Note: Descriptions are shown in the official language in which they were submitted.
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Combined doses of tiotropium and fluticasone
TECHNICAL FIELD
The present invention relates to combined doses of medicaments for
administration by an oral inhalation. In particular, combined doses of
tiotropium and fluticasone are packaged to fit a new method of aerosolizing
selected combined doses into air and more particularly, the invention relates
to combinations of separate dry powder entities of medicaments constituting
the combined doses intended for delivery in a single inhalation by a user.
BACI~GI~OUND
Asthma and chronic obstructive pulmonary disease (COPD) affect more than
30 million people in the United States. More than 100,000 deaths each year
are attributable to these conditions. Obstruction to airflow through the lungs
is the characteristic feature in each of these airway diseases, and the
medications utilized in treatment are often similar.
Up to 5% of the US population suffers from asthma, a respiratory condition
characterized by airway inflammation, airway obstruction (at least partially
2o reversible), and airway hyperresponsiveness to such stimuli as
environmental allergens, viral respiratory-tract infections, irritants, drugs,
food additives, exercise, and cold air. The major underlying pathology in
asthma is airway inflammation. Inflammatory cell -- eosinophils, CD4+
lymphocytes, macrophages, and mast cells -- release a broad range of
2s mediators, including interleukins, leukotrienes, histamine, granulocyte-
colony-stimulating factor, and platelet aggregating factor. These mediators
are responsible for the bronchial hyperreactivity, bronchoconstriction,
mucus secretion, and sloughing of endothelial cells.
3o Chronic obstructive pulmonary disease (COPD) is a widespread chronic lung
disorder encompassing chronic bronchitis and emphysema. The causes of
COPD are not fully understood. Experience shows that the most important
cause of chronic bronchitis and emphysema is cigarette smoking. Air
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pollution and occupational exposures may also play a role, especially when
combined with cigarette smoking. Heredity also causes some emphysema
cases, due to alphal anti-trypsin deficiency.
s Chronic bronchitis is caused by excess mucus production in the lungs
causing infection, which in turn causes inflammation and swelling, thus
narrowing the bronchial tubes. This narrowing impedes airflow in and out of
the lungs, causing shortness of breath. The condition usually begins with
intermittent tracheobronchitis; however, repeated attacks occur until the
disease and its symptoms persist continuously. If left untreated or if the
patient continues to smoke, chronic bronchitis can lead to emphysema.
Administration of asthma drugs by an oral inhalation route is very much in
focus today, because of advantages offered like rapid and predictable onset
1s of action, cost effectiveness and high level of comfort for the user. Dry
powder
inhalers (DPI) are especially interesting as an administration tool, compared
to other inhalers, because of the flexibility they offer in terms of nominal
dose range, i.e. the amount of active substance that can be administered in
a single inhalation. So far most development efforts have been directed
2o towards producing effective drugs and formulations for specific abnormal
conditions and not so much towards developing combined dose metering,
forming methods and a suitable delivery device, i.e. the inhaler.
When inhaling a combined dose of dry medication powder it is important to
2s obtain by mass a high fine paxticle fraction (FPF) of particles with an
aerodynamic size preferably less than 5 ~,m in the inspiration air. The
majority of laxger particles does not follow the stream of air into the many
bifurcations of the airways, but get stuck in the throat and upper airways. It
is not uncommon for prior art inhalers to have an efficacy of 10 - 20 % only,
3o i.e. only 10 - 20 % of the metered dose by mass is actually delivered as
particles with an aerodynamic size less than 5 ~.m. Since most drugs may
have undesirable side effects, e.g. steroids delivered to the system, it is
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important to keep the dosage to the user as exact as possible and to design
the delivery system, e.g. an inhaler, such that the efficacy becomes much
higher than 10 - 20 %, thereby reducing the required amount of drug in the
dose. Common, serious adverse effects of widely used corticosteroids are
s osteoporosis, growth retardation, candidiasis and muscle injuries and
serious adverse effects of beta2-agonists, first choice among bronchodilators,
are tremor, palpitations, headache, dizziness and oropharyngeal irritation.
In search of methods and devices for improving dose efficacy and reducing
the dosages necessary for adequate control of symptoms and respiratory
disorders, some developments are to be noted. For instance, in an article in
Journal of Aerosol Medicine, Volume 12, Supplement 1, 1999, Pp. S-33 - S-
39 the authors Pavia and Moonen report clinical studies comparing therapy
efficacy of a "soft mist inhaler" Respimat from Boehringer Ingelheim KG with
1s that of an MDI. The studies show that the Respimat gives at least the same
therapeutic bronchodilating effect as the MDI but using only half or less of
the dosage in the MDI. The Respimat produces a slow-moving cloud of
medicament droplets with a high fine particle fraction in a prolonged dose
delivery taking in the order of one second, which reduces the deposition in
2o the oropharynx and raises the topical delivery to the correct site of
action in
the lung. The challenge of developing inhalers capable of producing a
delivered dose with a high fine particle fraction in a prolonged dose delivery
is discussed in another article in Journal of Aerosol Medicine, Volume 12,
Supplement 1, 1999, Pp. S-3 - S-8 by the author Ganderton.
~s
Interestingly, research during the past decade into respiratory diseases,
their
prophylaxis and treatment, has shown conclusively that simultaneous
administration of combinations of different medicaments may improve the
clinical condition of patients considerably. See - for instance NIH, National
30 Heart, Lung, and Blood Institute "Guidelines for the Diagnosis and
Management of Asthma" NIH Publication No. 97-4051 July 1997, where a
combined use of a long-acting beta2-agonist and a corticosteroid drug is
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recommended, formoterol and fluticasone being mentioned as good examples
of substances of the two groups. The document stresses that it is important
to reduce the adverse effects of the medicaments in general and inhaled
corticosteroids in particular by reducing to a minimum the dosage, which
still keeps the inflammation under control. At the time when these
guidelines were compiled no medical products were available offering
comprehensive combined medication together with suitable administration
tools, at least not to the American public. The only possibility at the time
was to combine by prescribing two different medicaments, preferably for
1o inhalation, one from each group and separate inhalers for administration.
This method of treatment was well known to practitioners at the time.
Several studies in the mid-1990's have shown that by adopting a combined
treatment it has been possible to reduce the dose of steroid compared to
using the steroid as background treatment and a short-acting beta2-agonist
is as rescue medicine, besides improving lung function and reducing severity
and frequency of attacks of dyspnoea.
For instance, in Switzerland patients diagnosed with asthma have been
prescribed FORADIL (formoterol, a bronchodilating substance) together with
2o PULMICORT (budesonide, an anti-inflammatory steroid) since the 1980's for
treatment of their asthma. Until recently, however, different asthma
medicaments have generally been administered separately, in sequence or by
separate routes, not in compositions comprising more than one active
ingredient. However, there are several published patent applications and
25 approved patents teaching methods of treating respiratory disorders like
asthma and chronic obstructive pulmonary disease (COPD) as well as
pharmacologic compositions of different biological and chemical substances
for this purpose, where the combinations offer overall advantages in the
treatment of these conditions. See for instance EP 0416950B 1
30 "Medicaments", EP 041695181 "Medicaments comprising salmeterol and
fluticasone", EP 061337181 "New combination of formoterol and budesonid",
WO 98/ 15280 "New combination", WO 00/48587 "Combinations of
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formoterol and fluticasone propionate for asthma", WO O l / 70198A 1
"Stabilized dry powder formulations", WO O 1 / 78737A1 "Medical
combinations comprising formoterol and budesonid", WO O 1 / 78739A 1
"Medical combinations comprising tiotropium and fluticasone propionate",
s WO O 1 / 78745A 1 "Medical combinations comprising formoterol and
fluticasone propionate", WO 02 / 28368A 1 "New combination for the
treatment of asthma", WO 03/013547A1 "Pharmaceutical composition
comprising salmeterol and budesonid for the treatment of respiratory
disorders", US 5,603,918 "Aerosol composition of a salt of ipratropium and a
salt of albuterol", US 6,433,027 "Medicament compositions based on
tiotropium bromide and formoterol fumarate", US 2003/0096834
"Pharmaceutical compositions", WO 00/47200 "Combinations of formoterol
and a tiotropium salt". However, the quoted documents deal with aspects of
formulating, processing, stabilizing and using mixtures of at least two
~s ingredients. The mixing ratios between active ingredients and compositions.
thereof including suitable carriers, solvents and excipients are generally.
focused upon, not methods of administration or devices for that purpose.
A further document WO 01 / 78735, Sanders et al., claims a method of
2o treating a respiratory disorder by administering an effective amount of the
active ingredients formoterol and fluticasone separately, sequentially or
simultaneously, provided that the ingredients comprise separate
compositions. A dry powder inhaler containing formoterol and fluticasone in
separate compositions is also claimed. However, Sanders et al. fail to teach
25 how the skilled person should perform the method. Sanders goes on to teach
that each of the active ingredients should be administered as separate
compositions preferably once or twice daily. The document discloses that the
claimed method may comprise an improvement of from 35 - 50 % (in
glucocorticoid receptor translocation into the nucleus) over known
3o combination therapies, but no relevant information is given as to why the
claimed method is superior and novel in relation to prior art, e.g. as
exemplified in the previously mentioned documents. Further, no distinctive
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characteristics of the dry powder inhaler are disclosed, separating the
inhaler from prior art inhalers.
A common denominator for the quoted documents is that they have as their
s first objective to simplify and improve asthma therapy for the user. A
simple,
once or twice daily administration by inhalation of well-known, well
documented medicaments, one of which selected to address symptoms of
broncho-constriction and the other to address an underlying inflammation of
the bronchi, has proved in clinical testing to result in high user acceptance
and compliance with a prescribed dosing regimen. The results of this
therapy are in many reports compared with therapy using only the one or
the other medicament, sometimes with increased dosages, or compared to
separate prescriptions of said medicaments, but without specific
instructions to the user on how to combine the administration of the two
15 medicaments to achieve the best effect.
It comes as no surprise to a person of ordinary skill in the art that
combining two well-documented medicaments, one to give quick relief of
symptoms and the other to treat the cause in the long term, would be a good
2o idea. Many of the quoted documents teach compositions of a bronchodilating
drug, preferably long-acting with fast onset like formoterol or tiotropium,
and a corticosteroid, i.e. an anti-inflammatory drug e.g. budesonide or
fluitcasone propionate, in mixtures using effective amounts of the drugs and
varying ratios between drugs depending on the condition, age, sex etc of the
25 patient. The disclosed inventions in the quoted documents rely on existing
MDI or DPI inhalers to do the job of delivering the medicament mixtures
using a single inhaler. The documents also teach various techniques of
combining two drugs in order to simplify self therapy for asthmatics. The
disclosed techniques range from mixing the drugs in various ways into an
3o indivisable medicament to supplying medical kits composed of separately
packaged doses for insertion in separate inhalers for separate, sequential
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delivery of the selected drugs. In the latter case it is difficult to see
where the
improvement for the user is lying.
None of the quoted documents indicate that the claimed medicament
s composition offers a therapeutic benefit, or quote clinical studies in
support
of such benefits, in comparison with separate, sequential delivery of the
equivalent active medicaments. On the contrary, several documents teach
that there is no therapeutic difference between delivering the active
medicaments substantially simultaneously, sequentially or separately.
to
Furthermore, none of the quoted documents discusses in depth the
importance of formulating a dry powder medicament for inhalation, e.g. the
claimed compositions, such that an optimum distribution of particle
aerodynamic diameters for optimum therapeutic effects from the selected
1s drugs are arrived at. Also, there is no recommendation as to an order in
which the different medicament doses, if physically separated, should be
delivered to an inhaling user, presumably because a concept of delivering, in
a single inhalation, combined doses composed of separate, individual doses
of each medicament is unusual, if not completely unknown, in prior art.
2o Likewise, a concept of cutting back the quantities of active ingredients in
the
combined doses by implementing a giant increase in efficacy in the delivered
dosage by adopting a prolonged dose delivery is also practically unknown in
prior art.
25 The preferred embodiment of the inventions of the quoted documents is a
mixture of the active drugs involving preferred prior art methods of preparing
combined doses by mixing the ingredients. It is, however, difficult to mix dry
medicament powders and optional excipients in a certain proportion
consistently. The proportions in such a metered combined dose cannot easily
3o be controlled, because the ratio of medicaments in an individual, combined
dose depends significantly on the particle forces existing in each medicament
powder, between particles of different medicaments and between
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medicament powders and dose packaging materials. Hence, actual variations
in the ratio between active ingredients from combined dose to combined dose
may be too large, causing serious problems if a potent ingredient is delivered
in a higher or lower amount than expected.
Bronchodilating medicaments such as short-acting beta2-agonists have been
used for many years in control of asthma and particularly as rescue
medicines, administered as needed. Salbutarnol, for instance, has very fast
onset but short duration and may be administered, preferably by inhalation,
several times per day in order to control attacks of dyspnoea, such that a
puff of the drug provides immediate relief. Salmeterol and formoterol, both
long-acting beta2-agonists, are bronchodilators, which have been used with
great success for more than 20 years in the treatment of asthma.
Formoterol, but not salmeterol, may be used as a rescue medicine for a
~s quick relief of symptoms during an asthma attack. However, none of the
beta2-agonists have any significant effect on underlying inflammation of the
bronchi. Besides the already well-known adverse side effects of long-acting
beta2-agonists (LABAs), a recent study in the US reports statistically
positive
evidence that salmeterol may be at the root of premature deaths caused by
2o an acute asthma attack among salmeterol users with respiratory disorders.
This is especially pronounced in the afro-american population, which has
induced FDA to issue warning messages to users of salmeterol. It is too early
to say if other LABAs are afflicted with this problem. Apparently, at this
point no evidence points in this very disturbing direction for short-acting
25 beta2-agonists.
Anticholinergic agents, e.g. ipratropium, oxitropium and tiotropium,
particularly ipratropium bromide and tiotropium bromide, are also effective
bronchodilators, but act in a different way to beta2-agonists, with relatively
3o fast onset and long duration of action, especially ipratropium and
tiotropium, of which the latter may be active for up to 24 hours. Adverse side
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effects for inhaled anticholinergic agents are insignificant, dryness of mouth
and constipation are most common.
Fluticasone on the other hand, especially fluticasone propionate, is an anti-
s inflammatory corticosteroid, which during the past two decades has proven
to be a very successful and potent drug in reducing inflammation of nasal
passages and bronchial tissue to make breathing easier. However,
fluticasone propionate, like other anti-inflammatory steroids, does not have
an immediate relief for a person suffering an asthma attack, but the drug
1o will help to manage the inflammation and reduce the severity and number of
exacerbations, if taken regularly.
National health-care institutions in most countries have been slow to
actively promote the use of combined therapy, in the early days because of
15 unfounded feax, as it turned out, of negative long-term side effects from
the
beta2-agonist, although in the last decade combined treatment has -been
listed as an open option for physicians in treating asthma patients. Thus,
the full potential has not been realized of the obvious advantages, which may
be achieved in a physician-controlled therapy using a combination of a
2o bronchodilator and an anti-inflammatory drug in management of asthma
and COPD. A reason for the slowness has been a lack of understanding
among researchers and scientists of the complex mechanisms of airways
diseases. Today, although much remains to be learned about asthma and
COPD, many clinical tests have shown conclusively that combination
25 therapy is working and provides good therapeutic results for many
asthmatics.
Thus, there is a need for improvements regarding methods of treating
respiratory disorders using combined, consistently metered doses of
3o tiotropium and fluticasone for co-ordinated administration by inhalation,
using a new type of inhaler device.
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SUMMARY
The present invention discloses a method for the administration by
inhalation of co-ordinated, metered, combined doses of finely divided dry
powders of (A) tiotropium and (B) fluticasone by means of an adapted inhaler
5 designed for prolonged delivery of the combined doses. Metered dry powder
medicinal combined doses are prepared comprising separately metered
deposits of tiotropium, including pharmaceutically acceptable salts,
enantiomers, racemates, hydrates, solvates or mixtures thereof, and
fluticasone, including pharmaceutically acceptable salts, enantiomers,
racemates, hydrates, solvates or mixtures thereof, in suitable quantities and
ratios, optionally including diluents or other excipients. "Tiotropium" refers
hereinafter to all the various chemical forms of the active substance, which
are suitable for an intended therapeutic effect and particularly to tiotropium
bromide. "Fluticasone" refers hereinafter to all the various chemical forms of
the active substance, which are suitable for an intended therapeutic effect
and in particular to fluticasone propionate. Because of the potency of the
respective drugs it may be necessary to dilute the active substances,
tiotropium and fluticasone, separately using a pharmacologically acceptable
diluent or excipient in order to secure the correct amounts as well as the
2o ratio between the active substances in the formed combined doses. Careful
metering of the entities of deposited powder constituting the combination of
doses, A' and B' respectively, may control the very small, individual
quantities of active substances tightly. Hence, the sum of the metered
entities constitutes the metered quantities of powder of the combined doses.
A user introduces the medicinal combined doses comprising the separated
powder entities of tiotropium and fluticasone into an adapted inhaler device
for a prolonged delivery of the combined doses during the course of a single
inhalation. Delivery of the separated entities of powder deposits of
tiotropium
3o and fluticasone is preferably arranged to be sequential and more preferably
such that tiotropium is delivered first and fluticasone shortly after, so that
tiotropium may reach deeper into the lung for topical action and fast onset,
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while fluticasone may be topically deposited in the lung for best effect with
as little systemic effect as possible. The delivered doses are composed of a
high proportion of de-aggregated fine particles of the selected medicaments
respectively, although the particle flows are preferably separated in time,
whereby an intended prophylactic, therapeutic and psychologic effect on the
user is achieved.
Furthermore, pharmaceutical dry powder combined doses of tiotropium and
fluticasone are disclosed. The doses are adapted for inhalation, for the
prophylaxis or treatment of a respiratory disorder in a user. The
pharmaceutical dry powder combined doses are prepared comprising
separate entities of metered deposits of medicinally effective quantities of
tiotropium and fluticasone respectively, optionally including diluents or
excipients, where the sum of the entities constitutes the metered quantities
of powder in the pharmaceutical, combined doses suitable for being
introduced into an adapted inhaler device.
The present method is set forth by the independent claim 1 and the
dependent claims 2 to 8, and pharmaceutical combined doses are set forth
2o by the independent claim 9 and the dependent claims 10 to 15 and the use
of differently acting dry powder medicaments is set forth by the independent
claim 16.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention, together with further objects and advantages thereof, may
best be understood by referring to the following detailed description taken
together with the accompanying drawings, in which:
FIG. 1 illustrates in top and side views a first embodiment of combined
3o doses comprising two medicament entities deposited in separate
compartments onto a dose bed;
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FIG.2 illustrates in top and side views a second embodiment of
combined doses comprising three medicament entities deposited
in separate compartments onto a dose bed;
s FIG. 3 illustrates in top and side views a third embodiment of combined
doses comprising two parallel medicament entities deposited onto
a dose bed;
FIG. 4 illustrates in top and side views a fourth embodiment of combined
doses comprising several medicament entitie and separating
excipient entities deposited onto a dose bed;
FIG. 5 illustrates in top and side views a fifth embodiment of combined
doses comprising four medicament entities and separating
1s excipient entities deposited onto a dose bed;
FIG. 6 illustrates in top and side views a sixth embodiment of combined
doses comprising two parallel medicament entities deposited on
top of one another onto a dose bed;
FIG.7 illustrates in top and side views a seventh embodiment of
combined doses comprising two medicament entities deposited on
top of one another onto a dose bed, but separated by a deposited
excipient entity;
FIG. 8 illustrates in top and side views another embodiment of combined
doses comprising two medicament entities separately deposited
onto a dose bed;
3o FIG. 9 illustrates in top and side views yet another embodiment of
combined doses comprising two medicament entities separately
deposited onto a dose bed, but with some degree of overlap;
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FIG. 10a illustrates in a sectional view an example of combined doses
comprising two medicament entities deposited on top of one
another but separated by a deposited excipient entity onto a dose
s bed and adjacent to the combined doses a nozzle in a starting
position before the combined doses are released;
FIG. lOb illustrates in a sectional view an example of combined doses
comprising two medicament entities deposited on top of one
1o another but separated by a deposited excipient entity onto a dose
bed and adjacent to the combined doses a nozzle in a relative
motion sucking up the powder particles to be dispersed into the
air stream;
is DETAILED DESCRIPTION
The present invention discloses a new combination of active asthma drugs
comprising two co-ordinated, metered, combined doses of the medicaments
tiotropium, particularly tiotropium bromide, and fluticasone, in particular
fluticasone propionate. In a further aspect, the invention discloses a new
2o therapeutic method of treating respiratory diseases like asthma by
delivering
such co-ordinated combined doses by an inhalation route to a user of a dry
powder inhaler (DPI). "Asthma" is used in this document as a generic term
for the different respiratory disorders known in the field of medicine.
25 In the context of this application the word "medicament" is defined as a
pharmacologic substance, which comprises at least one chemically or
biologically active agent. Further, a medicament may exist in a pure form of
one or more pure active agents, or a medicament may be a compound
comprising one or more active agents, optionally formulated together with
30 other substances, e.g. enhancers, carriers, diluents or exipients.
Hereinafter,
the term "excipient" is used to describe any chemical or biologic substance
mixed in with a pure active agent for whatever purpose. In this document,
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only medicaments in dry powder form are discussed. Tiotropium and
fluticasone respectively are in this document generic terms for the respective
active chemical substances including pharmaceutically acceptable salts,
enantiomers, racemates, hydrates, solvates or mixtures thereof, which have
a desired, specific, pharmacologic and therapeutic effect.
A "dose bed" is henceforth defined as a member capable of harboring
metered combined doses comprising one or more entities of dry powders,
where the combined doses are intended for delivery to a user of a DPI in a
1o single inhalation performed by the user. Different types of pharmaceutical
blister packs or capsules are included in the term "dose bed". In the present
invention combined doses for treating asthma comprise metered, deposited
entities of tiotropium and fluticasone respectively, optionally including
excipients. The dose bed may be divided in two areas or incorporate two
compartments, i.e. cavities of smtabte volume, mtenaea ror aeposmea
entities of dry powders of tiotropium and fluticasone respectively. In a
preferred embodiment the combined doses are packaged for a prolonged
delivery, i.e. the delivery period for the combined doses is in a range from
0,01 to 6 s, usually in a range from 0,1 to 2 seconds, delivery taking place
2o sometime during the course of an inhalation as controlled by a purposefully
designed DPI, adapted for combined doses. Advantageously, such a DPI
adopts an Air-razor method of gradual aerosolization of the combined doses
by introducing a relative motion between an air-sucking nozzle and the
powder doses. Advantages of a prolonged delivery of a dose for inhalation are
2s disclosed in our US Patent No. 6,571,793 B1 (WO 02/24264 A1), which is
hereby incorporated in this document in its entirety as a reference.
A preferred embodiment of metered combined doses use a dose bed split up
in two separate compartments, where each compartment is intended for a
3o metered deposition of a particular asthma medicament, in this case
tiotropium and fluticasone respectively and more particularly tiotropium
bromide and fluticasone propionate. Each compartment containing a
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metered entity of a medicament powder may then be sealed, e.g. by foiling,
such that the different medicaments in the different compartments of the
dose bed cannot interact in any way and cannot be contaminated by foreign
substances or moisture. Alternatively, a common foil may enclose both
s compartments, and sealing between compartments may be excluded if
individual sealing is not a GMP or medicinal requirement. A dose carrier is
normally engaged to carry at least one dose bed loaded with combined doses,
whereby the dose carrier may be inserted into a DPI for administering the
combined doses, e.g. sequentially, to a user in need of treatment. A suitable
1o carrier of combined doses is disclosed in our US Patent No. b,622,723 B 1
(WO 01/34233 Al), which is hereby incorporated in this document in its
entirety as a reference. However, a dose bed may be designed to act as a
carrier, intended for direct insertion into a DPI. A suitable DPI for a
continuous, prolonged dose delivery is disclosed in our US Patent No.
1s 6,422,236 B 1, which is hereby incorporated in this document in its
entirety
as a reference.
If complete physical separation of the deposited entities of the two
medicaments making up the combined doses, is not required but some
2o degree of overlap or mixing is acceptable from a physical, chemical and
medical point of view, then other methods of separating the deposited
entities may be implemented. Depending on what degree of mixing is
permitted or in some cases desired, different ways of separating medicament
entities must be adopted. For example, the dose bed may use separate
indentations where different powders should be deposited, but flat target
areas for separate deposits in a single plane on the dose bed are equally
possible. In another embodiment the two medicaments are deposited
sequentially dot-wise or string-wise onto two target areas of the dose bed. If
necessary, to stop chemical or biological interaction or decomposition caused
3o by, for example, adjacent medicament powders being incompatible, an
isolating, biologically acceptable, inert substance like carbohydrates, e.g.
glucose or lactose, may be deposited between the medicament entities. When
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the combined dose entities have been completely formed they are usually
sealed from ingress of dirt and moisture by a foil covering the entire dose
bed. A method of depositing microgram and milligram quantities of dry
powders using electric field technology is disclosed in our US Patent No.
6,592,930 B2, which is hereby incorporated in this document in its entirety
as a reference.
Forming combined doses comprising two medicaments in separate dry
powder formulations may be done in different ways, known in prior. art. The
1o invention discloses that the finely divided powders to be included in the
combined doses, i.e. tiotropium and fluticasone respectively, need not be
mixed or processed together prior to dose forming and, indeed, should be
kept separated during dose forming as well as after the respective entities of
the combined doses are formed and sealed. The medicament entities of the
combined doses are thus kept separated on the dose bed by suitable
methods, as described in the foregoing, until the combined doses are about
to be delivered by an inhalation route to a user and thereby preferably
delivered in sequence, separated in time and therefore not mixed in the
inhaled air leaving the mouthpiece of the DPI.
The present invention offers inherent manufacturing advantages in
comparison with prior art methods, which are based on mixing the active
ingredients in bulk quantities, generally including diluents and/or carriers
before forming doses. The consequence of this mixing step in the
manufacturing process, apart from the regulatory problem of proving the
mixture as such, is that many different blends of mixture must be made and
verified to provide the correct ratios between the active ingredients in order
to correspond to given therapeutic requirements, since different patients
need different ratios, besides correct quantities. Disregarding the problem of
3o verifying a mixture in bulk quantity, besides the problem of verifying the
actual ratio between ingredients in each individual dose, a further
consequence of the mixing step is the extra time required for producing,
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storing and verifying the mixture before and during the dose forming
process. Also to be considered is the circumstance that it is not uncommon
for active substances to have a limited period of stability, which is often
even
shorter when mixed with other active ingredients.
The present invention avoids all of these problems, since the active
ingredients are kept separate, optionally in a mixture with excipient(s), all
the way through the dose manufacturing process, and, in fact, during
packaging, distribution and storing until the moment when the user has
1o introduced the combined doses into an inhaler and starts to inhale.
Furthermore, the ratio between the active ingredients represents no problem,
since it is a result of the metered quantities of the respective active
ingredients constituting the combined doses.
1s Although the medicament entities of the combined doses are separated on
the dose bed until the doses are to be delivered by a DPI, it is perfectly
possible according to alternative embodiments of the invention to suck up
the doses more or less mixed into the inspiration air during inhalation. In
one aspect the powder entities of the combined doses of tiotropium and
2o fluticasone may be sucked up simultaneously, partly or completely. The
degree of mixing of the delivered powders leaving the DPI mouthpiece may
vary between 0 and 100 % depending partly on the design of the DPI and its
suction system, partly on the physical relative positions between deposited
powder entities on the dose bed and partly on the relation between the dose
2s bed and the suction system. For instance, if fluticasone is deposited first
onto a dose bed and tiotropium is then deposited on top of the fluticasone,
the powders will be mixed practically to 100 % when sucked up.
In another aspect the powder entities of the combined doses may be sucked
3o up sequentially, e.g. if the powder entities are accessed one at a time by
the
suction system of the DPI in the course of a single inhalation. Naturally, in
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18
that case, no mixing of powders will happen, since the delivery of the doses
into inspiration air will be sequentially time separated.
In a third aspect, by selecting a pattern of physical positions and extensions
in space of the deposited powder entities when forming the doses, it will be
possible to tailor the delivery of the powders in the doses such that the
medicament powders get mixed into inspiration air to a selected degree
between 0 and 100 %.
1o Methods of dose forming include conventional mass or volumetric metering
and devices and machine equipment well known to the pharmaceutical
industry for filling blister packs, for example. Also see European Patent No.
EP 0 319 131 B 1 and US Patent No. 5,187,921 for examples of prior art in
volumetric and/or mass methods and devices for producing doses of
medicaments in powder form. Electrostatic forming methods may also be
used, for example as disclosed in US Patent Nos. 6,007,630 and 5,699,649.
Any suitable method capable of producing metered microgram and milligram
quantities of dry powder medicaments may be used. Even completely
different methods may be applied to suit the different medicaments selected
2o to be part of the combined doses to be produced. A dose may hold together
in a more or less porous entity by action of van der Waals forces,
electrostatic forces, electric forces, capillary forces etc interacting
between
particles and particle aggregates and the dose bed material.
Total mass in combined doses according to the present invention is typically
in a range from 5 ~,g to 5 mg, but may extend to 50 mg. Regardless of which
forming and filling method is being used for a particular medicament, it is
important during dose forming to make sure that selected medicaments are
individually metered and deposited onto their respective target areas or
3o compartments of the dose bed. The target areas or compartments of the dose
bed, which aggregate to hold combined doses, may be of a same size or
different sizes. The shape of compartments is governed by physical
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constraints defined by the type of dose bed used. As an example, a preferred
type of dose bed is an elongated strip of a biologically acceptable, inert
material, e.g. plastic or metal, between 5 and 50 mm long and between 1
and 10 mm wide. The strip is further divided into separate target areas or
compartments arranged along the length of the elongated strip. The dose bed
or, if necessary each compartment, receives an individual seal, for instance
in the form of a foil, in a step immediately subsequent to the dose forming.
An advantage of the present invention is that tiotropium and fluticasone are
1o selected on merits of their own for inclusion in combined doses, in
disregard
of whether or not the respective formulations are compatible with one
another. Thus, the regulatory process before introducing combined doses of
e.g. tiotropium bromide and fluticasone propionate on the market may be
drastically simplified. Another aspect of the invention is the use of the long-
acting anticholinergic bronchodilator tiotropium instead of a long-acting
beta2-agonist, thereby eliminating the adverse side effects of the latter
including possibly the risk of death in an asthma attack, the only trade-off
being the minor side effects of tiotropium. In a further aspect the
combination of a dose of tiotropium and a dose of fluticasone, which are
2o both long-acting, will permit a once daily administration by inhalation, in
order to control asthma, thereby improving the quality of life for many users.
Yet another advantage of the invention is the possibility of using pure,
potent
tiotropium and fluticasone substances for inclusion in the combined doses,
without any included excipients.
Table 1. Typical dosages of tiotropium and fluticasone respectively in asthma
therapy
Medicament active Delivered dosage Delivered dosage
agent range per dose (~,g) range per day for
adults (~,g)
Tiotropium 1-50 1-100
Fluticasone 40-2000 50-5000
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Combined doses are intended for administration in a single inhalation, either
irregularly when need arises, or more typically as part of a daily
management regime. The number of combined doses administered regularly
s may vary considerably depending on the type of disorder. Optimal dosages of
tiotropium and fluticasone respectively for prevention or treatment of
respiratory disorders may be determined by those skilled in the art, and will
vary with their respective potency and the advancement of the disease
condition. Furthermore, factors associated with the individual undergoing
to treatment determine correct dosages, such as age, weight, sex etc.
Depending on what are correct dosages per day and the number of planned
administrations per day, the correct deposits by mass for the prepared
medicaments may be calculated, such that metered deposits of each
medicament entity to be included in the metered combined doses may be
~s produced in a dose-forming step. In calculating a correct nominal deposit
of
mass for each medicament entity the fine particle fraction, i.e. particles
having a mass median aerodynamic diameter (MMAD) less than 5 ~,m, per
entity of the actual delivered doses must be taken into consideration. As
discussed in the foregoing, the efficacy of inhalers differs considerably and
it
2o is thus important to include the expected efficacy of the chosen inhaler in
the calculation of a suitable nominal mass in the deposited entity or
entities.
What constitutes suitable amounts of the two medicaments and the
respective optimal masses of tiotropium and fluticasone respectively depend
on the factors described in the foregoing, but generally the inhaled
2s tiotropium mass, e.g. in the form of tiotropium bromide, per dose should be
in a range from 1 to 50 fig, preferably between 2 to 40 ~g and inhaled
fluticasone, e.g. in the form of fluticasone propionate, per dose in a range
from 40 to 2000 ~,g, preferably between 50 to 500 ~.g.
3o There is generally a medical need to direct the delivery, i.e. the
deposition, of
inhaled doses of a medicament to the optimum site of action, where the
therapeutic effect is the best possible, in the lung, including the deep lung,
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21
either for a topical effect or for a systemic effect. Turning to the case in
point,
it is of course desirable to control the deposition of the combined doses of
tiotropium and fluticasone to their respective sites of action in the lung in
order to get highest possible overall efficacy for each dose with a minimum of
side effects. Aerodynamic particle size is a most important factor greatly
influencing where particle deposition is likely to take place in the lung.
From
a target site point of view, it is therefore desirable to tailor the physical
formulations of the respective medication powders in the combined doses in
such a way that they result in an advantageous particle aerodynamic size
to distribution by mass in the delivered dose. The present invention makes it
possible to deliver the combined doses, thus formulated, to the targeted sites
of action. Available data indicate that for best performance, the AD
(aerodynamic diameter) for fluticasone in the delivered dose should be in a
range from 2 to 8 ~.m whereas AD for tiotropium in the delivered dose should
be in a range from 1 to 5 ~.m.
Another circumstance to consider is the order of delivery for the combined
doses of the present invention. The first air to be sucked in by a person
inhaling reaches deep into the peripheral lung and air sucked in thereafter
2o fills up the lungs gradually. Generally, what this means is that powders
intended for a peripheral lung deposition should be inhaled early in the
inhalation cycle to maximize deposition in that area and powders intended
for a central lung deposition should be inhaled somewhat later in the cycle
to maximize deposition in the central lung. Since available data suggest that
a bronchodilator, e.g. tiotropium, should preferably deposit in the peripheral
lung area and an anti-inflammatory steroid, e.g. fluticasone, in the central
lung area, a dose of tiotropium should be the first to be sucked in followed
by a dose of fluticasone. Under the proviso that an adapted DPI is at hand
for a sequential delivery of the combined doses in the course of a single
3o inhalation, the present invention refutes prior art and claims that
sequential
delivery of combined doses, i.e. a dose of tiotropium first followed by a dose
of fluticasone thereafter, is to be preferred compared to simultaneous
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delivery, e.g. combined doses in the form of a mixture. Compared to prior art
the present invention presents a definite advantage regarding delivered dose
efficacy and benefits for the user.
The present invention makes use of proven dry powder formulations of
tiotropium and fluticasone, particularly tiotropium bromide and fluticasone
propionate, finely divided and adapted for separate deposition onto a
common dose bed, normally with no mixing of the two active substances.
Combined doses thus formed may be introduced into an adapted dry powder
1o inhaler (DPI) such that the medicament entities constituting the combined
doses may be aerosolized and delivered in the inspiration air during the
course of a single inhalation through a DPI by a user. Keeping the different
medicament entities separated according to the invention may reduce the
investment in time and resource necessary for getting the combined doses
is approved by the relevant regulatory bodies and released to the respective
markets. For instance, no added substance to stabilize the combined doses
will be needed and no testing to prove that an added substance is harmless
needs to be performed.
2o The present invention differs from prior art inhalers and related combined
dose delivery methods by providing combined doses comprising two co-
ordinated, individually proven asthma medicaments in form of separately
deposited entities onto a dose bed. The combined doses are therefore not a
single composition of asthma medicaments constituting a single physical
2s entity. The invention discloses combined doses comprising at least two co-
ordinated physical medicament entities loaded onto a common dose carrier
with an objective of providing more efficient treatment of asthma. Inserted
into an adapted DPI, the combined doses will be aerosolized during a single
inhalation by a user. Preferably, the entities of the combined doses of
3o tiotropium and fluticasone will be delivered sequentially or optionally
more
or less simultaneously into the inspiration air. Whether the combined doses
of medicaments are aerosolized sequentially or simultaneously depends on
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23
the physical form of the combined doses, i.e. how the deposited medicament
entities are interrelated, and on the type of inhaler used to administer the
combined doses.
s It is obvious that an inhaler, which instantaneously subjects all powders of
the combined doses to a jet-stream of air will aerosolize the aggregated
deposits more or less simultaneously, whereby the medicament powders,
still more or less agglomerated, become mixed into the air leaving the
mouthpiece. In contrast, an inhaler subjecting the combined doses to a jet
to stream gradually, like a moving tornado attacking adjacent corn fields, one
after the other, thereby not attacking all of the powder entities of the
combined doses instantly, may aerosolize the entities of the combined doses
gradually and efficiently over time. An object of the invention is to offer
better control of dose release and to facilitate a prolonging of dose delivery
in
~s order to produce a high fine particle fraction (FPF) in the delivered,
combined
doses. Another object of the invention is to achieve a high ratio of
delivered,
combined doses relative metered, combined doses. Although it is possible to
successfully apply the invention to prior art inhalers, they tend to deliver
the
combined doses more or less mixed in too short a time, resulting in a poor
2o FPF figure and low efficacy. On the other hand, a gradual, well-timed,
sequential delivery of combined doses is possible using a new inhaler design
where a relative movement is introduced between the combined doses and a
suction nozzle through which the inspiration airflow is channeled. This
arrangement utilizes the inhalation effort of the user to aerosolize the
25 combined doses gradually for a prolonged period of dose delivery, thus
using
the power of the suction more efficiently and eliminating in most cases a
need for external power to aerosolize the combined doses. A novel device for
aerosolizing a dry powder dose is disclosed in our US Application No. US
2003/0192538 Al and a method of de-aggregating and dispersing dry
3o medicament powder into air is disclosed in our US Application No. US
2003/0192539 Al. Both documents are hereby incorporated in this
document in their entirety as references.
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A powder Air-razor method is advantageously used for aerosolizing the
medicament powder entities of the combined doses, the Air-razor providing
de-aggregation and dispersal into air of the finely divided medication
powders. By utilizing an effort of sucking air through a mouthpiece of an
s inhaler, said mouthpiece connected to a nozzle, the particles of the
deposited
medicament powders, made available to the nozzle inlet, are gradually de-
aggregated and dispersed into a stream of air entering the nozzle. The
gradual de-aggregation and dispersal is produced by the high shearing forces
of the streaming air in connection with a relative motion introduced between
1o the nozzle and the powder entities of the combined doses. In a preferred
embodiment, the medicament powders are deposited onto a dose bed, such
that the powder deposits occupy an area of similar or larger size than the
area of the nozzle inlet. The nozzle is preferably positioned outside the area
of deposits, not accessing the powder by the relative motion until the air
15 stream into the nozzle, created by an applied suction, has passed a
threshold flow velocity. Coincidental with the application of the suction or
shortly afterwards the relative motion will begin such that the nozzle
traverses the powder entities constituting the combined doses gradually. The
high velocity air going into the nozzle inlet provides plenty of shearing
stress
2o and inertia energy as the flowing air hits the leading point of the border
of
the contour of the medicament entities, one after the other. This powder Air-
razor method, created by the shearing stress and inertia of the air stream, is
so powerful that the particles in the particle aggregates in the powder
adjacent to the inlet of the moving nozzle are released, de-aggregated to a
2s very high degree as well as dispersed and subsequently entrained in the
created air stream going through the nozzle. If the medicament deposits have
been made in separate compartments of the dose bed and individually
sealed, then obviously the compartments must be opened up first so that the
nozzle can access the deposited powder entities in each compartment when
3o suction is applied. Naturally, this is also true if the deposits share a
common
seal without an individual seal for each deposited entity. An arrangement for
cutting foil is disclosed in our Swedish patent publication SE 517 227 C2
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WO 2004/110404 PCT/SE2004/000954
(WO 02 / 24266 A 1 ) , which is hereby incorporated in this document in its
entirety as a reference. Depending on how the entities are laid out on the
dose bed, the nozzle will either suck up the powder entities sequentially or
in
parallel or in some serial/parallel combination.
s
The present invention improves the efficacy of tiotropium/fluticasone dose
delivery, compared to the best selling inhalers on the market today, by at
least a factor of two and typically 2.5. This is accomplished by raising the
FPF < 5 ~,m in the delivered dose to more than 40 %, preferably to more than
l0 50 %, by mass, compared to typically less than 30 % for prior art inhalers.
The implications of this vast improvement and the use of an anticholinergic
agent instead of a beta2-agonist are much less adverse reactions in users,
even to the point of eliminating the risk of death, due to high dosages of
beta2-agonists or corticosteroids systemically or in the wrong parts of the
15 airways.
Thus, the quality of asthma medicament delivery is dramatically improved
compared to prior art performance, leading to important advances in
delivering a majority of fine particles of the asthma medicaments of the
2o combined doses to the intended target area or areas in the user's airways
and lungs with very little loss of particles settling in the throat and upper
airways. Administering asthma medicament combinations according to the
present invention has a very positive therapeutic effect from a medical,
psychological and social point of view on a host in need of asthma treatment
2s with a co-ordinated combination of tiotropium and fluticasone.
Detailed descriptions of drawings
Referring to reference numbers 1 - 100 of the drawings wherein like
numbers indicate like elements throughout the several views of ten different
3o embodiments of combined doses comprising at least two deposited entities of
two medicaments onto a dose bed as illustrated in Figures 1 - 10 presented
here as non-limiting examples.
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26
Figure 1 illustrates combined doses 100 comprising two different
medicament entities deposited, 1 and 2, in separate compartments 21 and
22 onto a dose bed 20, said compartments may be capsules or blisters or
moldings in the dose bed. An individual seal 13 for each compartment
guarantees that the medicament doses cannot be contaminated by foreign
matter or by one another. The illustrated doses are intended for a sequential
delivery taking place during a single inhalation.
1o Figure 2 illustrates combined doses 100 comprising three different
medicament entities, 1, 2 and 3 in separate compartments 21, 22 and 23
similar to Figure 1, but arranged underneath the dose bed 20. Besides a
different arrangement of compartments on the dose bed 20 and the
respective seals 13, the main difference between Figure 1 and Figure 2 is
that entity 3 consists of the medicament of entity 2. It is thus possible not
only to administer two medicaments, but also to compose combined doses of
two medicaments with a very high ratio of mass between them. The
illustrated deposited entities are intended for a sequential delivery taking
place during a single inhalation.
Figure 3 illustrates combined doses 100 comprising two different
medicament entities, 1 and 2, laid out in parallel strips onto separate target
areas 11 and 12 respectively onto the dose bed 20. A common protective foil
13 protects the medicaments of the combined doses from being
contaminated by foreign matters. The illustrated entities are intended for a
fully simultaneous delivery of the two medicaments taking place during a
single inhalation.
Figure 4 illustrates combined doses 100 comprising two different
3o medicaments, 1 and 2, each comprising several deposited entities separated
by deposited entities of an inert excipient 3. The deposited entities are laid
out in a string of spots onto a target area 11 on a dose bed 20. The entities
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27
share a common seal 13. The combined doses are intended for a sequential
delivery of incorporated medicament and excipient entities, said delivery
taking place during an inhalation. The excipient deposits help to minimize
unintentional mixing of the medicaments. If some mixing of medicaments
can be accepted, then the excipient entities may be left out altogether.
Combined doses composed of spot entities may of course comprise more
medicaments than two. The mass ratio between medicament doses may be
easily set by controlling the ratio between the number of spot entities per
medicament in combination with the size of the respective spot entities in
1o terms of deposited mass. Naturally the spot entities need not necessarily
be
circular in shape, they may take an elongated or elliptical form, depending
on which types of combined dose forming methods are used.
Figure 5 illustrates combined doses 100 comprising deposited entities
~5 representing up to four different medicaments, 1, 2, 4 and 5, separated by
deposited entities of an inert excipient 3. The deposited entities are laid
out
in two parallel groups of two entities per group lined up in strips onto a
common target area 11 on a dose bed 20. The deposited entities share a
common seal 13. The excipient deposited entities help to minimize
2o unintentional interaction of the medicament doses. The combined doses are
intended for a combined parallel/ simultaneous and sequential delivery of
incorporated medicament doses, said delivery taking place during a single
inhalation.
2s Figure 6 illustrates combined doses 100 comprising two different
medicament entities, 1 and 2, each comprising a strip of deposited powder,
medicament 1 deposited onto a target area 11 of a dose bed 20 and
medicament 2 deposited on top of the entity of medicament 1. This method
of forming combined doses is an alternative to the ones previously disclosed
3o and may be used when a certain level of interaction or mixing of the
medicaments may be tolerated.
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Figure 7 illustrates combined doses 100 comprising two different
medicament entities, 1 and 2, and an excipient entity 3, each comprising a
strip of deposited powder. Medicament 1 is deposited onto a target area 11
of a dose bed 20 and excipient 3 is deposited onto medicament 1 to insulate
medicament 1 from a deposit of medicament 2 on top of the deposited entity
of excipient 3.
Figure 8 illustrates combined doses 100 comprising two different
medicament entities, 1 and Z, of somewhat irregular shapes but separately
to laid out onto a common target area 11 of the dose bed 20. The illustrated
entities are intended for a sequential delivery of the two medicament doses
taking place during an inhalation.
Figure 9 illustrates combined doses 100 comprising two different
1s medicament entities, 1 and 2, of somewhat irregular shapes but generally
separately laid out onto a common target area 11 of the dose bed 20. The
illustrated deposited entities overlap slightly, resulting in an arbitrary
mixture 9. The deposits are intended for a mostly sequential delivery of the
two medicament doses taking place during a single inhalation.
Figure 10a and 10b illustrate a delivery of combined doses 100 comprising
two different medicament entities, 1 and 2, and an excipient entity 3, each
comprising a strip of powder sequentially deposited in three different layers.
A nozzle 25 with an established flow of air 26 going into the inlet is put in
a
2s relative motion, parallel to the dose bed 20, such that the nozzle passes
over
the combined doses beginning at the right side R and ending at the left side
L of the dose bed. This Air-razor method results in a simultaneous, gradual
delivery of medicament entities 1 and 2 together with the excipient entity 3.
The powders of the entities are mixed into an aerosol 2? by the air flowing
3o into the nozzle leading to simultaneous delivery of the two medicament
doses
and the excipient. This Air-razor method may be applied to all embodiments
of the present invention and results in a simultaneous or sequential or a
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combined simultaneous/sequential delivery of all included medicament
doses and optional excipients.
