U.S. patent application number 13/752480 was filed with the patent office on 2013-06-06 for suspension formulations.
This patent application is currently assigned to INNOVATA BIOMED LIMITED. The applicant listed for this patent is INNOVATA BIOMED LIMITED, VECTURA LIMITED. Invention is credited to Tanya CHURCH, Christina Alexandra KEEBLE, David Andrew LEWIS, Nicola Kim WHITFIELD.
Application Number | 20130142879 13/752480 |
Document ID | / |
Family ID | 39204077 |
Filed Date | 2013-06-06 |
United States Patent
Application |
20130142879 |
Kind Code |
A1 |
LEWIS; David Andrew ; et
al. |
June 6, 2013 |
SUSPENSION FORMULATIONS
Abstract
The present invention relates to suspension formulations,
especially those for delivering a pharmaceutically active agent in
aerosol form using a spray or aerosol device, such as a pressurised
metered dose inhaler (pMDI). The formulations may be for pulmonary,
nasal, buccal or topical administration, but are preferably for
pulmonary inhalation.
Inventors: |
LEWIS; David Andrew;
(Chippenham, GB) ; KEEBLE; Christina Alexandra;
(Chippenham, GB) ; WHITFIELD; Nicola Kim;
(Ruddington, GB) ; CHURCH; Tanya; (Chippenham,
GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
VECTURA LIMITED;
INNOVATA BIOMED LIMITED; |
Chippenham
Ruddington |
|
GB
GB |
|
|
Assignee: |
INNOVATA BIOMED LIMITED
Ruddington
GB
VECTURA LIMITED
Chippenham
GB
|
Family ID: |
39204077 |
Appl. No.: |
13/752480 |
Filed: |
January 29, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12865142 |
Apr 13, 2011 |
|
|
|
PCT/GB2009/000261 |
Feb 2, 2009 |
|
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13752480 |
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Current U.S.
Class: |
424/490 ; 424/43;
424/45 |
Current CPC
Class: |
A61K 31/00 20130101;
A61P 11/08 20180101; A61K 9/0078 20130101; A61K 9/008 20130101;
A61K 31/167 20130101; A61K 2300/00 20130101; A61K 31/00 20130101;
A61K 31/58 20130101; A61K 9/50 20130101; A61P 11/06 20180101 |
Class at
Publication: |
424/490 ; 424/43;
424/45 |
International
Class: |
A61K 9/12 20060101
A61K009/12; A61K 9/50 20060101 A61K009/50; A61K 9/14 20060101
A61K009/14 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 1, 2008 |
GB |
0801876.4 |
Claims
1-21. (canceled)
22. A suspension formulation comprising: particles comprising
formoterol; a propellant; and an additive material.
23. The suspension formulation according to claim 22, wherein the
suspension formulation comprises a second pharmaceutically active
agent.
24. The suspension formulation according to claim 23, wherein the
second pharmaceutically active agent is glycopyrrolate.
25. The suspension formulation according to claim 22, wherein the
propellant comprises HFA 227, HFA 134a, or a combination
thereof.
26. The suspension formulation according to claim 22, wherein the
propellant is HFA 134a.
27. The suspension formulation according to claim 22, wherein the
additive material is a phospholipid.
28. The suspension formulation according to claim 22, wherein the
additive material is lecithin.
29. The suspension formulation according to claim 22, wherein the
additive material promotes formulation stability and controls
agglomeration of the particles.
30. The suspension formulation according to claim 22, wherein the
suspension comprises spray dried materials.
31. The suspension formulation according to claim 30, wherein the
spray dried materials comprise formoterol and the additive
material.
32. The suspension formulation according to claim 31, wherein the
additive material is a phospholipid.
33. The suspension formulation according to claim 22, wherein the
particles comprise the additive material and at least 90% of the
particles have a Mass Median Aerodynamic Diameter (MMAD) of no more
than about 10 .mu.m.
34. The suspension formulation according to claim 22, wherein at
least 90% of the particles have a Mass Median Aerodynamic Diameter
(MMAD) of from about 1 .mu.m to about 5 .mu.m.
35. A metered dose inhaler comprising the suspension formulation
according to claim 22.
36. The suspension formulation according to claim 22, wherein the
propellant is HFA 134a, the additive is a phospholipid, and the
suspension formulation comprises spray dried materials.
37. The suspension formulation according to claim 36, wherein the
spray dried materials comprise formoterol and the phospholipid.
38. The suspension formulation according to claim 22, wherein the
propellant is HFA 134a, the additive material is a phospholipid,
and the suspension formulation further comprises
glycopyrrolate.
39. The suspension formulation according to claim 38, wherein the
suspension formulation comprises spray dried materials comprising
formoterol and a phospholipid.
Description
[0001] The present invention relates to suspension formulations,
especially those for delivering a pharmaceutically active agent in
aerosol form using a spray or aerosol device, such as a pressurised
metered dose inhaler (pMDI). The formulations may be for pulmonary,
nasal, buccal or topical administration, but are preferably for
pulmonary inhalation.
BACKGROUND TO THE INVENTION
[0002] Since the pMDI was introduced in the mid 1950s, inhalation
has become the most widely used route for delivering bronchodilator
drugs and steroids to the airways of asthmatic patients. Compared
with oral administration of bronchodilators, inhalation offers a
rapid onset of action and a low instance of systemic side effects.
More recently, inhalation from a pressurized inhaler has been a
route selected for the administration of other drugs.
[0003] The pMDI is dependent upon the propulsive force of a
propellant system used in its manufacture to dispense the drug
formulation from the device in a form that may be inhaled by a
patient. The propellant generally comprises a mixture of liquefied
hydrofluorocarbons (HFAs) which are selected to provide the desired
vapour pressure and stability of the formulation. Propellants HFA
227 (1,1,1,2,3,3,3-heptafluoropropane) and HFA 134a
(1,1,1,2-tetrafluoroethane) are the currently the most widely used
propellants in aerosol formulations for inhalation
administration.
[0004] It has been suggested that hydrocarbons, such as n-butane,
isobutanol, and propane be considered as CFC replacements in
aerosol formulations. However, it has been found that such
hydrocarbons have low densities relative to the pharmaceutically
active agents included in the formulations. Where suspension
formulations are prepared using such propellants, the formulations
sediment rapidly and are unacceptable. Furthermore, the solubility
of many drugs in these hydrocarbons is poor, which means that it is
difficult to prepare formulations that are solutions which contain
suitable amounts of drug.
[0005] The formulations currently dispensed using pMDIs generally
comprise a pharmaceutically active agent, one or more propellants,
and optionally excipients and adjuvants such as co-solvents,
(conventional) surfactants, flavouring agents and lubricants.
[0006] The excipients should be miscible with the propellants in
the amounts employed. Suitable excipients include alcohols such as
ethyl alcohol, isopropyl alcohol, propylene glycol, hydrocarbons
such as propane, butane, isobutane, pentane, isopentane,
neopentane, and other propellants much as those commonly referred
to as propellants 11, L2, 114, 113, 142b, 152a 124, and dimethyl
ether.
[0007] Preferred adjuvants are liquids or gases at room temperature
and at atmospheric pressure. The combination of one or more of such
adjuvants with a propellant such as HFA 134a or HFA 227 provides a
propellant system which has comparable properties to those of
propellant systems based on CFCs of the past decades, allowing use
of known surfactants and additives in the pharmaceutical
formulations. This is particularly advantageous since the safety
and use of such compounds in metered dose inhalers for drug
delivery to the human lung is well established. Additives that are
well know include ethanol, water, glycerol and polyethylene
glycol.
[0008] The pharmaceutically active agents present in formulations
used in pMDIs and similar propellant-driven devices are either
dissolved or suspended in a liquefied propellant gas. Most
pharmaceutically active agents are not sufficiently soluble in pure
propellants, either HFAs or CFCs, for simple two component
formulations of active agent and propellant to be practical.
Although, through the incorporation of a co-solvent such as
ethanol, many active agents can be dissolved in the resulting
formulation, formulations in which the active agent, in a
micronised or particulate form, is suspended in the propellant are
generally preferred and more common. There are several reasons for
this. It is important to control the size of the particles or
droplets in the aerosol spray produced by a pMDI, or like device.
For example, if the particles or droplets are to penetrate deep
into the lungs, they should have a mass median aerodynamic diameter
(MMAD) of less than 10 .mu.m. Conversely, if the spray is for
buccal or nasal delivery, the particles or droplets must have an
MMAD of significantly greater than 10 .mu.m, in order to prevent
them from entering the lungs. Controlling the size of the particles
in an aerosol spray produced from a purely liquid formulation is
more difficult than it is with a formulation comprising a suspended
solid particulate pharmaceutically active agent. In the former
case, many environmentally influenced factors, such as solvent
evaporation rates, will have an effect on particle size, whereas
the size of the particles produced by a suspension formulation is
determined largely by the size of the active agent particles
employed in its preparation, and this is a parameter that can be
effectively controlled.
[0009] A second, but important, reason for suspension formulations
being preferred is that many pharmaceutically active agents are
chemically more stable as solids than they are when in solution.
For example, most pharmaceutically active compounds are much more
susceptible to degradation by acid or alkali when in solution than
they are when solid. It is also simply impossible to render many
pharmaceutically active agents sufficiently soluble in a
pharmaceutically acceptable propellant system, for a solution
formulation to be a realistic option for them.
[0010] A further, reason for suspension formulations being
preferred to solutions is that solution formulations may be
restricted by the drug loading capacity of the solvent. Drug
loading levels will vary depending on the solvent and solute used,
however, suspension systems are not limited in this way and
routinely allow higher drug loads to be incorporated into the
formulations.
[0011] Dissolving an active agent to form a solution negates the
need to micronise the drug to obtain a suitable particle size.
However, not all active agents are stable when in solution or in
direct contact with the excipients and propellant.
[0012] Previous disclosure, for example by 3M, has demonstrated
that the solubility of many drugs may be enhanced in the presence
of ethanol. However, high levels of ethanol may impart a negative
effect on a suspension system by dissolving the drug. Dispersing
agents, such as surfactants, are commonly employed in suspension
aerosol formulations in order to ensure that the particles of
pharmaceutically active agent can be dispersed within the
propellant system without an undue degree of agitation and remain
so dispersed for a sufficiently long period of time for the
effective operation of the pMDI to be ensured. Surfactants can also
provide useful lubrication to the metering valve's mechanism.
However, one of the problems which has arisen in the development of
HFA-based suspension formulations for use in pMDI and like devices,
is that many of the surfactants commonly employed as dispersing
agents in CFC-based formulations are substantially insoluble in HFA
134a and HFA 227 and, thus, are substantially ineffective in simple
formulations based on these latter two propellants, or other HFA
propellants.
[0013] One solution to this problem, which was proposed in EP 0 372
777, is to incorporate a co-solvent, such as ethanol, having a
greater polarity than the HFA propellant in the formulation, in
order to dissolve the surfactant or other dispersing agent. Whilst
the presence of such a co-solvent allows most dispersing agents to
be dissolved in HFA based formulations, it will also cause certain
pharmaceutically active agents to dissolve, at least partially, in
the co-solvent/propellant system. This phenomenon is especially
disadvantageous in formulations for delivery into the lungs
because, over time, it causes the particles of active agent in the
formulation to grow, possibly to a size in excess of that generally
considered to be acceptable for inhalation, i.e., to have a MMAD of
greater than 10 .mu.m. Further disadvantages associated with the
use of ethanol as a co-solvent include its potential toxicity, its
capacity to increase a formulation's propensity to absorb water and
the fact that many patients dislike the taste that its presence can
impart to a formulation.
[0014] Another method for incorporating a surfactant or dispersing
agent which has been previously proposed is to coat the particles
of pharmaceutically active agent with the surfactant or dispersing
agent before they are mixed with the propellant and to suspend the
coated particles in the HFA propellant without using any
co-solvent.
[0015] One process which has been proposed in order to achieve such
coating involves the steps of dissolving the surfactant in a
solvent in which the pharmaceutically active agent is substantially
insoluble, mixing a quantity of the pharmaceutically active agent,
in micronised form, into the surfactant solution and isolating
particles of surfactant coated active agent either by filtration
and drying, or by removal of the solvent by evaporation. Although
the literature suggests (see WO 92/08447 and WO 91/04011) that
formulations prepared in this manner are effective, in the sense
that they allow stable dispersions of powdered active agent to be
formed in the HFA propellant, it has so far not proven possible, in
practice, to manufacture useful formulations in this way. For
example, it is difficult to achieve a uniform coating using
techniques of this nature because the manner in which the
dispersing agent precipitates from the evaporating solvent can be
unpredictable.
[0016] WO 2006/059152 proposes coating the particles of
pharmaceutically active agent with a dispersing agent by fusing
solid, particulate dispersing agent to the surfaces of the active
particles by mechanical means, such as a milling step. The
resulting composite or hybrid particles are readily dispersible
within HFA propellant systems.
[0017] A further technique which has been proposed is to suspend a
powdered mixture consisting of particles of a calcium, magnesium or
zinc salt of palmitic or stearic acid and particles of
pharmaceutically active agent in the propellant.
[0018] A further problem that is often associated with known
formulations for delivery using devices such as pMDIs is their
stability and consequently their shelf life. This especially
applies to ethanol-free suspension formulations. These formulations
and the pMDI products have a reduced shelf life due to moisture
ingress. Generally, when the formulations are prepared they are
free of moisture. However, once opened from their foil packaging,
the shelf life of the pMDI formulation is dramatically reduced due
to the ingress of moisture. The ingress of moisture can change the
suspension characteristics, often leading to increased flocculation
rate which leads to poor product performance and poor drug
delivery.
[0019] It is an aim of the present invention to provide improved
suspension formulations comprising a pharmaceutically active agent
for delivery using a spray or aerosol device, such as a pressurised
metered dose inhaler (pMDI).
[0020] In particular, it is desirable for the active agent within
the suspension formulations to be stable, so that the physical and
chemical state of the active agent is retained when the formulation
is made and over time as it is stored and used. More specifically,
it is an aim of the present invention to provide suspension
formulations that allow the delivery of an active agent in
amorphous form (and therefore exhibiting preferable dissolution
characteristics).
[0021] It is also an aim of the present invention to provide a
suspension formulation in which the suspension itself is physically
stable, in that it exhibits a reduced tendency to flocculate and/or
for the suspended particles to sediment. It is also an aim of the
present invention to provide suspension formulations with a long
shelf-life and, in particular, formulations that are not sensitive
to moisture ingress.
SUMMARY OF THE INVENTION
[0022] In a first aspect of the present invention, a composition is
provided which is suitable for delivery using a pressurised metered
dose inhaler, the composition comprising a suspension of a
pharmaceutically active agent in one or more propellants, wherein
composition further comprises one or more suspension stabilisers to
maintain the physical state of the active agent in the composition,
said suspension stabilizer may be insoluable.
[0023] In a preferred embodiment of the invention, the composition
comprises the pharmaceutically active agent in amorphous form and
the suspension stabilisers serve to maintain that amorphous form in
the suspension.
[0024] Preferred suspension stabilisers include amino acids and
saccharides. Preferred amino acids include aspartame, leucine,
isoleucine, lysine, valine, methionine, cysteine, and
phenylalanine. Leucine is especially preferred. Preferred
saccharides include disaccharides such as trehalose.
[0025] An alternative suspension stabiliser is a vinyl polymer such
as polyvinylpyrrolidone (PVP).
[0026] In one embodiment of the invention, the compositions
comprise two or more active agents and these are preferably
compatible with one another. The active agents may be included as
separate particles in the suspension. Alternatively, a particle in
the suspension may comprise more than one active agent.
[0027] In a preferred embodiment of the present invention, the
active agent is included in the composition as coated particles.
The coating or encasement surrounding the particles preferably
stabilises the active agent, ensuring that it maintains its
physical state. Preferred coatings comprise suspension stabilisers
such as saccharides and amino acids, as discussed above. The coated
particles of active agent may be in the form of microcapsules,
microspheres, or microsponges. The coating materials may be
trehalose and/or leucine. In some embodiments, the coating may
further include at least one other amino acid. The compositions
and/or the coated particles may also include a surfactant. In some
preferred embodiments, the coated active particles are formed by
spray drying.
[0028] There are a number of reasons why a particulate active
substance might need to be formulated within a protective
encasement. For example, the active may be physically or chemically
unstable, or incompatible with another substance with which it
needs to be formulated. It may need protection against, for
example, moisture, light, oxygen or other incompatible chemicals.
The surface coating may alternatively be required to delay release
of the active for a desired time period or until it reaches an
appropriate site, or to target its delivery to such a site. The
surface coating may alternatively be required to minimise
interparticle and or particle device interaction.
[0029] In a preferred embodiment, the coating of encasement is
complete or substantially complete, so that the active agent is
completely surrounded by the coating material. In other
embodiments, the coating may be partial, in which case the coating
preferably covers at least 40%, at least 50%, at least 60%, at
least 70%, at least 80%, at least 90% or at least 95% of the
surface of the active particle.
[0030] Pharmaceutical formulations, including those to be dispensed
using a pMDI, containing one or more drugs are known in the art.
These multi-active formulations require the solubility
characteristics of the actives to be complementary in order for
this to be achieved for example solution and suspension, suspension
and suspension or solution and solution. The term active refer to
one or more drugs, prodrugs, salts or esters thereof as outlined
below.
[0031] It has been found that drugs which are at least slightly
soluble in hydrocarbon propellants will exhibit an enhanced
solubility in the propellant in the presence of high levels of a
co-solvent such as ethanol.
[0032] In the context of the present invention, an active agent is
said to be "insoluble" or "substantially insoluble" in the
formulation if it has a solubility in the formulation of less than
25 g/L. "Insoluble" active agents may also have a solubility of
less than 20 or less than 15 g/L. Where an active agent is said to
be "poorly soluble" or "slightly soluble" in the formulation, the
active has a solubility in the formulation of less than 50 g/L or
less than 40 g/L. Preferably, the solubility of an active agent in
the formulation is measured at ambient temperature (20.degree. C.)
and at atmospheric pressure.
[0033] Historically, ethanol was added to the pMDI formulation to
dissolve surfactants and valve lubricants. It has since been found
that the ethanol is also capable of dissolving the drug within the
pMDI formulation.
[0034] Surprisingly it has now been found that including
co-solvents such as ethanol in small amounts can be highly
beneficial. More specifically, it is desirable to include in the
suspension formulations of the present invention a co-solvent in an
amount which does not cause total dissolution of the active agent.
At such low concentrations, the co-solvent has a beneficial effect
on the suspension system, without destroying the suspension and
forming a solution. The co-solvent has been found to reduce
flocculation and sedimentation.
[0035] According to a second aspect of the present invention, a
composition is provided which is suitable for delivery using a
pressurised metered dose inhaler, the composition comprising a
suspension of a pharmaceutically active agent in one or more
propellants, wherein composition further comprises a co-solvent in
an amount which has little effect on the solubility of the active
agent and which does not cause significant dissolution of the
active agent in the composition.
[0036] Suitable co-solvents include, but are not limited to,
alcohols such as ethanol, methanol, ethers, and polyethylene
glycol.
[0037] A preferred co-solvent is ethanol and it is preferably
included in the formulations of the present invention in an amount
below 1% w/w. At this concentration, the ethanol tends to have
little effect on the solubility of an active agent and this small
amount of ethanol does not cause complete or significant
dissolution of the active agent in the formulation used.
[0038] With this information the skilled artisan would know that
the various components of the compositions according to the
invention would need to be altered slightly to account for the
inherent solubility of the active agent in the formulation.
[0039] The inclusion of between 0.1 and 0.5% w/w ethanol in the
compositions of the present invention is particularly advantageous
because this enhanced suspension has been shown to permit the
active agent to retain its physical state in the composition,
preferably remaining in the amorphous state and not reverting to
the crystalline state. In other words, there is enough ethanol in
the composition to assist in the maintenance of the suspension,
extending the duration of particle suspension and minimising
flocculation.
[0040] A particular advantage associated with the inclusion of
small amounts of co-solvent in the suspension compositions of the
invention is that this allows the compositions to be prepared so
that they include a level of moisture from the beginning of the
formulation procedure. This means that the suspension is not unduly
affected by moisture ingress when the product is first used and
removed from any protective packaging, as is observed with some
known suspension formulations, as discussed above. Desiccation
processes during the preparation of the compositions according to
the present invention are not required when the co-solvent is
present. What is more, the addition of these low levels of
co-solvents, such as ethanol, provide further composition
flexibility to the final formulation by permitting the addition of
water, acids and surfactants if so required. The addition of these
additives is not recommended and may be detrimental to desiccated
systems.
[0041] In a preferred embodiment of the present invention, the
suspension is prepared using spray dried materials. Spray drying
active agents in conjunction with a suspension stabiliser such as
leucine or derivatives thereof and/or trehalose results in an
unexpected level of protection of the amorphous drug state, thereby
further preventing reversion to the crystalline form. Furthermore
this arrangement confers an enhanced suspension characteristics
within propellant vehicles (such as HFA 134a and/or HFA 227) with
or without the addition of a co-solvent, thereby extending the
duration of particle suspension and minimising flocculation.
[0042] It has surprisingly been found that by the appropriate
selection and addition of a co-solvent, such as ethanol, to the
formulation a number of advantages are available to the final
system. These include suppression of propellant flashing at the
spray orifice thereby preventing drug deposition directly over the
spray orifice and thus reducing potential orifice blockage.
Surprisingly, low levels of ethanol, for example 0.1% w/w, have
been found to improve the consistency of the valve metering. In
addition to this benefit, low levels of co-solvents such as ethanol
allow dissolving of valve lubricants, surfactants and/or excipients
such as oleic acid, propylene glycol which may also act as
formulation excipients and/or stabilisers. However, to ensure the
physical state of the drug is not altered during suspension within
the pMDI, the selection of the co-solvent content must not result
in a significant increase in solubility of the active or additive
within the system.
[0043] Table 1 below reports the solubility of some typical drugs
used within inhalation products for treating respiratory diseases.
The data in Table 1 demonstrates that ethanol addition can increase
the solubility of drugs within HFA systems. However, it has been
surprisingly found that the addition of ethanol to HFA 227 systems
does not result in solubilisation of actives above that determined
for pure HFA 134a. It therefore follows that HFA 227 with small
additions of ethanol not only results in drug solubility levels
below that of HFA 134a systems but also results in the
aforementioned advantages of ethanol addition to the propellant
based systems. Therefore, in a preferred embodiment of the present
invention, the composition will comprise the propellant HFA 227 and
will contain quantities of ethanol that result in drug solubility
below 1 .mu.g per 54 .mu.l, or more preferably below 0.1 .mu.g per
50 .mu.l, or more preferably below 0.05 .mu.g per 50 .mu.l.
[0044] In some embodiments of the first aspect of the present
invention, the suspension composition comprising the suspension
stabiliser further comprises a co-solvent in an amount which has
little effect on the solubility of the active agent and which does
not cause significant dissolution of the active agent in the
composition.
[0045] In some embodiments of the second aspect of the present
invention, the suspension composition comprising the co-solvent
further comprises one or more suspension stabilisers.
[0046] It is important that the suspension stabilisers used in the
present invention do not dissolve within the composition and, in
particular, in the propellant system used. Trehalose has been
determined to be insoluble (observed to be <0.12 .mu.g/50 .mu.l)
in HFA 134a or HFA 227 with up to 12% w/w ethanol and only slightly
soluble in 30% w/w ethanol (3.3 .mu.g/54 .mu.l in HFA 134a, 2.7
.mu.g/50 .mu.l in HFA 227). Addition of 0.5% w/w propylene glycol
or 0.01% w/w oleic acid did not increase trehalose solubility
(<0.12 .mu.g/50 .mu.A) in either 3% w/w ethanol when
manufactured with either HFA 134a or HFA 227. The addition of 1.2%
w/w water was not found to increase trehalose solubility (<0.12
.mu.g/50 .mu.l) in 12% w/w ethanol formulation manufactured with
either HFA 134a or HFA 227.
[0047] Leucine has been determined to be insoluble (observed to be
<0.08 .mu.g/50 .mu.l) in HFA 134a or HFA 227 with up to 30% w/w
ethanol. Addition of 0.5% w/w propylene glycol or 0.01% w/w oleic
acid did not increase leucine solubility (<0.08 .mu.g/50 .mu.l)
in 3% w/w ethanol when manufactured with either HFA 134a or HFA
227. The addition of 1.2% w/w water was not found to increase
leucine solubility (<0.08 .mu.g/50 .mu.l) in 12% w/w ethanol
formulation manufactured with either HFA 134a or HFA 227.
TABLE-US-00001 TABLE 1 Solubility of drugs within HFA 134a,
represented as .mu.g per 50 .mu.l EtOH addition (% w/w) Drug 0 1 5
12 20 Fluticasone Propionate 0.48 1.45 9.41 48.80 86.60 Ipratropium
Bromide 0.03 0.24 3.50 Tiotropium Bromide 0.00 0.01 0.33 Budesonide
1.43 4.38 35.41 Formoterol 0.00 0.03 0.73
TABLE-US-00002 TABLE 2 Solubility of drugs within HFA 227,
represented as .mu.g per 50 .mu.l EtOH addition (% w/w) Drug 0 0.2
1 5 Fluticasone Propionate 0.22 0.23 0.83 4.78 Ipratropium Bromide
0.00 -- 0.04 4.32 Tiotropium Bromide 0.00 -- 0.00 0.07 Budesonide
1.66 -- 5.61 45.16 Formoterol 0.00 -- 0.02 0.23
[0048] There are few drugs which are soluble at therapeutic dosage
levels in aerosol propellants alone, and one example is estradiol
dipropinoate. Solution formulations comprising other, less soluble
active agents have been prepared using a toxicity approved polar
co-solvent, such as ethanol.
[0049] A particularly preferred formulation according to the
invention comprises particles comprising an active agent formulated
with leucine and optionally trehalose, for delivery to a patient,
wherein the particle remains substantially unaltered in a pMDI
formulation.
[0050] The skilled artisan would be able to determine the precise
drug loading for formulations according to the present invention.
As an example, the following compounds and their proposed
concentrations are disclosed, for reference.
[0051] Tiotropium bromide constitutes from about 0.001% (.about.0.4
.mu.g per dose in 100 .mu.l valve) to 0.16% by weight (.about.200
.mu.l per dose in 25 .mu.l valve), preferably from about 0.010 to
about 0.400% by weight, more preferably about 0.0150 to about
0.300% by weight, and most preferably about 0.0300 to about 0.200%
by weight of the formulation.
[0052] Ipratropium bromide constitutes from about 0.001%
(.about.0.4 .mu.g per dose in 100 .mu.l valve) to 0.16% (.about.200
.mu.g per dose in 25 .mu.l valve), preferably from about 0.010 to
about 0.400%, more preferably about 0.0150 to about 0.300%, and
most preferably about 0.0300 to about 0.200% by weight of the
formulation.
[0053] Salbutamol sulphate constitutes from about 0.01% (.about.3
.mu.g per dose in 100 .mu.l valve) to 0.98% (.about.1200 .mu.g per
dose in 25 .mu.l valve), preferably from about 0.025 to about 0.6%,
more preferably about 0.050 to about 0.5%, and most preferably
about 0.075 to about 0.4% by weight of the formulation.
[0054] Salbutamol constitutes from about 0.03% (.about.10 .mu.g per
dose in 100 .mu.l valve) to 0.8% (.about.1000 .mu.g per dose in 25
.mu.l valve), preferably from about 0.04 to about 0.7%, more
preferably about 0.05 to about 0.5, and most preferably about 0.06
to about 0.35% by weight of the formulation.
[0055] Formoterol fumarate constitutes from about 0.002%
(.about.0.6 .mu.g per dose in 100 .mu.l valve) to 0.12% (.about.150
.mu.g per dose in 25 .mu.l valve), preferably from about 0.025 to
about 0.06%, more preferably about 0.050 to about 0.03%, and most
preferably about 0.075 to about 0.02% by weight of the
formulation.
[0056] Fluticasone propionate constitutes from about 0.02%
(.about.5 .mu.g per dose in 100 .mu.l valve) to 2% (.about.2500
.mu.g per dose in 25 .mu.l valve), preferably from about 0.018 to
about 1%, more preferably about 0.012 to about 0.5%, and most
preferably about 0.010 to about 0.25% by weight of the
formulation.
[0057] Salbutamol xinafoate constitutes from about 0.014% (.about.5
.mu.g per dose in 100 .mu.l valve) to 2% (.about.2500 .mu.g per
dose in 25 .mu.l valve), preferably from about 0.016 to about 0.5%,
more preferably about 0.018 to about 0.1%, and most preferably
about 0.020 to about 0.06% by weight of the formulation.
[0058] The skilled artisan will be able to calculate the
appropriate drug loading based upon the values of one propellant
and relate HFA 227 (density 1.415 g/ml) to HFA 134a (density 1.216
g/ml) and vice versa. This approach assumes that the drug density
falls between that of HFA 227 (density 1.415 g/ml) to HFA 134a
(density 1.216 g/ml). The creation of a suspension formulation may
be achieved by initially using a single propellant to suspend the
drug particles. Initial attempts will most likely result in the
drug density falling either above or below the propellant density.
This may be rectified with the incremental addition of the second
propellant to the first, which will result in a combined "titrated"
propellant with a density which has been tailored to match the
density of the drug thereby creating a suspension.
[0059] The skilled artisan would be able to determine the
appropriate amounts of suspension stabilisers to be included in
formulations according to the present invention. As an example, the
following compounds and their proposed concentrations are
disclosed, for reference.
[0060] Leucine may be included in the compositions according to the
present invention in an amount of from about 0.00003% to 2%,
preferably from about 0.0001 to about 1%, more preferably about
0.0002 to about 0.2%, and most preferably about 0.0003 to about
0.02% by weight of the formulation.
[0061] Trehalose may be included in the compositions according to
the present invention in an amount of from about 0.00003% to 2%,
preferably from about 0.0001 to about 1%, more preferably about
0.0002 to about 0.2%, and most preferably about 0.0003 to about
0.02% by weight of the formulation.
[0062] Ethanol may be included in the compositions according to the
present invention in an amount of from about 0.0010 to about 2% by
weight of the total formulation, preferably about 0.0025 to about
0.5% by weight, preferably about 0.0050 to about 0.2% by weight and
most preferably about 0.01 to 0.15% by weight of the aerosol
formulation.
[0063] Oleic acid may be included in the compositions according to
the present invention in an amount of from about 0.0001% to about
1% by weight, preferably from about 0.0025 to about 0.5% by weight
preferably from about 0.0050 to about 0.1% by weight, more
preferably about 0.0075 to about 0.1 by weight, and most preferably
about 0.01 to 0.02% by weight of the aerosol formulation.
[0064] Glycerol may be included in the compositions according to
the present invention in an amount of from about 0.0001% to about
5% by weight, preferably from about 0.0025 to about 4% by weight,
more preferably about 0.005 to about 3% by weight, more preferably
about 0.0075 to about 2.5% by weight, and most preferably about
0.01 to 1.0% by weight of the aerosol formulation.
[0065] Propylene glycol may be included in the compositions
according to the present invention in an amount of from about
0.0001% to about 5% by weight, preferably from about 0.0025 to
about 4% by weight, more preferably about 0.005 to about 3% by
weight, more preferably about 0.0075 to about 2% by weight, and
most preferably about 0.01 to 1.0% by weight of the aerosol
formulation.
[0066] Polyvinylpyrrolidone may be included in the compositions
according to the present invention in an amount of from about
0.0001% to about 5% by weight, preferably from about 0.0025 to
about 4% by weight, more preferably about 0.005 to about 3% by
weight, more preferably about 0.0075 to about 2.5% by weight, and
most preferably about 0.01 to 1.0% by weight of the aerosol
formulation.
[0067] In one embodiment of the present invention, the aerosol
formulations do not contain a propellant other than HFA 227. Most
preferably, the aerosol formulations of the present invention do
not contain ingredients other than the propellant, ethanol, or the
excipients mentioned above.
[0068] Preferred compositions according to this invention exhibit
substantially no change in the amorphous or crystalline state of
the drug over a prolonged period. Preferably the prolonged period
is at least 1 year, more preferably at least 2 years, and even more
preferably at least 3 years and most preferably at least 4 years.
The formulations disclosed herein remain substantially and readily
redispersible and, upon redispersion, do not flocculate quickly,
thereby ensuring reproducible drug dosing.
[0069] The term "flocculate" in the context of the present
application is generally used to describe the process whereby
formulation components or particles assemble into floccules or
flocculent aggregates imparting a typically granular appearance to
the suspension.
[0070] The term suspension in the context of the present
application is generally used to describe a mixture in which
particles are uniformly suspended within a fluid. The suspension
often possesses a typically milky appearance for a period of
time.
[0071] When present in the compositions of the present invention as
an additive material, amino acids have been found to provide a high
respirable fraction of the active material and good flow properties
of the powder. The additive material may comprise one or more of
any of the following amino acids: aspartame, leucine, isoleucine,
lysine, valine, methionine, cysteine, and phenylalanine. A
preferred amino acid is leucine, in particular L-leucine,
di-leucine and tri-leucine. Although the L-form of the amino acids
is generally preferred, the D- and DL-forms may also be used.
Additive materials may also include, for example, metal stearates
such as magnesium stearate, phospholipids, lecithin, colloidal
silicon dioxide and sodium stearyl fumarate, and are described more
fully in WO 96/23485, which is hereby incorporated by
reference.
[0072] In one embodiment of the present invention, the composition
comprises active particles comprising additive, at least 50%, at
least 70% or at least 90% of the particles having a Mass Median
Aerodynamic Diameter (MMAD) of no more than about 10 .mu.m. In
another embodiment, at least 50%, at least 70% or at least 90% of
the active particles have an MMAD of from about 1 .mu.m to about 5
.mu.m. In yet another embodiment, at least 50%, at least 70% or at
least 90% of the active particles have aerodynamic diameters in the
range of about 0.05 .mu.m to about 3 .mu.m.
[0073] Microparticles refer to substantially spherical particles
having a mean diameter within about 0.020 .mu.m to 1000 .mu.m and
includes microcapsules, microspheres, and microsponges.
[0074] As used herein, the term "microcapsule" refers to a particle
wherein a wall, shell or coating encases a core. In some
embodiments, the core comprises the active agent. As used herein,
the term "microsphere" refers to a microparticle wherein an active
agent is embedded within a solid matrix. As used herein, the term
"microsponge" refers to a microparticle wherein an active agent is
embedded within a polymeric matrix comprising an open-cell
structure.
[0075] According to a particular embodiment of the present
invention, there is provided an aerosol formulation which contains
a dispersed phase, comprising a propellant selected from HFA 134a
or HFA 227 and mixtures thereof; a co-solvent; suspension
stabilizers and a pharmaceutically active agent, in which the
active agent is in the composition in a manner which permits the
preservation of its physical form.
[0076] The term suspension aerosol means that the active agent is
in particulate form and is substantially insoluble in other
components of the composition.
[0077] All weight percentages recited herein are based on the total
weight of the formulation unless otherwise indicated.
[0078] The compositions according to the present invention, and in
particular those including a co-solvent in the small amounts
discussed, have the further advantage that they can provide
improved valve metering performance. Conventional valves for use in
devices such as pMDIs tend to be specifically designed for either
an ethanol-containing solution formulation, or an ethanol-free
suspension. The compositions according to the present invention can
be dispensed using either type of valve and the nature of the
compositions means that they provide the composition flexibility to
allow them to be formulated to improve valve performance.
[0079] As used herein, the term "Nominal Dose" is the amount of
drug metered in the metering chamber, also known as the Metered
Dose (MD). This is different to the amount of drug that is
delivered to the patient which is referred to a Delivered Dose. The
Delivered Dose, also referred to as the Emitted Dose, (ED) refers
to the dose that leaves the device and it is measured as set out in
the current European Pharmacopoeia monograph for inhalation
products. The therapeutic dose is the dose range that is proven to
be clinically effective.
[0080] As used herein, the term "fine particle fraction" (FPF) is
normally defined as the FPD (the dose that is <5 .mu.m) divided
by the Delivered Dose (ED) which is the dose that leaves the
device. The FPF is expressed as a percentage. Herein, the FPF of ED
is referred to as FPF (ED) and is calculated as FPF
(ED)=(FPD/ED).times.100%.
[0081] The fine particle fraction (FPF) may also be defined as the
FPD divided by the Metered Dose (MD) which is the dose in the
blister or capsule, and expressed as a percentage. Herein, the FPF
of MD is referred to as FPF (MD), and is calculated as FPF
(MD)=(FPD/MD).times.100%.
[0082] The term "ultrafine particle fraction" (UFPD) is used herein
to mean the percentage of the total amount of active material
delivered by a device which has a diameter of not more than 3
.mu.m. The term percent ultrafine particle dose (% UFPD) is used
herein to mean the percentage of the total metered dose which is
delivered with a diameter of not more than 3 .mu.m (i.e., %
UFPD=100*UFPD/total metered dose). "Actuation of a pMDI inhaler"
refers to the process during which a dose is discharged from the
metering chamber.
Preparing pMDI Formulations
[0083] The spray drying of material for subsequent incorporation
into a pMDI surprisingly maintains the structural state prior to
and during atomisation. Traditionally used for dry powders, spray
drying is not the most efficient method of particle manufacture due
to the low powder recoveries. Amorphous material that has been
formulated as a dry powder often results in an unstable
formulation.
[0084] The suspension aerosol formulation of this embodiment may be
prepared by first preparing a solution of an active agent with a
suspension stabiliser, such as leucine and optionally trehalose,
and spray drying the solution at conditions known to those skilled
in the art. The resulting powder may then be added to a propellant.
The propellant may be present in a solution comprising a
co-solvent, such as ethanol. The amount of co-solvent present is
preferably not enough to dissolve the spray dried particles when
they are added. In the case of ethanol, it is preferably included
in an amount that means that the ethanol makes up less than 1% w/w
based upon the final composition. The propellant is preferably HFA
227. The particles in the suspension comprise the pharmaceutically
active agent.
[0085] In order to produce a pMDI comprising the composition, the
spray dried particles comprising the active agent are placed in a
separate aerosol vial, a metered valve is crimped onto the vial and
the vial is pressure filled with the previously prepared
propellant/excipient solution. The particles are then dispersed in
the solution by mixing or homogenizing. The addition of the
propellant/excipient solution minimises the likelihood of the
active being dissolved by the excipient, thereby retaining particle
integrity. The propellant dilutes the excipients further minimizing
undesirable excipient-active interaction. The final level of
excipient may need to be adjusted to minimise dissolution of active
in the excipient. This technical challenge may be avoided when the
active is not soluble in the excipient alone or in the
propellant/excipient solution.
[0086] Alternatively, the formulations can be prepared by first
placing the spray dried particles, the co-solvent and excipients
mentioned above in an aerosol vial. In order to prepare a
formulation in this manner, a continuous valve is crimped onto the
vial and the vial is then pressure filled with propellant and
shaken to disperse the active.
[0087] Certain composition according to the invention require the
inclusion of conventional surface active agents, to provide the
compositions with the conventional properties and benefits that
such agents are known to afford. For example, aside from the
ability to conserve the internal state of the particles, the
surface active agents minimise interparticle adherence thereby
minimising agglomerate formation.
Drug List
[0088] The present invention can be carried out with any
pharmaceutically active agent. Specific active agents or drugs that
may be used include, but are not limited to, agents of one or more
of the following classes listed below.
[0089] 1) Adrenergic agonists such as, for example, amphetamine,
apraclonidine, bitolterol, clonidine, colterol, dobutamine,
dopamine, ephedrine, epinephrine, ethylnorepinephrine, fenoterol,
formoterol, guanabenz, guanfacine, hydroxyamphetamine, isoetharine,
isoproterenol, isotharine, mephenterine, metaraminol,
methamphetamine, methoxamine, methpentermine, methyldopa,
methylphenidate, metaproterenol, metaraminol, mitodrine,
naphazoline, norepinephrine, oxymetazoline, pemoline,
phenylephrine, phenylethylamine, phenylpropanolamine, pirbuterol,
prenalterol, procaterol, propylhexedrine, pseudo-ephedrine,
ritodrine, salbutamol, salmeterol, terbutaline, tetrahydrozoline,
tramazoline, tyramine and xylometazoline.
[0090] 2) Adrenergic antagonists such as, for example, acebutolol,
alfuzosin, atenolol, betaxolol, bisoprolol, bopindolol, bucindolol,
bunazosin, butyrophenones, carteolol, carvedilol, celiprolol,
chlorpromazine, doxazosin, ergot alkaloids, esmolol, haloperidol,
indoramin, ketanserin, labetalol, levobunolol, medroxalol,
metipranolol, metoprolol, nebivolol, nadolol, naftopidil,
oxprenolol, penbutolol, phenothiazines, phenoxybenzamine,
phentolamine, pindolol, prazosin, propafenone, propranolol,
sotalol, tamsulosin, terazosin, timolol, tolazoline, trimazosin,
urapidil and yohimbine.
[0091] 3) Adrenergic neurone blockers such as, for example,
bethanidine, debrisoquine, guabenxan, guanadrel, guanazodine,
guanethidine, guanoclor and guanoxan.
[0092] 4) Drugs for treatment of addiction, such as, for example,
buprenorphine.
[0093] 5) Drugs for treatment of alcoholism, such as, for example,
disulfuram, naloxone and naltrexone.
[0094] 6) Drugs for Alzheimer's disease management, including
acetylcholinesterase inhibitors such as, for example, donepezil,
galantamine, rivastigmine and tacrin.
[0095] 7) Anaesthetics such as, for example amethocaine,
benzocaine, bupivacaine, hydrocortisone, ketamine, lignocaine,
methylprednisolone, prilocalne, proxymetacaine, ropivacaine and
tyrothricin.
[0096] 8) Angiotensin converting enzyme inhibitors such as, for
example, captopril, cilazapril, enalapril, fosinopril, imidapril
hydrochloride, lisinopril, moexipril hydrochloride, perindopril,
quinapril, ramipril and trandolapril.
[0097] 9) Angiotensin II receptor blockers, such as, for example,
candesartan, cilexetil, eprosartan, irbesartan, losartan,
medoxomil, olmesartan, telmisartan and valsartan.
[0098] 10) Antiarrhythmics such as, for example, adenosine,
amidodarone, disopyramide, flecamide acetate, lidocaine
hydrochloride, mexiletine, procainamide, propafenone and
quinidine.
[0099] 11) Antibiotic and antibacterial agents (including the
beta-lactams, fluoroquinolones, ketolides, macrolides,
sulphonamides and tetracyclines) such as, for example, aclarubicin,
amoxicillin, amphotericin, azithromycin, aztreonam chlorhexidine,
clarithromycin, clindamycin, colistimethate, dactinomycin,
dirithromycin, doripenem, erythromycin, fusafungine, gentamycin,
metronidazole, mupirocin, natamycin, neomycin, nystatin,
oleandomycin, pentamidine, pimaricin, probenecid, roxithromycin,
sulphadiazine and triclosan.
[0100] 12) Anti-clotting agents such as, for example, abciximab,
acenocoumarol, alteplase, aspirin, bemiparin, bivalirudin,
certoparin, clopidogrel, dalteparin, danaparoid, dipyridamole,
enoxaparin, epoprostenol, eptifibatide, fondaparin, heparin
(including low molecular weight heparin), heparin calcium,
lepirudin, phenindione, reteplase, streptokinase, tenecteplase,
tinzaparin, tirofiban and warfarin.
[0101] 13) Anticonvulsants such as, for example, GABA analogs
including tiagabine and vigabatrin; barbiturates including
pentobarbital; benzodiazepines including alprazolam,
chlordiazepoxide, clobazam, clonazepam, diazepam, flurazepam,
lorazepam, midazolam, oxazepam and zolazepam; hydantoins including
phenyloin; phenyltriazines including lamotrigine; and miscellaneous
anticonvulsants including acetazolamide, carbamazepine,
ethosuximide, fosphenyloin, gabapentin, levetiracetam,
oxcarbazepine, piracetam, pregabalin, primidone, sodium valproate,
topiramate, valproic acid and zonisamide.
[0102] 14) Antidepressants such as, for example, tricyclic and
tetracyclic antidepressants including amineptine, amitriptyline
(tricyclic and tetracyclic amitryptiline), amoxapine, butriptyline,
cianopramine, clomipramine, demexiptiline, desipramine, dibenzepin,
dimetacrine, dosulepin, dothiepin, doxepin, imipramine, iprindole,
levoprotiline, lofepramine, maprotiline, melitracen, metapramine,
mianserin, mirtazapine, nortryptiline, opipramol, propizepine,
protriptyline, quinupramine, setiptiline, tianeptine and
trimipramine; selective serotonin and noradrenaline reuptake
inhibitors (SNRIs) including clovoxamine, duloxetine, milnacipran
and venlafaxine; selective serotonin reuptake inhibitors (SSRIs)
including citalopram, escitalopram, femoxetine, fluoxetine,
fluvoxamine, ifoxetine, milnacipran, nomifensine, oxaprotiline,
paroxetine, sertraline, sibutramine, venlafaxine, viqualine and
zimeldine; selective noradrenaline reuptake inhibitors (NARIs)
including demexiptiline, desipramine, oxaprotiline and reboxetine;
noradrenaline and selective serotonin reuptake inhibitors (NASSAs)
including mirtazapine; monoamine oxidase inhibitors (MAOIs)
including amiflamine, brofaromine, clorgyline,
.alpha.-ethyltryptamine, etoperidone, iproclozide, iproniazid,
isocarboxazid, mebanazine, medifoxamine, moclobemide, nialamide,
pargyline, phenelzine, pheniprazine, pirlindole, procarbazine,
rasagiline, safrazine, selegiline, toloxatone and tranylcypromine;
muscarinic antagonists including benactyzine and dibenzepin;
azaspirones including buspirone, gepirone, ipsapirone, tandospirone
and tiaspirone; and other antidepressants including acetaphenazine,
ademetionine, S-adenosylmethionine, adrafinil, amesergide,
amineptine, amperozide, benactyzine, benmoxine, binedaline,
bupropion, carbamazepine, caroxazone, cericlamine, cotinine,
fezolamine, flupentixol, idazoxan, kitanserin, levoprotiline,
lithium salts, maprotiline, medifoxamine, methylphenidate,
metralindole, minaprine, nefazodone, nisoxetine, nomifensine,
oxaflozane, oxitriptan, phenyhydrazine, rolipram, roxindole,
sibutramine, teniloxazine, tianeptine, tofenacin, trazadone,
tryptophan, viloxazine and zalospirone.
[0103] 15) Anticholinergic agents such as, for example, atropine,
benzatropine, biperiden, cyclopentolate, glycopyrrolate, hyoscine,
ipratropium bromide, orphenadine hydrochloride, oxitroprium
bromide, oxybutinin, pirenzepine, procyclidine, propantheline,
propiverine, telenzepine, tiotropium, trihexyphenidyl, tropicamide
and trospium.
[0104] 16) Antidiabetic agents such as, for example, pioglitazone,
rosiglitazone and troglitazone.
[0105] 17) Antidotes such as, for example, deferoxamine,
edrophonium chloride, fiumazenil, nalmefene, naloxone, and
naltrexone.
[0106] 18) Anti-emetics such as, for example, alizapride,
azasetron, benzquinamide, bestahistine, bromopride, buclizine,
chlorpromazine, cinnarizine, clebopride, cyclizine, dimenhydrinate,
diphenhydramine, diphenidol, domperidone, dolasetron, dronabinol,
droperidol, granisetron, hyoscine, lorazepam, metoclopramide,
metopimazine, nabilone, ondansetron, palonosetron, perphenazine,
prochlorperazine, promethazine, scopolamine, triethylperazine,
trifluoperazine, triflupromazine, trimethobenzamide and
tropisetron.
[0107] 19) Antihistamines such as, for example, acrivastine,
astemizole, azatadine, azelastine, brompheniramine, carbinoxamine,
cetirizine, chlorpheniramine, cinnarizine, clemastine, cyclizine,
cyproheptadine, desloratadine, dexmedetomidine, diphenhydramine,
doxylamine, fexofenadine, hydroxyzine, ketotifen, levocabastine,
loratadine, mizolastine, promethazine, pyrilamine, terfenadine and
trimeprazine.
[0108] 20) Anti-infective agents such as, for example, antivirals
(including nucleoside and non-nucleoside reverse transcriptase
inhibitors and protease inhibitors) including aciclovir, adefovir,
amantadine, cidofovir, efavirenz, famiciclovir, foscarnet,
ganciclovir, idoxuridine, indinavir, inosine pranobex, lamivudine,
nelfinavir, nevirapine, oseltamivir, palivizumab, penciclovir,
pleconaril, ribavirin, rimantadine, ritonavir, ruprintrivir,
saquinavir, stavudine, valaciclovir, zalcitabine, zanamivir,
zidovudine and interferons; AIDS adjunct agents including dapsone;
aminoglycosides including tobramycin; antifungals including
amphotericin, caspofungin, clotrimazole, econazole nitrate,
fluconazole, itraconazole, ketoconazole, miconazole, nystatin,
terbinafine and voriconazole; anti-malarial agents including
quinine; antituberculosis agents including capreomycin,
ciprofloxacin, ethambutol, meropenem, piperacillin, rifampicin and
vancomycin; beta-lactams including cefazolin, cefinetazole,
cefoperazone, cefoxitin, cephacetrile, cephalexin, cephaloglycin
and cephaloridine; cephalosporins, including cephalosporin C and
cephalothin; cephamycins such as cephamycin A, cephamycin B,
cephamycin C, cephapirin and cephradine; leprostatics such as
clofazimine; penicillins including amoxicillin, ampicillin,
amylpenicillin, azidocillin, benzylpenicillin, carbenicillin,
carfecillin, carindacillin, clometocillin, cloxacillin,
cyclacillin, dicloxacillin, diphenicillin, heptylpenicillin,
hetacillin, metampicillin, methicillin, nafcillin,
2-pentenylpenicillin, penicillin N, penicillin O, penicillin S and
penicillin V; quinolones including ciprofloxacin, clinafloxacin,
difloxacin, grepafloxacin, norfloxacin, ofloxacine and
temafloxacin; tetracyclines including doxycycline and
oxytetracycline; miscellaneous anti-infectives including
linezolide, trimethoprim and sulfamethoxazole.
[0109] 21) Anti-neoplastic agents such as, for example,
droloxifene, tamoxifen and toremifene.
[0110] 22) Antiparkisonian drugs such as, for example, amantadine,
andropinirole, apomorphine, baclofen, benserazide, biperiden,
benztropine, bromocriptine, budipine, cabergoline, carbidopa,
eliprodil, entacapone, eptastigmine, ergoline, galanthamine,
lazabemide, levodopa, lisuride, mazindol, memantine, mofegiline,
orphenadrine, trihexyphenidyl, pergolide, piribedil, pramipexole,
procyclidine, propentofylline, rasagiline, remacemide, ropinerole,
selegiline, spheramine, terguride and tolcapone.
[0111] 23) Antipsychotics such as, for example, acetophenazine,
alizapride, amisulpride, amoxapine, amperozide, aripiprazole,
benperidol, benzquinamide, bromperidol, buramate, butaclamol,
butaperazine, carphenazine, carpipramine, chlorpromazine,
chlorprothixene, clocapramine, clomacran, clopenthixol,
clospirazine, clothiapine, clozapine, cyamemazine, drop eridol,
flupenthixol, fluphenazine, fluspirilene, haloperidol, loxapine,
melperone, mesoridazine, metofenazate, molindrone, olanzapine,
penfluridol, pericyazine, perphenazine, pimozide, pipamerone,
piperacetazine, pipotiazine, prochlorperazine, promazine,
quetiapine, remoxipride, risperidone, sertindole, spiperone,
sulpiride, thioridazine, thiothixene, trifluperidol,
triflupromazine, trifluoperazine, ziprasidone, zotepine and
zuclopenthixol; phenothiazines including aliphatic compounds,
piperidines and piperazines; thioxanthenes, butyrophenones and
substituted benzamides.
[0112] 24) Antirheumatic agents such as, for example, diclofenac,
heparinoid, hydroxychloroquine and methotrexate, leflunomide and
teriflunomide.
[0113] 25) Anxiolytics such as, for example, adinazolam, alpidem,
alprazolam, alseroxlon, amphenidone, azacyclonol, bromazepam,
bromisovalum, buspirone, captodiamine, capuride, carbcloral,
carbromal, chloral betaine, chlordiazepoxide, clobenzepam,
enciprazine, flesinoxan, flurazepam, hydroxyzine, ipsapiraone,
lesopitron, loprazolam, lorazepam, loxapine, mecloqualone,
medetomidine, methaqualone, methprylon, metomidate, midazolam,
oxazepam, propanolol, tandospirone, trazadone, zolpidem and
zopiclone.
[0114] 26) Appetite stimulants such as, for example,
dronabinol.
[0115] 27) Appetite suppressants such as, for example,
fenfluramine, phentermine and sibutramine; and anti-obesity
treatments such as, for example, pancreatic lipase inhibitors,
serotonin and norepinephrine re-uptake inhibitors, and
anti-anorectic agents.
[0116] 28) Benzodiazepines such as, for example, alprazolam,
bromazepam, brotizolam, chlordiazepoxide, clobazam, clonazepam,
clorazepate, demoxepam, diazepam, estazolam, flunitrazepam,
flurazepam, halazepam, ketazolam, loprazolam, lorazepam,
lormetazepam, medazepam, midazolam, nitrazepam, nordazepam,
oxazepam, prazepam, quazepam, temazepam and triazolam.
[0117] 29) Bisphosphonates such as, for example, alendronate
sodium, sodium clodronate, etidronate disodium, ibandronic acid,
pamidronate disodium, isedronate sodium, tiludronic acid and
zoledronic acid.
[0118] 30) Blood modifiers such as, for example, cilostazol and
dipyridamol, and blood factors.
[0119] 31) Cardiovascular agents such as, for example, acebutalol,
adenosine, amiloride, amiodarone, atenolol, benazepril, bisoprolol,
bumetanide, candesartan, captopril, clonidine, diltiazem,
disopyramide, dofetilide, doxazosin, enalapril, esmolol, ethacrynic
acid, flecanide, furosemide, gemfibrozil, ibutilide, irbesartan,
labetolol, losartan, lovastatin, metolazone, metoprolol,
mexiletine, nadolol, nifedipine, pindolol, prazosin, procainamide,
propafenone, propranolol, quinapril, quinidine, ramipril, sotalol,
spironolactone, telmisartan, tocamide, torsemide, triamterene,
valsartan and verapamil.
[0120] 32) Calcium channel blockers such as, for example,
amlodipine, bepridil, diltiazem, felodipine, flunarizine,
gallopamil, isradipine, lacidipine, lercanidipine, nicardipine,
nifedipine, nimodipine and verapamil.
[0121] 33) Central nervous system stimulants such as, for example,
amphetamine, brucine, caffeine, dexfenfluramine, dextroamphetamine,
ephedrine, fenfluramine, mazindol, methyphenidate, modafmil,
pemoline, phentermine and sibutramine.
[0122] 34) Cholesterol-lowering drugs such as, for example,
acipimox, atorvastatin, ciprofibrate, colestipol, colestyramine,
bezafibrate, ezetimibe, fenofibrate, fluvastatin, gemfibrozil,
ispaghula, nictotinic acid, omega-3 triglycerides, pravastatin,
rosuvastatin and simvastatin.
[0123] 35) Drugs for cystic fibrosis management such as, for
example, Pseudomonas aeruginosa infection vaccines (eg
Aerugen.TM.), alpha 1-antitripsin, amikacin, cefadroxil, denufosol,
duramycin, glutathione, mannitol, and tobramycin.
[0124] 36) Diagnostic agents such as, for example, adenosine and
aminohippuric acid.
[0125] 37) Dietary supplements such as, for example, melatonin and
vitamins including vitamin E.
[0126] 38) Diuretics such as, for example, amiloride,
bendroflumethiazide, bumetanide, chlortalidone, cyclopenthiazide,
furosemide, indapamide, metolazone, spironolactone and
torasemide.
[0127] 39) Dopamine agonists such as, for example, amantadine,
apomorphine, bromocriptine, cabergoline, lisuride, pergolide,
pramipexole and ropinerole.
[0128] 40) Drugs for treating erectile dysfunction, such as, for
example, apomorphine, apomorphine diacetate, moxisylyte,
phentolamine, phosphodiesterase type 5 inhibitors, such as
sildenafil, tadalafil, vardenafil and yohimbine.
[0129] 41) Gastrointestinal agents such as, for example, atropine,
hyoscyamine, famotidine, lansoprazole, loperamide, omeprazole and
rebeprazole.
[0130] 42) Hormones and analogues such as, for example, cortisone,
epinephrine, estradiol, insulin, Ostabolin-C, parathyroid hormone
and testosterone.
[0131] 43) Hormonal drugs such as, for example, desmopressin,
lanreotide, leuprolide, octreotide, pegvisomant, protirelin,
salcotonin, somatropin, tetracosactide, thyroxine and
vasopressin.
[0132] 44) Hypoglycaemics such as, for example, sulphonylureas
including glibenclamide, gliclazide, glimepiride, glipizide and
gliquidone; biguanides including metformin; thiazolidinediones
including pioglitazone, rosiglitazone, nateglinide, repaglinide and
acarbose.
[0133] 45) Immunoglobulins.
[0134] 46) Immunomodulators such as, for example, interferon (e.g.
interferon beta-1a and interferon beta-1b) and glatiramer.
[0135] 47) Immunosupressives such as, for example, azathioprine,
cyclosporin, mycophenolic acid, rapamycin, sirolimus and
tacrolimus.
[0136] 48) Mast cell stabilizers such as, for example,
cromoglycate, iodoxamide, nedocromil, ketotifen, tryptase
inhibitors and pemirolast.
[0137] 49) Drugs for treatment of migraine headaches such as, for
example, almotriptan, alperopride, amitriptyline, amoxapine,
atenolol, clonidine, codeine, coproxamol, cyproheptadine,
dextropropoxypene, dihydroergotamine, diltiazem, doxepin,
ergotamine, eletriptan, fluoxetine, frovatriptan, isometheptene,
lidocaine, lisinopril, lisuride, loxapine, methysergide,
metoclopramide, metoprolol, nadolol, naratriptan, nortriptyline,
oxycodone, paroxetine, pizotifen, pizotyline, prochlorperazine
propanolol, propoxyphene, protriptyline, rizatriptan, sertraline,
sumatriptan, timolol, tolfenamic acid, tramadol, verapamil,
zolmitriptan, and non-steroidal anti-inflammatory drugs.
[0138] 50) Drugs for treatment of motion sickness such as, for
example, diphenhydramine, promethazine and scopolamine.
[0139] 51) Mucolytic agents such as N-acetylcysteine, ambroxol,
amiloride, dextrans, heparin, desulphated heparin, low molecular
weight heparin and recombinant human DNase.
[0140] 52) Drugs for multiple sclerosis management such as, for
example, bencyclane, methylprednisolone, mitoxantrone and
prednisolone.
[0141] 53) Muscle relaxants such as, for example, baclofen,
chlorzoxazone, cyclobenzaprine, methocarbamol, orphenadrine,
quinine and tizanidine.
[0142] 54) NMDA receptor antagonists such as, for example,
mementine.
[0143] 55) Nonsteroidal anti-inflammatory agents such as, for
example, aceclofenac, acetaminophen, alminoprofen, amfenac,
aminopropylori, amixetrine, aspirin, benoxaprofen, bromfenac,
bufexamac, carprofen, celecoxib, choline, cinchophen, cinmetacin,
clometacin, clopriac, diclofenac, diclofenac sodium, diflunisal,
ethenzamide, etodolac, etoricoxib, fenoprofen, flurbiprofen,
ibuprofen, indomethacin, indoprofen, ketoprofen, ketorolac,
loxoprofen, mazipredone, meclofenamate, mefenamic acid, meloxicam,
nabumetone, naproxen, nimesulide, parecoxib, phenylbutazone,
piroxicam, pirprofen, rofecoxib, salicylate, sulindac, tiaprofenic
acid, tolfenamate, tolmetin and valdecoxib.
[0144] 56) Nucleic-acid medicines such as, for example,
oligonucleotides, decoy nucleotides, antisense nucleotides and
other gene-based medicine molecules.
[0145] 57) Opiates and opioids such as, for example, alfentanil,
allylprodine, alphaprodine, anileridine, benzylmorphine,
bezitramide, buprenorphine, butorphanol, carbiphene, cipramadol,
clonitazene, codeine, codeine phosphate, dextromoramide,
dextropropoxyphene, diamorphine, dihydrocodeine, dihydromorphine,
diphenoxylate, dipipanone, fentanyl, hydromorphone, L-alpha acetyl
methadol, levorphanol, lofentanil, loperamide, meperidine,
meptazinol, methadone, metopon, morphine, nalbuphine, nalorphine,
oxycodone, papavereturn, pentazocine, pethidine, phenazocine,
pholcodeine, remifentanil, sufentanil, tramadol, and combinations
thereof with an anti-emetic.
[0146] 58) Opthalmic preparations such as, for example, betaxolol
and ketotifen.
[0147] 59) Osteoporosis preparations such as, for example,
alendronate, estradiol, estropitate, raloxifene and
risedronate.
[0148] 60) Other analgesics such as, for example, apazone,
benzpiperylon, benzydamine, caffeine, cannabinoids, clonixin,
ethoheptazine, flupirtine, nefopam, orphenadrine, pentazocine,
propacetamol and propoxyphene.
[0149] 61) Other anti-inflammatory agents such as, for example,
B-cell inhibitors, p38 MAP kinase inhibitors and TNF
inhibitors.
[0150] 62) Phosphodiesterase inhibitors such as, for example,
non-specific phosphodiesterase inhibitors including theophylline,
theobromine, IBMX, pentoxifylline and papaverine; phosphodiesterase
type 3 inhibitors including bipyridines such as milrinone, aminone
and olprinone; imidazolones such as piroximone and enoximone;
imidazolines such as imazodan and 5-methyl-imazodan;
imidazo-quinoxalines; and dihydropyridazinones such as indolidan
and LY181512
(5-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-1,3-dihydro-indol-2-one);
dihydroquinolinone compounds such as cilostamide, cilostazol, and
vesnarinone; motapizone; phosphodiesterase type 4 inhibitors such
as cilomilast, etazolate, rolipram, oglemilast, roflumilast, ONO
6126, tolafentrine and zardaverine, and including quinazolinediones
such as nitraquazone and nitraquazone analogs; xanthine derivatives
such as denbufylline and arofylline; tetrahydropyrimidones such as
atizoram; and oxime carbamates such as filaminast; and
phosphodiesterase type 5 inhibitors including sildenafil,
zaprinast, vardenafil, tadalafil, dipyridamole, and the compounds
described in WO 01/19802, particularly
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxy-benzylamino)-
-5-[N-(2-pyrimidinylmethyl) carbamoyl]pyrimidine,
2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4-methoxybenzyla-
mino)-5-[N-(2-morpholinoethyl)carbamoyl]-pyrimidine, and
(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxy-benzylamino)-
-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl]-pyrimidine).
[0151] 63) Potassium channel modulators such as, for example,
cromakalim, diazoxide, glibenclamide, levcromakalim, minoxidil,
nicorandil and pinacidil.
[0152] 64) Prostaglandins such as, for example, alprostadil,
dinoprostone, epoprostanol and misoprostol.
[0153] 65) Respiratory agents and agents for the treatment of
respiratory diseases including bronchodilators such as, for
example, the .beta.2-agonists bambuterol, bitolterol, broxaterol,
carmoterol, clenbuterol, fenoterol, formoterol, indacaterol,
levalbuterol, metaproterenol, orciprenaline, picumeterol,
pirbuterol, procaterol, reproterol, rimiterol, salbutamol,
salmeterol, terbutaline and the like; inducible nitric oxide
synthase (iNOS) inhibitors; the antimuscarinics ipratropium,
ipratropium bromide, oxitropium, tiotropium, glycopyrrolate and the
like; the xanthines aminophylline, theophylline and the like;
adenosine receptor antagonists, cytokines such as, for example,
interleukins and interferons; cytokine antagonists and chemokine
antagonists including cytokine synthesis inhibitors, endothelin
receptor antagonists, elastase inhibitors, integrin inhibitors,
leukotrine receptor antagonists, prostacyclin analogues, and
ablukast, ephedrine, epinephrine, fenleuton, iloprost, iralukast,
isoetharine, isoproterenol, montelukast, ontazolast, pranlukast,
pseudoephedrine, sibenadet, tepoxalin, verlukast, zafirlukast and
zileuton.
[0154] 66) Sedatives and hypnotics such as, for example,
alprazolam, butalbital, chlordiazepoxide, diazepam, estazolam,
flunitrazepam, flurazepam, lorazepam, midazolam, temazepam,
triazolam, zaleplon, zolpidem, and zopiclone.
[0155] 67) Serotonin agonists such as, for example,
1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane, buspirone,
m-chlorophenylpiperazine, cisapride, ergot alkaloids, gepirone,
8-hydroxy-(2-N,N-dipropylamino)-tetraline, ipsaperone, lysergic
acid diethylamide, 2-methyl serotonin, mezacopride, sumatriptan,
tiaspirone, trazodone and zacopride.
[0156] 68) Serotonin antagonists such as, for example,
amitryptiline, azatadine, chlorpromazine, clozapine,
cyproheptadine, dexfenfluramine,
R(+)-.alpha.-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidi-
ne-methanol, dolasetron, fenclonine, fenfluramine, granisetron,
ketanserin, methysergide, metoclopramide, mianserin, ondansetron,
risperidone, ritanserin, trimethobenz amide and tropisetron.
[0157] 69) Steroid drugs such as, for example, alcometasone,
beclomethasone, beclomethasone dipropionate, betamethasone,
budesonide, butixocort, ciclesonide, clobetasol, deflazacort,
diflucortolone, desoxymethasone, dexamethasone, fludrocortisone,
flunisolide, fluocinolone, fluometholone, fluticasone, fluticasone
proprionate, hydrocortisone, methylprednisolone, mometasone,
nandrolone decanoate, neomycin sulphate, prednisolone, rimexolone,
rofleponide, triamcinolone and triamcinolone acetonide.
[0158] 70) Sympathomimetic drugs such as, for example, adrenaline,
dexamfetamine, dipirefin, dobutamine, dopamine, dopexamine,
isoprenaline, noradrenaline, phenylephrine, pseudoephedrine,
tramazoline and xylometazoline.
[0159] 71) Nitrates such as, for example, glyceryl trinitrate,
isosorbide dinitrate and isosorbide mononitrate.
[0160] 72) Skin and mucous membrane agents such as, for example,
bergapten, isotretinoin and methoxsalen.
[0161] 73) Smoking cessation aids such as, for example, bupropion,
nicotine and varenicline.
[0162] 74) Drugs for treatment of Tourette's syndrome such as, for
example, pimozide.
[0163] 75) Drugs for treatment of urinary tract infections such as,
for example, darifenicin, oxybutynin, propantheline bromide and
tolteridine.
[0164] 76) Vaccines.
[0165] 77) Drugs for treating vertigo such as, for example,
betahistine and meclizine.
[0166] 78) Therapeutic proteins and peptides such as acylated
insulin, glucagon, glucagon-like peptides, exendins, insulin,
insulin analogues, insulin aspart, insulin detemir, insulin
glargine, insulin glulisine, insulin lispro, insulin zinc, isophane
insulins, neutral, regular and insoluble insulins, and protamine
zinc insulin.
[0167] 79) Anticancer agents such as, for example, anthracyclines,
doxorubicin, idarubicin, epirubicin, methotrexate, taxanes,
paclitaxel, docetaxel, cisplatin, vinca alkaloids, vincristine and
5-fluorouracil.
[0168] 80) Pharmaceutically acceptable salts or derivatives of any
of the foregoing.
[0169] It should be noted that drugs listed above under a
particular indication or class may also find utility in other
indications. A plurality of active agents can be employed in the
practice of the present invention. A drug delivery system according
to the invention may also be used to deliver combinations of two or
more different active agents or drugs. Specific combinations of two
medicaments which may be mentioned include combinations of steroids
and (.beta..sub.2-agonists. Examples of such combinations are
beclomethasone and formoterol; beclomethasone and salmeterol;
fluticasone and formoterol; fluticasone and salmeterol; budesonide
and formoterol; budesonide and salmeterol; flunisolide and
formoterol; flunisolide and salmeterol; ciclesonide and formoterol;
ciclesonide and salmeterol; mometasone and formoterol; and
mometasone and salmeterol. Specifically drug delivery systems
according to the invention may also be used to deliver combinations
of three or more different active agents or drugs.
[0170] It will be clear to a person of skill in the art that, where
appropriate, the active agents or drugs may be linked to a carrier
molecule or molecules and/or used in the form of prodrugs, salts,
as esters, or as solvates to optimise the activity and/or stability
of the active agent or drug. The device used to deliver the
formulation will clearly affect the performance of the formulations
and the device is therefore a very important part of present
invention.
[0171] As mentioned above, in order to maintain the physical form
of an active substance, a protective coating may be applied to the
external surfaces of the particles comprising the active agent.
Several methods are known for applying such coatings.
Compressive Milling Processes
[0172] In an alternative process for preparing the compositions
according to the present invention, the powder components undergo a
compressive milling process, such as processes termed mechanofusion
(also known as `Mechanical Chemical Bonding`) and cyclomixing.
[0173] As the name suggests, mechanofusion is a dry coating process
designed to mechanically fuse a first material onto a second
material. It should be noted that the use of the terms
"mechanofusion" and "mechanofused" are supposed to be interpreted
as a reference to a particular type of milling process, but not a
milling process performed in a particular apparatus. The
compressive milling processes work according to a different
principle to other milling techniques, relying on a particular
interaction between an inner element and a vessel wall, and they
are based on providing energy by a controlled and substantial
compressive force. The process works particularly well where one of
the materials is generally smaller and/or softer than the
other.
[0174] The fine active particles and additive particles are fed
into the vessel of a mechanofusion apparatus (such as a
Mechano-Fusion system (Hosokawa Micron Ltd), where they are subject
to a centrifugal force and are pressed against the vessel inner
wall. The powder is compressed between the fixed clearance of the
drum wall and a curved inner element with high relative speed
between drum and element. The inner wall and the curved element
together form a gap or nip in which the particles are pressed
together. As a result, the particles experience very high shear
forces and very strong compressive stresses as they are trapped
between the inner drum wall and the inner element (which has a
greater curvature than the inner drum wall). The particles are
pressed against each other with enough energy to locally heat and
soften, break, distort, flatten and wrap the additive particles
around the core particle to form a coating. The energy is generally
sufficient to break up agglomerates and some degree of size
reduction of both components may occur.
[0175] These mechanofusion and cyclomixing processes apply a high
enough degree of force to separate the individual particles of
active material and to break up tightly bound agglomerates of the
active particles such that effective mixing and effective
application of the additive material to the surfaces of those
particles is achieved. An especially desirable aspect of the
processes is that the additive material becomes deformed in the
milling and may be smeared over or fused to the surfaces of the
active particles.
[0176] However, in practice, these compression milling processes
produce little or no size reduction of the drug particles,
especially where they are already in a micronised form (i.e. <10
.mu.m). The only physical change which may be observed is a plastic
deformation of the particles to a rounder shape.
Other Milling Procedures
[0177] The process of milling may also be used to formulate the dry
powder compositions according to the present invention. The
manufacture of fine particles by milling can be achieved using
conventional techniques. In the conventional use of the word,
"milling" means the use of any mechanical process which applies
sufficient force to the particles of active material that it is
capable of breaking coarse particles (for example, particles with a
MMAD greater than 100 .mu.m) down to fine particles (for example,
having a MMAD not more than 50 .mu.m). In the present invention,
the term "milling" also refers to deagglomeration of particles in a
formulation, with or without particle size reduction. The particles
being milled may be large or fine prior to the milling step. A wide
range of milling devices and conditions are suitable for use in the
production of the compositions of the inventions. The selection of
appropriate milling conditions, for example, intensity of milling
and duration, to provide the required degree of force will be
within the ability of the skilled person. Impact milling processes
may be used to prepare compositions comprising apomorphine
according to the present invention, with or without additive
material. Such processes include ball milling and the use of a
homogenizer.
[0178] Ball milling is a suitable milling method for use in the
prior art co-milling processes. Centrifugal and planetary ball
milling are especially preferred methods.
[0179] Alternatively, a high pressure homogeniser may be used in
which a fluid containing the particles is forced through a valve at
high pressure producing conditions of high shear and turbulence.
Shear forces on the particles, impacts between the particles and
machine surfaces or other particles, and cavitation due to
acceleration of the fluid may all contribute to the fracture of the
particles. Suitable homogenisers include EmulsiFlex high pressure
homogenisers which are capable of pressures up to 4000 bar, Niro
Soavi high pressure homogenisers (capable of pressures up to 2000
bar), and Microfluidics Microfluidisers (maximum pressure 2750
bar). The milling process can be used to provide the microparticles
with mass median aerodynamic diameters as specified above.
Homogenisers may be more suitable than ball mills for use in large
scale preparations of the composite active particles.
[0180] The milling step may, alternatively, involve a high energy
media mill or an agitator bead mill, for example, the Netzsch high
energy media mill, or the DYNO-mill (Willy A. Bachofen AG,
Switzerland).
[0181] If a significant reduction in particle size is also
required, co-jet milling is preferred, as disclosed in the earlier
patent application published as WO 2005/025536. The co-jet milling
process can result in composite active particles with low micron or
sub-micron diameter, and these particles exhibit particularly good
FPF and FPD, even when dispensed using a passive DPI.
[0182] The milling processes apply a high enough degree of force to
break up tightly bound agglomerates of fine or ultra-fine
particles, such that effective mixing and effective application of
the additive material to the surfaces of those particles is
achieved. These impact processes create high-energy impacts between
media and particles or between particles. In practice, while these
processes are good at making very small particles, it has been
found that neither the ball mill nor the homogenizer was
particularly effective in producing dispersion improvements in
resultant drug powders in the way observed for the compressive
process. It is believed that the second impact processes are not as
effective in producing a coating of additive material on each
particle.
[0183] Conventional methods comprising co-milling active material
with additive materials (as described in WO 02/43701) result in
composite active particles which are fine particles of active
material with an amount of the additive material on their surfaces.
The additive material is preferably in the form of a coating on the
surfaces of the particles of active material. The coating may be a
discontinuous coating. The additive material may be in the form of
particles adhering to the surfaces of the particles of active
material. Co-milling or co-micronising particles of active agent
and particles of additive (FCA) or excipient will result in the
additive or excipient becoming deformed and being smeared over or
fused to the surfaces of fine active particles, producing composite
particles made up of both materials. These resultant composite
active particles comprising an additive have been found to be less
cohesive after the milling treatment.
[0184] At least some of the composite active particles may be in
the form of agglomerates. However, when the composite active
particles are included in a pharmaceutical composition, the
additive material promotes the dispersal of the composite active
particles on administration of that composition to a patient, via
actuation of an inhaler.
[0185] Milling may also be carried out in the presence of a
material which can delay or control the release of the active
agent.
[0186] The co-milling or co-micronising of active and additive
particles may involve compressive type processes, such as
mechanofusion, cyclomixing and related methods such as those
involving the use of a Hybridiser or the Nobilta. The principles
behind these processes are distinct from those of alternative
milling techniques in that they involve a particular interaction
between an inner element and a vessel wall, and in that they are
based on providing energy by a controlled and substantial
compressive force, preferably compression within a gap of
predetermined width.
[0187] In one embodiment, if required, the microparticles produced
by the milling step can then be formulated with an additional
excipient. This may be achieved by a spray drying process, e.g.
co-spray drying (Need to expand). In this embodiment, the particles
are suspended in a solvent and co-spray dried with a solution or
suspension of the additional excipient. Preferred additional
excipients include polysaccharides. Additional pharmaceutical
effective excipients may also be used.
[0188] In another embodiment, the powder compositions are produced
using the two-step process. Firstly, the materials are milled or
blended. Next, they undergo mechanofusion and this mechanofusion
step is thought to "polish" the composite active particles, further
rubbing the additive material into the active particles. This
allows one to enjoy the beneficial properties afforded to particles
by mechanofusion, in combination with the very small particles
sizes made possible by the co-jet milling.
[0189] The reduction in the cohesion and adhesion between the
active particles can lead to equivalent performance with reduced
agglomerate size, or even with individual particles.
High Shear Blending
[0190] Scaling up of pharmaceutical product manufacture often
requires the use one piece of equipment to perform more than one
function. An example of this is the use of a mixer-granulator which
can both mix and granulate a product thereby removing the need to
transfer the product between pieces of equipment. In so doing, the
opportunity for powder segregation is minimised. High shear
blending often uses a high-shear rotor/stator mixer (HSM), which
has become used in mixing applications. Homogenizers or "high shear
material processors" develop a high pressure on the material
whereby the mixture is subsequently transported through a very fine
orifice or comes into contact with acute angles. The flow through
the chambers can be reverse flow or parallel flow depending on the
material being processed. The number of chambers can be increased
to achieve better performance. The orifice size or impact angle may
also be changed for optimizing the particle size generated.
Particle size reduction occurs due to the high shear generated by
the high shear material processors while it passes through the
orifice and the chambers. The ability to apply intense shear and
shorten mixing cycles gives these mixers broad appeal for
applications that require agglomerated powders to be evenly
blended. Furthermore conventional HSMs may also be widely used for
high intensity mixing, dispersion, disintegration, emulsification
and homogenization.
[0191] It is well known to those skilled in the production of
powder formulations that small particles, even with high-power,
high-shear, mixers a relatively long period of "aging" is required
to obtain complete dispersion, and this period is not shortened
appreciably by increases in mixing power, or by increasing the
speed of rotation of the stirrer so as to increase the shear
velocity. High shear mixers can also be used if the auto-adhesive
properties of the drug particles are so that high shear forces are
required together with use of a force-controlling agent for forming
a surface-energy-reducing particulate coating or film.
Spray Drying and Ultrasonic Nebulisers
[0192] Spray drying may be used to produce particles of inhalable
size comprising the active and excipient. The spray drying process
may be adapted to produce spray-dried particles that include active
agent and additive material which promotes formulation stability
and controls the agglomeration of particles and powder performance.
The spray drying process may also be adapted to produce spray-dried
particles that include the active agent dispersed or suspended
within a material that provides the controlled release
properties.
[0193] Spray drying is a well-known and widely used technique for
producing particles of active material of inhalable size.
Conventional spray drying techniques may be improved so as to
produce active particles with enhanced chemical and physical
properties so that they perform better when dispensed from a DPI
than particles formed using conventional spray drying techniques.
Such improvements are described in detail in the earlier patent
application published as WO 2005/025535.
[0194] In particular, it is disclosed that co-spray drying an
active agent with an FCA under specific conditions can result in
particles with excellent properties which perform extremely well
when administered by a DPI for inhalation into the lung.
[0195] It has been found that manipulating or adjusting the spray
drying process can result in the FCA being largely present on the
surface of the particles. That is, the FCA is concentrated at the
surface of the particles, rather than being homogeneously
distributed throughout the particles. This clearly means that the
FCA will be able to reduce the tendency of the particles to
agglomerate. This will assist the formation of unstable
agglomerates that are easily and consistently broken up upon
actuation of a DPI.
[0196] It has been found that it may be advantageous to control the
formation of the droplets in the spray drying process, so that
droplets of a given size and of a narrow size distribution are
formed. Furthermore, controlling the formation of the droplets can
allow control of the air flow around the droplets which, in turn,
can be used to control the drying of the droplets and, in
particular, the rate of drying. Controlling the formation of the
droplets may be achieved by using alternatives to the conventional
2-fluid nozzles, especially avoiding the use of high velocity air
flows. In particular, it is preferred to use a spray drier
comprising a means for producing droplets moving at a controlled
velocity and of a predetermined droplet size. The velocity of the
droplets is preferably controlled relative to the body of gas into
which they are sprayed. This can be achieved by controlling the
droplets' initial velocity and/or the velocity of the body of gas
into which they are sprayed, for example by using an ultrasonic
nebuliser (USN) to produce the droplets. Alternative nozzles such
as electrospray nozzles or vibrating orifice nozzles may be
used.
[0197] In one embodiment, an ultrasonic nebuliser (USN) is used to
form the droplets in the spray mist. USNs use an ultrasonic
transducer which is submerged in a liquid. The ultrasonic
transducer (a piezoelectric crystal) vibrates at ultrasonic
frequencies to produce the short wavelengths required for liquid
atomisation. In one common form of USN, the base of the crystal is
held such that the vibrations are transmitted from its surface to
the nebuliser liquid, either directly or via a coupling liquid,
which is usually water. When the ultrasonic vibrations are
sufficiently intense, a fountain of liquid is formed at the surface
of the liquid in the nebuliser chamber. Droplets are emitted from
the apex and a "fog" emitted.
[0198] Whilst ultrasonic nebulisers (USNs) are known, these are
conventionally used in inhaler devices, for the direct inhalation
of solutions containing drug, and they have not previously been
widely used in a spray drying apparatus. It has been discovered
that the use of such a nebuliser in spray drying has a number of
important advantages and these have not previously been recognised.
The preferred USNs control the velocity of the particles and
therefore the rate at which the particles are dried, which in turn
affects the shape and density of the resultant particles. The use
of USNs also provides an opportunity to perform spray drying on a
larger scale than is possible using conventional spray drying
apparatus with conventional types of nozzles used to create the
droplets, such as 2-fluid nozzles.
[0199] The attractive characteristics of USNs for producing fine
particle dry powders include: low spray velocity; the small amount
of carrier gas required to operate the nebulisers; the
comparatively small droplet size and narrow droplet size
distribution produced; the simple nature of the USNs (the absence
of moving parts which can wear, contamination, etc.); the ability
to accurately control the gas flow around the droplets, thereby
controlling the rate of drying; and the high output rate which
makes the production of dry powders using USNs commercially viable
in a way that is difficult and expensive when using a conventional
two-fluid nozzle arrangement.
[0200] USNs do not separate the liquid into droplets by increasing
the velocity of the liquid. Rather, the necessary energy is
provided by the vibration caused by the ultrasonic nebuliser.
[0201] Rather than pressurising the liquid, rotary atomisers use
the centrifugal energy created by a spinning disc or receptacle to
form droplets. Pressure based systems are somewhat limited in their
ability to create a droplet spectrum with a narrow distribution and
high kurtosis value. Additionally, rotary atomisers are not limited
by flow volume and are capable of operating effectively at very low
volumes.
[0202] Electrohydrodynamic (EHD) atomization requires the use of
electrical forces to assist in the dispersion of a fluid due.
Conventional EHD atomization, forces a conductive fluid through an
electrically conductive nozzle. The nozzle is connected to a high
negative voltage, whereby an electric field is created between the
conductive nozzle and a ground electrode. This field is strongest
at the tip of the nozzle. As the fluid exits the nozzle, electrical
and mechanical forces cause the fluid jet to nebulise. The
resulting droplets are further influences by the properties of the
fluid for example surface tension, electrical conductivity,
viscosity, density and viscoelastic behaviour. Further operational
parameters may be varied such as the rate of flow and the local
electric field to assist in obtaining the desired droplets. When
the fluid jet is sent in the direction of an electrically grounded
target or towards a target with either a potential of opposite
polarity, or a potential lower than that of the jet, the droplets
are attracted to and will deposit on the target.
Delivery Devices
[0203] The inhalable compositions in accordance with the present
invention are preferably administered via a pressurized metered
dose inhaler (pMDI), or even via a nebulised system.
[0204] In a yet further embodiment, the composition is a solution
or suspension and is administered using a pressurised metered dose
inhaler (pMDI), a nebuliser or a soft mist inhaler. Examples of
suitable devices include pMDIs such as Modulite.RTM. (Chiesi),
SkyeFine.TM. and SkyeDry.TM. (SkyePharma). Nebulisers such as
Porta-Neb.RTM., Inquaneb.TM. (Pari) and Aquilon.TM., and soft mist
inhalers such as eFlow.TM. (Pari), Aerodose.TM. (Aerogen),
Respimat.RTM. Inhaler (Boehringer Ingelheim GmbH), AERx.RTM.
Inhaler (Aradigm) and Mystic.TM. (Ventaira Pharmaceuticals,
Inc.).
[0205] In embodiments of the present invention, the propellant is
CFC-12 or an ozone-friendly, non-CFC propellant, such as
1,1,1,2-tetrafluoroethane (HFC 134a),
1,1,1,2,3,3,3-heptafluoropropane (HFC-227), HCFC-22
(difluororchloromethane), HFA-152 (difluoroethane and isobutene) or
combinations thereof. Such formulations may require the inclusion
of a polar surfactant such as polyethylene glycol, diethylene
glycol monoethyl ether, polyoxyethylene sorbitan monolaurate,
polyoxyethylene sorbitan monooleate, propoxylated polyethylene
glycol, and polyoxyethylene lauryl ether for suspending,
solubilising, wetting and emulsifying the active agent and/or other
components, and for lubricating the valve components of the
MDI.
Improving Percentage FPF in the Drug Formulation
[0206] The present disclosure also relates to the use of vinyl
polymers such as Vinylpyrrolidone Homopolymers and Copolymers, and
in particular polyvinylpyrrolidone (PVP), in improving the % FPF of
a drug particle during storage.
[0207] In one aspect the invention relates to use of vinyl
polymers, in particular PVP, in the preparation of a medicament
which has an increase in % FPF from time 0 (the date of
formulation) to at least week 7 of storage. In a further aspect the
invention relates to a pharmaceutical composition comprising a
vinyl polymer, in particular PVP, suitably which have enhanced %
FPF after storage.
[0208] The present invention further relates to a method for
manufacture of a drug for inhalation, the method comprising
formulating the drug with a vinyl polymer and storing the
formulation to allow a suitable fine particle fraction to be
obtained.
[0209] In the yet further aspect the invention relates to use of
PVP in the manufacturer of a medicament for inhalation.
General Statements
[0210] It will be understood that particular embodiments described
herein are shown by way of illustration and not as limitations of
the invention. The principal features of this invention can be
employed in various embodiments without departing from the scope of
the invention. Those skilled in the art will recognize, or be able
to ascertain using no more than routine study, numerous equivalents
to the specific procedures described herein. Such equivalents are
considered to be within the scope of this invention and are covered
by the claims. All publications and patent applications mentioned
in the specification are indicative of the level of skill of those
skilled in the art to which this invention pertains. All
publications and patent applications are herein incorporated by
reference to the same extent as if each individual publication or
patent application was specifically and individually indicated to
be incorporated by reference. The use of the word "a" or "an" when
used in conjunction with the term "comprising" in the claims and/or
the specification may mean "one," but it is also consistent with
the meaning of "one or more," "at least one," and "one or more than
one." The use of the term "or" in the claims is used to mean
"and/or" unless explicitly indicated to refer to alternatives only
or the alternatives are mutually exclusive, although the disclosure
supports a definition that refers to only alternatives and
"and/or." Throughout this application, the term "about" is used to
indicate that a value includes the inherent variation of error for
the device, the method being employed to determine the value, or
the variation that exists among the study subjects.
[0211] As used in this specification and claim(s), the words
"comprising" (and any form of comprising, such as "comprise" and
"comprises"), "having" (and any form of having, such as "have" and
"has"), "including" (and any form of including, such as "includes"
and "include") or "containing" (and any form of containing, such as
"contains" and "contain") are inclusive or open-ended and do not
exclude additional, unrecited elements or method steps.
[0212] The term "or combinations thereof as used herein refers to
all permutations and combinations of the listed items preceding the
term. For example, "A, B, C, or combinations thereof is intended to
include at least one of: A, B, C, AB, AC, BC, or ABC, and if order
is important in a particular context, also BA, CA, CB, CBA, BCA,
ACB, BAC, or CAB. Continuing with this example, expressly included
are combinations that contain repeats of one or more item or term,
such as BB, AAA, MB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth.
The skilled artisan will understand that typically there is no
limit on the number of items or terms in any combination, unless
otherwise apparent from the context.
[0213] All of the compositions and/or methods disclosed and claimed
herein can be made and executed without undue experimentation in
light of the present disclosure. While the compositions and methods
of this invention have been described in terms of preferred
embodiments, it will be apparent to those of skill in the art that
variations may be applied to the compositions and/or methods and in
the steps or in the sequence of steps of the method described
herein without departing from the concept, spirit and scope of the
invention. All such similar substitutes and modifications apparent
to those skilled in the art are deemed to be within the spirit,
scope and concept of the invention as defined by the appended
claims.
[0214] The preferred embodiments, as described for different
aspects of the invention, are the same for other aspects of the
invention mutatis mutandis
[0215] The present invention is illustrated by the by the
experimental data set out below, which is not limiting upon the
invention, wherein:
EXAMPLES
[0216] The following examples are provided to illustrate the
invention but should not be construed as limiting the invention.
Particle size, respirable fraction, and medication delivery are
determined using the test methods described below.
[0217] The spray dried powders were characterised by particle size
using a Sympatec laser sizer, infra-red spectroscopy using a Perkin
Elmer Spectrum GX ATR-FTIR, and thermal behaviour using a Perkin
Elmer Diamond differential scanning calorimeter.
[0218] Spray Drying Parameters:
Vessel Type Cyclone (1''/3'')
[0219] Pump setting: 87 rpm
Tubing: 1.6 mm
[0220] Feed rate: 5 g/min Inlet temp: 120.degree. C.
Atomisation Type: 2FN
Atomisation Pressure: 3.0 bar g
[0221] Atomisation Air Flow: 30 l/min Drying air pressure: 1.0 bar
g Drying airflow 4.5 l/min
[0222] The above spray drying process was repeated for different
tiotropium bromide/trehalose/leucine combinations outlined
below.
Manufacturing
[0223] Conventional manufacturing methods and machinery well known
to those skilled in the art of pharmaceutical aerosol manufacture
were employed for the preparation of pMDI batches. A known mass of
spray dried active (or combinations of active with trehalose and/or
leucine) were dispensed into an empty canister, a metering valve
was crimped on, and the propellant/excipient mixture was filled
into the canister through the valve. The cans were ultrasonicated
and inverted to mix.
[0224] Each filled canister was conveniently fitted into a suitable
channeling device prior to use to form a metered dose inhaler for
administration of the medicament into the lungs of a patient.
Suitable channeling devices comprise, for example a valve actuator
and a cylindrical or cone-like passage through which medicament may
be delivered from the filled canister via the metering valve to the
mouth of a patient e.g., a mouthpiece actuator.
[0225] In a typical arrangement the valve stem is seated in a
nozzle block which has an orifice leading to an expansion chamber.
The expansion chamber has an exit orifice which extends into the
mouthpiece. Actuator (exit) orifice diameters in the range
0.15-0.45 mm especially 0.2-0.45 mm are generally suitable e.g.,
0.25, 0.30, 0.33 or 0.42 mm. An orifice diameter of 0.22 mm is also
suitable.
Characterisation
[0226] The spray dried powders were characterised by particle size
using a Sympatec laser sizer, infra-red spectroscopy using a Perkin
Elmer Spectrum GX ATR-FTIR, and thermal behaviour using a Perkin
Elmer Diamond differential scanning calorimeter.
Particle Size Assay:
[0227] Metered dose(s) of the aerosol formulation are actuated into
an Anderson Cascade Impactor (ACI) (available from Westtech)
equipped with a USP throat using a Bespak 0.36 mm actuator for an
aerosol valve. The particle size distribution of the resulting
suspension was then analyzed using a bespoke HPLC assay.
[0228] The aerosol vial to be tested was shaken and primed 5 times
into a vented area away from the analyzer.
[0229] The Shot Weight and Delivered Dose and their variance were
measured using the Dosage Unit Sampling Apparatus (DUSA). The fine
particle fraction (FPF) was measured using an Andersen Cascade
Impactor (ACI). The measurement methodology and the apparatus are
well known in the art, and are described in the United States
Pharmacopoeia (USP) Chapter <601>, or in the inhalants
monograph of the European Pharmacopoeia (EP), both of which are
hereby incorporated by reference. The USP states that Delivered
Dose Uniformity should be measured with DUSA or its equivalent and
the dose determined using HPLC analysis.
[0230] Fine particle fraction measured according to the above
described methodology is considered to be the combined fractions
collected from the stages of an Andersen Cascade Impactor
calibrated at 28.3 l/min air flow rate. These fractions have an
aerodynamic particle size of less than 5 .mu.m.
[0231] The Andersen Cascade Impactor was assembled according to
manufacturer's instructions with a suitable filter in place to
ensure that the system was airtight. The apparatus was connected to
a flow system comprising flow control valve, two-way valve, timer
and vacuum pump.
[0232] The test was conducted at a flow rate of 28.3 l/min. The
flow rate was adjusted by connecting a flow meter, calibrated for
the volumetric flow leaving the meter, to the induction port. If
necessary, the flow control valve was adjusted to achieve steady
flow through the system at the required rate.
[0233] The metered dose inhaler was prepared for use by placing in
a Bespak BK356 series actuator. With the pump running and the
two-way valve open, the inhaler was shaken and the mouthpiece of
the inhaler was engaged in the mouthpiece adapter. The aerosol was
discharged into the apparatus by opening the actuating for 3
seconds before releasing the valve. The discharge sequence was
repeated 3 times.
[0234] 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. Between discharges, wait for 1 minute and then
switch off the pump.
[0235] The apparatus was dismantled and the filter was carefully
removed. The active ingredient was extracted into an aliquot of the
solvent. The throat and mouthpiece adapter were removed from the
apparatus and the drug was extracted into an aliquot of the
solvent. The active ingredient was extracted from the USP throat
into an aliquot of the solvent. The active ingredient was extracted
from the inner walls and the collection plates of each of the
stages of the apparatus into aliquots of solvent. Using a suitable
method of analysis, the quantity of active ingredient contained in
each of the ten volumes of solvent was determined.
[0236] The mass of active ingredient deposited on each stage per
discharge and the mass of active ingredient per discharge deposited
in the actuator, USP throat and mouthpiece adapter were
calculated
[0237] The aerosol vial to be tested was primed five times. The
aerosol vial and a clean, dry actuator were coupled to the USP
throat attached to the top of the impactor using an appropriate
firing adapter. The calibrated vacuum pump (28.3 L/min) was
attached to the cascade impactor and turned on. A total of 10
sprays were delivered into the cascade impactor by repeatedly
shaking the vial and then immediately delivering a single spray.
The time between sprays was approximately 60 seconds. The cascade
impactor was disassembled and each component was rinsed separately
with diluent (15 parts of methanol mixed with 85 parts water and
0.1 parts trifluoroacetic acid, v/v). Each solution was analyzed
for active content using high pressure liquid chromatography.
[0238] The respirable fraction was calculated using CITDAS
software, version 2.0 (Copley Scientific, UK).
Storage/Stability
[0239] Samples of each formulation 1-4 (100 mg) were stored at room
temperature and low relative humidity (RH) (20-30%) in 7 ml screw
top vials sealed with Parafilm and the characterisation repeated
after 9 and 14 days.
Differential Scanning calorimetry
[0240] The sample (5 to 10 mg) was sealed in a pierced 40 .mu.l
aluminium sample pan and heated from 25 to 250.degree. C. at
50.degree. C. per minute.
Infra-Red Spectroscopy
[0241] The absorbance spectra were measured using the Golden Gate
Attenuated Total Reflectance (ATR) accessory between 4000 and 600
cm.sup.1 acquiring 16 co-added scans. The spectra were compared
with that of the crystalline staring materials and between time
points.
[0242] Spectra were recorded at 9 and 14 days and demonstrated no
differences in position or intensity of any of the peaks from those
recorded on the day of manufacture. Comparison of the spectra with
those of the starting materials indicate that the formulations are
amorphous in that sharp peaks seen above 3000 cm.sup.-1 for
crystalline tiotropium bromide and trehalose dihydrate are absent
from the sample spectra. The fingerprint regions in the spectra are
too complex to allow clear assignment of any of the peaks.
Example 1
Control--Crystalline Tiotropium bromide (3.8 mg) was added into a
coated (DuPont 3200 200) canister, with Bespak 63 .mu.l valve. HFA
134a (14700 mg) was added to the canister. The solution was
shaken.
Anderson Cascade Impactor (ACI)
TABLE-US-00003 [0243] Delivered Dose (.mu.g) 18.1 FPD (.mu.g) 0.5
FPF (%) 2.8 MMAD (.mu.m) 11.5 GSD 1.8
Example 2
Control--Spray Dried
[0244] Spray dried tiotropium bromide (3.8 mg) was added into a
coated (DuPont 3200 200) canister, with Bespak 63 .mu.l valve. HFA
134a (14700 mg) was added to the canister. The solution was
shaken.
Anderson Cascade Impactor (ACI)
TABLE-US-00004 [0245] Delivered Dose (.mu.g) 18.1 FPD (.mu.g) 0.4
FPF (%) 2.2 MMAD (.mu.m) 11.4 GSD 1.8
Example 3
Formulation 1 (Tiotropium Bromide:Trehalose:Leucine 50:25:25 wt
%)
[0246] Tiotropium bromide (1.2 g), trehalose dehydrate (0.6 g), and
L-leucine (0.6 g) were dissolved into methanol (60 ml). The
solutions were combined by shaking. Water (60 ml) was added and
shaken until dissolution occurred. The resultant solution was spray
dried according to the parameters outlined above.
[0247] Bulk Particle Size Data--Sympatec Data
TABLE-US-00005 TABLE 3 Formulation 1: X10 (.mu.m) X50 (.mu.m) X90
(.mu.m) X99 (.mu.m) 0 days 0.56 1.15 2.10 3.96 9 days 0.49 1.12
2.12 3.84 14 days 0.51 1.13 2.12 3.95
Bulk DSC Data
[0248] T=0 days Tg=70.degree. C., no other events T=9 days
Tg=63.degree. C., broad re-crystallisation followed by melting with
decomposition above 200.degree. C. T=14 days Tg=61.degree. C.,
broad re-crystallisation followed by melting with decomposition
above 200.degree. C. T=35 days Tg=61.degree. C., broad
re-crystallisation followed by melting with decomposition above
200.degree. C.
Formulation A
[0249] Spray dried tiotropium bromide:trehalose:leucine 50:25:25 wt
% (6.3 mg) was added into a coated (DuPont 3200 200) canister, with
Bespak 63 .mu.l valve. HFA 227 (14300 mg) was added to the
canister. The solution was shaken.
Anderson Cascade Impactor
TABLE-US-00006 [0250] Delivered Dose (.mu.g) 10.6 FPD (.mu.g) 4.6
FPF (%) 43.8 MMAD (.mu.m) 2.8 GSD NA
Formulation B
[0251] Spray dried tiotropium bromide:trehalose:leucine 50:25:25 wt
% (6.3 mg) was added into a coated (DuPont 3200 200) canister, with
Bespak 63 .mu.l valve. HFA 227 with 0.1% w/w Abs Ethanol (14200 mg)
was added to the canister. The suspension was shaken.
Anderson Cascade Impactor
TABLE-US-00007 [0252] Delivered Dose (.mu.g) 13.5 FPD (.mu.g) 4.1
FPF (%) 30.7 MMAD (.mu.m) 4.2 GSD 2.4
Example 4
Formulation 2 (Tiotropium Bromide:Trehalose:Leucine 75:15:15 wt
%)
[0253] Tiotropium bromide (1.4 g), trehalose dehydrate (0.3 g) and
L-leucine (0.3 g) were dissolved into methanol (60 ml). The
solution was shaken. Water (60 ml) was added and shaken until
dissolution occurred. The resultant solution was spray dried
according to the parameters outlined below.
Bulk Particle Size Data--Sympatec Data
TABLE-US-00008 [0254] TABLE 4 Formulation 2 X10 (.mu.m) X50 (.mu.m)
X90 (.mu.m) X99 (.mu.m) 0 days 0.63 1.25 2.23 3.54 9 days 0.60 1.23
2.23 3.59 14 days 0.59 1.21 2.19 3.62
Bulk DSC Data
[0255] T=0 days Tg=69.degree. C., no other events T=9 days
Tg=59.degree. C., small re-crystallisation followed by melting with
decomposition above 200.degree. C. T=14 days Tg=72.degree. C. with
no other clear transitions, decomposition above 200.degree. C. T=35
days Tg=54.degree. C., broad re-crystallisation followed by melting
with decomposition above 200.degree. C.
Formulation A
[0256] Spray dried tiotropium bromide:trehalose:leucine 75:15:15 wt
% (4.5 mg) was added into a coated (DuPont 3200 200) canister, with
Bespak 63 .mu.l valve. HFA 227 (14300 mg) was added to the
canister. The solution was shaken.
Anderson Cascade Impactor
TABLE-US-00009 [0257] Delivered Dose (.mu.g) 10.7 FPD (.mu.g) 6.7
FPF (%) 62.0 MMAD (.mu.m) 2.8 GSD 1.8
Formulation B
[0258] Spray dried tiotropium bromide:trehalose:leucine 75:15:15 wt
% (4.48 mg) was added into a coated (DuPont 3200 200) canister,
with Bespak 63 .mu.l valve. HFA 227 with 0.1% w/w Abs Ethanol
(14200 mg) was added to the canister. The suspension was
shaken.
Anderson Cascade Impactor
TABLE-US-00010 [0259] Delivered Dose (.mu.g) 11.2 FPD (.mu.g) 5.8
FPF (%) 51.6 MMAD (.mu.m) 2.9 GSD 2.1
Example 5
Formulation 3 (Tiotropium Bromide:Leucine 75:25 wt %)
[0260] Tiotropium bromide (1.4 g) and L-leucine (0.5 g) were
dissolved into methanol (60 ml). Water (60 ml) was added and shaken
until dissolution occurred. The resultant solution was spray dried
according to the parameters outlined above.
Bulk Particle Size Data--Sympatec Data
TABLE-US-00011 [0261] TABLE 5 Formulation 3 X10 (.mu.m) X50 (.mu.m)
X90 (.mu.m) X99 (.mu.m) 0 days 0.74 1.41 2.53 3.78 9 days 0.73 1.39
2.52 4.33 14 days 0.72 1.39 2.50 4.53
Bulk DSC Data
[0262] T=0 days Tg=64.degree. C., no other events T=9 days
Tg=77.degree. C., broad re-crystallisation followed by melting with
decomposition above 200.degree. C. T=14 days Tg=64.degree. C.,
broad re-crystallisation followed by melting with decomposition
above 200.degree. C. T=35 days Tg=64.degree. C., broad
re-crystallisation followed by melting with decomposition above
180.degree. C.
Formulation A
[0263] Spray dried tiotropium bromide:leucine 75:25 wt % (4.2 mg)
was added into a coated (DuPont 3200 200) canister, with Bespak 63
.mu.l valve. HFA 227 (14300 mg) was added to the canister. The
solution was shaken.
Anderson Cascade Impactor
TABLE-US-00012 [0264] Delivered Dose (.mu.g) 10.5 FPD (.mu.g) 6.2
FPF (%) 59.0 MMAD (.mu.m) 2.7 GSD 2.1
Formulation B
[0265] Spray dried tiotropium bromide:leucine 75:25 wt % (4.2 mg)
was added into a coated (DuPont 3200 200) canister, with Bespak 63
.mu.l valve. HFA 227 with 0.1% w/w Abs Ethanol (14200 mg) was added
to the canister. The suspension was shaken.
Anderson Cascade Impactor
TABLE-US-00013 [0266] Delivered Dose (.mu.g) 13.5 FPD (.mu.g) 6.8
FPF (%) 49.9 MMAD (.mu.m) 2.5 GSD 1.9
Example 6
Formulation 4 (Tiotropium Bromide:Leucine 85:15 wt %)
[0267] Tiotropium bromide (1.9 g) and L-leucine (0.3 g) were
dissolved into 60 ml methanol. Water (60 ml) was added and shaken
until dissolution occurred. The resultant solution was spray dried
according to the parameters outlined below.
Bulk Particle Size Data--Sympatec Data
TABLE-US-00014 [0268] TABLE 6 Formulation 4 X10 (.mu.m) X50 (.mu.m)
X90 (.mu.m) X99 (.mu.m) 0 days 0.61 1.25 2.32 3.77 9 days 0.57 1.22
2.31 3.96 14 days 0.55 1.20 2.29 3.93
Bulk DSC Data
[0269] T=0 days Tg=79.degree. C., no other events T=9 days
Tg=65.degree. C., small re-crystallisation followed by melting with
decomposition above 200.degree. C. T=14 days Tg=62.degree. C.,
broad re-crystallisation followed by melting with decomposition
above 200.degree. C. T=35 days Tg=69.degree. C., melting with
decomposition above 200.degree. C.
Formulation A
[0270] Spray dried tiotropium bromide:leucine 85:15 wt % (3.7 mg)
was added into a coated (DuPont 3200 200) canister, with Bespak 63
.mu.l valve. HFA 227 (14300 mg) was added to the canister. The
solution was shaken.
Anderson Cascade Impactor
TABLE-US-00015 [0271] Delivered Dose (.mu.g) 13.5 FPD (.mu.g) 7.7
FPF (%) 57.5 MMAD (.mu.m) 2.9 GSD 1.9
Formulation B
[0272] Spray dried tiotropium bromide:leucine 85:15 wt % (3.7 mg)
was added into a coated (DuPont 3200 200) canister, with Bespak 63
.mu.l valve. HFA 227 with 0.1% w/w Abs Ethanol (14200 mg) was added
to the canister. The suspension was shaken.
Anderson Cascade Impactor
TABLE-US-00016 [0273] Delivered Dose (.mu.g) 10.8 FPD (.mu.g) 6.4
FPF (%) 58.8 MMAD (.mu.m) 2.7 GSD 2.0
Extra Budesonide Examples
[0274] All samples have a clear glass transition at each time
point, demonstrating that the spray dried formulations are
amorphous. For all samples except Formulation 2 above there is a
decrease in the T.sub.g during the storage time. All glass
transition temperatures (T.sub.g) are above 50.degree. C.
indicating that the samples are stable at room temperature.
Example 7
Formulation 5 (Budesonide:Trehalose 50:50)
[0275] Recrystallisation at 103.degree. C. and large melt at
254.degree. C. at 13 days indicates budesonide is, at least in
part, amorphous but has become able to recrystallise on
heating.
Example 8
Formulation 6 (Budesonide:Trehalose 75:25)
[0276] Budesonide remains amorphous at 13 days, but is more readily
crystallised than at t=0.
Example 9
Formulation 7 (Budesonide:Trehalose:Leucine 50:25:25)
[0277] Large melt indicates that budesonide is mostly
crystalline.
Example 10
Formulation 8 (Tiotropium Bromide:Trehalose 75:25)
[0278] Large recrystallisation at 98.degree. C. with melting point
of 186.degree. C. at 13 days indicates that the formulation remains
amorphous but is more readily crystallised than at t=0 days.
Example 11
Formulation 9 (Tiotropium Bromide:Trehalose:Leucine 50:25:25)
[0279] No indication of re-crystallisation, No information can be
drawn from the t=13 day trace.
[0280] From the above Examples, one can see that the spray dried
tiotropium bromide formulations produced have been shown to be
amorphous at the time of manufacture and after storage at room
temperature for 14 days.
[0281] It was also shown that tiotropium:leucine combinations (i.e.
no trehalose) sediment quickly (<10 seconds) and therefore are
poor suspension formulations.
[0282] FTIR data from the formulation comprising 50:25:25
Tiotropium Bromide:Trehalose:Leucine in HFA 134a shows that the
formulation is at least substantially crystalline, which suggests
that HFA 227 is preferred over HFA 134a.
Example 12
Spray Dried Tiotropium Bromide
[0283] Tiotropium bromide (1.0 g) was dissolved in water (200 ml).
The resultant solution was spray dried according to the parameters
outlined above.
Bulk Particle Size Data--Sympatec Data
TABLE-US-00017 [0284] TABLE 7 X10 (.mu.m) X50 (.mu.m) X90 (.mu.m)
X99 (.mu.m) 0 days 0.5 1.1 2.1 27.3 14 days 0.6 1.3 5.0 38.3
Bulk DSC Data
[0285] T=0 days Tg=64.degree. C., no other events T=14 days
Tg=53.degree. C., no other events
FTIR
[0286] No change over 14 days.
Formulation A
[0287] Spray dried tiotropium bromide (4.3 mg) was added into a
coated (DuPont 3200 200) canister, with Bespak 50 .mu.l valve. HFA
227 (17000 mg) was added to the canister. The solution was
shaken.
TABLE-US-00018 Anderson Cascade Impactor 0 week 7 weeks Delivered
Dose (.mu.g) 16.7 18.0 FPD (.mu.g) 1.5 0.9 FPF (%) 9.0 4.8 MMAD
(.mu.m) 9.8 9.9 GSD 2.8 2.0
Formulation B
[0288] Spray dried tiotropium bromide (4.3 mg) was added into a
coated (DuPont 3200 200) canister, with Bespak 50 .mu.l valve. HFA
134a (14300 mg) was added to the canister. The solution was
shaken.
TABLE-US-00019 Anderson Cascade Impactor 0 week 7 weeks Delivered
Dose (.mu.g) 18.9 22.7 FPD (.mu.g) 3.0 0.4 FPF (%) 10.5 1.9 MMAD
(.mu.m) 8.2 11.3 GSD 2.6 2.0
Example 13
Spray Dried Tiotropium Bromide:PVP 95:5 wt %
[0289] Tiotropium bromide (0.95 g) and PVP (0.05 g) were dissolved
into 50 ml water. The resultant solution was spray dried according
to the parameters outlined below
Bulk Particle Size Data--Sympatec Data
TABLE-US-00020 [0290] TABLE 8 X10 (.mu.m) X50 (.mu.m) X90 (.mu.m)
X99 (.mu.m) 0 days 0.5 1.1 2.2 3.6 14 days 0.5 1.2 2.4 4.2
Bulk DSC Data
[0291] T=0 days Tg=65.degree. C., no other events T=14 days
Tg=51.degree. C., no other events
FTIR
[0292] No change over 14 days.
Formulation A
[0293] Spray dried tiotropium bromide:PVP 95:5 wt % (4.5 mg) was
added into a coated (DuPont 3200 200) canister, with Bespak 50
.mu.l valve. HFA 227 (17000 mg) was added to the canister. The
solution was shaken.
TABLE-US-00021 Anderson Cascade Impactor 0 week 7 weeks Delivered
Dose (.mu.g) 20.6 21.0 FPD (.mu.g) 2.2 4.1 FPF (%) 10.6 19.3 MMAD
(.mu.m) 7.3 5.0 GSD 2.8 3.2
Formulation B
[0294] Spray dried tiotropium bromide:PVP 95:5 wt % (4.5 mg) was
added into a coated (DuPont 3200 200) canister, with Bespak 50
.mu.l valve. HFA 227 & 0.1% Ethanol (17000 mg) was added to the
canister. The solution was shaken.
TABLE-US-00022 Anderson Cascade Impactor 0 week 7 weeks Delivered
Dose (.mu.g) 17.6 17.0 FPD (.mu.g) 1.8 3.6 FPF (%) 10.4 21.2 MMAD
(.mu.m) 7.5 4.9 GSD 2.9 3.9
Example 14
Spray Dried Tiotropium Bromide:PVP 90:10 wt %
[0295] Tiotropium bromide (0.90 g) and PVP (0.09 g) were dissolved
into 50 ml water. The resultant solution was spray dried according
to the parameters outlined below
Bulk Particle Size Data--Sympatec Data
TABLE-US-00023 [0296] TABLE 9 X10 (.mu.m) X50 (.mu.m) X90 (.mu.m)
X99 (.mu.m) 0 days 0.5 1.3 2.8 4.2
Bulk DSC Data
[0297] T=0 days Tg=53.degree. C., no other events T=14 days
Tg=54.degree. C., no other events
FTIR
[0298] No change over 14 days.
Formulation A
[0299] Spray dried tiotropium bromide:PVP 90:10 wt % (4.8 mg) was
added into a coated (DuPont 3200 200) canister, with Bespak 50
.mu.l valve. HFA 227 (17000 mg) was added to the canister. The
solution was shaken.
TABLE-US-00024 Anderson Cascade Impactor 0 week 7 weeks Delivered
Dose (.mu.g) 16.4 18.3 FPD (.mu.g) 2.4 5.7 FPF (%) 14.9 31.0 MMAD
(.mu.m) 5.3 3.4 GSD 2.1 2.9
Formulation B
[0300] Spray dried tiotropium bromide:PVP 90:10 wt % (4.8 mg) was
added into a coated (DuPont 3200 200) canister, with Bespak 50
.mu.l valve. HFA 227 & 0.1% Ethanol (17000 mg) was added to the
canister. The solution was shaken.
TABLE-US-00025 Anderson Cascade Impactor 0 week 7 weeks Delivered
Dose (.mu.g) 16.2 15.7 FPD (.mu.g) 2.4 4.4 FPF (%) 14.9 28.3 MMAD
(.mu.m) 5.5 3.7 GSD 2.6 2.9
Example 15
Spray Dried Tiotropium Bromide:Lecithin 95:5 wt %
[0301] Tiotropium bromide (0.95 g) and lecithin (0.05 g) were
dissolved into methanol (30 ml). The solutions were combined by
shaking. Water (20 ml) was added and shaken until dissolution
occurred. The resultant solution was spray dried according to the
parameters outlined above.
Bulk Particle Size Data--Sympatec Data
TABLE-US-00026 [0302] TABLE 10 X10 (.mu.m) X50 (.mu.m) X90 (.mu.m)
X99 (.mu.m) 0 days 0.8 2.1 5.5 9.1 14 days 1.0 3.1 29.8 48.6
Bulk DSC Data
[0303] T=0 days Tg=56.degree. C., no other events T=14 days
Tg=53.degree. C.
FTIR
[0304] No change over 14 days.
Formulation A
[0305] Spray dried tiotropium bromide/lecithin 95:5 wt % (4.5 mg)
was added into a coated (DuPont 3200 200) canister, with Bespak 50
.mu.l valve. HFA 227 (17000 mg) was added to the canister. The
solution was shaken.
TABLE-US-00027 Anderson Cascade Impactor 0 Week Delivered Dose
(.mu.g) 28 FPD (.mu.g) 1.6 FPF (%) 5.8 MMAD (.mu.m) 12.5 GSD
2.2
Formulation B
[0306] Spray dried tiotropium bromide/Lecithin 95:5 wt % (4.5 mg)
was added into a coated (DuPont 3200 200) canister, with Bespak 50
.mu.l valve. HFA 134a (14300 mg) was added to the canister. The
solution was shaken.
TABLE-US-00028 Anderson Cascade Impactor 0 Week Delivered Dose
(.mu.g) 69.2 FPD (.mu.g) 2.1 FPF (%) 3.0 MMAD (.mu.m) 14.7 GSD
1.7
Example 16
Spray Dried Tiotropium Bromide:Lecithin 90:10 wt %
[0307] Tiotropium bromide (0.90 g) and lecithin (0.09 g) were
dissolved into methanol (30 ml). The solutions were combined by
shaking. Water (20 ml) was added and shaken until dissolution
occurred. The resultant solution was spray dried according to the
parameters outlined above.
Bulk Particle Size Data--Sympatec Data
TABLE-US-00029 [0308] TABLE 11 X10 (.mu.m) X50 (.mu.m) X90 (.mu.m)
X99 (.mu.m) 0 days 1.0 3.5 32.7 57.2
Bulk DSC Data
[0309] T=0 days Tg=54.degree. C., no other events T=14 days
Tg=50.degree. C.
FTIR
[0310] No change over 14 days.
Formulation A
[0311] Spray dried tiotropium bromide:lecithin 90:10 wt % (4.8 mg)
was added into a coated (DuPont 3200 200) canister, with Bespak 50
.mu.l valve. HFA 227 (17000 mg) was added to the canister. The
solution was shaken.
TABLE-US-00030 Anderson Cascade Impactor 0 Week Delivered Dose
(.mu.g) 27.2 FPD (.mu.g) 1.3 FPF (%) 4.7 MMAD (.mu.m) 14.7 GSD
2.0
Formulation B
[0312] Spray dried tiotropium bromide:lecithin 90:10 wt % (4.8 mg)
was added into a coated (DuPont 3200 200) canister, with Bespak 50
.mu.l valve. HFA 134a (14300 mg) was added to the canister. The
solution was shaken.
TABLE-US-00031 Anderson Cascade Impactor 0 Week Delivered Dose
(.mu.g) 27.5 FPD (.mu.g) 1.5 FPF (%) 5.4 MMAD (.mu.m) 12.2 GSD
2.0
Salbutamol Sulphate/Ipratropium Bromide Spray Dried Examples:
[0313] Formulations containing salbutamol sulphate, ipratropium
bromide, trehalose and leucine were prepared by spray drying using
a Mini spray dryer.
[0314] The spray dried powders were characterised by particle size
using a Sympatec laser sizer, infra-red spectroscopy using a Perkin
Elmer Spectrum GX ATR-FTIR, and thermal behaviour using a Perkin
Elmer Diamond differential scanning calorimeter.
[0315] Samples of each formulation (250 mg) were stored at room
temperature and low RH (20-30%) in glass 7 mL screw top vials and
the characterisation repeated after 7 and 14 days.
Differential Scanning Calorimetry
[0316] The sample (5 to 10 mg) was sealed in a pierced 40 .mu.l
aluminium sample pan and heated from 20 to 200.degree. C. at
50.degree. C. per minute.
[0317] There are no significant changes in the particle size
distributions for any of the formulations over fourteen days.
Example 17
Salbutamol:Ipratropium Bromide 85.7:14.3 wt % (100% API)
TABLE-US-00032 [0318] X10 (.mu.m) X50 (.mu.m) X90 (.mu.m) X99
(.mu.m) 0 days 0.48 1.17 2.45 4.14 7 days 0.45 1.15 2.47 4.11 14
days 0.47 1.17 2.47 4.13
T=0 days Tg=71.degree. C., broad re-crystallisation 110 to
160.degree. C. followed by melting with decomposition above
160.degree. C. T=7 days Tg=64.degree. C., broad re-crystallisation
110 to 170.degree. C. followed by melting with decomposition above
180.degree. C. T=14 days Tg=70.degree. C., broad re-crystallisation
110 to 170.degree. C. followed by melting with decomposition above
170.degree. C. pMDI Manufacture:
[0319] Spray dried salbutamol sulphate:ipratropium bromide (22.5
mg) was added into a coated (DuPont 3200 200) canister, with Bespak
63 .mu.l valve. HFA 227 (17000 mg) was added to the canister. The
solution was shaken.
Example 18
Salbutamol:Ipratropium Bromide:Trehalose:Leucine 77.1:12.9:5:5%
TABLE-US-00033 [0320] X10 (.mu.m) X50 (.mu.m) X90 (.mu.m) X99
(.mu.m) 0 days 0.51 1.18 2.30 3.78 7 days 0.54 1.20 2.32 3.86 14
days 0.55 1.23 2.39 3.88
T=0 days Tg=67.degree. C., broad re-crystallisation 110 to
160.degree. C. followed by melting with decomposition above
160.degree. C. T=7 days Tg=60.degree. C., broad re-crystallisation
110 to 160.degree. C. followed by melting with decomposition above
180.degree. C. T=14 days Tg=64.degree. C., broad re-crystallisation
110 to 170.degree. C. followed by melting with decomposition above
170.degree. C. pMDI Manufacture:
[0321] Spray dried salbutamolsulphate:ipratropium
bromide:Trehalose:Leucine 77.1:12.9:5:5 wt % (25.0 mg) was added
into a coated (DuPont 3200 200) canister, with Bespak 63 .mu.l
valve. HFA 227 (17000 mg) was added to the canister. The solution
was shaken.
Example 19
Salbutamol:Ipratropium Bromide:Trehalose:Leucine 68.6:11.4:10:10 wt
%
TABLE-US-00034 [0322] X10 (.mu.m) X50 (.mu.m) X90 (.mu.m) X99
(.mu.m) 0 days 0.65 1.34 2.50 3.73 7 days 0.58 1.28 2.46 3.72 14
days 0.64 1.36 2.58 3.81
T=0 days Tg=81.degree. C., broad re-crystallisation 110 to
170.degree. C. followed by melting with decomposition above
180.degree. C. T=7 days Tg=44.degree. C., possibly two broad
re-crystallisation events followed by melting with decomposition
above 180.degree. C. T=14 days Tg=72.degree. C., large broad
re-crystallisation 110 to 160.degree. C. followed by melting with
decomposition above 160.degree. C. pMDI Manufacture:
[0323] Spray dried salbutamol sulphate:ipratropium
bromide:Trehalose:Leucine 68.6:11.4:10:10 wt % (28.1 mg) was added
into a coated (DuPont 3200 200) canister, with Bespak 63 .mu.l
valve. HFA 227 (17000 mg) was added to the canister. The solution
was shaken.
Example 20
Salbutamol:Ipratropium Bromide:Trehalose:Leucine 60:10:15:15 wt
%
TABLE-US-00035 [0324] X10 (.mu.m) X50 (.mu.m) X90 (.mu.m) X99
(.mu.m) 0 days 0.65 1.40 2.72 4.05 7 days 0.62 1.37 2.65 3.98 14
days 0.68 1.44 2.79 4.19
T=0 days Tg=76.degree. C., re-crystallisation around 120.degree. C.
followed by melting with decomposition above 180.degree. C. T=7
days Tg=66.degree. C., re-crystallisation around 110.degree. C.
followed by melting with decomposition above 180.degree. C. T=14
days Tg=74.degree. C., re-crystallisation around 125.degree. C.
followed by melting with decomposition above 180.degree. C. pMDI
Manufacture:
[0325] Spray dried salbutamolsulphate:ipratropium
bromide:Trehalose:Leucine 60:10:15:15 wt % (32.1 mg) was added into
a coated (DuPont 3200 200) canister, with Bespak 63 .mu.l valve.
HFA 227 (17000 mg) was added to the canister. The solution was
shaken.
[0326] All samples have a clear glass transition at each time
point, demonstrating that the spray dried formulations are
amorphous. All glass transition temperatures (Tg) remain well above
room temperature. For all samples there is a decrease in the Tg
after 7 days which is partly recovered at 14 days. This is most
apparent for the batch in Example 19. The reason for this change
would have to be investigated further to be substantiated.
Infra-Red Spectroscopy
[0327] The absorbance spectra were measured using the Golden Gate
attenuated total reflectance (ATR) accessory between 4000 and 600
cm.sup.-1 acquiring 16 co-added scans. The spectra were compared
with that of the crystalline staring materials and between time
points.
[0328] Spectra recorded at 7 and 14 days showed broad, undefined
peaks in the fingerprint regions and lack of any sharp peaks above
3000 cm.sup.-1 indicating that the samples are amorphous. The
spectra showed only minor differences between batches,
demonstrating that the spectra are dominated by absorbances due to
salbutamol and ipratropium.
Conclusions
[0329] The spray dried formulations produced have been shown to be
amorphous at the time of manufacture and after storage at room
temperature and low humidity for 14 days.
pMDI Manufacture:
Examples 21
[0330] Spray dried salbutamol sulphate/ipratropium bromide (22.5
mg) as per Example 17 was added into a coated (DuPont 3200 200)
canister, with Bespak 63 .mu.l valve. 0.1% Ethanol, HFA 227 (17000
mg) was added to the canister. The solution was shaken.
Examples 22
[0331] Spray dried salbutamol sulphate/ipratropium
bromide:Trehalose:Leucine 77.1:12.9:5:5 wt % (25.0 mg) as per
Example 18 was added into a coated (DuPont 3200 200) canister, with
Bespak 63 .mu.l valve. 0.1% Ethanol, HFA 227 (17000 mg) was added
to the canister. The solution was shaken.
Examples 23
[0332] Spray dried salbutamol sulphate/ipratropium
bromide:Trehalose:Leucine 68.6:11.4:10:10 wt % (28.1 mg) as per
Example 19 was added into a coated (DuPont 3200 200) canister, with
Bespak 63 .mu.l valve. 0.1% Ethanol, HFA 227 (17000 mg) was added
to the canister. The solution was shaken.
Example 24
[0333] Spray dried salbutamol sulphate/ipratropium
bromide:Trehalose:Leucine 60:10:15:15 wt % (32.1 mg) as per Example
20 was added into a coated (DuPont 3200 200) canister, with Bespak
63 .mu.l valve. 0.1% Ethanol, HFA 227 (17000 mg) was added to the
canister. The solution was shaken.
TABLE-US-00036 TABLE 12 Anderson Cascade Impactor Salbutamol
Sulphate Summary DD (.mu.g) FPD (.mu.g) FPF (%) MMAD (.mu.m)
Example Weeks Weeks Weeks Weeks Number Product/Blend Formulation 0
10 0 10 0 10 0 10 17 85.7:14.3:0:0 HFA 227 81 79 35 30 43 38 3.6
3.7 18 77.1:12.9:5:5 HFA 227 83 81 36 33 43 41 3.8 3.8 19
68.6:11.4:10:10 HFA 227 73 69 42 32 58 46 3.3 3.7 20 60:10:15:15
HFA 227 75 71 30 26 39 28 3.9 4.1 21 85.7:14.3:0:0 0.1% EtOH, 227
77 67 32 15 41 22 3.8 4.8 22 77.1:12.9:5:5 0.1% EtOH, 227 72 69 31
18 43 41 3.7 4.8 23 68.6:11.4:10:10 0.1% EtOH, 227 73 69 42 19 58
46 3.3 4.7 24 60:10:15:15 0.1% EtOH, 227 66 70 25 20 38 36 3.9
4.6
TABLE-US-00037 TABLE 13 Anderson Cascade Impactor Ipratropium
Bromide Summary DD (.mu.g) FPD (.mu.g) FPF (%) MMAD (.mu.m) Example
Weeks Weeks Weeks Weeks Number; Product/Blend Formulation 0 10 0 10
0 10 0 10 17 85.7:14.3:0:0 HFA 227 14 13 6.1 4.9 45 37 3.6 3.8 18
77.1:12.9:5:5 HFA 227 12 13 6.1 5.5 50 42 3.6 3.8 19
68.6:11.4:10:10 HFA 227 13 12 7.4 5.6 57 46 3.3 3.7 20 60:10:15:15
HFA 227 12 11 4.7 3.8 39 35 3.7 4.2 21 85.7:14.3:0:0 0.1% EtOH, 227
13 11 5.3 2.2 40 20 3.8 5.2 22 77.1:12.9:5:5 0.1% EtOH, 227 13 12
5.7 3.1 45 26 3.6 4.8 23 68.6:11.4:10:10 0.1% EtOH, 227 12 11 5.6
3.1 48 27 3.7 4.7 24 60:10:15:15 0.1% EtOH, 227 11 11 3.9 3.0 37 26
4.0 4.8
[0334] (Formulations containing ethanol show a greater decrease in
FPD than formulations without ethanol after 10 weeks storage.
Metered and delivered dose remains consistent over 10 weeks.)
[0335] Spray Dried Salbutamol Sulphate with Alternative
Excipients
Example 25
Spray Dried Salbutamol
TABLE-US-00038 [0336] X10 (.mu.m) X50 (.mu.m) X90 (.mu.m) X99
(.mu.m) 0 days 0.5 1.4 3.2 5.0 14 days 0.6 1.4 3.0 4.9
Bulk DSC Data
[0337] T=0 days Tg=81.degree. C., no other events T=14 days
Tg=77.degree. C.
FTIR
[0338] No change over 14 days.
pMDI Manufacture:
Example 25A
[0339] Spray dried salbutamol sulphate (28.8 mg) was added into a
coated (DuPont 3200 200) canister, with Bespak 63 .mu.l valve. HFA
227 (17000 mg) was added to the canister. The solution was
shaken.
Example 25B
[0340] Spray dried salbutamol sulphate (22.8 mg) was added into a
coated (DuPont 3200 200) canister, with Bespak 63 .mu.l valve. HFA
134a (14300 mg) was added to the canister. The solution was
shaken.
Example 26
Spray Dried Salbutamol Sulphate:PVP (95:5 wt %)
TABLE-US-00039 [0341] X10 (.mu.m) X50 (.mu.m) X90 (.mu.m) X99
(.mu.m) 0 days 0.5 1.2 2.5 5.0 14 days 0.6 1.2 2.5 4.9
Bulk DSC Data
[0342] T=0 days Tg=77.degree. C., no other events T=14 days
Tg=78.degree. C.
FTIR
[0343] No change over 14 days
pMDI Manufacture:
Example 26A
[0344] Spray dried salbutamol sulphate:PVP 95:5 wt % (30.3 mg) was
added into a coated (DuPont 3200 200) canister, with Bespak 63
.mu.l valve. HFA 227 (17000 mg) was added to the canister. The
solution was shaken.
Example 26B
Spray dried salbutamol sulphate:PVP 95:5 Wt % (30.3 Mg) was Added
into a coated (DuPont 3200 200) canister, with Bespak 63 .mu.l
valve. 0.1% Ethanol in HFA 227 (17000 mg) was added to the
canister. The solution was shaken.
Example 27
[0345] Spray Dried Salbutamol Sulphate:PVP (90:10 wt %)
TABLE-US-00040 X10 (.mu.m) X50 (.mu.m) X90 (.mu.m) X99 (.mu.m) 0
days 0.5 1.4 3.4 5.2 14 days 0.6 1.5 3.4 5.3
Bulk DSC Data
[0346] T=0 days Tg=59.degree. C. T=14 days Tg=84.degree. C.
FTIR
[0347] No change over 14 days.
pMDI Manufacture:
Example 27A
Spray dried salbutamol sulphate:PVP 90:10 wt % (32.0 mg) was added
into a coated (DuPont 3200 200) canister, with Bespak 63 .mu.l
valve. HFA 227 (17000 mg) was added to the canister. The solution
was shaken.
Example 27B
[0348] Spray dried salbutamol sulphate:PVP 90:10 wt % (32.0 mg) was
added into a coated (DuPont 3200 200) canister, with Bespak 63
.mu.l valve. 0.1% Ethanol in HFA 227 (17000 mg) was added to the
canister. The solution was shaken.
Example 28
Spray Dried Salbutamol Sulphate:Lecithin (95:5 wt %)
TABLE-US-00041 [0349] X10 (.mu.m) X50 (.mu.m) X90 (.mu.m) X99
(.mu.m) 0 days 0.5 1.5 3.5 5.3 14 days 0.6 1.5 3.5 5.3
Bulk DSC Data
[0350] T=0 days Tg=71.degree. C., no other events T=14 days
Tg=76.degree. C.
FTIR
[0351] No change over 14 days.
pMDI Manufacture:
Example 28A
[0352] Spray dried salbutamol sulphate:Lecithin 95:5 wt % (30.3 mg)
was added into a coated (DuPont 3200 200) canister, with Bespak 63
.mu.l valve. HFA 227 (17000 mg) was added to the canister. The
solution was shaken.
Example 28B
Spray dried salbutamol sulphate:Lecithin 95:5 wt % (30.3 mg) was
added into a coated (DuPont 3200 200) canister, with Bespak 63
.mu.l valve. HFA 134a (14300 mg) was added to the canister. The
solution was shaken.
Example 29
Spray Dried Salbutamol Sulphate:Lecithin (90:10 wt %)
TABLE-US-00042 [0353] X10 (.mu.m) X50 (.mu.m) X90 (.mu.m) X99
(.mu.m) 0 days 0.5 1.1 2.2 4.8 14 days 0.6 1.2 2.2 4.6
Bulk DSC Data
[0354] T=0 days Tg=76.degree. C., no other events T=14 days
Tg=77.degree. C.
FTIR
[0355] No change over 14 days.
pMDI Manufacture:
Example 29A
[0356] Spray dried salbutamol sulphate:Lecithin 90:10 wt % (32.0
mg) was added into a coated (DuPont 3200 200) canister, with Bespak
63 .mu.l valve. HFA 227 (17000 mg) was added to the canister. The
solution was shaken.
Example 29B
[0357] Spray dried salbutamol sulphate:Lecithin 90:10 wt % (32.0
mg) was added into a coated (DuPont 3200 200) canister, with Bespak
63 .mu.l valve. HFA 134a (14300 mg) was added to the canister. The
solution was shaken.
TABLE-US-00043 TABLE 14 Summary data salbutamol sulphate with
excipients Exam- DD FPD FPF Excipient ple HFA (.mu.g) (.mu.g) (%)
MMAD GSD None 25A 227 86 42 49 3.3 1.5 25B 134 99 47 48 3.4 1.6 5%
PVP 26A 227 75 24 33 5.0 1.8 26B 0.1% EtOH, 78 37 48 3.3 NA 227 10%
PVP 27A 227 73 38 53 3.2 1.6 27B 0.1% EtOH, 85 39 46 3.4 1.6 227 5%
28A 227 65 16 24 4.4 NA Lecithin 28B 134 66 15 23 4.6 NA 10% 29A
227 88 18 21 5.1 NA Lecithin 29B 134 100 20 20 5.2 NA
Spray Dried Blends (not Used in pMDI Formulations)
Example 30
Spray Dried Fomoterol Fumarate
TABLE-US-00044 [0358] X10 (.mu.m) X50 (.mu.m) X90 (.mu.m) X99
(.mu.m) 14 days 0.9 1.9 3.6 5.7
Bulk DSC Data
[0359] T=0 days Tg=62.degree. C., no other events T=14 days
Tg=74.degree. C.
FTIR
[0360] No change over 14 days
Example 31
Spray Dried Fomoterol Fumarate:Leucine:Trehalose 80:10:10 wt %
TABLE-US-00045 [0361] X10 (.mu.m) X50 (.mu.m) X90 (.mu.m) X99
(.mu.m) 0 days 0.7 1.6 3.8 7.2 14 days 0.8 1.5 3.5 6.8
Bulk DSC Data
[0362] T=0 days Tg=65.degree. C., no other events T=14 days
Tg=65.degree. C.
FTIR
[0363] No change over 14 days
Example 32
Spray Dried Budesonide
TABLE-US-00046 [0364] X10 (.mu.m) X50 (.mu.m) X90 (.mu.m) X99
(.mu.m) 0 days 0.8 2.0 6.0 70.3 14 days 0.8 1.8 4.3 7.0
Bulk DSC Data
[0365] T=0 days Tg=82.degree. C., no other events T=14 days
Tg=81.degree. C.
FTIR
[0366] No change over 14 days
Example 33
Spray Dried Budesonide:Trehalose:Leucine 80:10:10 wt %
TABLE-US-00047 [0367] X10 (.mu.m) X50 (.mu.m) X90 (.mu.m) X99
(.mu.m) 0 days 0.9 1.9 3.8 6.3 14 days 0.9 1.9 3.7 5.9
Bulk DSC Data
[0368] T=0 days Tg=82.degree. C., no other events T=14 days
Tg=81.degree. C.
FTIR
[0369] No change over 14 days
Example 34
Spray Dried Budesonide & Fomoterol Fumarate:Trehalose:Leucine
80 (Budesonide & Fomoterol Fumarate):10:10 wt %
TABLE-US-00048 [0370] X10 (.mu.m) X50 (.mu.m) X90 (.mu.m) X99
(.mu.m) 0 days 0.8 1.7 3.6 6.3 14 days 0.8 1.7 3.4 5.6
Bulk DSC Data
[0371] T=0 days Tg=75.degree. C., no other events T=14 days
Tg=79.degree. C.
FTIR
[0372] No change over 14 days
* * * * *