U.S. patent application number 11/206006 was filed with the patent office on 2006-01-12 for new use.
This patent application is currently assigned to AstraZeneca AB. Invention is credited to David Gustafsson.
Application Number | 20060009397 11/206006 |
Document ID | / |
Family ID | 26663557 |
Filed Date | 2006-01-12 |
United States Patent
Application |
20060009397 |
Kind Code |
A1 |
Gustafsson; David |
January 12, 2006 |
New use
Abstract
According to the invention there is provided a kit of parts
comprising: (a) a pharmaceutical formulation including a low
molecular weight thrombin inhibitor, or a pharmaceutically
acceptable derivative thereof, in admixture with a pharmaceutically
acceptable adjuvant, diluent or carrier; and (b) a pharmaceutical
formulation including a prodrug of a low molecular weight thrombin
inhibitor, or a pharmaceutically acceptable derivative of that
prodrug, in admixture with a pharmaceutically acceptable adjuvant,
diluent or carrier, which components (a) and (b) are each provided
in a form that is suitable for administration in conjunction with
the other, as well as the use of such a kit of parts in the
treatment of a condition in which inhibition of thrombin is
required or desired.
Inventors: |
Gustafsson; David;
(Kullavik, SE) |
Correspondence
Address: |
NIXON & VANDERHYE, PC
901 NORTH GLEBE ROAD, 11TH FLOOR
ARLINGTON
VA
22203
US
|
Assignee: |
AstraZeneca AB
Sodertalje
SE
|
Family ID: |
26663557 |
Appl. No.: |
11/206006 |
Filed: |
August 18, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09582863 |
Jul 6, 2000 |
6962905 |
|
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PCT/SE00/00756 |
Apr 19, 2000 |
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11206006 |
Aug 18, 2005 |
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Current U.S.
Class: |
514/1.3 ;
514/14.7; 514/14.9; 514/21.91 |
Current CPC
Class: |
A61P 7/02 20180101; A61P
43/00 20180101; A61K 31/197 20130101; A61P 9/00 20180101; A61P 9/14
20180101; A61K 31/197 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/019 |
International
Class: |
A61K 38/04 20060101
A61K038/04 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 21, 1999 |
SE |
9901442-5 |
Dec 3, 1999 |
SE |
9904419-0 |
Claims
1. A kit of parts comprising: (a) a pharmaceutical formulation
including a low molecular weight thrombin inhibitor, or a
pharmaceutically acceptable derivative thereof, in admixture with a
pharmaceutically acceptable adjuvant, diluent or carrier; and (b) a
pharmaceutical formulation including a prodrug of a low molecular
weight thrombin inhibitor, or a pharmaceutically acceptable
derivative of that prodrug, in admixture with a pharmaceutically
acceptable adjuvant, diluent or carrier, which components (a) and
(b) are each provided in a form that is suitable for administration
in conjunction with the other.
2. A kit of parts as claimed in claim 1, wherein the prodrug of
component (b) is a prodrug of the thrombin inhibitor of component
(a).
3. A kit of parts as claimed in claim 1, wherein components (a) and
(b) are suitable for sequential, separate and/or simultaneous use
in the treatment of a condition in which inhibition of thrombin is
required or desired.
4. A kit of parts as claimed in claim 3, wherein the condition is
deep venous thrombosis.
5. A kit of parts as claimed in claim 1, wherein the thrombin
inhibitor is melagatran.
6. A kit of parts as claimed in claim 5, wherein the prodrug is of
the formula R.sup.1O.sub.2C--CH.sub.2--(R)Cgl-Aze-Pab-OH, wherein
R.sup.1 represents linear or branched C.sub.1-6 alkyl and the OH
group replaces one of the amidino hydrogens in Pab.
7. A kit of parts as claimed in claim 6, wherein R.sup.1 represents
methyl, ethyl or propyl.
8. A kit of parts as claimed in claim 1, wherein the formulation
comprising thrombin inhibitor, or derivative thereof, is a
parenteral formulation and that comprising the prodrug, or
derivative thereof, is an oral formulation.
9. A method of making a kit of parts as defined in claim 1, which
method comprises bringing a component (a) according to claim 1,
into association with a component (b) according to claim 1, thus
rendering the two components suitable for administration in
conjunction with each other.
10. A kit of parts comprising: (1) one of components (a) and (b) as
defined in claim 1; together with (2) instructions to use that
component in conjunction with the other of the two components.
11. A pharmaceutical formulation including a low molecular weight
thrombin inhibitor (or a pharmaceutically acceptable derivative
thereof) and a prodrug of a low molecular weight thrombin (or a
pharmaceutically acceptable derivative of that prodrug), in
admixture with a pharmaceutically acceptable adjuvant, diluent or
carrier.
12. A method of treatment of a condition in which inhibition of
thrombin is required or desired, which comprises administration of:
(a) a pharmaceutical formulation including a low molecular weight
thrombin inhibitor, or a pharmaceutically acceptable derivative
thereof, in admixture with a pharmaceutically acceptable adjuvant,
diluent or carrier; in conjunction with (b) a pharmaceutical
formulation including a prodrug of a low molecular weight thrombin
inhibitor, or a pharmaceutically acceptable derivative of that
prodrug, in admixture with a pharmaceutically acceptable adjuvant,
diluent or carrier, to a patient suffering from, or susceptible to,
such a condition.
13. A method as claimed in claim 12 in which component (a) is
administered prior to commencement of administration of component
(b).
14. A method of treatment of a condition in which inhibition of
thrombin is required or desired, which comprises administration of
a formulation as defined in claim 11 to a patient suffering from,
or susceptible to, such a condition.
15. A method as claimed in any one of claims 12 to 14, wherein the
condition is deep venous thrombosis.
16. A method as claimed in claim 15, wherein the thrombosis results
from surgery.
17. A method as claimed in claim 16, wherein the surgery is
gastrointestinal surgery or orthopaedic surgery.
18. A method as claimed in claim 16, wherein component (a) is
administered parenterally prior to and/or after surgery and
component (b) is administered orally following that surgery.
19. The use of a thrombin inhibitor, or a pharmaceutically
acceptable derivative thereof, in the manufacture of a medicament
for the treatment or prophylaxis of a condition in which inhibition
of thrombin is required or desired, which treatment or prophylaxis
comprises administration of: (a) a pharmaceutical formulation
including a low molecular weight thrombin inhibitor, or a
pharmaceutically acceptable derivative thereof, in admixture with a
pharmaceutically acceptable adjuvant, diluent or carrier; in
conjunction with (b) a pharmaceutical formulation including a
prodrug of a low molecular weight thrombin inhibitor, or a
pharmaceutically acceptable derivative of that prodrug, in
admixture with a pharmaceutically acceptable adjuvant, diluent or
carrier, to a patient suffering from, or susceptible to, such a
condition.
Description
FIELD OF THE INVENTION
[0001] This invention relates to a new use of low molecular weight
thrombin inhibitors.
BACKGROUND AND PRIOR ART
[0002] Blood coagulation is the key process involved in both
haemostasis (i.e. the prevention of blood loss from a damaged
vessel) and thrombosis (i.e. the formation of a blood clot in a
blood vessel, sometimes leading to vessel obstruction).
[0003] Coagulation is the result of a complex series of enzymatic
reactions. One of the ultimate steps in this series of reactions is
the conversion of the proenzyme prothrombin to the active enzyme
thrombin.
[0004] Thrombin is known to play a central role in coagulation. It
activates platelets, leading to platelet aggregation, converts
fibrinogen into fibrin monomers, which polymerise spontaneously
into fibrin polymers, and activates factor XIII, which in turn
crosslinks the polymers to form insoluble fibrin. Furthermore,
thrombin activates factor V and factor VIII leading to a "positive
feedback" generation of thrombin from prothrombin.
[0005] Effective inhibitors of thrombin are thus known, and/or are
expected, to be useful as anticoagulants and therefore useful in
the therapeutic treatment of thrombosis and related disorders.
[0006] The early development of low molecular weight inhibitors of
thrombin has been described by Claesson in Blood Coagul. Fibrinol.
(1994) 5, 411. Low molecular weight thrombin inhibitors have been
described more recently in U.S. Pat. No. 4,346,078; International
Patent Applications WO 93/11152, WO 93/18060, WO 93/05069, WO
94/20467, WO 94/29336, WO 95/35309, WO 95/23609, WO 96/03374, WO
96/06832, WO 96/06849, WO 96/25426, WO 96/32110, WO 97/01338, WO
97/02284, WO 97/15190, WO 97/30708, WO 97/40024, WO 97/46577, WO
98/06740, WO 97/49404, WO 97/11693, WO 97/24135, WO 97/47299, WO
98/01422, WO 98/57932, WO 99/29664, WO 98/06741, WO 99/37668, WO
99/37611, WO 98/37075, WO 99/00371, WO 99/28297, WO 99/29670, WO
99/40072, WO 99/54313, WO 96/31504, WO 00/01704 and WO 00/08014;
and European Patent Applications 648 780, 468 231, 559 046, 641
779, 185 390, 526 877, 542 525, 195 212, 362 002, 364 344, 530 167,
293 881, 686 642, 669 317, 601 459 and 623 596.
[0007] In particular, international patent application WO 94/29336
discloses a group of compounds, including
HOOC--CH.sub.2--(R)Cgl-Aze-Pab-H (in which Cgl represents
cyclohexylglycine, Aze represents S-azetidine-2-carboxylic acid and
Pab-H represents 4-aminomethyl-amidinobenzene), which is also known
as melagatran (see Example 1 of WO 94/29336). International Patent
Application WO 97/23499 discloses prodrugs of inter alia
melagatran.
[0008] None of the above-mentioned documents disclose or suggest
the administration of an active thrombin inhibitor in conjunction
with a prodrug of that thrombin inhibitor, or indeed in conjunction
with a prodrug of any thrombin inhibitor.
[0009] Deep venous thrombosis (DVT) and pulmonary embolism (PE) are
major health problems, which may give rise to serious outcomes. In
particular, PE may be fatal, or may result in the development of
pulmonary hypertension and heart failure from recurrent embolism.
DVT may result in post-thrombotic venous insufficiency and ulcers
in the affected part of the body (e.g. leg). Both are common
conditions, which have a great impact on worldwide healthcare
costs.
[0010] There is a considerable incidence of DVT and PE following
orthopaedic surgery. For example, in patients undergoing total hip
replacement, the incidence of DVT in the absence of
thromboprophylaxis may be as high as 45 to 57%. Further, the
incidence of proximal DVT may be between 23 and 36%, and that of
fatal PE, 0.34 to 6%. In patients undergoing total knee replacement
in the absence of thromboprophylaxis, the postoperative incidence
of DVT is between 40 and 84%, of proximal DVT is between 9 and 20%,
and of fatal PE is between 0.2 and 0.7%. In patients undergoing
general surgery in the absence of thromboprophylaxis, the
postoperative incidence of DVT is about 25%. (Reference: Chest
(1998) 114, 531S to 560S.)
[0011] Low-dose, subcutaneous (s.c.) unfractionated heparin is the
most widely used current prophylactic treatment for venous
thromboembolism resulting from orthopaedic and general surgery. The
incidence of DVT after total hip replacement has been shown to be
reduced (see Chest reference above).
[0012] The use of low-molecular weight heparin (LMWH) in the
prophylaxis of DVT following total hip and knee replacement
operations has been shown to further the reduce incidence (when
compared to low dose unfractionated heparin), without a concomitant
increase in bleeding (see Chest reference above).
[0013] However, prolonged treatment with heparins has been shown to
give rise to an increased risk of osteoporosis. Heparins may also
give rise to "heparin-induced thrombocytopenia" (HIT), are
dependent on the plasma level of the endogenous thrombin inhibitor,
antithrombin, and do not inactivate clot-bound thrombin.
[0014] Oral anticoagulants, such as warfarin (a vitamin K
antagonist), has also been shown to be effective in reducing DVT
after major surgery (see Chest reference above). However, due to
the risk of bleeding, and the need for frequent laboratory control,
the use of this substance is generally reserved for high risk
patients, and/or for long term use. Vitamin K antagonists also
demonstrate a notable risk of interaction with other drugs and
certain foods, and their use requires monitoring of the patient's
blood coagulation status.
[0015] Antiplatelet agents, such as aspirin, have been shown to
have limited efficacy in preventing DVT (see Chest reference
above).
[0016] Comparative clinical studies carried out during the course
of total hip replacement operations have shown that subcutaneous
administration of the thrombin inhibitor hirudin is superior to
unfractionated heparin and LMWH in reducing the frequency of total
and proximal DVT with no corresponding increase in bleeding (see
Eriksson et al in Lancet, 347, 635 (1996) and J. Bone Joint. Surg.,
September 11 (1996)). However, hirudin is expensive and has an
immunogenic potential.
[0017] Thus, there is a need for effective treatments of thrombotic
conditions such as DVT.
DISCLOSURE OF THE INVENTION
[0018] We have found, surprisingly, that administration of a low
molecular weight thrombin inhibitor in conjunction with a prodrug
of a (or a prodrug of that) thrombin inhibitor gives rise to a
notable anticoagulant effect.
[0019] According to a first aspect of the invention there is
provided a kit of parts comprising components: [0020] (a) a
pharmaceutical formulation including a low molecular weight
thrombin inhibitor, or a pharmaceutically acceptable derivative
thereof, in admixture with a pharmaceutically acceptable adjuvant,
diluent or carrier; and [0021] (b) a pharmaceutical formulation
including a prodrug of a low molecular weight thrombin inhibitor,
or a pharmaceutically acceptable derivative of that prodrug, in
admixture with a pharmaceutically acceptable adjuvant, diluent or
carrier, which components (a) and (b) are each provided in a form
that is suitable for administration in conjunction with the
other.
[0022] It is preferred that the prodrug of component (b) is a
prodrug of the active low molecular weight thrombin inhibitor of
component (a).
[0023] According to a further aspect of the invention, there is
provided a method of making a kit of parts as defined herein, which
method comprises bringing a component (a), as defined above, into
association with a component (b), as defined above, thus rendering
the two components suitable for administration in conjunction with
each other. By bringing the two components "into association with"
each other, we include that components (a) and (b) may be: [0024]
(i) provided as separate formulations (i.e. independently of one
another), which are subsequently brought together for use in
conjunction with each other in combination therapy; or [0025] (ii)
packaged and presented together as separate components of a
"combination pack" for use in conjunction with each other in
combination therapy.
[0026] Thus, there is further provided a kit of parts comprising:
[0027] (1) one of components (a) and (b) as defined herein;
together with [0028] (2) instructions to use that component in
conjunction with the other of the two components.
[0029] The kits of parts defined herein may comprise more than one
formulation including an appropriate quantity/dose of thrombin
inhibitor, and/or more than one formulation including an
appropriate quantity/dose of respective prodrug, in order to
provide for repeat dosing. If more than one formulation (comprising
thrombin inhibitor or prodrug) is present, such formulations may be
the same, or may be different in terms of the dose of thrombin
inhibitor/prodrug, chemical composition and/or physical form.
[0030] A further aspect of the invention provides a method of
treatment of a condition in which inhibition of thrombin is
required or desired, which comprises administration of: [0031] (a)
a pharmaceutical formulation including a low molecular weight
thrombin inhibitor, or a pharmaceutically acceptable derivative
thereof, in admixture with a pharmaceutically acceptable adjuvant,
diluent or carrier; in conjunction with [0032] (b) a pharmaceutical
formulation including a prodrug of a low molecular weight thrombin
inhibitor, or a pharmaceutically acceptable derivative of that
prodrug, in admixture with a pharmaceutically acceptable adjuvant,
diluent or carrier, to a patient suffering from, or susceptible to,
such a condition.
[0033] For the avoidance of doubt, as used herein, the term
"treatment" includes therapeutic and/or prophylactic treatment.
[0034] "Pharmaceutically acceptable derivatives" of thrombin
inhibitors and prodrugs includes salts, (e.g. pharmaceutically
acceptable non-toxic organic or inorganic acid addition salts) and
solvates. It will be appreciated that the term pharmaceutically
acceptable derivatives of active thrombin inhibitors includes those
derivatives that have the same biological function and/or activity
as that thrombin inhibitor but, for the purposes of this invention,
does not include prodrugs of that thrombin inhibitor.
[0035] By "administration in conjunction with", we include that
respective formulations comprising thrombin inhibitor and/or
prodrug are administered, sequentially, separately and/or
simultaneously, over the course of treatment of the relevant
condition, which condition may be acute or chronic. Preferably, the
term includes that the two formulations are administered
(optionally repeatedly) sufficiently closely in time for there to
be a beneficial effect for the patient, that is greater, over the
course of the treatment of the relevant condition, than if either
of the two formulations are administered (optionally repeatedly)
alone, in the absence of the other formulation, over the same
course of treatment. Determination of whether a combination
provides a greater beneficial effect in respect of, and over the
course of treatment of, a particular condition, will depend upon
the condition to be treated or prevented, but may be achieved
routinely by the skilled person.
[0036] Thus, the term "in conjunction with" includes that one or
other of the two formulations may be administered (optionally
repeatedly) prior to, after, and/or at the same time as,
administration with the other component. When used in this context,
the terms "administered simultaneously" and "administered at the
same time as" include that individual doses of thrombin inhibitor
and prodrug are administered within 48 hours (e.g. 24 hours) of
each other.
[0037] Components (a) and (b) as described herein may also be
presented (i.e. formulated) as a combined preparation (i.e.
presented as a single formulation including low molecular thrombin
inhibitor and prodrug).
[0038] Thus, there is further provided a pharmaceutical formulation
including a low molecular weight thrombin inhibitor (or a
pharmaceutically acceptable derivative thereof) and a prodrug of a
low molecular weight thrombin inhibitor (or a pharmaceutically
acceptable derivative of that prodrug), in admixture with a
pharmaceutically acceptable adjuvant, diluent or carrier.
[0039] The term "low molecular weight thrombin inhibitor" will be
understood by those skilled in the art. The term may also be
understood to include any composition of matter (e.g. chemical
compound) which inhibits thrombin to an experimentally determinable
degree in in vivo and/or in in vitro tests, and which possesses a
molecular weight of below 2,000, preferably below 1,000.
[0040] Preferred low molecular weight thrombin inhibitors include
low molecular weight peptide-based, amino acid-based, and/or
peptide analogue-based, thrombin inhibitors.
[0041] The term "low molecular weight peptide-based, amino
acid-based, and/or peptide analogue-based, thrombin inhibitors"
will be well understood by one skilled in the art to include low
molecular weight thrombin inhibitors with one to four peptide
linkages, and includes those described in the review paper by
Claesson in Blood Coagul. Fibrin. (1994) 5, 411, as well as those
disclosed in U.S. Pat. No. 4,346,078; International Patent
Applications WO 93/11152, WO 93/18060, WO 93/05069, WO 94/20467, WO
94/29336, WO 95/35309, WO 95/23609, WO 96/03374, WO 96/06832, WO
96/06849, WO 96/25426, WO 96/32110, WO 97/01338, WO 97/02284, WO
97/15190, WO 97/30708, WO 97/40024, WO 97/46577, WO 98/06740, WO
97/49404, WO 97/11693, WO 97/24135, WO 97/47299, WO 98/01422, WO
98/57932, WO 99/29664, WO 98/06741, WO 99/37668, WO 99/37611, WO
98/37075, WO 99/00371, WO 99/28297, WO 99/29670, WO 99/40072, WO
99/54313, WO 96/31504, WO 00/01704 and WO 00/08014; and European
Patent Applications 648 780, 468 231, 559 046, 641 779, 185 390,
526 877, 542 525, 195 212, 362 002, 364 344, 530 167, 293 881, 686
642, 669 317, 601 459 and 623 596, the disclosures in all of which
documents are hereby incorporated by reference.
[0042] Preferred low molecular weight peptide-based thrombin
inhibitors include HOOC--CH.sub.2--(R)Cha-Pic-Nag-H (wherein Cha
represents cyclohexylalanine, Pic represents (S)-pipecolinic acid
and Nag represents noragmatine; known as inogatran; see
International Patent Application WO 93/11152) and, especially,
HOOC--CH.sub.2--(R)Cgl-Aze-Pab-H (known as melagatran; see above
and International Patent Application WO 94/29336).
[0043] The term "prodrug" of a low molecular weight thrombin
inhibitor includes any compound that, following oral or parenteral
administration, is metabolised in vivo to form a low molecular
weight thrombin inhibitor (as defined herein), in an
experimentally-detectable amount, and within a predetermined time
(e.g. within a dosing interval of between 6 and 24 hours (i.e. once
to four times daily)), following oral or parenteral administration.
Prodrugs of the thrombin inhibitor melagatran that may be mentioned
include those disclosed in international patent application WO
97/23499. Preferred prodrugs are those of the formula
R.sup.1O.sub.2C--CH.sub.2--(R)Cgl-Aze-Pab-OH (see the list of
abbreviations above or in WO 97/23499), wherein R.sup.1 represents
C.sub.1-10 alkyl or benzyl, such as linear or branched C.sub.1-6
alkyl (e.g. C.sub.1-4 alkyl, especially methyl, propyl and,
particularly, ethyl) and the OH group replaces one of the amidino
hydrogens in Pab.
[0044] The term "condition in which inhibition of thrombin is
required or desired" will be understood by those skilled in the art
to include the following:
[0045] The treatment and/or prophylaxis of thrombosis and
hypercoagulability in blood and tissues of animals including man.
It is known that hypercoagulability may lead to thrombo-embolic
diseases. Conditions associated with hypercoagulability and
thrombo-embolic diseases which may be mentioned include inherited
or acquired activated protein C resistance, such as the factor
V-mutation (factor V Leiden), and inherited or acquired
deficiencies in antithrombin III, protein C, protein S, heparin
cofactor II. Other conditions known to be associated with
hypercoagulability and thrombo-embolic disease include circulating
antiphospholipid antibodies (Lupus anticoagulant), homocysteinemi,
heparin induced thrombocytopenia and defects in fibrinolysis.
[0046] The treatment of conditions where there is an undesirable
excess of thrombin without signs of hypercoagulability, for example
in neurodegenerative diseases such as Alzheimer's disease.
[0047] Particular disease states which may be mentioned include the
therapeutic and/or prophylactic treatment of venous thrombosis
(e.g. DVT) and pulmonary embolism, arterial thrombosis (e.g. in
myocardial infarction, unstable angina, thrombosis-based stroke and
peripheral arterial thrombosis) and systemic embolism usually from
the atrium during arterial fibrillation or from the left ventricle
after transmural myocardial infarction, or caused by congestive
heart failure; prophylaxis of re-occlusion (ie thrombosis) after
thrombolysis, percutaneous trans-luminal angioplasty (PTA) and
coronary bypass operations; the prevention of re-thrombosis after
microsurgery and vascular surgery in general.
[0048] Further indications include the therapeutic and/or
prophylactic treatment of disseminated intravascular coagulation
caused by bacteria, multiple trauma, intoxication or any other
mechanism; anticoagulant treatment when blood is in contact with
foreign surfaces in the body such as vascular grafts, vascular
stents, vascular catheters, mechanical and biological prosthetic
valves or any other medical device; and anticoagulant treatment
when blood is in contact with medical devices outside the body such
as during cardiovascular surgery using a heart-lung machine or in
haemodialysis; the therapeutic and/or prophylactic treatment of
idiopathic and adult respiratory distress syndrome, pulmonary
fibrosis following treatment with radiation or chemotherapy, septic
shock, septicemia, inflammatory responses, which include, but are
not limited to, edema, acute or chronic atherosclerosis such as
coronary arterial disease, cerebral arterial disease, peripheral
arterial disease, reperfusion damage, and restenosis after
percutaneous trans-luminal angioplasty (PTA).
[0049] Preferred conditions include thrombosis, especially DVT,
including distal and proximal DVT. The present invention finds
particular utility in the prophylactic treatment of DVT resulting
from surgery, such as gastrointestinal, or orthopaedic, surgery
(e.g. hip or knee replacement). This includes DVT resulting from
immobilisation after surgery.
[0050] In accordance with the invention, thrombin inhibitors,
prodrugs of thrombin inhibitors, and derivatives of either, may be
administered orally, intravenously, subcutaneously, buccally,
rectally, dermally, nasally, tracheally, bronchially, topically, by
any other parenteral route, or via inhalation, in the form of a
pharmaceutical preparation comprising the thrombin inhibitor or
prodrug in a pharmaceutically acceptable dosage form. Depending on
the disorder, and the patient, to be treated, as well as the route
of administration, the compositions may be administered at varying
doses.
[0051] Preferred modes of delivery are systemic. For melagatran and
derivatives thereof, preferred modes of administration are
parenteral, more preferably intravenous, and especially
subcutaneous. For prodrugs of melagatran, preferred modes of
administration are oral.
[0052] In the therapeutic treatment of mammals, and especially
humans, thrombin inhibitors, prodrugs of thrombin inhibitors, and
derivatives of either will generally be administered as a
pharmaceutical formulation in admixture with a pharmaceutically
acceptable adjuvant, diluent or carrier, which may be selected with
due regard to the intended route of administration and standard
pharmaceutical practice.
[0053] Suitable formulations for use in administering thrombin
inhibitors are known in the art, and include those known from U.S.
Pat. No. 4,346,078; International Patent Applications WO 93/11152,
WO 93/18060, WO 93/05069, WO 94/20467, WO 94/29336, WO 95/35309, WO
95/23609, WO 96/03374, WO 96/06832, WO 96/06849, WO 96/25426, WO
96/32110, WO 97/01338, WO 97/02284, WO 97/15190, WO 97/30708, WO
97/40024, WO 97/46577, WO 98/06740, WO 97/49404, WO 97/11693, WO
97/24135, WO 97/47299, WO 98/01422, WO 98/57932, WO 99/29664, WO
98/06741, WO 99/37668, WO 99/37611, WO 98/37075, WO 99/00371, WO
99/28297, WO 99/29670, WO 99/40072, WO 99/54313, WO 96/31504, WO
00/01704 and WO 00/08014; and European Patent Applications 648 780,
468 231, 559 046, 641 779, 185 390, 526 877, 542 525, 195 212, 362
002, 364 344, 530 167, 293 881, 686 642, 669 317, 601 459 and 623
596, the disclosures in all of which documents are hereby
incorporated by reference.
[0054] Suitable formulations for use with melagatran, derivatives
and prodrugs thereof are described in the literature, for example
as described in inter alia international patent applications WO
94/29336, WO 96/14084, WO 96/16671, WO 97/23499, WO 97/39770, WO
97/45138, WO 98/16252, WO 99/27912 and WO 99/27913, the disclosures
in which documents are hereby incorporated by reference. Otherwise,
the preparation of suitable formulations may be achieved
non-inventively by the skilled person using routine techniques.
[0055] The amounts of thrombin inhibitor, prodrug, or derivative of
either, in the formulation will depend on the severity of the
condition, and on the patient, to be treated, as well as the
compound(s) which is/are employed, but may be determined
non-inventively by the skilled person.
[0056] Suitable doses of thrombin inhibitors, prodrugs and
derivatives of either, in the therapeutic and/or prophylactic
treatment of mammalian, especially human, patients may be
determined routinely by the medical practitioner or other skilled
person, and include the respective doses discussed in the prior art
documents disclosing thrombin inhibitors that are mentioned
hereinbefore, the disclosures in which are hereby incorporated by
reference.
[0057] In the case of melagatran, suitable doses of active
compound, prodrugs and derivatives thereof, in the therapeutic
and/or prophylactic treatment of mammalian, especially human,
patients include those which give a mean plasma concentration of up
to 5 .mu.mol/L, for example in the range 0.001 to 5 .mu.mol/L over
the course of treatment of the relevant condition. Suitable doses
may thus be in the range 0.1 mg once daily to 25 mg three times
daily, and/or up to 100 mg infused parenterally over a 24 hour
period, for melagatran, and in the range 0.1 mg once daily to 100
mg three times daily for prodrugs of melagatran including those
specifically mentioned hereinbefore.
[0058] In any event, the physician, or the skilled person, will be
able to determine the actual dosage which will be most suitable for
an individual patient, which is likely to vary with the condition
that is to be treated, as well as the age, weight, sex and response
of the particular patient to be treated. The above-mentioned
dosages are exemplary of the average case; there can, of course, be
individual instances where higher or lower dosage ranges are
merited, and such are within the scope of this invention.
[0059] The sequence in which the formulations comprising thrombin
inhibitor, and prodrug, may be administered (i.e. whether, and at
what point, sequential, separate and/or simultaneous administration
takes place) may be determined by the physician or skilled person.
For example, the sequence may depend upon many factors that will be
evident to the skilled person, such as whether, at any time during
the course or period of treatment, one or other of the formulations
cannot be administered to the patient for practical reasons (e.g.
the patient is unconscious and thus unable to take an oral
formulation comprising either thrombin inhibitor or prodrug).
[0060] For example, in the treatment of thrombosis (e.g. DVT)
resulting from surgery, such as gastrointestinal, or orthopaedic,
surgery, and when the active thrombin inhibitor is melagatran, it
is preferred that the formulation comprising melagatran is
administered parenterally within two days (e.g. within 24 hours) of
surgery (either prior to or after surgery), and particularly
immediately prior to (e.g. within 2 hours), and/or within up to 12
hours after, surgery (e.g. at least one hour after surgery), and
thereafter for up to between 3 and 7 (e.g. between 0 and 2, such as
between 1 and 2) days after that surgery, and that the formulation
comprising prodrug is administered orally within 7 days following
that surgery (preferably once administration of melagatran has been
terminated) for up to e.g. between 11 and 40 days, preferably 9
days, more preferably up to 8 days.
[0061] The method described herein may have the advantage that, in
the treatment of conditions in which inhibition of thrombin is
required or desired, it may be more convenient for the physician
and/or patient than, be more efficacious than, be less toxic than,
have a broader range of activity than, be more potent than, produce
fewer side effects than, or that it may have other useful
pharmacological properties over, similar methods known in the prior
art for the treatment of such conditions.
[0062] The invention is illustrated, but in no way limited, by the
following example.
EXAMPLE 1
Clinical Trial--Melagatran and EtOOC--CH.sub.2--(R)Cgl-Aze-Pab-OH
Combination Therapy
[0063] A controlled, randomised, parallel group, Swedish
multi-centre pilot study was carried out. The study was open with
regard to the drugs under evaluation but was blind for the
patients, all personnel at the study sites, and for the person
monitoring the experiments with regard to the doses of melagatran
and the prodrug of melagatran, EtOOC--CH.sub.2--(R)Cgl-Aze-Pab-OH
(P; see WO 97/23499).
[0064] Dalteparin (Fragmin.RTM.; Pharmacia-Upjohn) was used as a
reference compound.
[0065] Patients scheduled for primary elective total hip or knee
replacement were eligible for inclusion, and were randomly selected
into one of three groups, each to receive different doses of
melagatran and P, or dalteparin. In all, 135 patients were included
in the study, of which 105 patients could be used for evaluation
with respect to thromboembolic events using central assessment of
locally performed phlebograms.
[0066] About 32 patients in each treatment group were evaluated
according to the protocol. A stratified randomisation, by centre
and type of surgery, was used to ensure that approximately equal
numbers of patients were given each of the drugs under evaluation
at all participating centres (in all six centres were used) for
both types of surgery (hip or knee). Each centre received study
drugs in blocks of four, separately for hips and knees. Within each
block, the order of the study drugs was randomised.
[0067] The following formulations were used in the study:
[0068] Melagatran--5, 10 or 20 mg/mL in aqueous saline
solution.
[0069] P--appropriate weight (see below) in a tablet also
comprising 59 to 63 mg corn starch, 115 mg microcrystalline
cellulose and 2 mg sodium stearyl fumarate.
[0070] The following doses of melagatran and P were used in the
study:
[0071] Treatment A--s.c. melagatran (1 mg) b.i.d. for 2 days,
followed by oral administration of P (6 mg) b.i.d. for 6 to 9
days.
[0072] Treatment B--s.c. melagatran (2 mg) b.i.d. for 2 days,
followed by an oral administration of P (12 mg) b.i.d. for 6 to 9
days.
[0073] Treatment C--s.c. melagatran (4 mg) b.i.d. for 2 days,
followed by an oral administration of P (24 mg) b.i.d. for 6 to 9
days.
[0074] The patients receiving melagatran and P received treatment
on the day of surgery. The patient received the first injection
after induction of anaesthesia immediately before surgery. For
knee-patients, the pre-operative melagatran injection was given
before tourniquets were applied. The second injection was given in
the evening the same day. The patient received one melagatran
injection in the morning and one in the evening over the next 24
hours, until oral administration of P, twice daily, started. The
first oral dose of P was always taken in the morning. Thus, the
total treatment period was between 8 and 11 days.
[0075] Treatment D--dalteparin (Fragmin.RTM.): one s.c. injection
of 5000 U during the evening of the day before surgery, continuing
with one s.c. injection every evening over a treatment period of 8
to 11 days.
[0076] The plasma concentrations of melagatran were recorded.
[0077] The results of the trial, in terms of the frequencies of
thromboembolism after hip or knee surgery, are tabulated below:
TABLE-US-00001 Treatment Treatment Treatment Treatment A B C D (n)
(%) (n) (%) (n) (%) (n) (%) Outcome 6/29 21 6/24 25 4/24 16 5/27
19
[0078] These data show that a combination of subcutaneously
administered melagatran and orally administered P is effective in
preventing DVT after orthopaedic surgery.
* * * * *