Ex Parte Ray et al

Patent Trial and Appeal Board

Sep 25, 2017

11831512 (P.T.A.B. Sep. 25, 2017)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O.Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
11/831,512 07/31/2007 Jay Richard Ray II 8138-1-1 (187158) 4521
30448 7590 09/27/2017
AKERMAN LLP
P.O. BOX 3188
WEST PALM BEACH, FL 33402-3188
EXAMINER
HAGHIGHATIAN, MINA
ART UNIT PAPER NUMBER
1616
NOTIFICATION DATE DELIVERY MODE
09/27/2017 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
ip @ akerman.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JAY RICHARD RAY II and CHARLES DAVID HODGE
Appeal 2015-0077111
Application 11/831,512
Technology Center 1600
Before RICHARD M. LEBOVITZ, TAWEN CHANG, and
RYAN H. FLAX, Administrative Patent Judges.
LEBOVITZ, Administrative Patent Judge.
DECISION ON APPEAL
This appeal involves claims directed to methods of delivery of a
combination therapy to a pulmonary system comprising tiotropium bromide,
formoterol fumarate, and budesonide.
The Examiner rejected the claims under 35 U.S.C. § 103 as obvious.
We have jurisdiction under 35 U.S.C. § 6(b). The rejections are reversed. A
1 The Appeal Brief (“Appeal Br.”) 2 identifies Richie’s Pharmacy and
Medical Supply, Incorporated, as the real-party-in-interest.
Appeal 2015-007711
Application 11/831,512
new ground of rejection under 35 U.S.C. § 103 is entered pursuant to 37
C.F.R. § 41.50(b).
STATEMENT OF THE CASE
Claims 61 and 63—69 stand rejected by the Examiner under four
different grounds of rejection. Final Act. 3, 7, 13, and 15. The rejections are
reversed because the Examiner failed to make a prima facie case,
particularly by establishing the obviousness of the claimed dosage of
tiotropium bromide. See Appeal Br. 19.
However, pursuant to 37 C.F.R. § 41.50(b), a new ground of rejection
has been entered under 35 U.S.C. § 103(a).
There are three independent claims in this appeal, claims 61, 66, and
69. Claim 61 is selected as representative and is reproduced below:
61. A method of delivery of a combination therapy to a
pulmonary system comprising:
providing an aqueous dosage for treatment of a
respiratory condition, the dosage being provided in a mixture
comprising:
a first dose of a long-acting anticholinergic, the long-
acting anticholinergic being in the form of tiotropium bromide;
a second dose of a long-acting beta-agonist, the long-
acting beta-agonist being in the form of formoterol fumarate;
and
a third dose of a long-acting corticosteroid, the long-
acting corticosteroid being in the form of budesonide,
wherein the first dose of the long-acting anticholinergic
consists of 1.5-4.5 pg of tiotropium bromide, the second dose of
the long-acting beta-agonist consists of 3-6 pg of formoterol
fumarate, and the third dose of the long-acting corticosteroid
consists of 100-600 pg of budesonide such that the mixture
provides a treatment for asthma or chronic obstructive
pulmonary disease, and
wherein the dosage has a pH of between 5.2 and 8.4.
2
Appeal 2015-007711
Application 11/831,512
NEW GROUND OF REJECTION
Claims 61, 66, and 69 are rejected under 35 U.S.C. § 103(a) as
obvious in view of Applicant’s Admitted Prior Art in paragraphs 4 and 5 of
the Specification, US Publ. Pat. Appl. 2001/0049396 Al, publ. Dec. 6, 2001
(“Ekstrom”), US Pat. 6,667,344 B2, iss. Dec. 23, 2003 (“Banerjee”), and US
Pat. 7,070,800 B2, iss. Jul. 4, 2006, filed Oct. 11, 2001 (“Bechtold-Peters”).
As evidence, the following abstract is cited: Pohunek, P. and Tal, A.,
Budesonide and formoterol in a single inhaler controls asthma in
adolescents, 16(2) Int. J. Adolesc. Med. Health,91-105 (2004) (Abstract
only provided).
This is a new ground of rejection.
We leave it to the Examiner to determine the obviousness of
dependent claims 63—65, 67, and 68.
Claims
Claim 61 is directed to a method of delivery of a combination therapy
to a pulmonary system. The method involves providing an aqueous dosage
of 1) tiotropium bromide, 2) formoterol fumarate, and 3) budesonide. Each
of these drugs is recited in the claim to be present in the following specific
amounts:
1.5—4.5 jig of tiotropium bromide,
3—6 jig of formoterol fumarate, and
100-600 pg of budesonide.
The dosage “provides a treatment for asthma or chronic obstructive
pulmonary disease.”
3
Appeal 2015-007711
Application 11/831,512
The dosage is provided in a “mixture” of the three aqueous dosages.
The claim does not require the drugs to be present in specific concentrations
in the mixture. As a result, the mixture could be prepared just prior to
delivering the drug combination to the patient by combining aqueous
solutions of each drug containing the claimed amounts.
Claim 66 is similar to claim to claim 61, but requires that the solution
is administered using a nebulizer. Claim 69 is directed to a composition
containing all three drugs in the same amounts recited in claim 61.
Rejection
The Specification contains the following teaching:
The Northeast Essex Medicines Management Committee
in the United Kingdom recommends the use of tiotropium with
Symbicort® for severe COPD sufferers, those with forced
expiratory volume in one second of less than 30%. Tiotropium
is a long-acting antimuscarinic agent, or anticholinergic. It is
supplied as a capsule containing 18 pg of tiotropium in a
lactose carrier for a once daily dose that is delivered via an
inhaler device trademarked as the HandiHaler®. An in vitro
study of the delivery of this medication under standard
conditions used a flow rate of 39 L/min for 3.1 seconds to
deliver 10.4 pg of tiotropium. Unfortunately, a normal elderly
patient or a patient with severe COPD cannot achieve such a
flow rate.
Spec. 1 5.
Symbiocort® contains formoterol and budesonide. See Pohunek and
Tal Abstract. Thus, the Specification provides an admission by the inventors
that it was known to administer the combination of formoterol, budesonide,
and tiotropium to treat COPD, the same drugs and same patient population
recited in all the independent claims. Because this admitted disclosure of
4
Appeal 2015-007711
Application 11/831,512
administering all three of the recited drugs is the closest prior art to the
claimed delivery method, we have reversed all of the Examiner’s four
rejections which relied on Banerjee for its suggestion of the claimed
combination of three drugs and also additional patent publications for the
well-known dosages of each.
The unit dosages of formoterol fumarate and budesonide recited in the
claims (3—6 pg of formoterol fumarate and 100—600 pg of budesonide)
overlap with the dosages of these drugs disclosed in Ekstrom (“1 pg to 48
pg, preferably from 2 pg to 24 pg, and more preferably between 3 pg and 12
pg” of formoterol fumarate and “from 20 pg to 1600 pg, suitably from 30 pg
to 800 pg, preferably from 50 pg to 400 pg, and more preferably between
100 pg and 200 pg” of budesonide; Ekstrom 27, 28). See also Spec. 14
(admittedly known dosage of budesonide falls within claimed ranges).
It is well established that, when there is a range disclosed in the prior
art, and the claimed invention overlaps or falls within that range, as there is
here, there is a presumption of obviousness. In re Peterson, 315 F.3d 1325,
1329 (Fed. Cir. 2003); Iron Grip Barbell Co. v. USA Sports, Inc., 392 F.3d
1317, 1322 (Fed. Cir. 2004). Accordingly, because the claimed dosage
ranges overlap or fall within the dosage ranges disclosed by Ekstrom, we
conclude that a preponderance of the evidence supports a finding that the
dosages of formoterol fumarate and budesonide would have been obvious to
one of ordinary skill in the art.
The dosage of tiotropium disclosed in the Specification is 18 pg as a
once daily dose which is outside the claimed range of 1.5-4.5 pg of
tiotropium bromide. Spec. 1 5. However, Bechtold-Peters teaches capsules
containing “between 1.2 and 80 pg of tiotropium” and “between 1.4 and
5
Appeal 2015-007711
Application 11/831,512
96.3 pg of tiotropium bromide.” Bechtold-Peters, col. 4,11. 4—19. The
claimed range falls within the range described in Bechtold-Pete and
therefore would have beenprima facie obvious. Peterson, 315 F.3d at 1329.
It would have been well within the purview of one with ordinary skill in the
art, namely a pharmacologist or physician, to have optimized the dosage of
tiotropium to achieve the desired therapeutic effect to treat COPD.
Claims 61 and 66 also require that “the dosage has a pH of between
5.2 and 8.4.” Banerjee teaches compositions having an overlapping pH of
about 2.0 to about 8.0 (col. 9,11. 18—19) that comprise the same type of
drugs recited in the claims, i.e., formoterol (col. 3,11. 24—25), budesonide
(col. 15,1. 13), and tiotropium bromide (col. 15,1. 23), rendering the claimed
pH range obvious under Peterson. The pH range of between 5.2 and 6.8 of
claim 69 is obvious for the same reasons.
For the foregoing reasons, claims 61, 66, and 69 are rejected as
obvious in view of Admitted Prior Art in paragraphs 4 and 5 of the
Specification, Ekstrom, Banerjee, and Bechtold-Peters.
TIME PERIOD FOR RESPONSE
This decision contains a new ground of rejection pursuant to 37
C.F.R. § 41.50(b). Section 41.50(b) provides “[a] new ground of rejection
pursuant to this paragraph shall not be considered final for judicial review.”
Section 41.50(b) also provides:
When the Board enters such a non-final decision, the appellant,
within two months from the date of the decision, must exercise
one of the following two options with respect to the new ground
of rejection to avoid termination of the appeal as to the rejected
claims:
6
Appeal 2015-007711
Application 11/831,512
(1) Reopen prosecution. Submit an appropriate
amendment of the claims so rejected or new Evidence relating to
the claims so rejected, or both, and have the matter reconsidered
by the examiner, in which event the prosecution will be
remanded to the examiner. The new ground of rejection is
binding upon the examiner unless an amendment or new
Evidence not previously of Record is made which, in the opinion
of the examiner, overcomes the new ground of rejection
designated in the decision. Should the examiner reject the claims,
appellant may again appeal to the Board pursuant to this subpart.
(2) Request rehearing. Request that the proceeding be
reheard under §41.52 by the Board upon the same Record. The
request for rehearing must address any new ground of rejection
and state with particularity the points believed to have been
misapprehended or overlooked in entering the new ground of
rejection and also state all other grounds upon which rehearing
is sought.
Further guidance on responding to a new ground of rejection can be
found in the MPEP § 1214.01.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1). See 37 C.F.R.
§§ 41.50(f), 41.52(b).
REVERSED; 37 C.F.R, § 41.50(b)
7
Notice of References Cited
Application/Control No.
11/831,512
Applicant(s)/Patent Under Patent
Appeal No.
Examiner Art Unit
1616 Page 1 of 1
U.S. PATENT DOCUMENTS
* Document Number
Country Code-Number-Kind Code
Date
MM-YYYY Name Classification
A US- 7,070,800 07-2006 Bechtold-Peters et al.
B US-
C US-
D US-
E US-
F US-
G US-
H US-
1 US-
J US-
K US-
L US-
M US-
FOREIGN PATENT DOCUMENTS
* Document Number
Country Code-Number-Kind Code
Date
MM-YYYY Country Name Classification
N
O
P
Q
R
S
T
NON-PATENT DOCUMENTS
* Include as applicable: Author, Title Date, Publisher, Edition or Volume, Pertinent Pages)
U Int. J Adolesc Med Health. 2004Apr-Jun;16(2):91-105 HTTPS://WWW.ncbi.nlm.nih.gov/pubmed/15266989
V
w
X
*A copy of this reference is not being furnished with this Office action. (See MPEP § 707.05(a).)
Dates in MM-YYYY format are publication dates. Classifications may be US or foreign.
U.S. Patent and Trademark Office
PTO-892 (Rev. 01-2001) Notice of References Cited Part of Paper No.
8/15/2017 Budesonide and formoterol in a single inhaler controls asthma in adolescents. - PubMed - NCBI
iPubMed ▼ j
ho mat: Abstract
int J Atioiesc Med Health. 2004 Apr-Jun;16(2):91-105.
Budesonide and formoterol in a single inhaler controls asthma in
adolescents.
Pohunek P1. Tai A.
1 Charles University Prague, 2nd School of Medicine, Prague, Czech Republic.
petr.pohunek@lfmotol.cuni.cz
Abstract
Despite the availability of effective treatments and national guidelines, morbidity from asthma
remains high among adolescents. Adolescents need to be considered as a distinct group of
individuals with different requirements to those of children and adults. In particular, their non­
adherence to prescribed treatment regimens is of concern and is a significant factor contributing to
the high rate of morbidity in adolescents. Studies in children aged 4 to 17 years suggest that the
combination of an inhaled corticosteroid (ICS) and a long-acting beta2-agonist effectively controls
asthma symptoms in patients who remain symptomatic on ICS alone. In order to improve adherence
to therapy, the use of combined therapy with an ICS and a long-acting beta2-agonist in a single
inhaler should be considered and the dosing frequency should be adjusted according to the severity
of asthma symptoms. This should empower patients with a greater degree of self-management and
may be important in helping adolescents feel responsible for the management of their asthma.
Results from a recent subanalysis demonstrate that the combination of budesonide and
formoterol administered twice daily via a single inhaler (Symbicort Turbuhaler) rapidly gains and
maintains control of asthma in adolescents whose asthma is not controlled on ICS alone. It is
anticipated that this will lead to improved adherence to therapy in this difficuIt-to-treat population.
PMIO 15266983
[indexed for MEDLINE]
Publication type, IVleSH terms,
LinkOut - more resources
https ://www. ncbi. nl m. ni h. gov/pubm ed/15266989 1/2
8/15/2017 Budesonide and formoterol in a single inhaler controls asthma in adolescents. - PubMed - NCBI
P u bMed C o m m o ns PubMedCommms home
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https ://www. ncbi. nl m. ni h. gov/pubm ed/15266989 2/2
US007070800B2
(12) United States Patent
Bechtold-Peters et al.
(io) Patent No.: US 7,070,800 B2
(45) Date of Patent: Jul. 4, 2006
(54) INHALABLE POWDER CONTAINING
TIOTROPIUM
(75) Inventors: Karoline Bechtold-Peters, Biberach
(DE); Michael Walz, Bingen (DE);
Georg Boeck, Mainz (DE); Rolf Doerr,
Ober-Olm (DE)
(73) Assignee: Boehringer Ingelheim Pharma KG,
Ingelheim (DE)
( * ) Notice: Subject to any disclaimer, the term of this
patent is extended or adjusted under 35
U.S.C. 154(b) by 103 days.
(21) Appl. No.: 09/975,418
(22) Filed: Oct. 11, 2001
6,482,429 B1 11/2002
6,486,321 B1 11/2002
6,506,900 B1 1/2003
6,517,865 B1 2/2003
6,585,959 B1 7/2003
6,589,536 B1 7/2003
6,645,466 B1 11/2003
6,881,422 B1 4/2005
6,905,239 B1 6/2005
2003/0043687 Al 3/2003
2003/0068278 Al 4/2003
2003/0070679 Al 4/2003
2003/0125350 Al 7/2003
2003/0202944 Al 10/2003
2003/0235538 Al 12/2003
2004/0002510 Al 1/2004
2004/0002548 Al 1/2004
2004/0029907 Al 2/2004
2004/0136919 Al 7/2004
Etzler
Banholzer et al.
Banholzer et al.
Cade et al.
Walz et al.
Brox et al.
Keller et al.
Banholzer et al.
Boeck et al.
Boeck et al.
Boeck et al.
Hochrainer et al.
Hassan et al.
Staniforth
Zierenberg
Bender et al.
Bozung et al.
Banholzer et al.
Hartig et al........................ 424/46
(65) Prior Publication Data
US 2002/0110529 Al Aug. 15, 2002
Related U.S. Application Data
(60) Provisional application No. 60/252,683, filed on Nov. 22,
2000.
(30) Foreign Application Priority Data
Oct. 12, 2000 (DE) .................................................. 100 50 635
(51) Int. Cl.
A61F13/02 (2006.01)
A61F 9/66 (2006.01)
A61F 9/14 (2006.01)
A61L 9/04 (2006.01)
FOREIGN PATENT DOCUMENTS
EP 0 172 258 2/1985
EP 0 418 716 9/1990
FR 8.142 M A 8/1970
WO WO 93/11746 Al 6/1993
WO WO 94/28956 12/1994
WO WO 95/11666 Al 5/1995
WO WO 95/24889 Al 9/1995
WO WO 96/02231 2/1996
WO WO 00/28979 Al 5/2000
WO WO 00/47200 Al 8/2000
WO WO 02/30389 4/2002
WO WO 02/098874 12/2002
WO WO 03/084502 10/2003
WO WO 03/084509 10/2003
OTHER PUBLICATIONS
(52) U.S. Cl............................ 424/434; 424/46; 424/435;
424/489; 424/493; 424/451; 424/456
(58) Field of Classification Search ................ 424/489,
424/493, 46, 434, 435, 451, 456
See application file for complete search history.
(56) References Cited
U.S. PATENT DOCUMENTS
3,634,582 A 1/1972 Hartley et al.
3,860,618 A 1/1975 Hartley et al.
3,957,965 A 5/1976 Hartley et al.
4,042,700 A 8/1977 Banholzer et al.
4,608,377 A 8/1986 Banholzer et al.
4,783,534 A 11/1988 Banholzer
5,478,578 A 12/1995 Arnold et al.
5,498,422 A 3/1996 Nakamichi et al.
5,610,163 A 3/1997 Banholzer et al.
5,654,314 A 8/1997 Banholzer et al.
5,770,738 A 6/1998 Banholzer et al.
5,947,118 A 9/1999 Hochrainer et al.
5,952,505 A 9/1999 Banholzer
6,183,782 B1 2/2001 Hallworth
6,221,338 B1 4/2001 Staniforth
6,228,394 B1 * 5/2001 Horhota et al..................
6,235,725 B1 * 5/2001 Ahmed .............................
6,274,287 B1 8/2001 Moriuma et al.
424/456
514/56
Walz, M. et al; “Process for Preparing Powder Formula­
tions”; USSN 09/977,911; Oct. 11, 2001.
U.S. Appl. No. 09/961,822; filed Sep. 24, 2001; Banholzer,
et al.
N.H. Shah, et al. “Elasticity of Soft Gelatin Capsules Con­
taining Polyethylene Glycol 400 -Quantitation and Resolu­
tion” Pharmaceutical Technology, pp. 126-133, Mar. 1992.
Mareke Hartig, et al. “New Tiotropium Containing Powder
Formulation for Inhalation” New U.S. Appl. No. 10/718,
404, filed Nov. 20, 2003.
* cited by examiner
Primary Examiner—Carlos A. Azpuru
(74) Attorney, Agent, or Firm—Michael Morris;
Mary-Ellen M. Devlin; Andrea D. Small
(57) ABSTRACT
The invention relates to powdered preparations containing
tiotropium for inhalation, processes for preparing them as
well as their use in preparing a pharmaceutical composition
for the treatment of respiratory complaints, particularly for
the treatment of COPD (chronic obstructive pulmonary
disease) and asthma.
41 Claims, No Drawings
US 7,070,800 B2
1
INHALABLE POWDER CONTAINING
TIOTROPIUM
RELATED APPLICATIONS
The present application is a continuation of U.S. Ser. No.
10/396,179 now U.S. Pat. No. 6,743,437 which is a con­
tinuation of U.S. Ser. No. 09/982,219, filed Oct. 17, 2001
now U.S. Pat. No. 6,537,568 which is a continuation of U.S.
Ser. No. 09/587,485, filed Jun. 5, 2000 now U.S. Pat. No.
6,306,426 which is a continuation-in-part of U.S. Ser. No.
09/356,074 filed Jul. 16, 1999, now U.S. Pat. No. 6,110,485
which is a continuation of U.S. Ser. No. 09/150,990 filed
Sep. 10, 1998, now abandoned which is a continuation of
U.S. Ser. No. 08/908,094 filed Aug. 11, 1997, now aban­
doned.
FIELD OF THE INVENTION
The invention relates to powdered preparations contain­
ing tiotropium for inhalation, processes for preparing them
as well as their use for preparing a pharmaceutical compo­
sition for treating respiratory complaints, particularly for
treating COPD (chronic obstructive pulmonary disease) and
asthma.
BACKGROUND OF THE INVENTION
Tiotropium bromide is known from European Patent
Application EP 418 716 A1 and has the following chemical
structure:
H3c^ + ^ch3
N
Tiotropium bromide is a highly effective anticholinergic
with a long-lasting activity which can be used to treat
respiratory complaints, particularly COPD (chronic obstruc­
tive pulmonary disease) and asthma. The term tiotropium
refers to the free ammonium cation.
For treating the abovementioned complaints, it is useful to
administer the active substance by inhalation. In addition to
the administration of broncholytically active compounds in
the form of metered aerosols and inhalable solutions, the use
of inhalable powders containing active substance is of
particular importance.
With active substances which have a particularly high
efficacy, only small amounts of the active substance are
needed per single dose to achieve the desired therapeutic
effect. In such cases, the active substance has to be diluted
with suitable excipients in order to prepare the inhalable
powder. Because of the large amount of excipient, the
properties of the inhalable powder are critically influenced
by the choice of excipient. When choosing the excipient its
particle size is particularly important. As a rule, the finer the
excipient, the poorer its flow properties. However, good flow
properties are a prerequisite for highly accurate metering
when packing and dividing up the individual doses of
preparation, e.g. when producing capsules (inhalettes) for
powder inhalation or when the patient is metering the
2
individual dose before using a multi-dose inhaler. Moreover,
the particle size of the excipient is very important for the
emptying characteristics of capsules when used in an
inhaler. It has also been found that the particle size of the
excipient has a considerable influence on the proportion of
active substance in the inhalable powder which is delivered
for inhalation. The term inhalable proportion of active
substance refers to the particles of the inhalable powder
which are conveyed deep into the branches of the lungs
when inhaled with a breath. The particle size required for
this is between 1 and 10 pm, preferably less than 6 pm.
The aim of the invention is to prepare an inhalable powder
containing tiotropium which, while being accurately
metered (in terms of the amount of active substance and
powder mixture packed into each capsule by the manufac­
turer as well as the quantity of active substance released and
delivered to the lungs from each capsule by the inhalation
process) with only slight variations between batches,
enables the active substance to be administered in a large
inhalable proportion. A further aim of the present invention
is to prepare an inhalable powder containing tiotropium
which ensures good emptying characteristics of the
capsules, whether it is administered to the patient using an
inhaler, for example, as described in WO 94/28958, or in
vitro using an impactor or impinger.
The fact that tiotropium, particularly tiotropium bromide,
has a therapeutic efficacy even at very low doses imposes
further conditions on an inhalable powder which is to be
used with highly accurate metering. Because only a low
concentration of the active substance is needed in the
inhalable powder to achieve the therapeutic effect, a high
degree of homogeneity of the powder mixture and only
slight fluctuations in the dispersion characteristics from one
batch of capsules to the next are essential. The homogeneity
of the powder mixture and minor fluctuations in the disper­
sion properties are crucial in ensuring that the inhalable
proportion of active substance is released reproducibly in
constant amounts and with the lowest possible variability.
Accordingly, a further aim of the present invention is to
prepare an inhalable powder containing tiotropium which is
characterised by a high degree of homogeneity and unifor­
mity of dispersion. The present invention also sets out to
provide an inhalable powder which allows the inhalable
proportion of active substance to be administered with the
lowest possible variability.
DETAILED DESCRIPTION OF THE
INVENTION
It was found that, surprisingly, the objective outlined
above can be achieved by means of the powdered prepara­
tions for inhalation (inhalable powders) according to the
invention described hereinafter.
Accordingly, the present invention relates to inhalable
powders containing 0.04 to 0.8% of tiotropium mixed with
a physiologically acceptable excipient, characterised in that
the excipient consists of a mixture of coarser excipient with
an average particle size of 15 to 80 pm and finer excipient
with an average particle size of 1 to 9 pm, the proportion of
finer excipient representing 1 to 20% of the total amount of
excipient. Inhalable powders which contain 0.08 to 0.64%,
most preferably 0.16 to 0.4% of tiotropium, are preferred
according to the invention.
By tiotropium is meant the free ammonium cation. The
counter-ion (anion) may be chloride, bromide, iodide,
methanesulphonate, para-toluenesulphonate or methyl sul­
phate. Of these anions, the bromide is preferred.
5
10
15
20
25
30
35
40
45
50
55
60
65
US 7,070,800 B2
Accordingly, the present invention preferably relates to
inhalable powders which contain between 0.048 and 0.96%
of tiotropium bromide. Of particular interest according to
the invention are inhalable powders which contain 0.096 to
0.77%, most preferably 0.19 to 0.48% of tiotropium bro­
mide.
The tiotropium bromide which is preferably contained in
the inhalable powders according to the invention may
include solvent molecules during crystallisation. Preferably,
the hydrates of tiotropium bromide, most preferably tiotro­
pium bromide monohydrate, are used to prepare the
tiotropium-containing inhalable powder according to the
invention. Accordingly the present invention relates to pow­
ders for inhalation which contain between 0.05 and 1% of
tiotropium bromide monohydrate. Of particular interest
according to the invention are inhalable powders which
contain 0.1 to 0.8%, most preferably 0.2 to 0.5% of tiotro­
pium bromide monohydrate.
The inhalable powders according to the invention are
preferably characterised in that the excipient consists of a
mixture of coarser excipient with an average particle size of
17 to 50 pm, most preferably 20 to 30 pm, and finer excipient
with an average particle size of 2 to 8 pm, most preferably
3 to 7 pm. The phrase average particle size used here denotes
the 50% value from the volume distribution measured with
a laser diffractometer using the dry dispersion method.
Inhalable powders in which the proportion of finer excipient
in the total amount of excipient is from 3 to 15%, most
preferably 5 to 10%, are preferred.
The percentages given within the scope of the present
invention are always percent by weight.
When reference is made to a mixture within the scope of
the present invention, this always means a mixture obtained
by mixing together clearly defined components.
Accordingly, when an excipient mixture of coarser and finer
excipients is mentioned, this can only denote mixtures
obtained by mixing a coarser excipient component with a
finer excipient component.
The coarser and finer excipient fractions may consist of
chemically identical or chemically different substances,
while inhalable powders in which the coarser excipient
fraction and the finer excipient fraction consist of the same
chemical compound are preferred.
Examples of physiologically acceptable excipients which
may be used to prepare the inhalable powders according to
the invention include, for example, monosaccharides (e.g.
glucose or arabinose), disaccharides (e.g. lactose,
saccharose, maltose), oligo- and polysaccharides (e.g.
dextrane), polyalcohols (e.g. sorbitol, mannitol, xylitol),
salts (e.g. sodium chloride, calcium carbonate) or mixtures
of these excipients with one another. Preferably, mono- or
disaccharides are used, while the use of lactose or glucose is
preferred, particularly, but not exclusively, in the form of
their hydrates. For the purposes of the invention, lactose is
the particularly preferred excipient, while lactose monohy­
drate is most particularly preferred.
preferred application mentioned above, it is advisable to fill
the capsules with amounts of from 3 to 10 mg, preferably
from 4 to 6 mg of inhalable powder per capsule. These will
preferred filling of 4 to 6 mg of inhalable powder per
capsule, the content of tiotropium per capsule is between 1.6
and 48 pg, preferably between 3.2 and 38.4 pg, most
preferably between 6.4 and 24 pg. A content of 18 pg of
tiotropium, for example, corresponds to a content of about
21.7 pg of tiotropium bromide.
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If the inhalable powder according to the invention is to be
packed into capsules (inhalettes) in accordance with the
Consequently, capsules containing 3 to 10 mg of powder
for inhalation preferably hold between 1.5 and 100 pg of
tiotropium bromide monohydrate. When the filling is from 4
to 6 mg of inhalable powder per capsule, as is preferred,
each capsule contains between 2 and 60 pg, preferably
between 4 and 48 pg, most preferably between 8 and 30 pg
of tiotropium bromide monohydrate.
The inhalable powders according to the invention are
characterised, in accordance with the objective on which the
present invention is based, by a high degree of homogeneity
in terms of the accuracy of metering of single doses. This is
in the range of<8%, preferably <6%, most preferably<4%.
The inhalable powders according to the invention may be
obtained by the method described hereinafter.
After the starting materials have been weighed out, first of
all the excipient mixture is prepared from the defined
fractions of the coarser excipient and finer excipient. Then
the inhalable powder according to the invention is prepared
from the excipient mixture and the active substance. If the
inhalable powder is to be administered using inhalettes in
suitable inhalers, the preparation of the inhalable powders is
followed by the manufacture of the powder-filled capsules.
In the preparation processes described hereinafter, the
abovementioned components are used in the amounts by
weight described in the abovementioned compositions of the
inhalable powders according to the invention.
The powders for inhalation according to the invention are
prepared by mixing the coarser excipient fractions with the
finer excipient fractions and subsequently mixing the result­
ing excipient mixtures with the active substance.
To prepare the excipient mixture, the coarser and finer
excipient fractions are placed in a suitable mixing container.
The two components are preferably added using a granulat­
ing sieve with a mesh size of 0.1 to 2 mm, preferably 0.3 to
1 mm, most preferably 0.3 to 0.6 mm. Preferably, the coarser
excipient is put in first and then the finer excipient fraction
is added to the mixing container. During this mixing process
the two components are preferably added in batches, with
some of the coarser excipient being put in first and then finer
and coarser excipient being added alternately. It is particu­
larly preferred when producing the excipient mixture to
sieve in the two components in alternate layers. The two
components are preferably sieved in alternately in 15 to 45,
most preferably 20 to 40 layers each. The mixing of the two
excipients may take place while the two components are still
being added. Preferably, however, mixing is only done once
the two components have been sieved in layer by layer.
US 7,070,800 B2
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Once the excipient mixture has been produced, this and
the active substance are placed in a suitable mixing con­
tainer. The active substance used has an average particle size
of 0.5 to 10 pm, preferably 1 to 6 pm, most preferably 2 to
5 pm. The two components are preferably added using a
granulating sieve with a mesh size of 0.1 to 2 mm, preferably
0.3 to 1 mm, most preferably 0.3 to 0.6 mm. Preferably, the
excipient mixture is put in first and then the active substance
is added to the mixing container. During this mixing process
the two components are preferably added in batches. It is
particularly preferred when producing the excipient mixture
to sieve in the two components in alternate layers. The two
components are preferably sieved in alternately in 25 to 65,
most preferably 30 to 60 layers. The mixing of the excipient
mixture with the active substance may take place while the
two components are still being added. Preferably, however,
mixing is only done once the two components have been
sieved in layer by layer.
The powder mixture thus obtained may optionally be
added once or repeatedly using a granulating sieve and then
subjected to another mixing process.
One aspect of the present invention relates to an inhalable
powder containing tiotropium, which may be obtained by
the methods described hereinbefore.
When the term active substance is used within the scope
of the present invention, this is intended as a reference to
tiotropium. According to the invention, any reference to
tiotropium, which is the free ammonium cation, corresponds
to a reference to tiotropium in the form of a salt (tiotropium
salt) which contains an anion as the counter-ion. Tiotropium
salts which may be used within the scope of the present
invention are those compounds which contain chloride,
bromide, iodide, methanesulphonate, para-
toluenesulphonate or methyl sulphate, in addition to tiotro­
pium as counter-ion (anion). Within the scope of the present
invention, tiotropium bromide is preferred of all the tiotro­
pium salts. References to tiotropium bromide within the
scope of the present invention should always be taken as
references to all possible amorphous and crystalline modi­
fications of tiotropium bromide. These may, for example,
include molecules of solvent in their crystalline structure. Of
all the crystalline modifications of tiotropium bromide, those
which also include water (hydrates) are preferred according
to the invention. It is particularly preferable to use tiotro­
pium bromide monohydrate within the scope of the present
invention.
In order to prepare the formulations according to the
invention, first of all tiotropium has to be prepared in a form
which can be used for pharmaceutical purposes. For this,
tiotropium bromide, which may be prepared as disclosed in
EP 418 716 Al, is preferably subjected to another crystal­
lisation step. Depending on the reaction conditions and
solvent used, different crystal modifications are obtained.
These modifications may be told apart, for example, by DSC
(Differential Scanning Calorimetry).
The following Table summarises the melting points of
different crystal modifications of tiotropium bromide
depending on the solvent, which are determined by DSC.
solvent DSC
methanol 228° C.
ethanol 227° C.
ethanol/water 229° C.
-continued
solvent DSC
water 230° C.
isopropanol 229° C.
acetone 225° C.
ethyl acetate 228° C.
tetrahydrofuran 228° C.
Tiotropium bromide monohydrate has proved particularly
suitable for preparing the formulation according to the
invention. The DSC diagram of tiotropium bromide mono­
hydrate shows two characteristic signals. The first, relatively
broad, endothermic signal between 50-120° C. can be
attributed to the dehydration of the tiotropium bromide
monohydrate to produce the anhydrous form. The second,
relatively sharp endothermic peak at 230±5° C. can be put
down to the melting of the substance. These data were
obtained using a Mettler DSC 821 and evaluated with the
Mettler STAR software package. These data, like the other
values given in the above Table, were obtained at a heating
rate of 10 K/min.
The following Examples serve to illustrate the present
invention further without restricting its scope to the embodi­
ments provided hereinafter by way of example.
Starting Materials
In the Examples which follow, lactose-monohydrate
(200M) is used as the coarser excipient. It may be obtained,
for example, from Messrs DMV International, 5460 Veghel/
NL under the product name Pharmatose 200M.
In the Examples which follow, lactose-monohydrate (5p)
is used as the finer excipient. It may be obtained from
lactose-monohydrate 200M by conventional methods
(micronising). Lactose-monohydrate 200M may be
obtained, for example, from Messrs DMV International,
5460 Veghel/NL under the product name Pharmatose 200M.
Preparation of Tiotropium Bromide Monohydrate
15.0 kg of tiotropium bromide are added to 25.7 kg of
water In a suitable reaction vessel. The mixture is heated to
80-90° C. and stirred at constant temperature until a clear
solution is formed. Activated charcoal (0.8 kg), moistened
with water, is suspended in 4.4 kg of water, this mixture is
added to the solution containing the tiotropium bromide and
rinsed with 4.3 kg of water. The mixture thus obtained is
stirred for at least 15 min at 80-90° C. and then filtered
through a heated filter into an apparatus which has been
preheated to an outer temperature of 70° C. The filter is
rinsed with 8.6 kg of water. The contents of the apparatus are
cooled at 3-5° C. every 20 minutes to a temperature of
20-25° C. The apparatus is further cooled to 10-15° C. using
cold water and crystallisation is completed by stirring for at
least one hour. The crystals are isolated using a suction drier,
the crystal slurry isolated is washed with 9 liters of cold
water (10-15° C.) and cold acetone (10-15° C.). The crys­
tals obtained are dried in a nitrogen current at 25° C. over 2
hours. Yield: 13.4 kg of tiotropium bromide monohydrate
(86% of theory)
The crystalline tiotropium bromide monohydrate thus
obtained is micronised by known methods, to bring the
active substance into the average particle size which meets
the specifications according to the invention.
The method of determining the average particle size of the
various ingredients of the formulation according to the
invention is described as follows.
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US 7,070,800 B2
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A) Determining the particle size of finely divided lactose:
Measuring Equipment and Settings
The equipment is operated according to the manufactur­
er’s instructions.
Measuring equipment: HELOS Laser-diffraction spectrometer,
(SympaTec)
Dispersing unit: RODOS dry disperser with suction funnel,
(SympaTec)
Sample quantity: from 100 mg
Product feed: Vibri Vibrating channel, Messrs. Sympatec
Frequency of vibrating
channel:
40 rising to 100%
Duration of sample feed: 1 to 15 sec. (in the case of 100 mg)
Focal length: 100 mm (measuring range: 0.9-175 pm)
Measuring time: about 15 s (in the case of 100 mg)
Cycle time: 20 ms
Start/stop at: 1% on channel 28
Dispersing gas: compressed air
Pressure: 3 bar
Vacuum: maximum
Evaluation method: HRLD
Sample Preparation/Product Feed 25
At least 100 mg of the test substance are weighed onto a
piece of card. Using another piece of card all the larger
lumps are broken up. The powder is then sprinkled finely
over the front half of the vibrating channel (starting about 1 3Q
cm from the front edge). After the start of the measurement
the frequency of the vibrating channel is varied from about
40% up to 100% (towards the end of the measurement). The
time taken to feed in the entire sample is 10 to 15 sec.
B) Determining the particle size of micronised tiotropium 35
bromide monohydrate:
Measuring Equipment and Settings
The equipment is operated according to the manufactur­
er’s instructions. 40
Measuring equipment:
Dispersing unit:
Sample quantity:
Product feed:
Frequency of vibrating channel:
Duration of sample feed:
Focal length:
Measuring time:
Cycle time:
Start/stop at:
Dispersing gas:
Pressure:
Vacuum:
Evaluation method:
Laser diffraction spectrometer
(HELOS), Sympatec
RODOS dry disperser with
suction funnel, Sympatec
50 mg^-00 mg
Vibri Vibrating channel,
Messrs. Sympatec
40 rising to 100%
15 to 25 sec. (in the case of 200 mg)
100 mm (measuring range: 0.9-175 pm)
about 15 s (in the case of 200 mg)
20 ms
1% on channel 28
compressed air
3 bar
maximum
HRLD
45
50
55
Sample Preparation/Product Feed ^
About 200 mg of the test substance are weighed onto a
piece of card. Using another piece of card all the larger
lumps are broken up. The powder is then sprinkled finely
over the front half of the vibrating channel (starting about 1
cm from the front edge). After the start of the measurement 65
the frequency of the vibrating channel is varied from about
40% up to 100% (towards the end of the measurement). The
8
sample should be fed in as continuously as possible.
Flowever, the amount of product should not be so great that
adequate dispersion cannot be achieved. The time over
which the entire sample is fed in is about 15 to 25 seconds
for 200 mg, for example.
C) Determining the particle size of lactose 200M
Measuring Equipment and Settings
The equipment is operated according to the manufactur­
er’s instructions.
Measuring equipment:
Dispersing unit:
Sample quantity:
Product feed:
Frequency of vibrating channel:
Focal length (1):
Focal length (2):
Measuring time:
Cycle time:
Start/stop at:
Pressure:
Vacuum:
Evaluation method:
Laser diffraction spectrometer
(HELOS), Sympatec
RODOS dry disperser with
suction funnel, Sympatec
500 mg
VIBRI Vibrating channel,
Messrs. Sympatec
18 rising to 100%
200 mm (measuring range: 1.8-350 pm)
500 mm (measuring range: 4.5-875 pm)
10 s
10 ms
1% on channel 19
3 bar
maximum
HRLD
Sample Preparation/Product Feed
About 500 mg of the test substance are weighed onto a
piece of card. Using another piece of card all the laiger
lumps are broken up. The powder is then transferred into the
funnel of the vibrating channel. A gap of 1.2 to 1.4 mm is set
between the vibrating channel and funnel. After the start of
the measurement the amplitude setting of the vibrating
channel is increased from 0 to 40% until a continuous flow
of product is obtained. Then it is reduced to an amplitude of
about 18%. Towards the end of the measurement the ampli­
tude is increased to 100%.
Apparatus
The following machines and equipment, for example,
may be used to prepare the inhalable powders according to
the invention:
Mixing container or powder mixer: Gyrowheel mixer 200
L; type: DFW80N-4; made by:
Messrs Engelsmann, D-67059 Ludwigshafen.
Granulating sieve: Quadro Comil; type: 197-S; made by:
Messrs Joisten & Kettenbaum, D-51429 Bergisch-
Gladbach.
EXAMPLE 1
1.1: Excipient Mixture
31.82 kg of lactose monohydrate for inhalation (200M)
are used as the coarser excipient component. 1.68 kg of
lactose monohydrate (5 pm) are used as the finer excipient
component. In the resulting 33.5 kg of excipient mixture the
proportion of the finer excipient component is 5%.
About 0.8 to 1.2 kg of lactose monohydrate for inhalation
(200M) are added to a suitable mixing container through a
suitable granulating sieve with a mesh size of 0.5 mm. Then
alternate layers of lactose monohydrate (5 pm) in batches of
about 0.05 to 0.07 kg and lactose monohydrate for inhalation
(200M) in batches of 0.8 to 1.2 kg are sieved in. Lactose
US 7,070,800 B2
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monohydrate for inhalation (200M) and lactose monohy­
drate (5 (im) are added in 31 and 30 layers, respectively
(tolerance:±6 layers).
The ingredients sieved in are then mixed together (mixing
at 900 rpm).
1.2: Final Mixture
To prepare the final mixture, 32.87 kg of the excipient
mixture (1.1) and 0.13 kg of micronised tiotropium bromide
monohydrate are used. The content of active substance in the
resulting 33.0 kg of inhalable powder is 0.4%.
About 1.1 to 1.7 kg of excipient mixture (1.1) are added
to a suitable mixing container through a suitable granulating
sieve with a mesh size of 0.5 mm. Then alternate layers of
tiotropium bromide monohydrate in batches of about 0.003
kg and excipient mixture (1.1) in batches of 0.6 to 0.8 kg are
sieved in. The excipient mixture and the active substance are
added in 46 or 45 layers, respectively (tolerance:±9 layers).
The ingredients sieved in are then mixed together (mixing
at 900 rpm). The final mixture is passed through a granu­
lating sieve twice more and then mixed (mixing at 900 rpm).
EXAMPLE 2
Inhalation capsules (inhalettes) having the following composition
were produced using the mixture obtained according to Example 1:
tiotropium bromide monohydrate: 0.0225 mg
lactose monohydrate (200 M): 5.2025 mg
lactose monohydrate (5 pm): 0.2750 mg
hard gelatine capsule: 49.0 mg
Total: 54.5 mg
EXAMPLE 3:
Inhalation capsules having the composition:
tiotropium bromide monohydrate: 0.0225 mg
lactose monohydrate (200 M): 4.9275 mg
lactose monohydrate (5 pm): 0.5500 mg
hard gelatine capsule: 49.0 mg
Total: 54.5 mg
The inhalable powder needed to prepare the capsules was
obtained analogously to Example 1.
Example 4:
Inhalation capsules having the composition:
tiotropium bromide monohydrate: 0.0225 mg
lactose monohydrate (200 M): 5.2025 mg
lactose monohydrate (5 pm): 0.2750 mg
polyethylene capsule: 100.0 mg
Total: 105.50 mg
The inhalable powder needed to prepare the capsules was
obtained analogously to Example 1.
For the purposes of the present invention the mean
particle size denotes the value in pm at which 50% of the
10
particles from the volume distribution have a particle size
which is smaller than or equal to the value specified. Laser
diffraction/dry dispersion is used as the method of measure­
ment for determining the total distribution of the particle
size distribution.
We claim:
1. An inhalable powder comprising 0.04 to 0.8% of
tiotropium in admixture with a physiologically acceptable
excipient, wherein the excipient consists of a mixture of
coarser excipient with an average particle size of 15 to 80
pm and finer excipient with an average particle size of 1 to
9 pm, the proportion of the finer excipient constituting 1 to
20% of the total amount of excipient, wherein the inhalable
proportion of active substance is released reproducibly in
low variability amounts when administered to a patent.
2. An inhalable powder according to claim 1, wherein the
tiotropium is present in the form of the chloride, bromide,
iodide, methanesulphonate, para-toluenesulphonate or
methyl sulphate thereof.
3. An inhalable powder comprising between 0.048 and
0.96% of tiotropium bromide in admixture with a physi­
ologically acceptable excipient, wherein the excipient con­
sists of a mixture of coarser excipient with an average
particle size of 15 to 80 pm and finer excipient with an
average particle size of 1 to 9 pm, the proportion of the finer
excipient constituting 1 to 20% of the total amount of
excipient, wherein the inhalable proportion of active sub­
stance is released reproducibly in low variability amounts
when administered to a patent.
4. An inhalable powder comprising between 0.05 and 1%
of tiotropium bromide monohydrate in admixture with a
physiologically acceptable excipient, wherein the excipient
consists of a mixture of coarser excipient with an average
particle size of 15 to 80 pm and finer excipient with an
average particle size of 1 to 9 pm, the proportion of the finer
excipient constituting 1 to 20% of the total amount of
excipient, wherein the inhalable proportion of active sub­
stance is released reproducibly in low variability amounts
when administered to a patent.
5. An inhalable powder according to one of claims 1, 2,
3 or 4, wherein the excipient consists of a mixture of coarser
excipient with an average particle size of 17 to 50 pm and
finer excipient with an average particle size of 2 to 8 pm.
6. An inhalable powder according to one of claims 1, 2,
3 or 4, wherein the proportion of finer excipient in the total
amount of excipient is 3 to 15%.
7. An inhalable powder according to one of claims 1, 2,
3 or 4, wherein the tiotropium used has an average particle
size of 0.5 to 10 pm.
8. An inhalable powder according to one of claims 1, 2,
3 or 4, wherein one or more monosaccharides, disaccharides,
oligo- or polysaccharides, polyalcohols, salts thereof, or
mixtures thereof are used as the excipients.
9. An inhalable powder according to claim 8, wherein
glucose, arabinose, lactose, saccharose, maltose, dextrane,
sorbitol, mannitol, xylitol, sodium chloride, calcium carbon­
ate or mixtures thereof are used as the excipients.
10. An inhalable powder according to claim 9, wherein
glucose or lactose or mixtures thereof are used as the
excipients.
11. A process for preparing an inhalable powder according
to one of claims 1 to 4, comprising: (a) mixing coarser
excipient fractions with finer excipient fractions to obtain an
excipient mixture, and (b) mixing the excipient mixture thus
obtained with the tiotropium.
12. Amethod of treating a disease that is responsive to the
administration of tiotropium, comprising administering to a
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US 7,070,800 B2
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host in need thereof an inhalable powder according to one of
claims 1 to 4 or 12.
13. A method according to claim 12, wherein the disease
is asthma or COPD.
14. An inhalable powder according to claim 4 comprising
0.1 to 0.8% of tiotropium bromide monohydrate.
15. An inhalable powder according to claim 4 comprising
0.2 to 0.5% of tiotropium bromide monohydrate.
16. An inhalable powder according to one of claim 1, 2,
3 or 4, wherein the excipient consists of a mixture of coarser
excipient with an average particle size of 20 to 30 pm and
finer excipient with an average particle size of 3 to 7 pm.
17. An inhalable powder according to one of claim 1, 2,
3 or 4, wherein the proportion of finer excipient in the total
amount of excipient is 5 to 10%.
18. An inhalable powder according to one of claim 1, 2,
3 or 4, wherein the tiotropium used has an average particle
size of 1 to 6 pm.
19. An inhalable powder according to one of claim 1, 2,
3 or 4, wherein the tiotropium used has an average particle
size of 2 to 5 pm.
20. An inhalable powder according to claim 10, wherein
lactose monohydrate is used as the excipient.
21. An inhalable powder comprising between 0.2 and
0.5% of tiotropium bromide monohydrate in admixture with
lactose monohydrate as the physiologically acceptable
excipient, wherein the excipient consists of a mixture of
coarser excipient with an average particle size of 20 to 30
pm and finer excipient with an average particle size of 3 to
7 pm, the proportion of the finer excipient constituting 5 to
10% of the total amount of excipient, wherein the inhalable
proportion of active substance is released reproducibly in
low variability amounts when administered to a patent.
22. An inhalable powder comprising 0.04 to 0.8% of
tiotropium in admixture with a physiologically acceptable
excipient, said inhalable powder prepared by a process
comprising: (a) mixing coarser excipient having an average
particle size of 15 to 80 pm and finer excipient having an
avenge particle size of 1 to 9 pm, wherein the proportion of
the finer excipient constitutes 1 to 20% of the total amount
of excipient, to obtain an excipient mixture, and (b) mixing
the excipient mixture thus obtained with the tiotropium,
wherein the inhalable proportion of active substance is
released reproducibly in low variability amounts when
administered to a patent.
23. An inhalable powder according to claim 22, wherein
the tiotropium is present in the form of the chloride,
bromide, iodide, methanesulphonate, para-
toluenesulphonate or methyl sulphate thereof.
24. An inhalable powder comprising between 0.048 and
0.96% of tiotropium bromide in admixture with a physi­
ologically acceptable excipient, said inhalable powder pre­
pared by a process comprising: (a) mixing coarser excipient
having an average particle size of 15 to 80 pm and finer
excipient having an average particle size of 1 to 9 pm,
wherein the proportion of the finer excipient constitutes 1 to
20% of the total amount of excipient, to obtain an excipient
mixture, and (b) mixing the excipient mixture thus obtained
with the tiotropium bromide, wherein the inhalable propor­
tion of active substance is released reproducibly in low
variability amounts when administered to a patent.
25. An inhalable powder comprising between 0.05 and
1% of tiotropium bromide monohydrate in admixture with a
physiologically acceptable excipient, said inhalable powder
prepared by a process comprising: (a) mixing coarser excipi­
ent having an average particle size of 15 to 80 pm and finer
excipient having an average particle size of 1 to 9 pm,
wherein the proportion of the finer excipient constitutes 1 to
12
20% of the total amount of excipient, to obtain an excipient
mixture, and (b) mixing the excipient mixture thus obtained
with the tiotropium bromide monohydrate, wherein the
inhalable proportion of active substance is released repro­
ducibly in low variability amounts when administered to a
patent.
26. An inhalable powder according to claim 25 compris­
ing 0.1 to 0.8% of tiotropium bromide monohydrate.
27. An inhalable powder according to claim 25 compris­
ing 0.2 to 0.5% of tiotropium bromide monohydrate.
28. An inhalable powder according to one of claim 22, 23,
24 or 25, wherein the coarser excipient has an average
particle size of 17 to 50 pm and the finer excipient has an
average particle size of 2 to 8 pm.
29. An inhalable powder according to one of claim 22, 23,
24 or 25, wherein the coarser excipient has an average
particle size of 20 to 30 pm and the finer excipient has an
average particle size of 3 to 7 pm.
30. An inhalable powder according to one of claim 22, 23,
24 or 25, wherein the proportion of finer excipient in the
total amount of excipient is 3 to 15%.
31. An inhalable powder according to one of claim 22, 23,
24 or 25, wherein the proportion of finer excipient in the
total amount of excipient is 5 to 10%.
32. An inhalable powder according to one of claim 22, 23,
24 or 25, wherein the tiotropium used has an average particle
size of 0.5 to 10 pm.
33. An inhalable powder according to one of claim 22, 23,
24 or 25, wherein the tiotropium used has an average particle
size of 1 to 6 pm.
34. An inhalable powder according to one of claim 22, 23,
24 or 25, wherein the tiotropium used has an average particle
size of 2 to 5 pm.
35. An inhalable powder according to one of claim 22, 23,
24 or 25, wherein one or more monosaccharides,
disaccharides, oligo- or polysaccharides, polyalcohols, salts
thereof, or mixtures thereof are used as the excipients.
36. An inhalable powder according to claim 35, wherein
glucose, arabinose, lactose, saccharose, maltose, dextrane,
sorbitol, mannitol, xylitol, sodium chloride, calcium carbon­
ate or mixtures thereof are used as the excipients.
37. An inhalable powder according to claim 36, wherein
glucose or lactose or mixtures thereof are used as the
excipients.
38. An inhalable powder according to claim 37, wherein
lactose monohydrate is used as the excipient.
39. An inhalable powder comprising between 0.2 and
0.5% of tiotropium bromide monohydrate in admixture with
lactose monohydrate as a physiologically acceptable
excipient, said inhalable powder prepared by a process
comprising: (a) mixing coarser lactose monohydrate excipi­
ent having an average particle size of 20 to 30 pm and finer
lactose monohydrate excipient having an average particle
size of 3 to 7 pm, wherein the proportion of the finer lactose
monohydrate excipient constitutes 5 to 10% of the total
amount of excipient, to obtain an excipient mixture, and (b)
mixing the excipient mixture thus obtained with the tiotro­
pium bromide monohydrate, wherein the inhalable propor­
tion of active substance is released reproducibly in low
variability amounts when administered to a patent.
40. Amethod of treating a disease that is responsive to the
administration of tiotropium, comprising administering to a
host in need thereof an inhalable powder according to one of
claim 22, 23, 24 or 25 or 39.
41. A method according to claim 40, wherein the disease
is asthma or COPD.
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UNITED STATES PATENT AND TRADEMARK OFFICE
CERTIFICATE OF CORRECTION
PATENT NO. : 7,070,800 B2 Page 1 of 1
APPLICATION NO. : 09/975418
DATED : July 4, 2006
INVENTOR(S) : Karoline Bechtold-Peters et al.
It is certified that error appears in the above-identified patent and that said Letters Patent is
hereby corrected as shown below:
In column 10, line 15 delete “patent” and replace with -patient--.
Signed and Sealed this
Eighth Day of August, 2006
JON W. DUDAS
Director of the United States Patent and Trademark Office
UNITED STATES PATENT AND TRADEMARK OFFICE
CERTIFICATE OF CORRECTION
PATENT NO.
APPLICATION NO.
DATED
INVENTOR(S)
7,070,800 B2
09/975418
July 4, 2006
Karin Bechtold Peters et al.
Page 1 of 1
It is certified that error appears in the above-identified patent and that said Letters Patent is
hereby corrected as shown below:
In column 10, line 29, delete “patent” and replace with -patient—
In column 10, line 39, delete “patent” and replace with -patient—
In column 11, line 32, delete “patent” and replace with -patient—
In column 11, line 43, delete “patent” and replace with -patient—
In column 11, line 58, delete “patent” and replace with -patient—
In column 12, line 6, delete “patent” and replace with -patient-
In column 12, line 57, delete “patent” and replace with -patient—
Signed and Sealed this
Twelfth Day of August, 2008
JON W. DUDAS
Director of the United States Patent and Trademark Office