U.S. patent application number 13/447468 was filed with the patent office on 2012-10-11 for pharmaceutical manufacturing process.
This patent application is currently assigned to Norton Healthcare Limited. Invention is credited to Adrian Ashley, Paul Lamb, Donald MacDonald, John Miller, Martin Oliver, Matthew Pollard, Paul Ronald.
Application Number | 20120258939 13/447468 |
Document ID | / |
Family ID | 33523819 |
Filed Date | 2012-10-11 |
United States Patent
Application |
20120258939 |
Kind Code |
A1 |
Miller; John ; et
al. |
October 11, 2012 |
PHARMACEUTICAL MANUFACTURING PROCESS
Abstract
The present invention provides a method for preparing a sterile
suspension of a glucocorticosteroid. The glucocorticosteroids used
in the invention are preferably antiinflammatory
glucocorticosteroids. By making the last stage of product
preparation be the sterilization process, the potential for
contamination during manufacture and heat degradation of products
is greatly reduced.
Inventors: |
Miller; John; (Cheshire,
GB) ; MacDonald; Donald; (Cheshire, GB) ;
Oliver; Martin; (Cheshire, GB) ; Pollard;
Matthew; (Cheshire, GB) ; Ronald; Paul;
(Cheshire, GB) ; Ashley; Adrian; (Cheshire,
GB) ; Lamb; Paul; (Cheshire, GB) |
Assignee: |
Norton Healthcare Limited
London
GB
|
Family ID: |
33523819 |
Appl. No.: |
13/447468 |
Filed: |
April 16, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11667872 |
Jan 14, 2008 |
8178519 |
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PCT/US2005/041524 |
Nov 16, 2005 |
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13447468 |
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Current U.S.
Class: |
514/171 ;
514/169; 514/174; 514/176; 514/181 |
Current CPC
Class: |
A61P 11/06 20180101;
A61P 11/00 20180101; A61P 43/00 20180101; A61P 37/08 20180101; A61P
17/00 20180101; A61P 11/02 20180101; A61K 9/0073 20130101; A61K
47/26 20130101; A61K 9/10 20130101; A61K 31/573 20130101; A61P
29/00 20180101 |
Class at
Publication: |
514/171 ;
514/169; 514/181; 514/174; 514/176 |
International
Class: |
A61K 31/56 20060101
A61K031/56 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 16, 2004 |
GB |
0425266.4 |
Claims
1-21. (canceled)
22. A composition comprising a sterile suspension of a
glucocorticosteroid made by a process comprising the following
steps: (i) heating a glucocorticosteroid suspension comprising a
glucocorticosteroid, water and a surfactant in a mixing vessel to
sterilize the glucocorticosteroid suspension, (ii) re-circulating
the glucocorticosteroid suspension via a homogenizer before, during
and/or after step (i), and subsequently (iii) mixing the
glucocorticosteroid suspension with sterile water or a sterile
excipient liquid comprising water and one or more pharmaceutically
acceptable excipients.
23. A composition as claimed in claim 22, wherein the method
further comprises, prior to step (iii), the step of preparing the
sterile water or sterile excipient liquid by passing water or an
excipient liquid through a sterilizing grade filter.
24. A composition as claimed in claim 22, wherein the sterile
excipient liquid is used in step (iii) and the one or more
pharmaceutically acceptable excipients comprises a surfactant.
25. A composition as claimed in claim 22, wherein the sterile
excipient liquid is used in step (iii) and the one or more
pharmaceutically acceptable excipients comprises at least one of a
buffer, a salt, a wetting agent, a stabilizing agent and an
isotonic agent.
26. A composition as claimed in claim 22, wherein the
re-circulating in step (ii) occurs during the heating in step
(i).
27. A composition as claimed in claim 22, wherein the concentration
of the glucocorticosteroid in the glucocorticosteroid suspension of
step (i) is from about 15 to about 300 mg/ml.
28. A composition as claimed in claim 22, wherein at least 50% of
the glucocorticosteroid in the glucocorticosteroid suspension is in
the form of a suspension during heating.
29. A composition as claimed in 28, wherein at least 60% of the
glucocorticosteroid in the glucocorticosteroid suspension is in the
form of a suspension during heating.
30. A composition as claimed in claim 22, wherein the
glucocorticosteroid is selected from the group consisting of at
least one of beclomethasone, budesonide, ciclesonide, cortivazol,
deflazacort, flumethasone, flunisolide, fluocinolone, fluticasone,
mometasone, refleponide, tipredane and triamcinolone.
31. A composition as claimed in claim 29, wherein the
glucocorticosteroid is beclomethasone or budesonide.
32. A composition as claimed in claim 24, wherein the concentration
of the surfactant in the sterile excipient liquid is from about 0.2
to about 300 mg/ml.
33. A composition as claimed in claim 22, wherein heating is
carried out at a temperature of from about 101.degree. C. to about
145.degree. C.
34. A composition as claimed in claim 33, wherein heating is
carried out at a temperature of from about 122.degree. C. to about
138.degree. C.
35. A composition as claimed in claim 22, wherein heating is
carried out for about 2 to about 180 mins.
36. A composition as claimed in claim 35, wherein heating is
carried out for at least about 30 mins.
37. A composition as claimed in claim 22, wherein the homogenizer
is an in-line homogenizer or a high-pressure homogenizer.
38. A composition as claimed in claim 22, wherein, in step (iii),
the sterile excipient liquid is used and the glucocorticosteroid
suspension is diluted with the sterile excipient liquid to a
pharmaceutically suitable concentration.
39. A composition as claimed in claim 22, wherein the sterile
suspension of a glucocorticosteroid is packaged.
40. A composition as claimed in claim 39, wherein the sterile
suspension of a glucocorticosteroid is packaged by a blow-fill-seal
(BFS) machine.
41. A composition as claimed in claim 22, wherein the particle size
of the glucocorticosteroid is such that the Dv100 is less than 20
.mu.m, the Dv90 is less than 10 .mu.m and the Dv50 is less than 5
.mu.m.
42. A composition as claimed in claim 22, wherein the sterile
suspension is additionally comprised of a second active ingredient
selected from the group consisting of albuterol, ipratropium
bromide, cromolyn, formoterol, tiotropium, oxitropium and
azelastine.
Description
TECHNICAL FIELD OF THE INVENTION
[0001] The present invention relates to a pharmaceutical
manufacturing process and particularly to a process for sterilizing
glucocorticosteroids.
BACKGROUND OF THE INVENTION
[0002] Sterile drug products provide a number of benefits, both
medically and economically. The medical ramifications requiring
sterile drug preparations are clear in that the use of non-sterile
preparations may subject the patient to an unnecessary risk of
secondary infection from the contaminating microbe, a microbe that
is at least resistant to the drugs of the preparation. Furthermore,
even if the contaminant is innocuous, the growth can result in loss
of active drug products per se with possible concomitant generation
of toxic by-products. Economically, contaminated drug products have
a shortened shelf life, which requires increased production
expenses to replace product on a more frequent basis.
[0003] Methods are needed for the preparation of sterile products
for patient use. However, the problem associated with many
sterilization procedures is that the process often results in
unfavorable changes in the drug profile. These changes in the drug
profile can range from loss of activity, to increased degradation
products being created, or possible alteration of the chemical or
physical characteristics of the compound sterilized. These problems
are especially pronounced when glucocorticosteroids are
sterilized.
[0004] Sterilization of materials relies on the input of sufficient
energy to be lethal to any potential microbial contamination.
Numerous methods including heat, radiation, and chemicals have been
proposed for the sterilization of glucocorticosteroids. However, to
date these methods often result in the excess production of
degradants or a loss of activity for the glucocorticosteroid being
sterilized. Additionally, as in the case of glucocorticosteroid
suspension formulations for metered dose inhalation, the commonly
used sterilization procedures often results in unacceptable changes
to drug particle size.
[0005] Chemical sterilization, for the most part, has been based on
exposure to toxic compounds, for example, ethylene oxide. However,
when used to sterilize glucocorticosteroids, ethylene oxide has
been found to leave residual amounts of ethylene oxide in the drug
preparation. Ethylene oxide is toxic and the residual levels are
often above the pharmaceutically acceptable limits as set by most
regulatory agencies.
[0006] Irradiation based sterilization is known and has been
recommended for glucocorticosteroids (see Illum and Moeller in
Arch. Pharm. Chemi. Sci., Ed. 2, 1974, pp. 167-174). However,
significant degradation has been reported when irradiation has been
used to sterilize micronized glucocorticosteroids.
[0007] WO 00/25746 (Chiesi) discloses a process for preparing a
suspension of a glucocorticosteroid. In a first step an aqueous
carrier is mixed in a turboemulsifier and sterilized by heat
treatment or filtration. In a second step a micronized active
ingredient (e.g. a glucocorticosteroid), pre-sterilized by gamma
irradiation, is added to the aqueous carrier.
[0008] WO 03/086347 (Chiesi) describes some of the disadvantages of
WO 00/25746 and discloses an improvement in the process whereby the
active ingredient is introduced into a turboemulsifier as a powder
by exploiting the vacuum in the turboemulsifier. Again the active
ingredient is sterilized prior to dispersion in the aqueous
carrier.
[0009] Neither of these documents disclose the sterilisation by
heating of an aqueous suspension of a glucocorticosteroid and hence
the problem of particle size growth during the heating and
subsequent cooling steps is not addressed.
[0010] U.S. Pat. No. 3,962,430 (O'Neill) discloses a method for the
production of sterile isotonic solutions of medicinal agents. The
method comprises adding the medicinal agent to a saturated solution
of sodium chloride in water at 100.degree. C. The drag/saturated
sodium chloride solution is then heated to 100-130.degree. C. This
method, which purportedly is based on the theory that the sodium
chloride ions tie up free water thereby preventing hydrolytic
degradation, is not suitable for suspensions of fine particles of
glucocorticosteroids intended for inhalation, as the procedure
produces unfavorable changes in the size of the particles.
Additionally, the procedure can result in bridge formation between
drug particles producing large aggregates, which do not break up on
administration.
[0011] In order to address the problem of particle growth, U.S.
Pat. No. 6,392,036 (Karlsson) discloses a method for the dry heat
sterilization of powdered glucocorticosteroids that can then be
used for drug formulations. However, this method results in
unacceptable levels of heat-degradation products.
[0012] WO 2004/078102 (Dompe) discloses a method for sterilizing an
aqueous suspension of a glucocorticosteroid consisting of the
glucocorticosteroid and water only. Minimal detail is provided of
the sterilisation apparatus.
SUMMARY OF THE INVENTION
[0013] The present invention provides a method for preparing a
sterile suspension of a glucocorticosteroid comprising the
following steps: (i) heating a glucocorticosteroid suspension
comprising a glucocorticosteroid, water and a surfactant in a
mixing vessel to sterilize the glucocorticosteroid suspension, (ii)
re-circulating the glucocorticosteroid suspension via a homogenizer
before, during and/or after step (i), and subsequently, (iii)
mixing the glucocorticosteroid suspension with sterile water or a
sterile excipient liquid comprising water and one or more
pharmaceutically acceptable excipients.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1: Representation of the apparatus used for the
sterilization of a suspension of a glucocorticosteroid in
accordance with the present invention.
[0015] FIG. 2: Flow chart showing the methodology for the
sterilization of the suspension of the glucocorticosteroid using
the apparatus represented in FIG. 1.
[0016] FIGS. 3-5: Representation of specific parts of the apparatus
represented in FIG. 1.
DETAILED DESCRIPTION OF THE INVENTION
[0017] As used herein, "glucocorticosteroid" refers to any of a
group of steroid hormones (including derivatives, synthetic
analogs, and pro-drugs), such as cortisone, which are produced by
the adrenal cortex. These compounds are involved in carbohydrate,
protein, and fat metabolism. Additionally, the glucocorticosteroids
may have anti-inflammatory properties.
[0018] Non-limiting examples of glucocorticosteroids, which may be
used in the present invention, include beclomethasone, budesonide,
ciclesonide, cortivazol, deflazacort, flumethasone, flunisolide,
fluocinolone, fluticasone, mometasone, rofleponide, tipredane and
triamcinolone. Preferably, use is made of budesonide,
beclomethasone (e.g. the dipropionate), ciclesonide, fluticasone,
mometasone and triamcinolone. Most preferably, use is made of
budesonide and beclomethasone (e.g. the dipropionate).
[0019] Technical and scientific terms used herein have the meaning
commonly understood by one of skill in the art to which the present
invention pertains, unless otherwise defined. Reference is made
herein to various methodologies and materials known to those of
skill in the art. Standard reference works setting forth the
general principles of pharmacology include Goodman and Gilman's The
Pharmacological Basis of Therapeutics, 10.sup.th Ed., McGraw Hill
Companies Inc., New York (2001). Any suitable materials and/or
methods known to those of skill can be utilized in carrying out the
present invention.
[0020] The patent and scientific literature referred to herein
establish the knowledge of those with skill in the art and are
hereby incorporated by reference in their entirety to the same
extent as if each was specifically and individually indicated to be
incorporated by reference. Any conflict between any reference cited
herein and the specific teachings of this specification shall be
resolved in favor of the latter. Likewise, any conflict between an
art-understood definition of a word or phrase and a definition of
the word or phrase as specifically taught in this specification
shall be resolved in favor of the latter.
[0021] In the specification and the appended claims, singular
forms, including the singular fouls "a," "an" and "the",
specifically also encompass the plural referents of the terms to
which they refer unless the context clearly dictates otherwise. In
addition, as used herein, unless specifically indicated otherwise,
the word "or" is used in the "inclusive" sense of "and/or" and not
the "exclusive" sense of "either/or."
[0022] As used in this specification, whether in a transitional
phrase or in the body of a claim, the terms "comprise(s)" and
"comprising" are to be interpreted as having an open-ended meaning.
That is, the terms are to be interpreted synonymously with the
phrases "having at least" or "including at least". When used in the
context of a process, the term "comprising" means that the process
includes at least the recited steps, but may include additional
steps. When used in the context of a compound or composition, the
term "comprising" means that the compound or composition includes
at least the recited features or components, but may also include
additional features or components.
[0023] Reference is made hereinafter in detail to specific
embodiments of the invention. While the invention will be described
in conjunction with these specific embodiments, it will be
understood that it is not intended to limit the invention to such
specific embodiments. On the contrary, it is intended to cover
alternatives, modifications, and equivalents as may be included
within the spirit and scope of the invention as defined by the
appended claims. In the following description, numerous specific
details are set forth in order to provide a thorough understanding
of the present invention. The present invention may be practiced
without some or all of these specific details. In other instances,
well known process operations have not been described in detail, in
order not to unnecessarily obscure the present invention
[0024] FIG. 1 shows a schematic representation of the apparatus 1
used to manufacture and fill batches of a sterile
glucocorticosteroid suspension. An excipient liquid, preferably an
excipient solution, is prepared in a first vessel 2. Alternatively,
the first vessel 2 is simply charged with water. The first vessel 2
is provided with a mixer 3 and a re-circulation line 4. A
concentrated glucocorticosteroid suspension is then manufactured
and sterilized before being diluted with the sterile water or
sterile excipient liquid. Accordingly, the apparatus 1 is provided
with second and third vessels 5 and 6. The second and third vessels
5 and 6 are connected to the first vessel 2 by line 7 having a
sterilizing-grade filter 8. Before, during and/or after the
sterilization of the concentrated glucocorticosteroid suspension,
the suspension is re-circulated via re-circulation line 9 and
homogenizer 10. After sterilization the sterilized concentrated
glucocorticosteroid suspension is passed via re-circulation line 11
for dilution with the sterile water or excipient liquid in the
second vessel 5. The suspension is then passed via line 12 for
packaging into suitable containers at blow-fill-seal (BFS) machine
13. These process steps are summarized in FIG. 2.
[0025] Each step will now be described in more detail.
[0026] The excipient liquid is prepared in a first vessel 2. Prior
to mixing, the first vessel 2 is cleaned and either sanitized or
sterilized in place, for example using hot water for injections
(WFI) followed by steam sanitization using steam at temperatures of
not less than 100.degree. C. for not less than 15 mins. After
sanitization or sterilization the water is introduced or the
excipient liquid is prepared as required. The excipient liquid
comprises water and a pharmaceutically acceptable excipient, such
as a surfactant and preferably further comprises other
pharmaceutically acceptable excipients, diluents, etc., such as at
least one buffer, at least one salt, and at least one wetting
agent, stabilizing agent and/or isotonic agent. Pharmaceutically
acceptable surfactants are well known in the art and are
exemplified by Polysorbates, e.g. Polysorbate 80. The components
may be added in any order although preferably the required quantity
of water, e.g. WFI, is charged into the mixing vessel followed by
the other components which are added to the circulating water via
an additions hopper (not shown).
[0027] Preferably at least about 50%, more preferably about 70-90%
of the total quantity of surfactant required in the sterile
glucocorticosteroid suspension is added at this stage. Following
this addition, the additions hopper is rinsed with the circulating
solution and the solution is mixed, e.g. for 10 mins, to ensure
complete dissolution using a mixer 3 and re-circulation line 4 to
form the excipient liquid which is preferably a homogenous
excipient solution.
[0028] A concentrated suspension of a glucocorticosteroid is
prepared and sterilized in the third vessel 6 (also termed the
"concentrate vessel"). The third vessel 6 has a re-circulation line
9 incorporating a homogenizer 10. However, prior to sterilisation
of the glucocorticosteroid suspension, the remainder of the
apparatus 1 including the second vessel 5, the third vessel 6 and
the filtration line 7 as well as any additional components, may be
cleaned and sterilized in place, for example using hot WFI followed
by steam at temperatures of about 122.degree. C. to about
138.degree. C. for not less than 30 mins. Following sterilization,
second vessel 5 and any other cleaned and sterilized components of
apparatus 1 are continuously held under positive pressure to
maintain the sterility of the system and contents during subsequent
batch manufacture and filling. The positive pressure may be
maintained using sterile compressed air.
[0029] The water or excipient liquid is sterilized and the second
vessel 5 and the third vessel 6 are charged with the water or
excipient liquid. Sterilization of the water or excipient liquid is
completed by filtration via a sterilizing grade filter 8 during
transfer of the water or excipient solution from first vessel 2 to
both the second vessel 5 and the third vessel 6. However,
alternative methods of sterilization could be employed, such as
heat-treating the excipient liquid.
[0030] The third vessel 6 is isolated from second vessel 5 and the
third vessel 6 is opened. At this stage surfactant is added to the
water or additional surfactant may be added to the excipient liquid
in the third vessel 6 in order to facilitate formation of a stable
suspension. Preferably the concentration of the surfactant in the
concentrated glucocorticosteroid suspension is from about 0.2 to
about 300, more preferably from about 0.2 to about 60 mg/ml. The
glucocorticosteroid is then added to the third vessel 6. The
glucocorticosteroid does not need to have been sterilized at this
stage. An overage of the glucocorticosteroid may be added if there
are any process losses of the glucocorticosteroid during bulk
product suspension manufacture and filling.
[0031] The concentration of the glucocorticosteroid in this
"concentrated" glucocorticosteroid suspension is preferably from
about 15 to about 300, more preferably about 15 to about 150 mg/ml.
In addition, it is preferred that at least 50% of the
glucocorticosteroid in the glucocorticosteroid suspension is in the
faun of a suspension during heating, the remainder being held in
solution. More preferably, at least 60% is in the form of a
suspension.
[0032] The third vessel 6 is then sealed. The contents of the third
vessel 6 are preferably re-circulated, e.g. for at least about 1
min, preferably for at least about 10 mins forming a homogenous
suspension of glucocorticosteroid.
[0033] The third vessel 6 has at least two openings served by a
re-circulation line 9. The re-circulation line 9 allows the content
of the third vessel 6 to be removed from the third vessel 6 at a
first opening and re-charged into the third vessel 6 at a second
opening. It is preferred that the first opening is at the bottom of
the third vessel 6 and that the second opening is at the top. The
force required to re-circulate the content is provided by the
homogenizer 10. The content of the third vessel 6 is also caused to
pass through the homogenizer 10 as it is re-circulated. Since
homogenisation of the content, i.e. the glucocorticosteroid
suspension, occurs as it passes through the re-circulation line 9,
the third vessel 6 does not require any internal mechanism for
agitation of the content. Indeed, in a preferred embodiment, the
third vessel 6 is free of any agitation mechanism and most
preferably the third vessel 6 consists essentially of a metallic
(e.g. stainless steel) casing having a plurality of openings for
charging and evacuating the vessel. Whilst the shape of the third
vessel 6 is not critical, in order to avoid any dead space where
the content may become trapped and unable to be evacuated, the
third vessel is preferably cylindrical and more preferably has a
conical bottom tapering towards the first opening. The simplicity
of the third vessel 6 is particularly advantageous since it reduces
the number of working parts and the overall surface area onto which
the glucocorticosteroid suspension comes in contact, thereby
reducing any loss of drug by adhesion to the surfaces, reducing the
possible sources of contamination and reducing the time required
for cleaning the apparatus.
[0034] Heat is applied to the sealed third vessel 6 using a heater
14, such as a steam jacket. The glucocorticosteroid suspension,
third vessel 6, re-circulation line 9 and homogenizer 10 are
sterilized in situ via heat transfer from the heater. Heating is
carried out at a sterilizingly effective temperature for a
sterilizingly effective time, preferably at a temperature of from
about 101 to about 145.degree. C., more preferably from about
122.degree. C. to about 138.degree. C., for about 2 to about 180
mins, more preferably for at least about 30 mins.
[0035] At this stage, the glucocorticosteroid suspension is
circulated around the third vessel 6, re-circulation line 9 and
homogenizer 10 to ensure effective sterilization of the system and
glucocorticosteroid suspension. FIG. 3 shows the re-circulation of
the glucocorticosteroid suspension during heat sterilization
detailing the re-circulation line 9. Optionally, the concentrate
may be pre-treated to reduce the particle size distribution of the
glucocorticosteroid to a pre-specified value, including by
circulation through the homogenizer. The glucocorticosteroid
suspension is preferably circulated during the heating step
although it may alternatively, or in addition, be circulated before
or after the heating step. By re-circulating the concentrated
glucocorticosteroid suspension through a homogenizer 10, an
unwanted increase in particle size may be avoided.
[0036] The homogenizer 10 is a device known in the art in which a
suspension of a particulate material, here the glucocorticosteroid
suspension, is subjected to an energetic shear as the suspension is
forced to pass therethrough. The homogenizer provides a
sufficiently high shear force to cause the break up of aggregates
of particles in the suspension and a reduction in the solid
particles sizes. A precise numerical range for the level of shear
is not appropriate given that the level of shear will depend on the
viscosity of the suspension. The homogenizer 10 may be an in-line
high-shear homogenizer (e.g. a Silverson 150L) or, for more
efficient and better particle size reduction, a high-pressure
homogenizer (e.g. a Niro Panda). A high-shear homogeniser typically
has a mixing workhead comprising rotatable rotor blades and a
perforated stator with the rotor blades located within the stator.
A high-pressure homogeniser typically comprises a pump, which can
supply pressures up to about 1500 bar, and one or more interaction
chambers where the passage of fluid through minute flow passages
under high pressure and controlled flow action subjects the fluid
to conditions of high turbulence and shear.
[0037] The sterilized glucocorticosteroid suspension is then mixed
with the sterile water or sterile excipient solution held within
the second vessel 5 via a re-circulation line 11 to form a diluted
sterilized glucocorticosteroid suspension, as shown in FIG. 4.
Typically the glucocorticosteroid suspension is diluted with the
sterile water or sterile excipient liquid to a pharmaceutically
suitable concentration. Preferably re-circulation is performed for
about 45 mins. The diluted glucocorticosteroid suspension is held
within second vessel 5 until required for filling. During the hold
of the suspension it is continually circulated via re-circulation
line 12 between second vessel 5 and BFS machine 13 to maintain the
active material in suspension, as shown in FIG. 5. BFS machines are
well known in the art and are exemplified by Rommelag Blow Fill
Seal 3012, 305 and 4010 machines and Weiler Engineering ASEP-TECH
Blow Fill Seal 624, 628 and 640 machines.
[0038] Prior to filling, BPS machine 13 is sterilized, e.g. by
steam at temperatures of about 122.degree. C. to about 138.degree.
C. for not less than 30 mins. The BFS machine 13 may use any
pharmaceutically acceptable primary container material. Typically
low-density polyethylene granulate is used to form the primary
container/closure system on the BFS machine 13 although
high-density polyethylene, polypropylene, poly vinyl chloride or
polyethylene terephthalate may also be used. Mixtures of these
materials may also be used. The BFS machine 13 is configured to
present open topped units to the filling head for each machine
filling cycle. The sterile glucocorticosteroid suspension is filled
into the formed units through a time/pressure/dosing unit which
delivers a precise measure of the suspension via filling needles.
Following filling the filling needles are withdrawn and the head
section of the mould closes to seal the units completely. The
filled units are then removed from the BFS machine 13.
[0039] To be "sterile" means that a product or composition meets
the criteria of sterility according to the US Pharmacopoeia
27/NF22, 2004, or its counterpart in other jurisdictions, and which
provides a therapeutically acceptable glucocorticosteroid and/or
pharmaceutical formulation.
[0040] The term "about" is used herein to mean approximately, in
the region of, roughly, or around. When the term "about" is used in
conjunction with a numerical range, it modifies that range by
extending the boundaries above and below the numerical values set
forth. In general, the term "about" is used herein to modify a
numerical value above and below the stated value by a variance of
20%.
[0041] As used herein, the recitation of a numerical range for a
variable is intended to convey that the invention may be practiced
with the variable equal to any of the values within that range.
Thus, for a variable that is inherently discrete, the variable can
be equal to any integer value of the numerical range, including the
end-points of the range. Similarly, for a variable, which is
inherently continuous, the variable can be equal to any real value
of the numerical range, including the end-points of the range. As
an example, a variable which is described as having values between
0 and 2, can be 0, 1 or 2 for variables which are inherently
discrete, and can be 0.0, 0.1, 0.01, 0.001, or any other real value
for variables which are inherently continuous.
[0042] The methods and compositions of the present invention are
intended for use with any mammal that may experience the benefits
of the methods of the invention. Foremost among such mammals are
humans, although the invention is not intended to be so limited,
and is applicable to veterinary uses. Thus, in accordance with the
invention, "mammals" or "mammal in need" include humans as well as
non-human mammals, particularly domesticated animals including,
without limitation, cats, dogs, and horses.
[0043] Another aspect of the invention provides suspension
compositions of sterilized glucocorticosteroids prepared according
to the methods of the first aspect of the invention described
above. In some embodiments, the composition is a pharmaceutical
composition for treating or alleviating the symptoms of allergic
and/or inflammatory conditions in a mammalian patient. In these
embodiments, the compositions comprise a therapeutically effective
amount of sterilized, labile glucocorticosteroid(s) in a
pharmaceutically acceptable vehicle.
[0044] The term "therapeutically effective amount" is used to
denote treatments at dosages effective to achieve the therapeutic
result sought. Furthermore, one of skill will appreciate that the
therapeutically effective amount of the compound of the invention
may be lowered or increased by fine tuning and/or by administering
more than one compound of the invention, or by administering a
compound of the invention with another compound. The invention
therefore provides a method to tailor the administration/treatment
to the particular exigencies specific to a given mammal.
[0045] Other embodiments contemplate compositions presenting the
glucocorticosteroid in combination with a second active ingredient.
In some embodiments, the second active ingredient may be selected
from albuterol, ipratropium bromide, cromolyn, formoterol,
tiotropium, oxitropium and azelastine.
[0046] In yet other embodiments of this aspect, the compositions of
the invention are formulated to be suitable for oral, inhalation,
rectal, ophthalmic (including intravitreal or intracameral), nasal,
topical (including buccal and sublingual), vaginal, or parenteral
(including subcutaneous, intramuscular, intravenous, intradermal,
and intratracheal) administration. Preferably the composition is
formulated for inhalation in which case the particle size of the
glucocorticosteroid is preferably such that the Dv100 is less than
20 .mu.m, the Dv90 is less than 10 .mu.m and the Dv50 is less than
5 .mu.m, where Dvn represents the volume diameter at the nth
percentile. The volume diameter is a known term in the art and
indicates the diameter that a sphere would have when it has the
volume of the particle. The particle sizes may be measured by
standard techniques, such as by laser diffraction as described in
the examples hereinbelow. Such a particle sizes may be achieved
using the heat sterilisation conditions as described herein.
[0047] The formulations of the compositions of the invention may
conveniently be presented in unit dosage form and may be prepared
by conventional pharmaceutical techniques. Such techniques include
the step of bringing into association the compounds of the
invention and the pharmaceutically acceptable carrier(s), such as a
diluent or an excipient. In general, the compositions are prepared
by uniformly and intimately bringing into association the active
ingredient with liquid or finely divided solid carriers or both,
and then, if necessary, shaping the product.
[0048] The sterile glucocorticosteroids prepared according to the
invention are optionally formulated in a pharmaceutically
acceptable vehicle with any of the well known pharmaceutically
acceptable carriers, including diluents and excipients (see
Remington's Pharmaceutical Sciences, 18.sup.th Ed., Gennaro, Mack
Publishing Co., Easton, Pa. 1990 and Remington: The Science and
Practice of Pharmacy, Lippincott, Williams & Wilkins, 1995).
The type of pharmaceutically acceptable carrier/vehicle employed in
generating the compositions of this aspect of the invention will
vary depending upon the mode of administration of the composition
to the mammal. Generally, pharmaceutically acceptable carriers are
physiologically inert and non-toxic. Formulations of compositions
according to the invention may contain more than one type of
pharmacologically active ingredient useful for the treatment of the
symptom/condition being treated.
[0049] In yet another aspect, the invention provides methods for
using compositions of the invention for treating or alleviating the
symptoms of allergic and/or inflammatory conditions in a mammalian
patient. Such methods comprise the administration of a
therapeutically effective amount of the labile glucocorticosteroid
in a pharmaceutically acceptable vehicle. In various embodiments of
this aspect, administration of a therapeutically effective amount
of the glucocorticosteroid, either alone or in combination with a
second active agent, is by oral, inhalation, rectal, ophthalmic,
vaginal, or parenteral administration. In some embodiments, the
glucocorticosteroid is budesonide while in yet other embodiments
the glucocorticosteroid is beclomethasone.
[0050] The invention further provides a sterile
glucocorticosteroid, preferably an anti-inflammatory
glucocorticosteroid, for use in the treatment of allergic and/or
inflammatory conditions. The allergic and/or inflammatory
conditions to be treated need not be confined to one anatomic site,
for example, the nose or lungs, and the compositions of the
invention are formulated for administration appropriate to the site
of treatment. Allergic and/or inflammatory conditions include,
without limitation, contact dermatitis, asthma, rhinitis, or
chronic obstructive pulmonary disease. The invention also provides
for the use of sterile glucocorticosteroid compositions, in the
manufacture of a medicament (preferably a sterile medicament) for
use in the treatment of allergic and/or inflammatory
conditions.
[0051] The following examples are intended to illustrate further
certain embodiments of the invention and are not limiting in
nature. Those skilled in the art will recognize, or be able to
ascertain, using no more than routine experimentation, numerous
equivalents to the specific substances and procedures described
herein.
EXAMPLES
Examples 1 to 3
Heat Sterilization of Budesonide
[0052] Three batches of a sterile budesonide suspension were
prepared. Example 1 (applicant's batch W15711) contained 0.125
mg/ml of budesonide, Example 2 (applicant's batch W15641) contained
0.25 mg/ml of budesonide and Example 3 (applicant's batch Z00581)
contained 0.5 mg/ml of budesonide.
[0053] A 500 L stainless steel mixing vessel was cleaned using hot
water for injections (WFI) and steam sanitized. WFI at 25.degree.
C. was added to the vessel. The vessel was then charged with the
following excipients in the following order: sodium chloride USP,
citric acid monohydrate USP, tri-sodium citrate dihydrate USP,
disodium edetate dihydrate USP and Polysorbate 80 USP from an
additions hopper. For Examples 1 and 3, 80 g of Polysorbate 80 was
added at this stage. For Example 2, 30 g of Polysorbate 80 was
added at this stage. The quantities of each component are set out
in Table 1. The solution was then re-circulated through a mixer and
a stainless-steel line for 10 mins to ensure complete dissolution.
During circulation, the additions hopper was rinsed with the
circulating solution.
TABLE-US-00001 TABLE 1 Materials in whole batch Example 1 Example 2
Example 3 Water for Injection 500 kg 250 kg 500 kg Sodium Chloride
4250 g 2125 g 4250 g Citric Acid Monohydrate 155 g 77.5 g 155 g
Tri-Sodium Citrate Dihydrate 250 g 125 g 250 g Disodium Edetate
Dihydrate 50 g 25 g 50 g Polysorbate 80 100 g 50 g 100 g
[0054] A stainless steel 500 L excipient vessel and stainless steel
4 L concentrate vessel were cleaned and sterilized in place, using
hot WFI followed by steam.
[0055] The excipient and concentrate vessels were charged with the
excipient liquid having been passed via a sterilizing grade filter
(0.1 .mu.m Fluorodyne PVDF filter, PALL Europe Limited). The
concentrate vessel was isolated and additional 20 g of Polysorbate
80 was added. The composition of the concentrated suspension is set
out in Table 2.
TABLE-US-00002 TABLE 2 Materials in drug concentrate (portion of
batch which was heat sterilized) Example 1 Example 2 Example 3
Water for Injection 4 kg 4 kg 4 kg Budesonide 66.7 g 64.1 g 251.2 g
Sodium Chloride 34 g 34 g 34 g Citric Acid Monohydrate 1.24 g 1.24
g 1.24 g Tri-Sodium Citrate 2 g 2 g 2 g Dihydrate Disodium Edetate
0.4 g 0.4 g 0.4 g Dihydrate Polysorbate 80 20.64 g 20.48 g 20.64
g
[0056] The concentrated suspension was then sterilized under the
conditions set out in Table 3. Before, during and after the
sterilization, the concentrated suspension was re-circulated
through a Silverson 150L homogenizer via a stainless steel
re-circulation line.
TABLE-US-00003 TABLE 3 Sterilisation conditions Example 1 Example 2
Example 3 Temperature 126-129.degree. C. 124-129.degree. C.
124-132.degree. C. Time 32 min 32 min 32 min
[0057] The sterilized glucocorticosteroid suspension was then mixed
with the sterile excipient solution held in the excipient vessel to
form a diluted sterilized budesonide suspension. The final product
strength was 0.125 mg/ml for the suspension of Example 1, 0.25
mg/ml for the suspension of Example 2 and 0.5 mg/ml for the
suspension of Example 3.
[0058] A sample of the suspension was analysed for related
substances/impurities using HPLC and the results are set out in
Table 4. The analysis of the suspension showed pharmaceutically
acceptable level of impurities.
TABLE-US-00004 TABLE 4 Related substances/impurities after
sterilization (wt % based on the amount of budesonide) Example 1
Example 2 Example 3 21-dehydro-budesonide 0.11 0.11 0.08 Desonide
ND ND ND 16.alpha.-hydroxypredinisolone <0.05 ND ND Budesonide
1,2 dihydro ND ND ND 22-Methyl homologue ND ND <0.05
D-homobudesonide ND ND <0.05 14,15-dehydrobudesonide ND ND ND
S-11-Keto budesonide <0.05 <0.05 <0.05 R-11-Keto
budesonide <0.05 <0.05 <0.05 S-21-Acetate budesonide ND ND
ND R-21-Acetate budesonide ND ND ND Maximum individual <0.05
<0.05 <0.05 unknown Total Impurities 0.11 0.11 0.08 (ND = Not
Detected, <0.05 = Reporting Level)
[0059] The diluted suspension was continually circulated via a
Rommelag 3012 BFS machine and packaged into containers using
low-density polyethylene.
[0060] Samples of the suspension were analysed for particle size
distribution by laser light diffraction using a Malvern.
Mastersizer S. The parameters considered are the volumetric
diameters in .mu.m of the 10.sup.th, 50.sup.th and 90.sup.th
percentiles of the particles, expressed as Dv10, Dv50 and Dv90
respectively, which are determined by assuming that the particles
have a geometric shape equivalent to a sphere. The results are set
out in Table 5.
TABLE-US-00005 TABLE 5 Particle size distribution after
sterilization Example 1 Example 2 Example 3 Dv10 0.6 0.6 0.7 Dv50
2.3 2.5 2.7 Dv90 4.7 5.4 5.6
[0061] The particle size distributions obtained are within the
recognised region required for effective delivery in Inhalation
products.
[0062] The batches were submitted to the sterility test and
complied with the sterility requirements of Ph. Eur. and USP.
Examples 4 and 5
Heat Sterilization of BDP
[0063] Two batches of a sterile BDP (Beclomethasone Dipropionate)
suspension were prepared. Example 4 (applicant's batch W16531) and
Example 5 (applicant's batch W17211) both contained 0.4 mg/ml of
BDP.
[0064] A 500 L stainless steel mixing vessel was cleaned using hot
water for injections (WFI) and steam sanitized. WFI at 25.degree.
C. was added to the vessel. The vessel was then charged with the
following excipients in the following order: sodium chloride EP,
Polysorbate 20 EP, and Span 20 EP from an additions hopper. For
Example 4, 400 g of Polysorbate 20 was added at this stage. For
Example 5, 475 g of Polysorbate 20 and 95 g of Span 20 were added
at this stage. The quantities of each component are set out in
Table 6. The solution was then re-circulated through a mixer and a
stainless-steel line for 10 mins to ensure complete dissolution.
During circulation, the additions hopper was rinsed with the
circulating solution.
TABLE-US-00006 TABLE 6 Materials in whole batch Example 4 Example 5
Water for Injection 500 kg 500 kg Sodium Chloride 4500 g 4500 g
Polysorbate 20 500 g 500 g Span 20 100 g 100 g
[0065] A stainless steel 500 L excipient vessel and stainless steel
4 L concentrate vessel were cleaned and sterilized in place, using
hot WFI followed by steam.
[0066] The excipient and concentrate vessels were charged with the
excipient liquid having been passed via a sterilizing grade filter
(Example 4-0.1 .mu.m Fluorodyne PVDF filter, PALL Europe Limited
Example 5-0.2 .mu.m Fluorodyne PVDF filter, PALL Europe Limited).
The concentrate vessel was isolated and an additional Polysorbate
20 (100 g for Example 4, 25 g for Example 5) and Span 20 (100 g for
Example 4, 5 g for Example 5) was added. The composition of the
concentrated suspension is set out in Table 7.
TABLE-US-00007 TABLE 7 Materials in drug concentrate (portion of
batch which was heat sterilized) Example 4 Example 5 Water for
Injection 4 kg 4 kg BDP 206 g 210 g Sodium Chloride 36 g 36 g
Polysorbate 20 103.2 g 28.8 g Span 20 100 g 5.8 g
[0067] The concentrated suspension was then sterilized under the
conditions set out in Table 8. Before and during the sterilization,
the concentrated suspension was re-circulated through a lobe pump
via a stainless steel re-circulation line. After sterilisation the
concentrated suspension was re-circulated through a homogeniser via
the lobe pump and stainless steel re-circulation line.
TABLE-US-00008 TABLE 8 Sterilisation conditions Example 4 Example 5
Temperature 124-132.degree. C. 124-132.degree. C. Time 32 min 32
min
[0068] The sterilized glucocorticosteroid suspension was then mixed
with the sterile excipient solution held in the excipient vessel to
form a diluted sterilized BDP suspension. The final product
strength was 0.4 mg/ml for the suspension of Example 4 and Example
5.
[0069] A sample of the suspension was analysed for related
substances/impurities using HPLC and the results are set out in
Table 9. The analysis of the suspension showed pharmaceutically
acceptable level of impurities.
TABLE-US-00009 TABLE 9 Related substances/impurities after
sterilization (wt % based on the amount of SDP) Example 4 Example 5
Beclomethasone ND ND Beclomethasone 17 Propionate 0.05 ND
Beclomethasone 21 Propionate ND ND Beclomethasone 21 Acetate 21
Propionate ND ND Beclomethasone Dipropionate 9.beta., 11 0.60 0.12
epoxy analog.beta. Beclomethasone Dipropionate 9 bromo ND ND analog
Beclomethasone Dipropionate .delta.9,11 ND ND analog Beclomethasone
Dipropionate 21 Butyrate ND ND Beclomethasone Dipropionate 6.alpha.
chloro ND ND Beclomethasone Dipropionate 6.alpha. bromo ND ND
Maximum individual unknown 0.12 0.08 Total Impurities 0.89 0.20 (ND
= Not Detected)
[0070] The diluted suspension was continually circulated via a BFS
machine and packaged into containers using low-density
polyethylene.
[0071] Samples of the suspension were analysed for particle size
distribution by laser light diffraction using a Malvern Mastersizer
S. The parameters considered are the volumetric diameters in .mu.m
of the 10.sup.th, 50.sup.th and 90.sup.th percentiles of the
particles, expressed as Dv10, Dv50 and Dv90 respectively, which are
determined by assuming that the particles have a geometric shape
equivalent to a sphere. The results are set out in Table 10.
TABLE-US-00010 TABLE 10 Particle size distribution after
sterilization Example 4 Example 5 Dv10 0.4 0.4 Dv50 1.4 1.5 Dv90
3.6 3.6
[0072] The particle size distributions obtained are within the
recognised region required for effective delivery in Inhalation
products.
[0073] The batches were submitted to the sterility test and
complied with the sterility requirements of Ph. Eur.
* * * * *