U.S. patent application number 14/151172 was filed with the patent office on 2014-05-08 for process for preparing solid amorphous particles comprising tiotropium bromide and a co-solid.
This patent application is currently assigned to Norton Healthcare Ltd.. The applicant listed for this patent is Norton Healthcare Ltd.. Invention is credited to Xian-Ming ZENG.
Application Number | 20140127304 14/151172 |
Document ID | / |
Family ID | 38566522 |
Filed Date | 2014-05-08 |
United States Patent
Application |
20140127304 |
Kind Code |
A1 |
ZENG; Xian-Ming |
May 8, 2014 |
PROCESS FOR PREPARING SOLID AMORPHOUS PARTICLES COMPRISING
TIOTROPIUM BROMIDE AND A CO-SOLID
Abstract
A method of making an inhalable medicament is provided, in
particular a new solid-state form of tiotropium bromide. The
medicament can be in the form of solid amorphous particles
containing an intimate admixture of tiotropium bromide together
with a pharmaceutically acceptable co-solid having a glass
transition temperature of at least -50.degree. C., such as a sugar
and/or sugar alcohol.
Inventors: |
ZENG; Xian-Ming; (Mitcham,
GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Norton Healthcare Ltd. |
|
|
|
|
|
Assignee: |
Norton Healthcare Ltd.
|
Family ID: |
38566522 |
Appl. No.: |
14/151172 |
Filed: |
January 9, 2014 |
Current U.S.
Class: |
424/489 ;
514/291 |
Current CPC
Class: |
A61P 43/00 20180101;
A61K 47/26 20130101; A61P 11/08 20180101; A61K 9/0075 20130101;
A61K 31/439 20130101; A61K 9/19 20130101; A61P 11/00 20180101; A61K
9/1694 20130101; A61P 11/06 20180101 |
Class at
Publication: |
424/489 ;
514/291 |
International
Class: |
A61K 31/439 20060101
A61K031/439; A61K 9/00 20060101 A61K009/00 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 16, 2007 |
GB |
0716026.0 |
Claims
1. A process for preparing solid amorphous particles of tiotropium
bromide comprising lyophilizing an aqueous solution of tiotropium
bromide together with a pharmaceutically acceptable co-solid having
a glass transition temperature of at least -50.degree. C.
2. The process as claimed in claim 1, wherein the co-solid has a
water solubility of at least 20 mg per 100 mL, at 20.degree. C.
3. The process as claimed in claim 1, wherein the co-solid
comprises at least one of a sugar and a sugar derivative.
4. The process as claimed in claim 3, wherein the co-solid
comprises the sugar derivative and the sugar derivative is a sugar
polyol or an amino sugar.
5. The process as claimed in claim 3, wherein the co-solid
comprises the sugar and the sugar is a monosaccharide or a
disaccharide.
6. The process as claimed in claim 3, wherein the co-solid is
selected from the group consisting of glucose, lactose, mannitol,
mannose, sucrose, trehalose and combinations thereof.
7. A process as claimed in claim 1, further comprising, after
lyophilizing, micronizing the particles.
8. A process as claimed in claim 1, wherein the particles formed
have a particle size of 1-10 microns.
9. A process for preparing solid amorphous particles of tiotropium
bromide comprising freeze-drying an aqueous solution of tiotropium
bromide and lactose by spraying droplets of the solution into
liquid nitrogen to form the particles.
10. The process of claim 9 wherein said droplets are about 10
.mu.m.
11. The process of claim 9 further comprising collecting and
placing the particles in a vacuum freezer for 24 hours.
12. The process of claim 10 wherein the resulting particles are
suitable for inhalation.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 12/668,546, filed on Apr. 15, 2010. That application is a
national phase filing of International Application No.
PCT/GB2008/002294, filed Jul. 3, 2008, which claims priority to
U.S. Provisional Application No. 60/958,823, filed Jul. 9, 2007,
and British Application No. 0716026.0, filed Aug. 16, 2007. The
disclosures of International No. PCT/GB2008/002294, U.S.
Provisional Application No. 60/958,823, and British Application No.
0716026.0 are each incorporated herein by reference in their
entirety for all purposes.
FIELD OF THE INVENTION
[0002] This invention relates to an inhalable medicament and in
particular to a new solid-state form of tiotropium bromide.
BACKGROUND OF THE INVENTION
[0003] Tiotropium bromide has the systematic name
(1.alpha.,2.beta.,4.beta.,7.beta.)-7-[(hydroxidi-2-thienylacetyl)oxy]-9,9-
- -dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0.sup.2,4]nonane and has
the following formula:
##STR00001##
[0004] Tiotropium bromide is known per se and is described in more
detail in EP 0 418 716.
[0005] Tiotropium bromide is a known muscarinic receptor antagonist
and, on topical application, acts predominantly on the M.sub.3
muscarinic receptors located in the airways to produce smooth
muscle relaxation, thus producing a bronchodilatory effect.
Tiotropium bromide is therefore suitable for the treatment of
chronic obstructive pulmonary disease (COPD) and asthma.
[0006] Several attempts have been made to formulate stable,
easy-to-handle solid-state forms of tiotropium bromide for use as
an inhalable medicament, to varying degrees of success. EP 1 468
998 discloses crystalline tiotropium bromide monohydrate. EP 1 401
445 and EP 1 682 542 disclose an anhydrous form of crystalline
tiotropium bromide. EP 1 487 832 discloses crystalline tiotropium
bromide micronisate. U.S. 2005/0676760 discloses crystalline forms
of tiotropium bromide selected from an anhydrate, methanol solvate,
THF solvate, 1,4-dioxane solvate, dimethylformamide solvate, mixed
methylene chloride/methyl ethyl ketone solvate, and 1-butanol
solvate. Similarly U.S. 2005/0676807 discloses crystalline forms of
tiotropium bromide selected from an anhydrate, 1,4 dioxane solvate,
ethanol solvate, methanol solvate, anisol solvate, n-butanol
solvate, N,N-dimethyl acetamide solvate, N,N-dimethyl formamide
solvate, isopropanol solvate, 1,2-propanediol solvate, pyridine
solvate, tert-butanol solvate, terahydrofuran solvate and
tetrahydropyran solvate.
[0007] However, there remains a need in the art for solid state
forms which are both stable, in particular to moisture, and easy to
handle.
SUMMARY OF THE INVENTION
[0008] Accordingly, the present invention provides solid amorphous
particles comprising an intimate admixture of tiotropium bromide
together with a pharmaceutically acceptable co-solid having a glass
transition temperature of at least -50.degree. C.
[0009] The present invention also provides a process for preparing
solid amorphous particles of tiotropium bromide comprising
lyophilizing an aqueous solution of tiotropium bromide together
with a pharmaceutically acceptable co-solid having a glass
transition temperature of at least -50.degree. C.
[0010] The present invention further provides another process for
preparing solid amorphous particles of tiotropium bromide
comprising freeze-drying an aqueous solution of tiotropium bromide
and lactose by spraying droplets of the solution into liquid
nitrogen to form the particles.
DETAILED DESCRIPTION OF THE INVENTION
[0011] The present invention therefore provides a new solid-state
form of tiotropium bromide. The particles are an intimate admixture
of tiotropium bromide and a co-solid defined by its glass
transition temperature, such as a sugar, a sugar derivative or a
combination thereof. That is, substantially all of the individual
particles are composed of both the tiotropium bromide and the
co-solid. Preferably the particles consist essentially of
tiotropium bromide and the co-solid. Reference is made to
substantially all of the particles because it is possible from a
purely statistical stand point that a small number of the particles
might contain only the co-solid if such particles solidify in the
absence of tiotropium bromide.
[0012] The particles of tiotropium bromide of the present invention
are an amorphous solid, i.e. a glass. That is, the particles are a
solid in which there is no long-range order in the positions of the
molecules. The amorphous solid is obtained by rapidly cooling an
aqueous solution of the components of the solid so that a solid is
formed before the molecules can crystallize into a more
thermodynamically favorable crystalline state.
[0013] The solid particles of the present invention are stable and
tend not to absorb water even under conditions of high humidity.
This is an important property for an inhalable medicament,
particularly when formulated as a dry powder. In addition, the
co-solid provides additional bulk to the active ingredient.
Tiotropium bromide is highly potent and is typically used in a dose
of 18 .mu.g based on the amount of tiotropium. Such small
quantities of active ingredient can be difficult to handle and can
hinder accurate metering. However, incorporation of the co-solid
allows for easier handling and more accurate metering of the active
ingredient.
[0014] The co-solid used in the particles must be pharmaceutically
acceptable which has its standard meaning in the art, namely that
it may be incorporated into a medicament. That is, the co-solid
will be non-toxic, biodegradable and biocompatible. It will ideally
be physicochemically stable and non-hygroscopic.
[0015] The co-solid must also have a glass transition temperature
of at least -50.degree. C., more preferably at least -25.degree. C.
and most preferably at least 0.degree. C. This lower limit on the
glass transition temperature ensures that the amorphous (i.e.
glass) state is stable at ambient temperature (i.e. 20.degree. C.),
and preferably at elevated temperatures that the medicament may
experience during storage, e.g. 50.degree. C. or above and even
75.degree. C. or above. By stable is meant that the amorphous state
does not crystallize or otherwise degrade. The upper limit to the
glass transition temperature is less relevant and is only limited
by the practicalities of the lyophilization process and the
co-solids available.
[0016] The co-solid is preferably water soluble and more preferably
has a water solubility of at least 20 mg per 100 mL at 20.degree.
C., more preferably at least 50 mg per 100 mL at 20.degree. C. and
most preferably 80 mg per 100 mL.
[0017] The co-solid used in the particles of the present invention
is typically a sugar or a sugar derivative, or a combination
thereof. The derivative may be a sugar polyol or an amino sugar.
Sugars, sugar alcohols and amino sugars are well known in the art
and the present invention is not restricted to any particular
sugar, sugar alcohol or amino sugar. Any sugar, sugar alcohol or
amino sugar which is capable of forming an amorphous solid in the
presence of tiotropium bromide may be used. Preferably the sugar is
a mono or disaccharide, or the derivative is based on a mono or
disaccharide. The sugar alcohol is a sugar in which at least one of
the carboxyl groups (aldehyde or ketone) in the sugar has been
reduced to an alcohol (primary or secondary alcohol). Sugar polyols
are sometimes referred to in the art simply as sugar alcohols. The
amino sugar is a sugar in which at least one of the hydroxyl groups
has been replaced with an amino group. Specific examples of sugars
used in the present invention are dextrose, fructose, glucose,
lactose, mannose, sucrose and trehalose. Particularly preferred
sugars are glucose, lactose, mannose, sucrose and trehalose.
Specific examples of sugars alcohols used in the present invention
are mannitol, maltitol, sorbitol and xylitol. A particularly
preferred sugar alcohol is mannitol. A particularly preferred amino
sugar alcohol is glucosamine.
[0018] Other examples of suitable co-solids include PEG, HMPC and
PLG.
[0019] The solid amorphous particles of the present invention may
be prepared by lyophilizing (freeze drying) an aqueous solution of
tiotropium bromide and the sugar and/or sugar derivative.
Accordingly, the present invention provides a process for preparing
solid amorphous particles of tiotropium bromide comprising
lyophilizing an aqueous solution of tiotropium bromide together
with a sugar and/or a sugar alcohol. Preferably the aqueous
solution is prepared by forming an aqueous solution of the sugar
and/or sugar derivative, dissolving the tiotropium bromide therein
and optionally adjusting the pH to a value from 4 to 6. The process
may further comprise micronizing the particles.
[0020] The aqueous solution may be prepared simply by dissolving
the components in water or a mixture of water and a water-miscible
pharmaceutically acceptable co-solvent. A suitable co-solvent is an
alcohol and preferably methanol, ethanol, n-propanol, iso-propanol,
n-butanol, tert-butanol iso-butanol or combinations thereof. In a
preferred embodiment, the co-solid, e.g. sugar and/or sugar
derivative, is added to an aqueous solvent and the solution is
optionally heated to dissolve the co-solid. Once dissolved, the
aqueous solution is allowed to cool to provide a hyper-saturated
solution. Tiotropium bromide is then added thereto. The mixture may
be heated and/or sonicated to dissolve the tiotropium bromide. The
resulting solution may be filtered if required and the pH may be
adjusted. The preferred pH is from 4 to 6.
[0021] The solution is then lyophilized using standard techniques
in the art. There are typically three stages in the lyophilization
process, namely freezing, primary drying, and secondary drying.
[0022] The freezing step may be performed in a shell freezer by
placing the aqueous solution in a freeze-drying flask and rotating
the flask in a bath cooled, for example, by mechanical
refrigeration, dry ice, methanol or liquid nitrogen. Alternatively,
the freezing step may be performed using a freeze-drying machine.
In the freeze drying machine, fine droplets of the aqueous solution
are sprayed into the refrigerant, e.g. liquid nitrogen. The freeze
drying machine is preferred for the industrial preparation of the
material.
[0023] During the primary drying step the pressure is lowered and
enough heat is supplied to the material for the aqueous solution to
sublimate. The secondary drying step may be used if required to
sublimate the solvent molecules that are adsorbed during the
freezing step.
[0024] The mean particle diameter of the solid amorphous particles
of the present invention is preferably 1-10 microns and more
preferably 1-5 microns. The particles size of the particles
disclosed herein is the aerodynamic particle size. See J. P.
Mitchell and M. W. Nagel in "Particle size analysis of aerosols
from medicinal inhalers" KONA No. 22 (2004) 32 for further details
concerning the measurement of particles sizes. The appropriate
particle size may be provided by the lyophilization process
described hereinabove although further micronization may be
performed by grinding in a mill, e.g. an air jet, ball or vibrator
mill, by sieving, by crystallization, by spray-drying or by further
lyophilization.
[0025] The present invention further provides solid amorphous
particles obtainable by the above-described process. The particles
thus formed are characterized by the intimate admixture of the
tiotropium bromide and the co-solid, e.g. the sugar and/or sugar
derivative.
[0026] The weight ratio of tiotropium bromide to sugar and/or a
sugar alcohol in the particles is from 1:1 to 1:1000, preferably
from 1:10 to 1:500 (measured as a property of the bulk
material).
[0027] The present invention also provides an inhalable medicament
comprising the particles described herein and one or more
pharmaceutically acceptable excipients. The pharmaceutically
acceptable excipients include carriers, including diluents,
propellants, surfactants, and flavorings (see Remington's
Pharmaceutical Sciences, 18th Ed., Gennaro, Mack Publishing Co.,
Easton, Pa. 1990 and Remington: The Science and Practice of
Pharmacy, Lippincott, Williams & Wilkins, 1995). The
pharmaceutical composition may be a dry powder for a dry-powder
inhaler in which the one or more pharmaceutically acceptable
excipients includes an inert carrier, or an aerosol for a
pressurized metered-dose inhaler in which the one or more
pharmaceutically acceptable excipients includes a propellant.
[0028] Examples of particulate carriers for preparing an inhalable
dry powder include lactose, glucose, or sodium starch glycolate,
preferably lactose and most preferably alpha lactose monohydrate.
In general, the particle size of the carrier should be such that it
can be entrained in an air stream but not deposited in the key
target sites of the lung. Accordingly, the carrier preferably has a
mean particle size of 40 microns or more, more preferably the
carrier particles have a VMD of 50-250 microns. The particle size
may be determined using laser light scattering (Sympatec GmbH,
Claasthal-Zellerfeld, Germany).
[0029] The dry powder composition may be metered and filled into
capsules, e.g. gelatin or hydroxypropyl methylcellulose capsules,
such that the capsule contains a unit dose of active ingredient
When the dry powder is in a capsule containing a unit dose of
active ingredient, the total amount of composition will depend on
the size of the capsules and the characteristics of the inhalation
device with which the capsules are being used. However, typical
examples of total fill weights of dry powder per capsule are 1-25
mg. Alternatively, the dry powder composition according to the
invention may be filled into the reservoir of a multi-dose dry
powder inhaler (MDPI), for example of the type disclosed in WO
92/10229. Such inhalers comprise a chassis, a dosing chamber, a
mouthpiece and the medicament
[0030] The particles of the present invention may also be
formulated as an aerosol. Examples of a propellant gas for
preparing an aerosol formulation include HFA134a, HFA227 or
mixtures thereof. See EP 0 372 777, EP 0 616 525 and WO 98/05302
for further details of aerosol formulations. Pressured metered-dose
inhalers of this type typically comprise a chassis, a mouthpiece
and a canister comprising the medicament as described in the
aforementioned documents.
[0031] The present invention will now be described with reference
to the following examples which are not intended to be
limiting.
EXAMPLES
Example 1
[0032] Lactose is added to water and the solution is heated to
dissolve the lactose. Once dissolved, the aqueous solution is
allowed to cool to provide a hyper-saturated solution. Tiotropium
bromide is added such that the ratio of lactose to tiotropium
bromide is 100 parts by weight lactose to one part by weight
tiotropium bromide. The mixture is sonicated to dissolve the
tiotropium bromide. The resulting solution is then filtered through
filter paper and the pH is adjusted to 5.
[0033] The solution is then transferred to a round-bottomed flask
and the flask is submerged in liquid nitrogen. The flask is swirled
such the inside wall of the flask becomes coated in a thin layer of
a solid material. The flask is then placed under vacuum at a
temperature of -20.degree. C. for 24 hours to produce fluffy
particles. The particles are collected and micronized so that they
are suitable for inhalation.
Example 2
[0034] An aqueous solution of tiotropium bromide and lactose is
formed as set out in Example 1. The solution is placed into a
freeze-drier which sprays small droplets (about 10 .mu.m) into
liquid nitrogen. The particles are collected and placed in a vacuum
freezer for 24 hours. The resulting particles are suitable for
inhalation and do not require micronization. The particles may,
however, be micronized if desired.
Example 3
[0035] An inhalable medicament is formed by combining the particles
formed in Examples 1 or 2 with coarse lactose using techniques
described in, for example, WO 2004/017942
* * * * *