U.S. patent application number 10/140682 was filed with the patent office on 2002-10-31 for pharmaceutical combination preparations containing erythropoietin and modified haemoglobins.
Invention is credited to Feuerstein, Jurgen, Lehmann, Paul, Town, Michael Harold.
Application Number | 20020160956 10/140682 |
Document ID | / |
Family ID | 8226937 |
Filed Date | 2002-10-31 |
United States Patent
Application |
20020160956 |
Kind Code |
A1 |
Lehmann, Paul ; et
al. |
October 31, 2002 |
Pharmaceutical combination preparations containing erythropoietin
and modified haemoglobins
Abstract
The invention is concerned with pharmaceutical combination
preparations containing erythropoietin preparations and one or more
modified haemoglobins. The combination preparations are especially
useful for the treatment of manifest anaemias.
Inventors: |
Lehmann, Paul; (Worms,
DE) ; Feuerstein, Jurgen; (Ladenburg, DE) ;
Town, Michael Harold; (Oberhausen, DE) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.
PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
|
Family ID: |
8226937 |
Appl. No.: |
10/140682 |
Filed: |
May 8, 2002 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10140682 |
May 8, 2002 |
|
|
|
09446378 |
Feb 7, 2000 |
|
|
|
6440932 |
|
|
|
|
Current U.S.
Class: |
514/7.7 ;
514/13.4; 514/5.4 |
Current CPC
Class: |
A61K 38/42 20130101;
A61P 7/06 20180101; A61P 43/00 20180101; A61K 38/42 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
514/12 ;
514/6 |
International
Class: |
A61K 038/22 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 21, 1997 |
EP |
97110168.8 |
Jun 3, 1998 |
EP |
PCT/EP98/03299 |
Claims
1. Pharmaceutical combination preparation comprising a) individual
administration forms of an erythropoietin preparation suitable for
the individual dosing of the active substance in an amount of
3,000-7,000 U, and b) 50-100 ml of one or more modified
haemoglobins.
2. Combination preparation according to claim 1, characterized in
that it contains 3,000-7,000 U of an erythropoietin preparation and
80-100 ml of modified haemoglobin.
3. Combination preparation according to claim 1 or 2, characterized
in that it contains 5,000-7,000 U of an erythropoietin preparation
and 80-100 ml of modified haemoglobin.
4. Combination preparation according to any one of claims 1-3,
characterized in that it contains 6,000-7,000 U of an
erythropoietin preparation and about 100 ml of modified
haemoglobin.
5. Combination preparation according to claim 1, characterized in
that it contains 3,000-5,000 U of an erythropoietin preparation and
80-100 ml, preferably 85-95 ml, of modified haemoglobin.
6. Combination preparation according to claim 1 for the treatment
of manifest anaemias.
7. Combination preparation according to any one of claims 1 to 4
for the treatment of manifest anaemias with iron utilization
disorders.
8. Combination preparation according to claim 5 for the treatment
of manifest anaemias without iron utilization disorders.
9. Process for the production of pharmaceutical combination
preparations according to claims 1 to 8, characterized by
formulating 3,000-7,000 U of an erythropoietin preparation in the
form of individual administration forms and 50-100 ml of modified
haemoglobin together or separately from each another with
pharmaceutically usual carriers or adjuvants and making the
respective preparations available in the form of combination
preparations.
10. Use of erythropoietin preparations with 3,000-7,000 U of EPO
and 50-100 ml of one or more modified haemoglobins for the
production of a pharmaceutical combination preparation for the
treatment of manifest anaemias.
11. Use of erythropoietin preparations with 5,000-7,000 U of EPO
and 80-100 ml of one or more modified haemoglobins for the
production of a pharmaceutical combination preparation for the
treatment of manifest anaemias with iron utilization disorders.
12. Use of erythropoietin preparations with 3,000-5,000 U of EPO
and 80-100 ml of one or more modified haemoglobins for the
production of a pharmaceutical combination preparation for the
treatment of manifest anaemias without iron utilization
disorders.
13. Pharmaceutical unit pack comprising 3,000-7,000 U of an
erythropoietin preparation in individual administration forms and
50-100 ml of one or more modified haemoglobins as a single
administration form in one container or as separate administration
forms in separate containers.
14. Unit pack according to claim 13, characterized in that in each
case the erythropoietin preparation and the modified haemoglobin
are present in separate administration forms in the form of
solutions for injection or infusion purposes.
Description
DESCRIPTION OF THE INVENTION
[0001] The invention is concerned with pharmaceutical combination
preparations containing erythropoietin preparations and one or more
modified haemoglobins. The combination preparations are especially
useful for the treatment of manifest anaemias.
[0002] The object of the present invention is a pharmaceutical
combination preparation which comprises a) individual
administration forms of an erythropoietin preparation suitable for
the individual dosing of the active substance in an amount of
3,000-7,000 U and b) 50-100 ml of one or more modified
haemoglobins, with the erythropoietin preparation and modified
haemoglobin being present in separate administration forms or in a
single administration form.
[0003] The macromolecule ferritin (molecular weight at least 440 kD
depending on the iron content) plays a significant role in the
diagnosis of anaemias. An estimation of the fullness level of the
iron reservoir is possible by determining the ferritin and the
transferrin saturation (M. Wick, W. Pingerra, P. Lehmann "Ferritin
in iron metabolism and diagnosis of anaemias", pages 5-22, 38-50,
65-77, 94-97, 2.sup.nd expanded edition 1994, published by Springer
Vienna, New York), with the totality of the iron stored as basic
ferritin in the depot organs liver, spleen and bone marrow
amounting to about 800-1200 mg. A lower ferritin concentration is
the definitive characteristic for detecting iron deficiency states
and their difference from other causes of hypochromic anaemia, such
as e.g. chronic inflammations and tumours.
[0004] It is known to treat transfusion-mediated anaemias in
haemodialysis patients with recombinant erythropoietin (rhEPO),
with it being necessary as a rule to carry out an iron substitution
in parallel to the EPO therapy. This iron substitution is effected
by the intravenous administration of iron(III) salts, with two
intravenously administerable iron preparations being available on
the German medicament market at present. These are the medicaments
"Ferrlecit" and "Ferrum Vites". "Ferrlecit" is an iron(III)
gluconate complex, while "Ferrum Vites" is an iron(III) oxide
saccharate complex.
[0005] It has, however, become evident that in the case of manifest
anaemias with manifest iron deficiency and iron utilization
disorders (<30 mg/dl ferritin) iron substitution with the
mentioned preparations has disadvantages, since for the treatment
of manifest anaemias relatively large amounts of a
pharmacologically harmless iron salt have to be infused. The use of
the aforementioned iron preparations holds the possibility of
unexpected circulatory reactions up to collapse, especially when
large amounts have to be injected relatively rapidly.
[0006] In WO 96/15805 there is described a haemoglobin therapy for
haemodialysis according to which very low doses of stroma-free
haemoglobin are administered over a period of 10 to 45 minutes in
order to achieve a haemostabilization and to avoid a lowering of
blood pressure in sensitive patients. However, this described
therapy is not successful in the case of manifest iron deficiency
anaemias.
[0007] Also, WO 95/24213 describes the use of natural or
recombinant haemoglobin or their chemically modified derivatives
for anaemia treatment. Furthermore, this document discloses the
combined administration of one of the aforementioned haemoglobins
with one or more haematopoietic growth factors, inter alia with
EPO. Examples 4 and 5 as well as some of the Figures show that a
combined administration of EPO and rh haemoglobin lead to an
increased haematopoesis.
[0008] However, this document does not disclose a practical
therapeutic regime for an optimal regulation and treatment of
patients with manifest anaemias. Also, it is not evident therefrom,
as in the case of patients treated with EPO, that it is possible to
produce an optimal EPO effect without avoiding an EPO
resistance.
[0009] It has now been found that the use of relatively high
infusion amounts of 50-100 ml of haemoglobin (about 100-200 mg
Fe.sup.2+) together with 3,000-7,000 U of EPO is surprisingly
advantageous for the treatment of manifest anaemias (the
abbreviation "IU" can also be used in place of the abbreviation "U"
for International Units).
[0010] The object of the invention are accordingly also combination
preparations which contain 3,000-7,000 U of EPO and 50-100 ml of
one or more modified haemoglobins, with the EPO and the modified
haemoglobin being present in separate administration forms or in a
single administration form.
[0011] In accordance with the invention 3,000-7,000 U of an
erythropoietin preparation and 50-100 ml of one or more modified
haemoglobins are used as the optimal dose depending on the clinical
picture of the anaemia. Thus, in the case of manifest anaemias
without iron distribution disorders, a high dose of Fe.sup.2+,
about 80-100 ml (about 160-200 mg Fe.sup.2+), preferably 85-95 ml,
in the form of a modified haemoglobin and a lower dose of EPO
between 3,000 and 5,000 U is administered in accordance with the
invention.
[0012] When there are iron distribution disorders in the case of
manifest anaemias, a higher EPO dose of about 5,000-7,000 U of EPO,
preferably 6,000-7,000 U, especially about 7,000 U of EPO, and a
high Fe.sup.2+ dose, about 80-100 ml, preferably about 100 ml, in
the form of one or more modified haemoglobins is preferably
administered.
[0013] For the treatment of iron utilization disorders in the case
of manifest anaemias the combination preparation in accordance with
the invention preferably contains 3,000-7,000 U of EPO and 80-100
ml of a modified haemoglobin, preferably about 5,000 U of EPO, and
about 100 ml of one or more modified haemoglobins. For the
treatment of manifest iron deficiency anaemias the combination
preparation likewise preferably contains 3,000-7,000 U of EPO and
80-100 ml of a modified haemoglobin.
[0014] As modified haemoglobins in the meaning of the invention
there are suitable in principle all haemoglobins described in WO
95/24213 page 20, line 15 to page 27, line 2. In particular, these
are also cross-linked haemoglobins or cross-linked haemoglobin
polymerizates, such as e.g. diacetylsalicylic acid (diaspirin),
cross-linked haemoglobin (DCL-Hb) or other blood substitutes based
on modified haemoglobins. For example, the following preparations
come into consideration as modified haemoglobins: Hem Assist.RTM.
(Baxter; DCL human Hb); PolyHeme.RTM. (Northfield, Upjohn, human
Hb, cross-linked and polymerized); Hemopure.RTM. (Biopure, Upjohn;
bovine Hb, polymerized); Optro.RTM. (Somatogen, Eli Lilly;
recombinant human Hb); HemOlink.RTM. (Hemosol, Fresenius; human Hb,
cross-linked and polymerized); PEG-modified bovine Hb (manufactured
by Enzon; polyethylene glycol-modified Hb);
polyoxyethylene-modified human Hb (manufactures Apex and
Ajinimoto). The haemoglobins can also be used in accordance with
the invention in the form of haemoglobin preparations which contain
pharmaceutically compatible adjuvants known per se. Such
preparations are described, for example, in WO 95/24213.
[0015] As suitable erythropoietin preparations in the meaning of
the present invention there come into consideration those active
substances which are comparable with respect to the physiological
effect of human EPOs. Suitable EPO preparations are, for example,
recombinant human EPO (rhEPO; see European Patent EP 0,205,564 or
EP 0,411,678) or also corresponding modifications of these
proteins. As modifications there come into consideration, for
example, such proteins with molecular weights higher or lower than
34,000 Da (molecular weight of urinary EPO), likewise isoforms of
the enzyme or proteins with different glycosylation. In particular,
proteins chemically modified by PEG (polyethylene glycol) can also
be used. Further, there basically also come into consideration such
proteins which are derived by deletions, substitutions or additions
from the amino acid sequence of the natural EPO with a length of
166 amino acids. These proteins have essentially comparable
physiological properties to rhEPO. In particular, these proteins
have biological properties which cause bone marrow cells to
increase the production of reticulocytes and red blood corpuscles
and/or to increase haemoglobin synthesis or iron uptake. In place
of these proteins there can also be used low molecular substances,
which are denoted as EPO mimetics, and which bind to the same
biological receptor. These mimetics can preferably also be
administered orally. The amount of such proteins or mimetics to be
administered is determined by comparing the biological activity
between EPO and these active substances.
[0016] The concentrations in accordance with the invention of EPO
and haemoglobin-Fe.sup.2+ permit in their combination an optimal
anaemia treatment, especially the treatment of manifest anaemias.
The treatment with the combination preparation is preferably
effected once weekly, whereby the amount of haemoglobin of 300 ml
per week should not be exceeded (e.g. 3.times.100 ml
infusions).
[0017] In the meaning of the present invention there should be
understood under the term "combination preparation" not only those
medicament packs in which the EPO preparation and the haemoglobin
are presented in juxtaposition in a finished marketable unit pack
(so-called combination pack), but also those medicament packs which
either contain a suitable amount of an EPO preparation or a
suitable amount of a haemoglobin in the form of the respective
individual preparations, with the individual preparations with
respect to the amount of contents being presented such that they
can be administered in the meaning of the invention for the
combined dose with the respective other preparation. In these cases
there is usually enclosed with the preparations from the
pharmaceutical manufacturer or the medicament importer a medicament
package insert which is required by law in many countries and in
which are contained directions or information concerning the
combined dose of the individual preparations.
[0018] The combination preparations can preferably be present in a
single administration form in which the respective amounts of the
EPO preparation and the haemoglobin are present in juxtaposition in
one container.
[0019] This can be e.g. an injection solution or infusion solution
or its lyophilizate, which, for example, is filled into ampoules.
This administration form has the advantage that the EPO is
stabilized by the modified haemoglobin during the production and
storage of the administration form. In the case of a lyophilizate,
the EPO, after its dissolution, is activated by the modified
haemoglobin. The fixed combination of the two active substances in
the form of a lyophilizate has the further advantage that it can be
handled simply and safely. The lyophilizate is dissolved in the
ampoule by the addition of pharmaceutically usual injection media
and is administered intravenously.
[0020] It is also possible to administer the EPO preparation and
the modified haemoglobin in the form of separate pharmaceutical
formulations (free combination) simultaneously or, however, also in
succession. This free combination, which can be made available in a
unit pack, has the advantage of greater flexibility. Thus, these
administration forms also enable the modified haemoglobins to be
administered 1-3 days prior to the EPO administration.
[0021] This free combination, which can be made available in a
single unit pack (medicament pack) also has the advantage that each
patient to be treated can be prescribed a particular individual
amount of an EPO preparation and of a haemoglobin. Furthermore,
these combination preparations offer the advantage of greater
safety when performing the therapy, since in each case the optimal
synchronized amount of the individual preparation is fixed. A safe
therapy and simple handling by the personnel performing the
treatment or in the area of self medication performed by patients
is guaranteed by the combination preparation in accordance with the
invention.
[0022] Where the EPO preparation is made available as a
lyophilizate, the medicament packs (combination packs) contain the
corresponding amount of the EPO preparation in glass ampoules or in
cartridges. The haemoglobin can be present in solid form
(lyophilizate) or also in liquid form in a separate container.
Further, the combination pack preferably contains a reconstitution
solution in order to dissolve either the EPO lyophilizate alone or
also together with the haemoglobin. If the haemoglobin is present
as a ready-for-use solution, the solution can be mixed together
with the EPO solution when the combined administration of EPO and
haemoglobin has to be effected. Basically, the haemoglobin can also
be made available as a concentrate for addition to conventional
infusion solutions, by which means a longer administration over
several hours can be effected.
[0023] Combination preparations in the meaning of the present
invention are also those unit packs which in each case make
available individual administration forms of the erythropoietin
preparation or of the haemoglobin as independent medicaments, with
the individual preparations being provided such that they contain
the requisite amounts of the individual substances for the
combination in accordance with the invention of the EPO preparation
and the hemoglobin. As a rule, the medicament packs contain the
previously described package insert containing corresponding
instructions for the combined administration with EPO or with
haemoglobin in the required amount. A corresponding instruction can
also be present as a pack imprint on the medicament pack (secondary
packaging) or on the primary packaging (ampoule, blister strips,
etc.). Thus, in the case of the EPO-containing medicament with
3,000-7,000 U of EPO it is, for example, indicated thereon that
this preparation should especially be administered together with a
haemoglobin preparation containing 50-100 ml of one or more
modified haemoglobins. In the case of the haemoglobin preparation
there is a reverse indication to the combined administration with
3,000-7,000 U of an erythropoietin preparation.
[0024] A further possibility for providing the EPO preparation
comprises making available corresponding multi-dose preparations
which contain the EPO preparation in higher amounts compared with
individual doses. These preparations are especially suitable for
use in clinics in which a large number of patients are treated
daily. These multi-dose preparations contain the EPO preparation in
dosages of up to 500,000 U, especially up to 100,000 or 50,000 U.
The multi-dose preparations have the advantage that they permit the
skilled medical personnel to withdraw any dosage of the EPO
preparation, for example by withdrawing corresponding amounts by
volume of the finished injection solution. This is especially
advantageous in the treatment of patients with different dosage
requirements of the active substance or in the treatment of
children in which a lower dosage of the EPO preparation is
required. From an injection solution of, for example, 100,000 U of
EPO, preferably freshly prepared at the beginning of the day, there
can be performed, circumstances permitting, all patient treatments
required during this day without the need to prepare separate
injection solutions for each of the individual patients. This can
lead to a significant time saving or to an easing of the burden of
work for skilled medical personnel. Preferably, the individual EPO
dosages are withdrawn in the range of 3,000 U, 5,000 U and 7,000
U.
[0025] The multi-dose preparations can also be present in the form
of solutions, which are filled into cartridges. These cartridges
are suitable for use in so-called pens, which permit administration
by patients themselves and an individual dosage withdrawal. For
example, these cartridges contain the EPO preparation in an amount
of 10,000 or 20,000 U, whereby different dosing intervals can be
realized by appropriate adjustment of the withdrawal volume.
[0026] The production of the pharmaceutical administration forms of
the invention is effected according usual processes known in
galenical technology with pharmaceutically usual adjuvants. The
process for the production of the pharmaceutical combination
preparation in accordance with the invention and the pharmaceutical
unit pack, which contains the combination of preparations in
accordance with the invention, are likewise objects of the
invention.
[0027] In carrying out the therapy, the diagnostic parameters
ferritin and transferrin saturation have to be controlled. The
ferritin value is in the normal range when it amounts to 400
.mu.g/l.+-.50%. The transferrin saturation should amount to
20-40%.
[0028] The invention will be illustrated hereinafter in more detail
on the basis of working Examples.
EXAMPLE 1
[0029] Patients with manifest iron deficiency (ferritin<12
ng/ml, transferrin saturation<15% and haemoglobin<12 g/dl)
are given by infusion 5,000 U of rhEPO once per week and 100 ml of
a modified haemoglobin preparation, preferably DCL-Hb, three times
per week. This treatment is repeated for a further five weeks until
the values for ferritin, transferrin saturation and haemoglobin or
haemocrit lie in the normal range.
* * * * *