U.S. patent application number 10/575656 was filed with the patent office on 2007-03-29 for dry powder formulations.
Invention is credited to Rudi Mueller-Walz, Roland Steiner.
Application Number | 20070071690 10/575656 |
Document ID | / |
Family ID | 29726600 |
Filed Date | 2007-03-29 |
United States Patent
Application |
20070071690 |
Kind Code |
A1 |
Mueller-Walz; Rudi ; et
al. |
March 29, 2007 |
Dry powder formulations
Abstract
A dry powder suitable for inhalation in a dry powder inhaler,
the powder comprising a carrier, an active agent and at least 0.5%
by weight of magnesium stearate, the powder being further
characterized in that the less than 10% of the surface of the
carrier material is covered with particles of magnesium stearate .
The invention is also directed to a method of making dry powders by
blending together the ingredients mentioned in a diffusion blender
for a period time that is less than 60 minutes.
Inventors: |
Mueller-Walz; Rudi;
(Schopfheim, DE) ; Steiner; Roland; (Rheinfelden,
CH) |
Correspondence
Address: |
MINTZ LEVIN COHN FERRIS GLOVSKY & POPEO
666 THIRD AVENUE
NEW YORK
NY
10017
US
|
Family ID: |
29726600 |
Appl. No.: |
10/575656 |
Filed: |
November 11, 2004 |
PCT Filed: |
November 11, 2004 |
PCT NO: |
PCT/IB04/03804 |
371 Date: |
November 28, 2006 |
Current U.S.
Class: |
424/46 ; 514/1.9;
514/10.3; 514/10.8; 514/10.9; 514/11.4; 514/11.6; 514/11.7;
514/12.4; 514/14.6; 514/15.2; 514/16.1; 514/17.4; 514/179;
514/18.1; 514/20.3; 514/252.16; 514/255.06; 514/262.1; 514/282;
514/291; 514/311; 514/44R; 514/53; 514/54; 514/649; 514/8.1;
514/8.2; 514/8.4; 514/9.1; 514/9.5 |
Current CPC
Class: |
A61P 11/06 20180101;
A61P 11/00 20180101; A61P 29/00 20180101; A61P 25/04 20180101; A61K
9/0075 20130101 |
Class at
Publication: |
424/046 ;
514/002; 514/044; 514/054; 514/053; 514/282; 514/291; 514/311;
514/179; 514/649; 514/255.06; 514/252.16; 514/262.1 |
International
Class: |
A61K 48/00 20060101
A61K048/00; A61K 38/17 20060101 A61K038/17; A61K 31/716 20060101
A61K031/716; A61K 31/573 20060101 A61K031/573; A61K 31/4965
20060101 A61K031/4965; A61K 31/485 20060101 A61K031/485; A61K 31/47
20060101 A61K031/47; A61K 31/137 20060101 A61K031/137 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 14, 2003 |
GB |
0326632.7 |
Claims
1. A dry powder formulation for inhalation, comprising active
particles and carrier particles for supporting the active
particles, the formulation-further comprising magnesium stearate in
an amount of at least 0.5% by weight of the formulation, wherein
particles of magnesium stearate are disposed on the surface of the
carrier particles to provide a surface coverage of less than 10% on
the carrier particles.
2. The dry powder formulation according to claim 1, wherein the
surface coverage of carrier particles is from 1 to 5%.
3. The dry powder formulation according to claim 1, wherein the
magnesium stearate is present in amounts of 0.5 to 2% by
weight.
4. The dry powder formulation according to claim 1, wherein the
magnesium stearate is present in amounts of form 0.6 to 1% by
weight.
5. The dry powder formulation according to claim 1, wherein the
active particles comprise an active substance selected from the
group consisting of beta-mimetics, anticholinergics,
corticosteroids, leukotrienantagonists, phosphodiesterase
inhibitors, PAF-inhibitors, potassium channel openers, analgesics,
potency agents, macromolecules, pharmaceutically acceptable salts
thereof and mixtures thereof.
6. The dry powder formulation according to claim 1, wherein the
carrier particles comprise a carrier material selected from
monosaccharides, disaccharides, sugar alcohols, polylactic acid, or
mixtures thereof.
7. The dry powder formulation according to claim 6, wherein the
carrier is lactose mono-hydrate.
8. A method of making the dry powder formulation for inhalation
according to claim 1, comprising the step of blending magnesium
stearate with a carrier material in a diffusion blender for a
period of less than 30 minutes to form a mixture.
9. The method according to claim 8, further comprising the step of:
blending the mixture of magnesium stearate and carrier material
with an active substance in a diffusion blender for a period of
less than 30 minutes.
10. A multi-dose dry powder inhaler containing the formulation
according to claim 1.
11. A method of making a dry powder consisting essentially of the
consecutive steps of: (i) admixing magnesium stearate with a
carrier material in a diffusion blender for a period of less than
30 minutes; and (ii) blending the mixture of step (i) with an
active substance in a diffusion blender for a period of less than
30 minutes.
12. The dry powder formulation according to claim 5, wherein the
beta-mimetic is selected from the group consisting of Levalbuterol,
Terbutalin, Reproterol, Salbutamol, Salmeterol, Formoterol,
Fenoterol, Clenbuterol, Bambuterol, Tulobuterol, Broxaterol,
Epinephrin, Isoprenaline and Hexoprenaline.
13. The dry powder formulation according to claim 5, wherein the
anticholinergic is selected from the group consisting of
Tiotropium, Ipratropium, Oxitropium and Glycopyrronium.
14. The dry powder formulation according to claim 5, wherein the
corticosteroid is selected from the group consisting of Butixocart,
Rofleponide, Budesonide, Ciclosenide, Mometasone, Fluticasone,
Beclomethasone, Loteprednol and Triamcinolone.
15. The dry powder formulation according to claim 5, wherein the
leukotrienantagonist is selected from the group consisting of
Andolast, Iralukast, Pranlukast, Imitrodast, Seratrodast, Zileuton,
Zafirlukast and Montelukast.
16. The dry powder formulation according to claim 5, wherein the
phosphodiesterase-inhibitor is selected from Filaminast or
Piclamilast.
17. The dry powder formulation according to claim 5, wherein the
PAF-inhibitor is selected from the group consisting of Apafant,
Forapafant and Israpafant.
18. The dry powder formulation according to claim 5, wherein the
potassium channel opener is selected from Amiloride or
Furosemide.
19. The dry powder formulation according to claim 5, wherein the
analgesic is selected from the group consisting of Morphine,
Fentanyl, Pentazocine, Buprenorphine, Pethidine, Tilidine,
Methadone and Heroin.
20. The dry powder formulation according to claim 5, wherein the
potency agent is selected from the group consisting of Sildenafil,
Alprostadil and Phentolamine.
21. The dry powder formulation according to claim 5, wherein the
macromolecule is selected from the group consisting of proteins,
peptides, oligopeptides, polypeptides, polyamino acids, nucleic
acids, polynucleotides, oligo-nucleotides and high molecular weight
polysaccharides.
22. The dry powder formulation according to claim 6, wherein the
monosaccharide or disaccharide is selected from the group
consisting of glucose, lactose, lactose monohydrate, sucrose,
trehalose and mixtures thereof.
23. The dry powder formulation according to claim 6, wherein the
sugar alcohol is selected from mannitol, xylitol, or a mixture
thereof.
Description
[0001] The present invention is concerned with dry powder
formulations for use in dry powder inhalers.
[0002] Dry Powder inhalers (DPIs) represent an alternative to
Metered Dose Inhalers (MDIs) for the administration of medicaments
to the lung.
[0003] Active substances for use in dry powders for inhalation must
be provided in the form of very fine particles in order that they
can penetrate deep within the lung. Indeed, if the lung is to be
used to administer drug substances systemically, the active
substance must be sufficiently fine that it penetrates into the
alveolar ducts and sacs whereupon it can be most efficiently
absorbed into the blood.
[0004] However, fine particulates can present major formulation
difficulties. For example such particulates possess strong adhesive
and cohesive properties that can cause the active particles to
aggregate and can lead to poor bulk properties of the powder such
as poor flowability.
[0005] The mechanical properties of dry powders can be improved by
mixing the fine particles of active substance with relatively
coarser particles of an inert carrier material. The ordered mixture
of carrier and active enables the dry powder to be handled more
easily during manufacture and during filling of the powder into DPI
devices. Additionally, the active substance is maintained in a
relatively dispersed state on the surface of the carrier particles.
However, the adhesive force between carrier and active must not be
so great that upon actuation of the DPI the efficient and
reproducible re-dispersion of the active into fine dispersible
particles is prevented.
[0006] A common approach used by formulators to achieve an
appropriate balance between the competing forces of adhesion and
re-dispersion is to treat the carrier with a ternary component in
order to cover or coat the carrier particles and thereby modulate
the adhesive force between the active particles and the carrier
surface.
[0007] Numerous ternary components have been suggested in the art.
There are still further suggestions in the prior art as to the
amount of ternary component that should be employed, and the extent
to which the ternary component must coat or cover the carrier
surface in order to achieve an appropriate compromise between
adhesion and re-dispersion such that active particles are not
liable to prematurely segregate from the carrier surface (e.g.
during storage and handling), but are readily released upon
actuation initiated and driven in passive dry powder inhalers by a
patient's inspiration.
[0008] U.S. Pat. No. 6,521,260 describes the use of ternary
components in dry powder formulations containing active and
carrier. The nature and amount of ternary component is selected in
order to alter the surface properties of the carrier with the
purpose of promoting release of active particles upon actuation of
an inhaler. However, the amount of ternary component must not be so
great such that active and carrier particles prematurely segregate
during storage.
[0009] This reference mentions that surface active materials may be
employed as ternary components. In this regard magnesium stearate
may be used but it is stated clearly that it is not preferred. This
reference does not state how much magnesium stearate should be
employed to achieve the purpose of promoting release of the active
upon actuation. We are told only that 1.5% by weight of magnesium
stearate is too much as it promotes premature segregation. The only
other comment relating to the use of magnesium stearate is that it
is highly surface active and should be used only in "particularly
small amounts". By contrast, phosphatidyl cholines, being less
surface active than magnesium stearate can be used in higher
quantities. Conspicuously, this reference exemplifies a formulation
employing lecithin (a natural mixture of phosphatidyl cholines) in
an amount of 0.5% by weight.
[0010] Insofar as the skilled person would be motivated to use
magnesium stearate despite the clear prejudice towards its use, it
would be employed in only a "particularly small amount" relative to
the 0.5% by weight suggested for lecithin and other less surface
active materials
[0011] Indeed in a paper (J. Pharm. Pharmacol. 1982, 34: 141-145, a
named inventor on U.S. Pat. No. 6,521,260 teaches that magnesium
stearate can affect the adhesion of active substances to carrier
particles, and that its use in amounts of 0.5% to 4.0% by weight
de-stabilises formulations to the extent that significant
segregation occurs.
[0012] The benefits of using magnesium stearate in dry powders is
taught in U.S. Pat. No. 6,528,096. Specifically it teaches that it
can be used to alter the surface properties of carrier particles
and thereby improve the properties of dry powder formulations.
However, the skilled person is informed that it should be used in
amounts of less than 0.5% by weight, and no significant improvement
in the fine particle fraction of a delivered dose is achieved with
concentrations above 0.25% by weight. Additionally, this reference
reports an "advantageous relationship" between the degree of
carrier surface coating by magnesium stearate and the respirable
fraction of a delivered dose. Critical to the working of this
invention is the need to ensure a continuous coating of magnesium
stearate over more than 10% of the surface of the carrier
particles. The requisite coating can be achieved by conventional
blending of carrier and magnesium stearate, or alternatively higher
shear mixing techniques can be employed. High shear mixing can
achieve the requisite coating within about 0.5 hours, however; the
skilled person is clearly taught that if conventional blending is
to be employed the blending time must be in excess of 2 hours.
[0013] In The Journal of Aerosol Medicine Vol 11, No. 3, 1998 at
143-152, an inventor of U.S. Pat. No. 6,528,096 teaches that
pre-treatment of lactose particles with 0.25% magnesium stearate
significantly improves the disaggregation of beclamethasone
dipropionate without causing segregation during filling, transport
or use.
[0014] It is clear from the prior art that any beneficial
properties that derive from the use of magnesium stearate are
predicated on its apparent ability to alter the surface properties
of carrier particles. In this regard, the skilled person is taught
that in order to advantageously influence the fine particle
fraction of a delivered dose, as high a surface coating should be
obtained with as little magnesium stearate as possible.
[0015] Certain mixing techniques are taught for achieving this
result, which involve either high energy mixing, or long duration
low energy mixing. Other suggestions involve combining low energy
blending coupled with carrier treatment steps involving high energy
milling or mixing.
[0016] The problem with the suggestions made in the prior art is
that no consideration is given to the nature of the active
substance employed, and the constraints that the physical and
chemical properties can impose on the amounts of magnesium stearate
that can be used in practice. For example, it is known that dry
powders are sensitive to atmospheric humidity, and are difficult to
use for that reason in multi-dose dry powder inhaler devices. It is
also known that many active substances can be hygroscopic and can
exacerbate the moisture sensitivity of dry powders. Dry powders for
inhalation should be excluded from humid conditions to the greatest
extent possible. Moisture sensitivity is often manifested in a
dramatic reduction of the inhalable proportion of an emitted dose
(the so-called "fine particle fraction"), which can be determined
according to in-vitro measurements described below. Moisture can
also influence adversely the accuracy and reproducibility of shot
weight and emitted dose content uniformity.
[0017] The use of magnesium stearate to improve the moisture
resistance of dry powders is described in WO 00/28979.
[0018] It is not only the hygroscopic nature of certain active
substances that can have a destabilsing effect on dry powders. The
amount of active substance that needs to be delivered in a single
inhalation by from a DPI device is dictated by the medical
condition that is intended to be treated, and in certain situations
the drug loading can be quite high. This can also adversely affect
the mechanical properties of dry powders, e.g. flowability, absent
the use of sufficient magnesium stearate, e.g. for lubricating
purposes.
[0019] Accordingly, whereas the prior art teaches the skilled
person that only small amounts, i.e. less than 0.5% magnesium
stearate can be tolerated in dry powder formulations, this is
generally an unacceptably low amount taking into consideration the
demands imposed by the quantity and properties of the active
substance employed.
[0020] Applicant has surprisingly found that the effect of surface
coverage of magnesium stearate on the performance of dry powders
appears to be minor compared to the moisture protection and
lubricating properties of this substance, in terms of the
uniformity of the delivered dose and the fine particle fraction of
the delivered dose. Accordingly, provided one ensures that during
the preparation a dry powder for inhalation the surface coverage of
the carrier particles by magnesium stearate is kept low, one can
employ relatively large amounts of magnesium stearate and yet
obtain reproducibly high fine particle fraction, even after
prolonged periods of storage, and through life of a device.
[0021] Accordingly, in a first aspect the invention provides a dry
powder for inhalation comprising active particles and carrier
particles for supporting active particles, the formulation further
containing magnesium stearate in an amount of at least 0.5% by
weight of the formulation, and wherein particles of magnesium
stearate are disposed on the surface of the carrier particles such
that the surface coverage of carrier particles is less than
10%.
[0022] The amount of magnesium stearate employed should be at least
0.5% by weight. The upper limit depends on the toxicological
acceptability of large amounts of magnesium stearate delivered to
the lungs. A level of up to 2.0% is preferred. Within these limits,
the amount of magnesium stearate employed will depend on the nature
of the active substance, and the amount to be employed. The skilled
person will have regard the physical and chemical properties of the
active substance and be able to select an appropriate amount
without undue burden or without having to resort to inventive
activity.
[0023] In a particular embodiment the magnesium stearate may be
employed in an amount of 0.5 to 2.0% by weight, more particularly
0.5 to 1.5% by weight, still more particularly 0.5 to 1.0% by
weight, even more particularly 0.6 to 1.0% by weight.
[0024] The extent to which the magnesium stearate covers the
surface of the carrier particles can be determined from scanning
electron microscope (SEM) images. Scanning electron microscopy is
one of the most versatile analytical techniques and it is well
known in the art. Compared to conventional optical microscopes, an
electron microscope offers advantages including high magnification,
large depth of focus, great resolution and ease of sample
preparation and observation. Electrons generated from an electron
gun enter a surface of a sample and generate many low energy
secondary electrons. The intensity of these secondary electrons is
governed by the surface topography of the sample. An image of the
sample surface is therefore constructed by measuring secondary
electron intensity as a function of the position of the scanning
primary electron beam.
[0025] Such microscopes may be equipped with an EDX analyzer (an
Electron Dispersive X-ray analyzer), that can produce an image
selective to certain types of atoms, for example magnesium atoms.
In this manner it is possible to obtain a clear data set on the
distribution of magnesium stearate on the surface of carrier
particles.
[0026] Backscattered electron (BSE) imaging and Energy Dispersive
X-ray (EDX) analysis are used for chemical analysis. The intensity
of backscattered electrons generated by electron bombardment can be
correlated to the atomic number of an element within a sampling
volume. Hence, qualitative elemental information can be revealed.
The characteristic X-rays emitted from a sample serve as
fingerprints and give elemental information of samples that can be
as a semi-quantitative analysis, a quantitative analysis, line
profiling and spatial distribution of elements. SEM with X-ray
analysis is an efficient, inexpensive, and non-destructive surface
analysis method.
[0027] In order to carry out BSE and EDX measurements, dry powder
particles are typically scattered onto a medium such as a carbon
tape, and the tape is then shadowed with gold or platinum prior to
analysis. Analysis is then carried out on a representative sample
of particles of the powder.
[0028] BSE provides information on the atomic contrast within a
sample. In BSE images high atomic number elements appear as bright
spots whereas low atomic number elements are dark. This contrast
gives further information as to the position different elements on
the sample, and therefore the nature and extent of coverage of
magnesium stearate are revealed.
[0029] EDX provides an X-ray mapping for chosen elements. In this
way, one can see where on the sample material magnesium atoms (and
therefore magnesium stearate) are concentrated.
[0030] In this manner it can be shown that the magnesium stearate
forms aggregates on the surface of the carrier particles. These
aggregates cannot be considered as forming a surface "coating" in
any conventional meaning of the word. It is also clear that the
aggregates cover less than 10% of the surface even with relatively
high loadings of magnesium stearate, e.g. 2% by weight. More
particularly the coverage is less than 5%, still more particularly
less than 2%, e.g. from 0.5 to 2%.
[0031] Contrary to the teaching in U.S. Pat. No. 6,528,096 that it
is advantageous to obtain the highest surface coverage possible
(and in any event greater than 10%) to achieve a better respirable
fraction, applicant has found that low coverage, below 10% is
required. In fact by using particular mixing conditions, it is
possible to achieve very low coverage notwithstanding that high
amounts of magnesium stearate, i.e. 0.5% at least are employed.
[0032] The formulations of the present invention are prepared in a
manner to ensure the lowest possible coverage of magnesium stearate
on the carrier particles.
[0033] Accordingly, the invention provides in another of its
aspects a method of producing dry powder formulations comprising
the step of blending carrier material with magnesium stearate in a
powder blender. Such powder blenders include diffusion blenders and
tumble blenders.
[0034] Applicant has found that one can improve the fine particle
fraction of a delivered dose of a dry powder, if the method of
forming the powder is relatively low energy and of short duration.
Preferably, the blending operation is carried out by diffusion
blending, which is an operation whereby different particles are
reoriented in relation to one another when they are placed in
random motion, and the interparticle friction is reduced as a
result of bed expansion. Bed expansion is achieved using a rotating
container. Suitable powder blenders or diffusion blenders are
primarily distinguished by their geometric shapes and position of
the axis of rotation. Suitable diffusion blenders may be selected
from the group consisting of V-blenders, Double-cone Blenders,
Slant Cone Blenders, Cube Blenders, Bin Blenders, Horizontal or
Vertical Drum Blenders, Static Continuous Blenders, and Dynamic
Continuous Blenders.
[0035] Diffusion blenders suitable for use in the present invention
preferably operate under a low energy consumption, such as 0.1-1 kW
per 100 litres. The period of blending should not exceed one hour
and preferably is less than 30 minutes, more particularly less than
20 minutes, for example about 15 to 20 minutes.
[0036] The applicant has found that low energy mixing for the
shortest possible time has the primary function of ensuring low
surface coverage, notwithstanding the relatively high amounts of
magnesium stearate that are employed. In addition, low energy,
short duration mixing reduces the amount of energy fed into the
powder and therefore reduces the possibility of de-mixing of the
powder.
[0037] As is well known to the person skilled in the art, powder
blenders are distinct from high shear mixing equipment such as
convection mixers that operate on the principle of reorienting
particles as a result of mechanical movement (e.g. paddle or plow
mixing), or pneumatic mixing whereby particles are re-orientated as
a result of the expansion of a powder bed by gas.
[0038] High shear mixers generally work with an energy consumption
orders of magnitude higher than powder blenders (e.g. 10-100 kW/100
litres), and so exert a much higher shear force, thereby
introducing much higher energy into the powders, which may have the
effect of agglomerating the particles of active substance.
[0039] The blending step described above is preferably carried out
as one of a series of blending steps described below.
[0040] In a first step, carrier and magnesium stearate are mixed in
a powder blender, for a period not exceeding one hour and
preferably less than 30 minutes, more particularly less than 20
minutes, for example about 15 to 20 minutes.
[0041] In a second step the mixture from the first step is mixed in
a powder blender with the active substance, for a period not
exceeding one hour and preferably less than 30 minutes, more
particularly less than 20 minutes, for example about 15 to 20
minutes.
[0042] If the amount of active substance used in the mixture is
low, e.g. less than about 30% by weight of the composition, more
particularly about 0.01 to 10% by weight of the composition, it is
preferred that after the first step, a small portion of the
mixture, e.g. about 10% of the mixture is mixed with the active
substance in the second step, to form a powder mixture relatively
concentrated with respect to the active substance. This is to
ensure adequate mixing of the active substance with the carrier
material.
[0043] Subsequently, a third blending step is employed to mix the
remaining material from step 1 with the concentrated mixture from
step 2 in a powder blender, for a period not exceeding one hour and
preferably less than 30 minutes, more particularly less than 20
minutes, for example about 15 to 20 minutes.
[0044] It is preferred that no other blending step is carried out.
Furthermore, no high shear mixing or milling steps should be
carried out in relation to any of the powder ingredients if
improvements in fine particle fraction are to be observed. However,
to ensure the powder ingredients are of the appropriate particle
size it is customary to prepare the ingredients by screening
through appropriate sized sieves, e.g. 25 to 500 micrometre size
(500 to 30 mesh according to BS 410), more particularly 63 to 250
micrometre (240 to 60 mesh according to BS 410).
[0045] The rotation of the blender may be suitably carried out at a
speed in the range of from 20 rpm to 120 rpm, preferably, from 50
rpm to 100 rpm.
[0046] Where the concentration of active ingredient in the final
formulation is low, e.g. less than 5% w/w, it may be convenient to
prepare the formulation by blending the active substance with an
amount of magnesium stearate in the range of from 10% to 50% of the
final amount, suitably of from 15% to 45%, preferably of from 20%
to 40%, after which the remainder of the magnesium stearate is
added.
[0047] The active substance may be practically any pharmaceutically
active compound which can be administered by inhalation in dry
powders.
[0048] Active substances may be chosen from beta-mimetics such as
Levalbuterol, Terbutalin, Reproterol, Salbutamol, Salmeterol,
Formoterol, Fenoterol, Clenbuterol, Bambuterol, Tulobuterol,
Broxaterol, Epinephrin, Isoprenaline or Hexoprenaline; an
Anticholinergic such as Tiotropium, Ipratropium, Oxitropium or
Glycopyrronium; a Corticosteroid, such as Butixocart, Rofleponide,
Budesonide, Ciclosenide, Mometasone, Fluticasone, Beclomethasone,
Loteprednol or Triamcinolone; a Leukotrienantagonist, such as
Andolast, Iralukast, Pranlukast, Imitrodast, Seratrodast, Zileuton,
Zafirlukast or Montelukast; a Phosphodiesterase-Inhibitor, such as
Filaminast or Piclamilast; an PAF-Inhibitor, such as Apafant,
Forapafant or Israpafant; a potassium channel opener such as
Amiloride or Furosemide; a pain killer such as Morphine, Fentanyl,
Pentazocine, Buprenorphine, Pethidine, Tilidine, Methadone or
Heroin; a potency agent such as Sildenafil, Alprostadil or
Phentolamine; or a pharmaceutically acceptable derivative or salt
of any of the foregoing compounds or classes of compounds. In as
much as any of these compounds possess chiral centres, the
compounds can be used in optically pure form, or can be presented
as diastereomeric mixtures or racemic mixtures.
[0049] Dry powders of the present invention may also employ
proteins, peptides, oligopeptides, polypeptides, polyamino acids
nucleic acid, polynucleotides, oligonucleotides and high molecular
weight polysaccharides.
[0050] Examples of macromolecules that find use in the present
invention are:
[0051] Albumins (preferably, human serunm Isulin; albumin); BSA;
IgG; IgM; insulin; GCSF; GMCSF; LHRH; VEGF; hGH; lysozyme;
alpha-lactoglobulin; basic fibroblast growth factor basic
fibroblast growth factor; (bFGF); asparaginase; tPA;
urokinase-VEGF; chymotrypsin; trypsin; streptokinase; interferon;
carbonic anhydrase; ovalbumin; glucagon; ACTH; oxytocin;
phosphorylase b; alkaline phosphatase-secretin; vasopressin;
levothyroxin; phatase; beta-galactosidase; parathyroid hormone,
calcitonin; fibrinogen; polyaminoacids (e.g., DNAse, alphal
antitrypsin; polylysine, polyarginine); angiogenesis inhibitors or
pro- immunoglobulins (e.g., antibodies); moters; somatostatin and
analogs; casein; collagen; gelatin; soy protein; and cytokines
(e.g., interferon, interleukin); immunoglobulins;
[0052] Physiologically active proteins such as peptide hormones,
cytokines, growth factors, factors acting on the cardiovascular
system, factors acting on the central and peripheral nervous
systems, factors acting on humoral electrolytes and hemal
substances, factors acting on bone and skeleton, factors acting on
the gastrointestinal system, factors acting on the immune system,
factors acting on the respiratory system, factors acting on the
genital organs, and enzymes;
[0053] Hormones and hormone modulators including insulin,
proinsulin, C-peptide of insulin, a mixture of insulin and
C-peptide of insulin, hybrid insulin cocrystals (Nature
Biotechnology, 20, 800-804, 2002), growth hormone, parathyroid
hormone, luteinizing hormone-releasing hormone (LH-RH),
adrenocorticotropic hormone (ACTH), amylin, oxytocin, luteinizing
hormone, (D-Tryp6)-LHRH, nafarelin acetate, leuprolide acetate,
follicle stimulating hormone, glucagon, prostaglandins, estradiols,
testosterone, and other factors acting on the genital organs and
their derivatives, analogues and congeners. As analogues of said
LH-RH, such known substances as those described in U.S. Pat. Nos.
4,008,209, 4,086,219, 4,124,577, 4,317,815 and 5,110,904 can be
mentioned;
[0054] Hematopoietic or thrombopoietic factors include, among
others, erythropoietin, granulocyte colony stimulating factor
(G-CSF), granulocyte-macrophage stimulating factor (GM-CSF) and
macrophage colony stimulating factor (M-CSF), leukocyte
proliferation factor preparation (Leucoprol, Morinaga Milk),
thrombopoietin, platelet proliferation stimulating factor,
megakaryocyte proliferation (stimulating) factor, and factor
VIII;
[0055] Therapeutic factors acting on bone and skeleton and agents
for treating osteoporosis including bone GLa peptide, parathyroid
hormone and its active fragments (osteostatin, Endocrinology 129,
324, 1991), histone H4-related bone formation and proliferation
peptide (OGP, The EMBO Journal 11, 1867, 1992) and their muteins,
derivatives and analogs thereof;
[0056] Enzymes and enzyme cofactors including pancrease,
L-asparaginase, hyaluronidase, chymotrypsin, trypsin, tPA,
streptokinase, urokinase, pancreatin, collagenase, trypsinogen,
chymotrypsinogen, plasminogen, streptokinase, adenyl cyclase, and
superoxide dismutase (SOD);
[0057] Vaccines include Hepatitis B, MMR (measles, mumps, and
rubella), and Polio vaccines;
[0058] Growth factors include nerve growth factors (NGF,
NGF-2/NT-3), epidermal growth factor (EGF), fibroblast growth
factor (FGF), insulin-like growth factor (IGF), transforming growth
factor (TGF), platelet-derived cell growth factor (PDGF), and
hepatocyte growth factor (HGF);
[0059] Factors acting on the cardiovascular system including
factors which control blood pressure, arteriosclerosis, etc., such
as endothelins, endothelin inhibitors, endothelin antagonists
described in EP 436189, 457195, 496452 and 528312, JP [Laid Open]
No. H-3-94692/1991 and 130299/1991, endothelin producing enzyme
inhibitors vasopressin, renin, angiotensin I angiotensin II,
angiotensin III, angiotensin I inhibitor, angiotensin II receptor
antagonist, atrial naturiuretic peptide (ANP), and antiarrythmic
peptide;
[0060] Factors acting on the central and peripheral nervous systems
including opioid peptides (e.g. enkephalins, endorphins),
neurotropic factor (NTF), calcitonin gene-related peptide (CGRP),
thyroid hormone releasing hormone (TRH), salts and derivatives of
TRH [JP [Laid Open]No. 50-121273/1975 (U.S. Pat. No. 3,959,247), JP
[Laid Open]No. 52-116465/1977 (U.S. Pat. No. 4,100,152)], and
neurotensin;
[0061] Factors acting on the gastrointestinal system including
secretin and gastrin;
[0062] Factors acting on humoral electrolytes and hemal substances
including factors which control hemagglutination, plasma
cholesterol level or metal ion concentrations, such as calcitonin,
apoprotein E and hirudin. Laminin and intercellular adhesion
molecule 1 (ICAM 1) represent exemplary cell adhesion factors;
[0063] Factors acting on the kidney and urinary tract including
substances which regulate the function of the kidney, such as
brain-derived natriuretic peptide (BNP), and urotensin;
[0064] Factors which act on the sense organs including factors
which control the sensitivity of the various organs, such as
substance P;
[0065] Chemotherapeutic agents, such as paclitaxel, mytomycin C,
BCNU, and doxorubicin;
[0066] Factors acting on the immune system including factors which
control inflammation and malignant neoplasms and factors which
attack infective microorganisms, such as chemotactic peptides and
bradykinins; and
[0067] Naturally occurring, chemically synthesized or recombinant
peptides or proteins which may act as antigens, such as cedar
pollen and ragweed pollen, and these materials alone or together
with coupled to haptens, or together with an adjuvant.
[0068] The present invention is particularly useful in the
formulation of moisture sensitive active substances, such as any
compounds mentioned above that are in salt form such as a chloride,
bromide, iodide, nitrate, carbonate, sulphate, methylsulphate,
phosphate, acetate, benzoate, benzensulphonate, fumarate, malonate,
tartrate, succinate, citrate, lactate, gluconate, glutamate,
edentate, mesylate, pamoate, pantothenate or hydroxynaphthoate; or
an ester form such as an acetate, propionate, phosphate, succinate
or etabonate.
[0069] Formulations containing a beta-mimetic, an anti-cholinergic
or a corticosteroid, alone or in any combination thereof constitute
particular embodiments of the present invention. These actives may
be present in salt or ester form, such as a beta-mimetic in salt
form, e.g. levalbuterol sulphate, formoterol fumarate, formoterol
tartrate, salbutamol sulphate or salmeterol xinafoate (salmeterol
1-hydroxy-2-naphthoate); an anti-cholinergic in salt form such as
oxitropium bromide, glycopyrronium bromide, ipratropium bromide or
tiotropium bromide; or a corticosteroid in the form of an ester,
such as beclamethasone dipropionate, fluticasone propionate,
triamcinoline 16,21-diacetate, triamcinoline acetonide 21-acetate,
triamcinoline acetonide 21-disodium phosphate, triamcinoline
acetonide 21-hemisuccinate, mometasone furoate, or loteprednol
etabonate.
[0070] In order that the active substance is inhalable, i.e. it can
pass into the deep lung such as the terminal and respiratory
bronchioles and the alveolar ducts and sacs, it must be in
particulate form having a mean particle diameter (measured as the
mass mean aerodynamic diameter) of at most about 10 microns, e.g.
from 1 to 10 microns, and preferably 1 to 6 microns. Such microfine
particles can be obtained in a manner known per se, for example by
micronisation, controlled precipitation from selected solvents, or
by spray drying.
[0071] The amount of active substance employed may vary within wide
limits depending on the nature of the active substance, the type
and severity of the condition to be treated and the condition of
the patient in need of treatment.
[0072] For active substances employed to treat local conditions of
the lung such as all manner of asthma and chronic obstructive
pulmonary disease, relatively low doses of active substance can be
employed, for example about 5 to 5000 micrograms, more particularly
5 to 500 micrograms.
[0073] For active substances that are intended to be delivered
systemically through the lung, one may need higher doses to take
into account issues relating to absorption through the lung and
into the blood plasma. Typically, one might employ active
substances at levels of about 20 micrograms to 50 milligrams, more
particularly 50 micrograms to 20 milligrams.
[0074] Expressed as a concentration based on the total weight of
the formulation, the active substance may be present in amounts of
0.01 to 30% by weight, more particularly 0.1 to 10% by weight, more
particularly 0.1 to 5% by weight. It is not surprising therefore
that to achieve dosage accuracy, the active substance must be
diluted with carrier material. In a typical formulation the carrier
material may be present in amounts of up to 99% by weight or more,
in particular 50 to 99% by weight, depending on the particular
dilution desired and on the amount of magnesium stearate employed
in the formulation. The dilution is chosen such that an acceptable
shot weight delivered from an inhaler contains exactly the desired
dose of active substance. In this regard, the exact dose may be
delivered in a single shot or multiple shots. Dilution is also used
to affect powder mixtures having good macroscopic properties such
as flowability, and to balance adhesive or cohesive forces of the
microfine active substance to ensure good homogeneity of the
formulation.
[0075] The carrier material may be any carrier material that
customarily finds use in dry powder formulations. As examples
thereof, one can mention mono- or di-saccharides such as glucose,
glucose mono-hydrate, lactose, lactose mono-hydrate, sucrose or
trehalose; sugar alcohols such as mannitol or xylitol; polylactic
acid or cycoldextrin; or mixtures thereof. Preferably lactose
mono-hydrate is employed.
[0076] Nucleic acids, including double-stranded or single-stranded
polynucleotide, oligonucleotide or short nucleic acid sequences may
also be formulated according to the present invention. The term
nucleic acid includes both RNA (e.g. siRNA, mRNA, ribozymes,
aptamers) and DNA (e.g. cDNA or genomic DNA). The nucleic acid may
be present in the form of a vector (e.g. a plasmid or other
construct) with suitable sequences to direct or control expression
(i.e. a promoter sequence).
[0077] Carrier materials must be in the form of sufficiently large
particle size such that they can be easily handled during
manufacture and filling operations. They should also be large
enough such that they are not inhalable into the deep lung.
Typically a carrier material will have a mean particle diameter
(measured as the mass mean aerodynamic diameter) of about 10 to 500
micrometres, and preferably 50 to 300 micrometres.
[0078] Dry powder formulations of the present invention are
particularly suitable for use in multidose dry powder inhalers. In
particular, the formulations are suitable for use in such inhalers,
which comprise a reservoir from which individual therapeutic
dosages can be withdrawn on demand through actuation of the device.
However, formulations of the present invention are also useful in
multi-dose inhalers that contain a plurality of capsules containing
single or multiple pre-dosed units.
[0079] Typical of such multi-dose inhaler device suitable for use
with formulations of the present invention is described in U.S.
Pat. No. 6,182,655, which is hereby incorporated by reference in
its entirety.
[0080] The present invention in another of its aspects is directed
to such multidose inhalers containing the formulation of the
present invention.
[0081] Multi-dose inhalers may contain a reservoir of dry powder
that contains tens or even hundreds of therapeutic doses. The term
"therapeutic dose(s)" as used herein means an amount of inhalation
formulation containing a requisite amount of active substance to
illicit a therapeutic effect, e.g. to alleviate, prevent or inhibit
the particular condition to be treated, when delivered to a
patient. A therapeutic dose may be delivered with one or more
actuations of a DPI device. This is because the amount of powder
that can be delivered to a patient without irritating the patient,
e.g. making the patient cough, or what can reasonably or
comfortably be delivered within a single inspiration, is limited to
about 50mg per actuation, more particularly 25 mg per actuation.
Accordingly, depending on the nature of the active substance and
the nature and severity of the condition to be treated, one or more
actuations may be necessary per number of hours, per day, for any
number of days, weeks, months and so-forth.
[0082] The therapeutic dose will depend largely on the nature of
the active substance, the condition of the patient, and the nature
and severity of the condition to be treated. A therapeutic dose may
range between as little as 1 ng/kg, for example when treating a
local condition such as asthma with a potent active substance to as
much as 10 mg/kg, more particularly dose will range from 20 ng/kg
to 1 mg/kg. The therapeutic dose will be indicated on packaging or
labeling accompanying the DPI device and is specifically referred
to in the Label Claim.
[0083] In order to ensure inter-batch quality and reproducibility,
formulations should be tested in order to ensure that the mean dose
of formulation emitted from a MDI, should not vary considerably
from the Label Claim. In this regard, the formulations of the
present invention are particularly stable, for example they meet
the following standards:
[0084] The Mean Delivered Dose is within .+-.15% of the Label
Claim, and 9 from 10 at least of single doses are not outside
.+-.25% of the mean, and all single doses are within .+-.35% of the
mean; or
[0085] At least 9 from 10 single doses are within .+-.20% of the
Label Claim, and all single doses are within .+-.25% of the Label
Claim.
[0086] The Shot Weight and Delivered Dose and their variance can be
measured using the Dosage Unit Sampling Apparatus (DUSA). The fine
particle fraction (FPF) can be measured using an Andersen Cascade
Impactor (ACI). The measurement methodology and the apparatus
therefore are well known in the art, and are described in the
United States Pharmacopoeia Chapter <601>, or in the
inhalants monograph of the European Pharmacopoeia, both of which
documents are hereby incorporated by reference. The USP states that
the Apparatus 1 should be used for the measurement of FPF. The USP
also states that Delivered Dose Uniformity should be measured with
DUSA or its equivalent. However, the Delivered Dose and Delivered
Dose uniformity are preferably measured using the so-called Funnel
Method. The Funnel Method is described in Drug Delivery to the
Lungs, VIII p 116 to 119, which is hereby incorporated by
reference. In summary, the Funnel Method consists of discharging a
formulation from a DPI into a Funnel Apparatus, which basically
consists of a standard Buchner Funnel. The discharged dose is
captured on the glass sinter of the Funnel, and can be washed off,
and the dose determined using HPLC analysis. The Funnel Method
gives comparable results to the standard USP apparatus, and is
generally considered to be an equivalent of the DUSA apparatus.
[0087] Fine particle fraction measured according to the above
described methodology is considered to consist of the combined
fractions collected from stages 2 to Filter Stage of an Andersen
Cascade Impactor calibrated at 60 L/min air flow rate. These
fractions have an aerodynamic particle size of less than 4.7
micrometers.
[0088] Alternatively, Fine Particle Fraction can be measured by the
Twin Impinger Method and the Multi-stage Liquid Impinger Method as
are described in the Pharmacopoea, and as are set forth in the
Examples below
[0089] Formulations of the present invention meet pharmacopoeia
requirements as to Delivered Dose Uniformity as set forth, for
example in the United States and European Pharmacopoeias. For
example, formulations of the present invention meet the requirement
set out in the USP26-NF21 chapter <601> "Delivered Dose
Uniformity". Indeed, the formulations appear to be so stable that
they may even meet the relatively more stringent Delivered Dose
Uniformity requirements set forth in the current Draft Guidance
from the FDA, published by the CDER in October 1998.
[0090] Still further, the Delivered Dose of the formulations
contains a high fraction of fine particles, i.e. particles that are
capable of penetrating the deep lung, e.g. having a diameter of
less than about 4.7 microns, as measured by the ACI; below 6.4 as
measured by the Twin Impinger; and below 6.8 as measured by the
Multi-stage Liquid Impinger.
[0091] Preferred features for the second and subsequent aspects of
the invention are as for the first aspect mutatis mutandis.
[0092] There now follows a series of examples that serve to
illustrate the invention.
[0093] Method
[0094] Particle Fraction Size Measurement Method
[0095] Assemble the Andersen Cascade Impactor according to
manufacturer's instructions with a suitable filter in place and
ensure that the system is airtight. To ensure efficient particle
capture, coat each plate with a high viscosity liquid deposited
from a volatile solvent. The pre-separator should be coated in the
same way or should contain 10 ml of a suitable solvent. Connect the
apparatus to a flow system comprising flow control valve, two-way
valve, timer and vacuum pump.
[0096] The test is conducted at a flow rate adapted to the internal
resistance of the inhaler device drawing 4 litres of air through
the apparatus. At high flow rates it may be necessary to remove the
lowest stages from the stack. For adjustment of the flow rate
connect a flow meter, calibrated for the volumetric flow leaving
the meter, to the induction port. Adjust the flow control valve to
achieve steady flow through the system at the required rate. Ensure
that critical flow occurs in the flow control valve by measuring
the absolute pressure on both sides of the flow control valve.
Switch off the airflow.
[0097] Prepare the dry-powder inhaler for use according to the
patient instructions. With the pump running and the two-way valve
closed, locate the mouthpiece of the inhaler in the mouthpiece
adapter. Discharge the powder into the apparatus by opening the
valve for the time required for drawing 4 litres of air through.
Repeat the discharge sequence. The number of discharges should be
minimised and typically would not be greater than ten. The number
of discharges should be sufficient to ensure an accurate and
precise determination of fine particle dose. After the final
discharge, wait for 5 s and then switch off the pump.
[0098] Dismantle the apparatus. Carefully remove the filter and
extract the active ingredient into an aliquot of the solvent.
Remove the pre-separator, induction port and mouthpiece adapter
from the apparatus and extract the drug into an aliquot of the
solvent. Extract the active ingredient from the inner walls and the
collection plate of each of the stages of the apparatus into
aliquots of solvent. Using a suitable method of analysis, determine
the quantity of active ingredient contained in each of the nine
volumes of solvent.
[0099] Calculate the mass of active ingredient deposited on each
stage per discharge and the mass of active ingredient per discharge
deposited in the induction port, mouthpiece adapter and where used
the pre-separator. The total mass of the active ingredient is not
less than 75 per cent and not more than 125 per cent of the average
delivered dose determined during testing for uniformity of
delivered dose. If the total mass is outside this range the test
must be repeated.
[0100] Starting at the filter, derive a cumulative mass vs. cut-off
diameter of the respective stages. Calculate the Fine Particle Dose
(FPD) by interpolation the mass of active ingredient less than 5
.mu.m. If necessary, and where appropriate, plot the cumulative
fraction of active ingredient versus cut-off diameter on log
probability paper, and use this plot to determine values for the
Mass Median Aerodynamic Diameter (MMAD) and the Geometric Standard
Deviation (GSD).
EXAMPLE 1
[0101] Formulation 1
[0102] A dry powder formulation consisting of 2.5% w/w salbutamol
sulphate, 2.0% w/w magnesium stearate, and 95.5% w/w lactose
monohydrate.
[0103] All ingredients are screened through a 180 micron sieve
before blending.
[0104] Magnesium stearate and lactose monohydrate are mixed in a
Turbula T2C powder blender and 62 rpm for 20 minutes.
[0105] Active substance is added to 20% of the magnesium
stearate-lactose blend in the blender and the mixture mixed for a
further 20 minutes at 62 rpm.
[0106] The remaining magnesium stearate-lactose blend is added and
the mixture blended for a further 20 minutes at 62 rpm in the
blender.
[0107] Formulation 2
[0108] A dry powder formulation consisting of 4% w/w budesonide;
95%w/w Lactose monohydrate; and 1% magnesium stearate. The blending
operation is identical to that described for formulation 1.
[0109] The powder blends thus produced may be filled into
SkyePharma proprietary dry powder inhalers Skyehaler.TM. as more
fully described in U.S. Pat. No. 6,182,655 for assessment of Dose
Content Uniformity and fine particle fraction of the delivered
dose.
EXAMPLE 2
[0110] Particles of the Formulation 1 of Example 1 are scattered
and glued onto a carbon tape and shadowed with gold/platinum. Back
scattered electron micrographs and X-ray mapping are then carried
out using They are then analysed on a StereoScan 360 Scanning
Electron Microscope/EDX.
[0111] BSE and X-ray mapping analysis shows only very localized
coverage of magnesium stearate and a very low surface coverage
(less than 10%).
EXAMPLE 3
Measurement of Fine Particle Fraction
[0112] The formulations 1 and 2 employed are those formed according
to Example 1 above.
[0113] After filling the formulations in the DPI devices, the
devices are allowed to stand for at least 24 hours before
testing.
[0114] The aerodynamic particle size distribution of Formulation 1
is determined using Twin Impinger at 60 L/min flow rate (apparatus
A of the Eur. Pharmacopoeia 4.4 section 2.9.18). The effective
cut-off diameter for stage 3 of this apparatus collecting the fine
particle fraction is 6.4 microns. The fine particle dose is the
amount of drug that is found in the lower impingement chamber of
this apparatus (stage 2).
[0115] The aerodynamic particle size distribution of the
Formulation 2 is determined using a Multi Stage Liquid Impinger at
60L/min flow rate (Apparatus C of the Eur Pharmacopoeia 4.4 section
2.9.18). The effective cut-off diameter for stage 3 of this
apparatus is 6.8 microns. The fine particle dose is calculated by
determining and adding the amount of drug found on stage 3,4 and
the filter stage.
[0116] 10 shots of the formulations of Example 1 are discharged
into the particle sizing apparatus specified above at a set flow
rate of 60 L/min. Delivered and aerosolised drug particles are
classified in accordance with their particle momentum achieved in
the flow which depends on the equivalent aerodynamic particle size.
Thus fractions of the dose are deposited at different parts or
collecting stages of the apparatus, in accordance with the
aerodynamic particle size of the drug particles. Each fraction is
collected, adjusted to volume and analysed using HPLC.
[0117] HPLC analysis of Formulation 1 showed that the fine particle
fraction (less than 6.4 microns) of the dose delivered to the Twin
Impinger apparatus is about 37%.
[0118] HPLC analysis of Formulation 2 showed that the fine particle
fraction (less than 6.8 microns) of the dose delivered to the
Multi-Stage apparatus is about 32%.
EXAMPLE 4
Effects of Method of Mixing or Blending the Dry Powders is
Examined
[0119] Comparative Examples are prepared by mixing the ingredients
of Formula 1 and ingredients of Formula 2 under high shear mixing
conditions according to the following representative
methodology:
[0120] Lactose and magnesium stearate are mixed in a higher shear
mixer (Aeromatic-Fielder PP1) at 600 rpm for 6 minutes. Thereafter
the active substance is added to the mixer and the whole is mixed
for a further 6 minutes at 600 rpm.
[0121] These comparative formulations are filled into DPI devices
as defined above and the fine particle fraction of the delivered
doses determined as in Example 3 using the Multi Stage Liquid
Impinger at 60 L/min flow rate (Apparatus C).
[0122] For both formulations, HPLC analysis shows fine particle
fraction of less than 20%.
EXAMPLE 5
[0123] The formulation 1 of Example 1 is tested for Fine Particle
Fraction according to the appropriate method for Formulation 1
defined in Example 3. As comparative examples, powder blends are
produced substantially as described in Formulation 1, except the
magnesium stearate is omitted, and the mass is made up with
lactose.
[0124] The formulation 1 and comparative formulation are stored for
24 hours before taking fine particle fraction measurements. The
formulations are kept in open storage for the duration of the
experiment. The first measurement after this period is consider
time=0. Similar measurements are carried out on DPI devices at
weekly intervals up to 6 weeks. During the test period the
formulations are stored at 40.degree. C. and 75% r.h.
[0125] At Time=0, the fine particle fraction of the formulation 1
containing magnesium stearate is about 37%. For the comparative
formulation, the fine particle fraction is practically the same at
38%. However, whereas for the formulation containing magnesium
stearate the fine particle fraction does not differ by more than
about 2% over the test period, the fine particle fraction of the
formulation containing no magnesium stearate is reduced by more
than 25% in the first week, and by about 50% over the course of the
test period.
[0126] The results demonstrate the stabilising effect of magnesium
stearate on the fine particle fraction dry powder formulations.
However, it is interesting that there is practically no difference
in the fine particle fraction of the two formulations at time=0.
This is possibly an indication that the surface coverage of
magnesium stearate is so low that it plays practically no role in
affecting the adhesive properties of the active substance to the
carrier.
* * * * *