from about 30 to about 70 µm and the VMD of the r particulate excipient is within the range of from about 80 to about 150 µm.
4. A method of preparing a dry powder inhalation composition comprising a 20 first and a second active ingredient in ized form comprising the steps of: (a) mixing the first active ingredient and a portion of the second active ingredient with a first ulate excipient having VMD within the range of from about 30 to about 70 µm to provide a first preblend; (b) mixing the remaining portion of the second active ingredient with a 25 second particulate excipient having VMD within the range of from about 80 to about 150 µm to provide a second preblend; and (c) mixing the first and the second preblends, optionally with additional first or second particulate excipient, together and (d) optionally mixing the obtained blend with additional first or second 30 particulate excipient.
5. A method according to any one of claims 1 to 4, n the first and second particulate excipient is lactose.
6. A method according to any one of claims 1 to 5, wherein the first and second active ingredients are selected from anti-inflammatory steroids and bronchodilators.
7. A method according to any one of claims 1 to 6, wherein the first active ingredient is an anti-inflammatory steroid and the second active ingredient is a bronchodilator.
8. A method according to any one of claims 1 to 6, wherein the first active 5 ingredient is a bronchodilator and the second active ingredient is an antiinflammatory steroid.
9. A method according to any one of claims 1 to 8, wherein the antiinflammatory steroid is budesonide, asone, beclomethasone or a pharmaceutically acceptable 10 salt thereof.
10. A method according to any one of claims 1 to 9, wherein the bronchodilator is formoterol, salmeterol or a pharmaceutically acceptable salt thereof.
11. A method according to claim 7, wherein the first active ient is budesonide or a pharmaceutically acceptable salt thereof and the second 15 active ingredient is formoterol or a ceutically acceptable salt thereof.
12. A method according to claim 7, wherein the first active ingredient is asone or a pharmaceutically acceptable salt thereof and the second active ingredient is salmeterol or a pharmaceutically acceptable salt thereof.
13. A method according to claim 7, wherein the first active 20 ingredient is beclomethasone or a pharmaceutically acceptable salt thereof and the second active ingredient is formoterol or a pharmaceutically acceptable salt thereof.
14. The method ing to any one of claims 1 to 13, ntially as herein described with reference to any example thereof and with or without reference to the accompanying drawings.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361913024P | 2013-12-06 | 2013-12-06 | |
US61/913,024 | 2013-12-06 | ||
PCT/FI2014/000038 WO2015082756A1 (en) | 2013-12-06 | 2014-12-05 | Method for preparing dry powder inhalation compositions |
Publications (2)
Publication Number | Publication Date |
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NZ719346A NZ719346A (en) | 2021-01-29 |
NZ719346B2 true NZ719346B2 (en) | 2021-04-30 |
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