U.S. patent application number 13/701228 was filed with the patent office on 2013-08-15 for oral dosage forms of bendamustine and therapeutic use thereof.
This patent application is currently assigned to ASTELLAS DEUTSCHLAND GMBH. The applicant listed for this patent is Taoufik Ouatas, Ulrich Patzak. Invention is credited to Taoufik Ouatas, Ulrich Patzak.
Application Number | 20130209558 13/701228 |
Document ID | / |
Family ID | 44261747 |
Filed Date | 2013-08-15 |
United States Patent
Application |
20130209558 |
Kind Code |
A1 |
Patzak; Ulrich ; et
al. |
August 15, 2013 |
Oral Dosage Forms of Bendamustine and Therapeutic Use Thereof
Abstract
In the present invention there is provided a pharmaceutical
composition for oral administration which comprises bendamustine or
a pharmaceutically acceptable, ester, salt or solvate thereof as an
active ingredient, and a pharmaceutically acceptable excipient and
which shows a dissolution of the bendamustine of at least 60% in 20
minutes, 70% in 40 minutes and 80% in 60 minutes, as measured with
a paddle apparatus at 50 rpm according to the European
Pharmacopoeia in 500 ml of a dissolution medium at a pH of 1.5, and
wherein the pharmaceutically acceptable excipient is either a
pharmaceutically acceptable non-ionic surfactant, selected from the
group consisting of a polyethoxylated castor oil or derivative
thereof and a block copolymer of ethylene oxide and propylene oxide
or a pharmaceutically acceptable saccharide selected from the group
consisting of one or more of a monosaccharide, a disaccharide, an
oligosaccharide, a cyclic oligosaccharide, a polysaccharide and a
saccharide alcohol, wherein the ratio by weight of the active
ingredient to the saccharide excipient(s) is in the range of 1:1-5.
The invention further relates to the above pharmaceutical
composition for use for the oral treatment of a medical condition
which is selected from chronic lymphocytic leukemia, acute
lymphocytic leukaemia, chronic myelocytic leukaemia, acute
myelocytic leukaemia, Hodgkin's disease, non-Hodgkin's lymphoma,
multiple myeloma, breast cancer, ovarian cancer, small cell lung
cancer and non-small cell lung cancer. The invention moreover
relates to the above pharmaceutical composition for the above use
wherein the dosage regimen comprises at least the administration of
a dose of 100 to 600 mg/m2/per person of bendamustine on day 1 and
day 2, optionally a dose of 50 to 150 mg/m.sup.2 i.v. or orally of
a corticosteroid on days 1 to 5, and optionally a suitable dose of
a further active agent selected from the group consisting of an
antibody specific for CD20, an anthracyclin derivative, a vinca
alkaloid or a platin derivative; and the repetition of said dosage
regimen 4 to 15 times after intervals of two to four weeks.
Inventors: |
Patzak; Ulrich; (EW
Leiderdorp, NL) ; Ouatas; Taoufik; (AC Leiderdorp,
NL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Patzak; Ulrich
Ouatas; Taoufik |
EW Leiderdorp
AC Leiderdorp |
|
NL
NL |
|
|
Assignee: |
ASTELLAS DEUTSCHLAND GMBH
Munchen
DE
|
Family ID: |
44261747 |
Appl. No.: |
13/701228 |
Filed: |
June 1, 2011 |
PCT Filed: |
June 1, 2011 |
PCT NO: |
PCT/EP2011/002763 |
371 Date: |
February 7, 2013 |
Current U.S.
Class: |
424/465 ;
424/172.1; 424/490; 424/649; 514/171; 514/283; 514/34; 514/394 |
Current CPC
Class: |
A61K 47/10 20130101;
A61K 9/145 20130101; A61K 31/573 20130101; A61K 9/4866 20130101;
A61P 35/02 20180101; A61K 9/1623 20130101; A61K 9/2846 20130101;
A61K 39/39558 20130101; A61K 9/4808 20130101; A61K 9/485 20130101;
A61P 35/00 20180101; A61K 9/4825 20130101; A61K 9/2072 20130101;
A61K 9/4858 20130101; A61K 31/475 20130101; A61K 31/4184 20130101;
A61K 45/06 20130101; A61K 9/2018 20130101 |
Class at
Publication: |
424/465 ;
514/394; 424/490; 424/172.1; 514/34; 514/283; 424/649; 514/171 |
International
Class: |
A61K 31/4184 20060101
A61K031/4184; A61K 45/06 20060101 A61K045/06 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 2, 2010 |
EP |
10005762.9 |
Mar 14, 2011 |
EP |
11075046.0 |
Claims
1. A pharmaceutical composition for oral administration which
comprises bendamustine or a pharmaceutically acceptable, ester,
salt or solvate thereof as an active ingredient, and a
pharmaceutically acceptable excipient and which shows a dissolution
of the bendamustine of at least 60% in 20 minutes, 70% in 40
minutes and 80% in 60 minutes, as measured with a paddle apparatus
at 50 rpm according to the European Pharmacopoeia in 500 ml of a
dissolution medium at a pH of 1.5, and wherein the pharmaceutically
acceptable excipient is either a pharmaceutically acceptable
non-ionic surfactant, selected from the group consisting of a
polyethoxylated castor oil or derivative thereof and a block
copolymer of ethylene oxide and propylene oxide or a
pharmaceutically acceptable saccharide selected from the group
consisting of one or more of a monosaccharide, a disaccharide, an
oligosaccharide, a cyclic oligosaccharide, a polysaccharide and a
saccharide alcohol, wherein the ratio by weight of the active
ingredient to the saccharide excipient(s) is in the range of
1:1-5.
2. The pharmaceutical composition according to claim 1,
characterised in that the active ingredient is bendamustine
hydrochloride.
3. The pharmaceutical composition according to claim 1,
characterised in that it comprises 10 to 1000 mg, preferably 25 to
600 mg, more preferably 50 to 200 mg and most preferably about 100
mg of the active ingredient.
4. The pharmaceutical composition according to claim 1,
characterised in that the polyoxyethylated castor oil or derivative
thereof is macrogol glycerol hydroxystearate.
5. The pharmaceutical composition according to claim 1,
characterised in that the polyoxyethylated castor oil or derivative
thereof is polyoxyl-35 castor oil.
6. The pharmaceutical composition according to claim 1,
characterised in that the block copolymer of ethylene oxide and
propylene oxide is ethylene oxide/propylene oxide block copolymer
(Pluronic.RTM. L44 NF or Poloxamer.RTM. 124).
7. The pharmaceutical composition according to claim 1,
characterised in that the pharmaceutically acceptable excipient is
a pharmaceutically acceptable non-ionic surfactant and that it
further comprises colloidal silicon dioxide.
8. The pharmaceutical composition according to claim 1,
characterised in that it further comprises lauroyl macrogol
glycerides (Gelucire.RTM. 44/14).
9. The pharmaceutical composition according to claim 1,
characterised in that the excipient is a pharmaceutically
acceptable non-ionic surfactant and the composition is in a hard
gelatine capsule.
10. The pharmaceutical composition of claim 1, wherein the
excipient is a pharmaceutically acceptable saccharide and the
composition is in a solid dosage form.
11. The pharmaceutical composition of claim 10, wherein the ratio
by weight of the active ingredient to the saccharide is 1:2-5.
12. The pharmaceutical composition according to claim 10, which is
in the form of a tablet, a granulate, or a pill.
13. The pharmaceutical composition according to claim 10, wherein
the tablet or tablet granules, the granulate or the pill are
provided with a coating.
14. The pharmaceutical composition according to claim 10, which
comprises 10 to 1000 mg of the active ingredient and 30 to 5000 mg
of the saccharide excipient.
15. The pharmaceutical composition according to claim 10, wherein
the saccharide excipient is selected from mannitol, maltitol,
erythritol, xylitol, lactose, sucrose, glucose, sorbitol, maltose,
trehalose, lactitol, dextrose and fructose.
16. The pharmaceutical composition according to claim 10, wherein
the saccharide excipient is selected from dextrose anhydrous,
dextrose monohydrate, lactitol monohydrate, trehalose, sorbitol,
erythritol, maltose monohydrate, mannitol, lactose anhydrous,
lactose monohydrate, maltitol, xylitol, sucrose, sucrose
97%+maltodextrin 3%, .beta.-cyclodextrin, D-raffinose pentahydrate,
D-melezitose monohydrate and microcrystalline cellulose.
17. The pharmaceutical composition according to claim 10, which
further comprises a pharmaceutically acceptable lubricant, filler
and/or disintegrant.
18. A method of oral treatment of a medical condition which is
selected from chronic lymphocytic leukemia, acute lymphocytic
leukaemia, chronic myelocytic leukaemia, acute myelocytic
leukaemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple
myeloma, breast cancer, ovarian cancer, small cell lung cancer and
non-small cell lung cancer in a person comprising oral
administration of the pharmaceutical composition of claim 1 to the
person.
19. The method according to claim 18 wherein the pharmaceutical
composition is administered in combination with at least one
further active agent, wherein said at least one further active
agent is administered prior, concurrently, or subsequently to the
pharmaceutical composition and is selected from the group
consisting of an antibody specific for CD20, an anthracyclin
derivative, a vinca alkaloid or a platin derivative.
20. The method according to claim 19, characterised in that the
antibody specific for CD20 is rituximab; the anthracyclin
derivative is doxorubicin or daunorubicin; the vinca alkaloid is
vincristine and the platin derivative is cisplatin or
carboplatin.
21. The method according to claim 18 wherein the pharmaceutical
composition is administered in combination with at least one
corticosteroid, wherein said use of the corticosteroid is prior,
concurrently, or subsequently to the use of the pharmaceutical
composition.
22. The method according to claim 21, characterised in that the
corticosteroid is prednisone or prednisolone.
23. The method according to claim 18, wherein the active ingredient
is administered in a dose between 50 mg to 1000 mg/m.sup.2/per
person per therapeutic cycle.
24. The method according to claim 18 wherein the dosage regimen
comprises at least the administration of a dose of 100 to 600
mg/m.sup.2/per person of bendamustine on day 1 and day 2,
optionally a dose of 50 to 150 mg/m.sup.2 i.v. or orally of a
corticosteroid on days 1 to 5, and optionally a suitable dose of a
further active agent selected from the group consisting of an
antibody specific for CD20, an anthracyclin derivative, a vinca
alkaloid or a platin derivative; and the repetition of said dosage
regimen 4 to 15 times after intervals of two to four weeks.
25. The method according to claim 18, wherein the active ingredient
bendamustine is administered in a dosage regimen selected from
200-300 mg on day 1 and day 2, optionally followed by a maintenance
dose of 50 mg once a day, 50 mg each day from day 1 up till and
including day 14, or 150 mg once a week for 3 weeks.
26. The method according to claim 18, wherein the person is one
having non-Hodgkin's lymphoma and the dosage regimen comprises
administering a total amount of 200 mg/person/day of active
ingredient bendamustine on days 1 to 5, 2 mg i.v. of vincristine on
day 1 and 100 mg/m.sup.2 i.v. of prednisone on days 1 to 5 and
repeating said treatment every three weeks until the non-Hodgkin's
lymphoma has improved.
27. The method according to claim 18, wherein the person is one
having multiple myeloma and the dosage regimen comprises
administering an amount of 100-250, preferably 174 to 217
mg/m.sup.2 body surface area bendamustine hydrochloride on days 1
and 2, 60 mg/m.sup.2 i.v. or orally of prednisone on days 1 to 4
and repeating said treatment every four weeks until the multiple
myeloma has improved.
28. The method according to claim 18, wherein the person is one
having chronic lymphocytic leukaemia and the dosage regimen
comprises administering an amount of 100 to 200, preferably 145
mg/m.sup.2 body surface area bendamustine hydrochloride on days 1
and 2 and 60 mg/m.sup.2 i.v. or orally of prednisone on days 1 to 4
and repeating said treatment every four weeks until the chronic
lymphocytic leukaemia has improved.
29. The method according to claim 18, wherein the person is one
having follicular, indolent or mantle cell lymphoma and the dosage
regimen comprises administering a dose of 375 mg/m.sup.2 rituximab
on day 1 plus 100 to 200, preferably 130 mg/m.sup.2 oral
bendamustine on days 1 and 2 every 28 days until the respective
lymphoma has improved.
Description
[0001] The present invention relates to oral dosage forms
comprising bendamustine or a pharmaceutically acceptable ester,
salt or solvate thereof and therapeutic use thereof.
BACKGROUND OF THE INVENTION
[0002] Bendamustine
(4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazo-2-yl]butanoic
acid, a nitrogen mustard) is an alkylating agent with bifunctional
alkylating activity. It corresponds to the following formula
(I):
##STR00001##
Bendamustine appears to be free of any cross-resistance with other
alkylating agents, which offers advantages in terms of chemotherapy
for patients who have already received treatment with an alkylating
agent.
[0003] Bendamustine was initially synthesized in the German
Democratic Republic (GDR). The hydrochloric acid of bendamustine
was the active ingredient in a commercial product available from
1971 to 1992 under the trade name Cytostasan.RTM.. Since that time,
it has been marketed in Germany under the trade name
Ribomustin.RTM. and has been widely used to treat chronic
lymphocytic leukemia, non-Hodgkin's lymphoma and multiple
myeloma.
[0004] The marketed product contains a lyophilized powder of
bendamustine hydrochloride which is reconstituted with water for
injection yielding a concentrate. This is subsequently diluted with
an aqueous solution of 0.9% sodium chloride resulting in the final
solution for infusion. This final solution is administered to the
patient by intravenous infusion over a period of about 30 to 60
minutes.
[0005] Hydrolysis of the bis-2-chloroethylamino-group of
bendamustine in water leads to reduction in potency and to impurity
formation (B. Maas et al. (1994) in Pharmazie 49: 775-777). Hence
administration, usually in a hospital or at least under medical
supervision, must occur immediately after reconstitution of the
lyophilized powder. Furthermore, reconstitution has been reported
to be difficult. It may require more than 30 minutes. Further, it
is burdensome and time-consuming for the healthcare professionals
responsible for reconstituting the product in the 2 step
process.
[0006] Preiss et al. (1985) in Pharmazie 40:782-784 compared the
pharmacokinetics of bendamustine hydrochloride in plasma in 7
patients after intravenous and oral administration respectively in
a dose ranging between 4.2-5.5 mg/kg. The intravenous infusion
prepared from the commercially available Cytostasan.RTM. product
was given over 3 minutes, whereas oral medication in an equivalent
dose was taken in the form of capsules, containing 25 mg of
bendamustine hydrochloride. The number of capsules to be taken by
the patients varied from 10-14, referring to absolute oral doses of
250-350 mg. After oral administration maximal plasma levels were
detectable within 1 hour. The mean oral bioavailability was
calculated to be 57%, ranging from 25% to 94% indicating a large
inter-individual variability (% CV=44%). A similar study with an
even larger inter-individual variability (25-121%) was published in
a later document by Preiss et al. (Z. Klin. Med. 44 (1989):
125-129).
[0007] Weber (1991) (Pharmazie 46(8): 589-591) investigated the
bioavailability of bendamustine hydrochloride in B6D2F1-mice and
found that the absorption of the drug from the gastro-intestinal
tract is incomplete resulting in a bioavailability of about 40%
only.
[0008] US 2006/0128777 A1 describes methods for treating cancers,
characterised by death-resistant cells and bendamustine-containing
compositions in general. Amongst these compositions are oral dosage
forms, which are capsules, tablets, pills, powders or granules,
wherein the active compound may be admixed with at least one inert
excipient, such as sucrose, lactose or starch. However, specific
compositions were not exemplified.
[0009] Bendamustine hydrochloride is only sparingly soluble in
water at a pH of 2.0 and is slightly or very slightly soluble in a
range of organic solvents. A good solubility has been observed
however in ethanol and methanol. Therefore it is not surprising
that the oral bendamustine compositions, as investigated by Preiss
et al. and Weber gave rise to relatively poor bioavailability
results and a large inter-individual variability.
[0010] In view of the stability problems with the intravenous
marketed formulation, once reconstituted with water, and in order
to improve the patient compliance there has been a long-felt need
for a stable dosage-form comprising bendamustine which is easy to
administer to the patient and which provides good bioavailability
without large inter- and intra-individual variability. There is
also a need for a pharmaceutical composition from which the
bendamustine is absorbed completely or at least to a high extend in
the stomach, thereby avoiding or reducing the degradation of the
bendamustine in the small or large intestine.
SUMMARY OF THE INVENTION
[0011] In order to solve the above problems the present inventors
have carried out detailed investigations. They finally succeeded in
obtaining the stable pharmaceutical compositions according to the
invention. These compositions are suitable for oral administration
and comprise bendamustine or a pharmaceutically acceptable ester,
salt or solvate thereof as an active ingredient, and at least one
pharmaceutically acceptable excipient, which compositions apart
from having a good stability also have a good dissolution profile
in acidic media, a good bioavailability and a therapeutically
acceptable inter- and intraindividual variability.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 shows the mean plasma concentration vs. time curve
obtained after administering bendamustine hydrochloride in the form
of the prior art capsule (reference example 1) and the liquid
filled hard capsule formulation of Example 2 to dogs. It is
apparent from FIG. 1 that the liquid filled hard capsule
formulation provides for a higher maximum concentration of
bendamustine, as compared with the prior art reference capsule
formulation.
[0013] FIG. 2 shows the mean plasma vs. time profile obtained after
administering bendamustine hydrochloride in the form of the
intravenous preparation, as marketed in Germany under the trademark
Ribomustin.RTM., and the liquid filled hard capsule formulation of
example 2 to patients with cancer.
[0014] FIG. 3 shows the mean plasma concentration (tablets versus
capsule) vs. time curve obtained after administering bendamustine
hydrochloride in the form of prior art capsules and the tablet
formulations of Examples 15 to 17 (Tablets 1-3) and example 18
(formulation 3) (Tablet 4) to dogs. It is apparent from FIG. 3 that
the tablet formulations provide for higher maximum concentrations
of bendamustine, as compared to the prior art capsule.
[0015] FIG. 4 shows a flow sheet of wet granulation manufacturing
trials.
DETAILED DESCRIPTION OF THE INVENTION
[0016] The present invention relates to a pharmaceutical
composition for oral administration which comprises bendamustine or
a pharmaceutically acceptable, ester, salt or solvate thereof as an
active ingredient, and a pharmaceutically acceptable excipient and
which shows a dissolution of the bendamustine of at least 60% in 20
minutes, 70% in 40 minutes and 80% in 60 minutes, as measured with
a paddle apparatus at 50 rpm according to the European
Pharmacopoeia in 500 ml of a dissolution medium at a pH of 1.5, and
wherein the pharmaceutically acceptable excipient is either a
pharmaceutically acceptable non-ionic surfactant, selected from the
group consisting of a polyethoxylated castor oil or derivative
thereof and a block copolymer of ethylene oxide and propylene oxide
or a pharmaceutically acceptable saccharide selected from the group
consisting of one or more of a monosaccharide, a disaccharide, an
oligosaccharide, a cyclic oligosaccharide, a polysaccharide and a
saccharide alcohol, wherein the ratio by weight of the active
ingredient to the saccharide excipient(s) is in the range of
1:1-5.
[0017] In a first embodiment the present invention relates to a
pharmaceutical composition for oral administration, the composition
comprising bendamustine or a pharmaceutically acceptable, ester,
salt or solvate thereof as an active ingredient, and a
pharmaceutically acceptable excipient, which is a non-ionic
surfactant, selected from the group consisting of a polyethoxylated
castor oil or derivative thereof and a block copolymer of ethylene
oxide and propylene oxide.
[0018] An embodiment of the first embodiment of the invention is a
pharmaceutical composition, comprising bendamustine or a
pharmaceutically acceptable ester, salt or solvate thereof and a
pharmaceutically acceptable excipient, which is a non-ionic
surfactant, selected from the group consisting of a polyethoxylated
castor oil or derivative thereof and a block copolymer of ethylene
oxide and propylene oxide, wherein the composition is suitable for
oral administration by including it into a hard gelatine
capsule.
[0019] A further embodiment of the first embodiment of the
invention is a pharmaceutical composition for oral administration
in a solid dosage-form, which is a hard gelatine capsule, the
composition comprising bendamustine or a pharmaceutically
acceptable ester, salt or solvate thereof and a pharmaceutically
acceptable excipient, selected from the group consisting of a
polyethoxylated castor oil or derivative thereof and a block
copolymer of ethylene oxide and propylene oxide and preferably
selected from the group consisting of macrogol glycerol
hydroxystearate, polyoxyl-35-castor oil and ethylene
oxide/propylene oxide block copolymer (Pluronic.RTM. L44 NF or
Poloxamer.RTM. 124), wherein the use of the specific non-ionic
surfactant leads to a dissolution profile of at least 60%
bendamustine dissolved after 20 minutes, 70% dissolved after 40
minutes and 80% dissolved after 60 minutes, as measured with a
paddle apparatus at 50 rpm according to the European Pharmacopoeia
in 500 ml of a dissolution medium at a pH of 1.5 and preferably it
results in a dissolution of at least 60% bendamustine dissolved
after 10 minutes, 70% after 20 minutes and 80% after 30
minutes.
[0020] A preferred embodiment of the first embodiment is a
pharmaceutical composition for oral administration in a solid
dosage-form, which is a hard gelatine capsule, the composition
comprising bendamustine hydrochloride and a pharmaceutically
acceptable excipient, which is macrogol glycerol hydroxystearate,
wherein the use of the specific non-ionic surfactant results in a
dissolution of at least 60% bendamustine dissolved after 10
minutes, 70% after 20 minutes and 80% after 30 minutes, as measured
with a paddle apparatus at 50 rpm according to the European
Pharmacopoeia in 500 ml of a dissolution medium at a pH of 1.5.
[0021] In a second embodiment the present invention relates to a
pharmaceutical composition comprising bendamustine or a
pharmaceutically acceptable ester, salt or a solvate thereof as an
active ingredient and at least one pharmaceutically acceptable
excipient selected from monosaccharides, disaccharides,
oligosaccharides, cyclic oligosaccharides, a polysaccharide and
saccharide alcohols. Preferably, the ratio by weight between the
active ingredient and excipient is in the range of 1 to 1-5,
preferably 1 to 2-5, more preferably a ratio selected from 1:5 and
1:2.
[0022] In an embodiment of the second embodiment of the invention
the present invention relates to a pharmaceutical composition in a
solid dosage form for oral administration, the composition
comprising bendamustine or a pharmaceutically acceptable ester,
salt or solvate thereof as an active ingredient, and at least one
pharmaceutically acceptable excipient, which is a pharmaceutically
acceptable saccharide selected from the group consisting of one or
more of a monosaccharide, a disaccharide, an oligosaccharide, a
cyclic oligosaccharide, a polysaccharide and a saccharide alcohol,
wherein the ratio by weight of the active ingredient to the
excipient is in the range of 1:1.
[0023] In a further embodiment of the second embodiment of the
present invention relates to a pharmaceutical composition in a
solid dosage form suitable for oral administration, the composition
comprising bendamustine or pharmaceutically acceptable ester, salts
or solvates thereof as an active ingredient and at least one
pharmaceutically acceptable excipient which is a pharmaceutically
acceptable saccharide selected from the group consisting of one or
more of a monosaccharide, a disaccharide, an oligosaccharide, a
cyclic oligosaccharide, a polysaccharide and a saccharide alcohol,
wherein the ratio by weight of the active ingredient to the
saccharide excipient(s) is in the range of 1:2-5 and which
composition shows a dissolution of the bendamustine of at least 60%
in 20 minutes, 70% in 40 minutes and 80% in 60 minutes as measured
with a paddle apparatus at 50 rpm according to the European
Pharmacopoeia in 500 ml of a dissolution medium at a pH of 1.5.
[0024] Further preferred embodiments within the scope of the above
second embodiments are pharmaceutical compositions wherein the
pharmaceutically acceptable saccharide is selected from the group
consisting of one or more of a monosaccharide, a disaccharide and
an oligosaccharide, wherein the ratio by weight of the active
ingredient to the saccharide excipient(s) is in the range of 1:2-5
and which composition shows a dissolution of the bendamustine of at
least 60% in 20 minutes, 70% in 40 minutes and 80% in 60 minutes as
measured with a paddle apparatus at 50 rpm according to the
European Pharmacopoeia in 500 ml of a dissolution medium at a pH of
1.5.
[0025] The present invention is based on the surprising finding
that stable compositions of bendamustine having a specific and
desirable dissolution profile can be obtained by incorporating into
the pharmaceutical composition certain non-ionic surfactants or
certain saccharides or saccharide alcohols. It has been found that
if a pharmaceutically acceptable non-ionic surfactant, selected
from the group consisting of a polyethoxylated castor oil or
derivative thereof and a block copolymer of ethylene oxide and
propylene oxide and preferably selected from the group consisting
of macrogol glycerol hydroxystearate, polyoxyl-35-castor oil and
ethylene oxide/propylene oxide block copolymer (Pluronic.RTM. L44
NF or Poloxamer.RTM. 124) is used as an excipient in a
pharmaceutical composition comprising bendamustine or a
pharmaceutically acceptable ester, a salt or a solvate thereof as
an active ingredient, a particularly favourable profile of the
composition with respect to stability and degradation products,
dissolution, bioavailability and a reduced variability in
bioavailability is achieved. The incorporation of the
above-mentioned non-ionic surfactants in bendamustine-containing
compositions results in a dissolution profile of at least 60%
bendamustine dissolved after 20 minutes, 70% dissolved after 40
minutes and 80% dissolved after 60 minutes, as measured with a
paddle apparatus at 50 rpm according to the European Pharmacopoeia
in 500 ml of a dissolution medium at a pH of 1.5 and preferably it
results in a dissolution of at least 60% bendamustine dissolved
after 10 minutes, 70% after 20 minutes and 80% after 30
minutes.
[0026] It has further been found that if a pharmaceutically
acceptable saccharide selected from the group consisting of one or
more of a monosaccharide, a disaccharide, an oligosaccharide, a
cyclic oligosaccharide, a polysaccharide or a saccharide alcohol
and preferably selected from the group consisting of one or more of
a monosaccharide, a disaccharide and an oligosaccharide is used as
an excipient in a pharmaceutical composition comprising
bendamustine or pharmaceutically acceptable ester, salt or solvate
thereof as an active ingredient, a particularly favourable profile
of the composition as regards stability, tabletting properties,
dissolution and impurity formation is achieved. The above
saccharides result in a composition which shows a dissolution of
the bendamustine of at least 60% in 20 minutes, 70% in 40 minutes
and 80% in 60 minutes as measured with a paddle apparatus at 50 rpm
according to the European Pharmacopoeia in 500 ml of a dissolution
medium at a pH of 1.5.
[0027] Within the above scope of the second embodiment of the
invention, any combination of one or more of a monosaccharide, a
disaccharide, an oligosaccharide, a cyclic oligosaccharide, a
polysaccharide and a saccharide alcohol may be used.
[0028] It has particularly been found that particular saccharides
are associated with a particularly favourable profile of a
pharmaceutical composition as regards stability and dissolution.
Preferred saccharides of the composition according to the second
embodiment of the present invention are dextrose anhydrous,
dextrose monohydrate, lactitol monohydrate, trehalose, sorbitol,
erythritol, maltose monohydrate, mannitol, lactose anhydrous,
lactose monohydrate, maltitol, xylitol, sucrose, sucrose
97%+maltodextrin 3%, .beta.-cyclodextrin, D-raffinose pentahydrate,
D-melezitose monohydrate and microcrystalline cellulose. The
pharmaceutical compositions according to the present invention show
good tabletting characteristics, fast dissolution and a
pharmaceutically acceptable stability.
[0029] The above saccharides constitute preferred embodiments of
the second embodiment of the present invention and any combination
thereof may be used. Preferably, the ratio between the active
ingredient and the above saccharides is in the range of 1:1-5,
preferably 1:2-5 and more preferably a ratio selected from 1:5 and
1:2.
[0030] A further preferred embodiment of the second embodiment of
the invention is a pharmaceutical composition in a solid dosage
form for oral administration, the composition comprising
bendamustine or a pharmaceutically acceptable ester, salt or
solvate thereof as an active ingredient and at least one
pharmaceutically acceptable excipient selected from dextrose
anhydrous, dextrose monohydrate, lactitol monohydrate, trehalose,
sorbitol, erythritol, maltose monohydrate, mannitol, lactose
anhydrous, lactose monohydrate, maltitol, xylitol, sucrose, sucrose
97%+maltodextrin 3%, .beta.-cyclodextrin, D-raffinose pentahydrate,
D-melezitose monohydrate and microcrystalline cellulose and which
composition shows a dissolution of the bendamustine of at least 60%
in 10 minutes, 70% in 20 minutes and 80% in 30 minutes.
[0031] Particularly preferred saccharides are mannitol, maltitol,
erythritol, xylitol, lactose, sucrose, glucose, sorbitol, maltose,
trehalose, lactitol and dextrose (anhydrous or monohydrate) and the
weight ratio of the active ingredient to said saccharide is
preferably in the range of 1:2-5. Combinations of two or more
saccharides within the scope of the above saccharides are also
included within the present invention.
[0032] A person skilled in the art is well in a position to select
suitable combinations within the saccharide excipients mentioned
above and obtain a composition which shows a dissolution of
bendamustine of at least 60% in 20 minutes, 70% in 40 minutes and
80% in 60 minutes as measured with a paddle apparatus at 50 rpm
according to the European Pharmacopoeia in 500 ml of a dissolution
medium at a pH of 1.5.
[0033] In a preferred embodiment the composition is in the form of
a tablet, a granulate, or a pill.
[0034] A preferred dosage form is a tablet, preferably an immediate
release tablet, which means that the tablet releases the active
ingredient very fast after being placed in an aqueous medium,
preferably an acidic medium. The term tablet also comprises
fast-disintegrating tablets, amongst which are dispersible tablets
and effervescent tablets.
[0035] The most commonly used methods of tablet preparation are
direct compression, dry granulation and wet granulation. Direct
compression involves compressing a mixture containing the active
ingredient(s) and the excipient(s) on a tablet press (L. Lachman et
al., in: The Theory and Practice of Industrial Pharmacy, 3rd ed.,
1986). The mixture to be compressed must possess both good flow and
compression properties in order to produce tablets having a uniform
content of the active ingredient(s). Good flow properties cannot
always be achieved by adding appropriate excipients, such as
lubricants, anti-adhesive agents and flow-promoters to the mixture.
Hence frequently the mixture is granulated prior to
compression.
[0036] Granulation is a process by which sphere-like or regularly
shaped aggregates called granules are formed out of the powder
mixture. This can be achieved by dry granulation methods and wet
granulation methods. Granulation is also used for converting a
mixture of powders with poor cohesion into aggregates, which when
compressed result in tablets that have good cohesion
properties.
[0037] In the case of fast-disintegrating tablets, the active
ingredient(s), optionally in admixture with one or more excipients,
is (are) advantageously provided with a coating in order to mask
the taste of such ingredient(s) and/or to protect the same against
possible harmful effects by light and/or moisture and in the case
of bendamustine to protect the mucosa in the mouth against the
harmful effects exerted by the active compound. For that purpose a
granulate preferably is prepared and processed as further outlined
below.
[0038] The expression "granulate" refers to aggregates of
particles, sometimes called granules. A granulate in general is
prepared by compaction and/or compression techniques (dry
granulation) or by wet granulation techniques, using a liquid in
which optionally a wet granulation binding agent is dissolved
(Remington's Pharmaceutical Sciences 18th ed. 1990, page 1641). Wet
granulation techniques also include extrusion techniques.
Accordingly the term granulate also comprises pellets, spherules,
and extrudates, of which pellets preferably are used as examples of
a granulate.
[0039] A pellet may be described as a small particle of
approximately 1.0-1.6 mm in diameter and having a certain density,
which particle is prepared by application of the pharmaceutical
processes of extrusion and spheronisation to powder mixtures.
[0040] The active ingredient(s), optionally in admixture with one
or more excipients, may be advantageously provided with a coating
in order to mask the taste of such ingredient and/or to protect the
same against possible harmful effects by light and/or moisture
and/or to protect the mucosa in the mouth against the harmful
effects exerted by the active compound.
[0041] Pills are small, round solid dosage forms, prepared by
adding the active ingredient to a doughy mixture of triglycerides.
The mixture is rolled into a long string, which is then cut into
pieces and rolled (J. T. Carstensen: Pharmaceutical principles of
solid dosage forms, 1993, Technomic Publishing Company, Inc. page
63).
[0042] Preferably the dosage forms according to the invention are
prepared by dry compaction techniques. Suitable techniques are for
example described in Remington's Pharmaceutical Science 18th. ed.
1990, page 1644. They comprise dry granulation, roller compaction
and direct compression. When tablets are prepared by these
techniques, it is even more advantageous to use direct
compression.
[0043] The dosage forms according to the present invention are
preferably provided with a coating. The coating has different
purposes: it may serve for masking the taste of the active
ingredient(s) used in the composition, whilst at the same time it
is protecting the active ingredient against possible harmful
effects by light and/or moisture such as oxidation, degradation,
etc. Furthermore, the coating layer may prevent the subject from
damage of the oral mucosa by the active ingredient.
[0044] The coating layer can be applied to the dosage forms by
techniques well-known in the art such as spray-coating and
microencapsulation. For tablets it can be in the form of a
film-coating, a saccharide-coating or a compression coating.
Preferably a film-coating process is used (Remington's
Pharmaceutical Sciences 18th ed. 1990, page 1666). In case an
active ingredient requires the application of a coating for
fast-disintegrating tablets the individual granules can suitably be
provided with a coating prior to compression into tablets.
[0045] The expression "pharmaceutically acceptable ester thereof"
describes any pharmaceutically acceptable ester of bendamustine,
such as esters with alkyl alcohols and sugar alcohols. Examples of
the alkyl alcohols are C.sub.1-6-alkyl alcohols such as methanol,
ethanol, propanol, isopropanol, butanol and tert-butanol. Examples
of the sugar alcohols are mannitol, maltitol, sorbitol, erythritol,
glycol, glycerol, arabitol, xylitol and lactitol. Preferred
examples of the bendamustine esters are the ethyl ester, the
isopropyl ester, the mannitol ester and the sorbitol ester, most
preferred is the ethylester thereof.
[0046] The expression "pharmaceutically acceptable salt thereof"
describes any pharmaceutically acceptable salt of bendamustine that
administered to a patient (directly or indirectly) provides
bendamustine. This term further comprises the pharmaceutically
acceptable salt of a bendamustine ester. Nevertheless, it will be
considered that the pharmaceutically non-acceptable salts also are
included within the limits of this invention since these compounds
can be useful in the preparation of pharmaceutically acceptable
salts. For example, pharmaceutically acceptable salts of
bendamustine are synthesized from the corresponding compound that
contains an acid or basic group, by conventional chemical methods.
Generally, these salts are, for example, prepared by means of the
reaction of free acidic or basic forms of these compounds in a
stoichiometric amount with a corresponding base or acid in water or
an organic solvent or a mixture of both. Nonaqueous media like
ether, ethyl acetate, isopropanol or acetonitrile are generally
preferred. Examples of acids which may be used for the salt
formation of pharmaceutically acceptable salts of bendamustine
include inorganic acids such as hydrochloride, hydrobromide,
hydriodide, sulphuric, nitric, and phosphoric acids, and organic
acids such as acetic, maleic, fumaric, citric, oxalic, succinic,
tartaric, malic, lactic, methylsulphonic and p-toluenesulphonic
acids. Pharmaceutically acceptable salts of bendamustine may be
derived from either inorganic or organic bases to yield ammonium
salts; alkali metal salts (lithium, sodium, potassium, etc.),
alkaline earth salts like calcium or magnesium, aluminium salts,
lower alkylamine salts like methylamine or ethylamine salts, lower
alkyldiamine salts like ethylenediamine salts, ethanolamine,
N,N-dialkyleneethanolamine, triethanolamine, and glucamine salts,
as well as basic salts of amino acids. Especially preferred are
acid salts prepared from the hydrochloride, the hydrobromide, and
the hydroiodide, whereas the hydrochloride salt is the most
preferred pharmaceutically acceptable salt of bendamustine. The
pharmaceutically acceptable salts are produced by conventional
techniques well-known in the art.
[0047] The expression "pharmaceutically acceptable solvate thereof"
describes any pharmaceutically acceptable solvate that,
administered to a patient (directly or indirectly) provides
bendamustine. This term further comprises the pharmaceutically
acceptable solvate of a bendamustine ester. Preferably, the solvate
is a hydrate, a solvate with an alcohol such as methanol, ethanol,
propanol, or isopropanol, a solvate with an ester such as ethyl
acetate, a solvate with an ether such as methyl ether, ethyl ether
or THF (tetrahydrofuran) or a solvate with DMF (dimethylformamide),
of which a hydrate or a solvate with an alcohol such as ethanol is
more preferred. A solvent for constituting the solvate is
preferably a pharmaceutically acceptable solvent.
[0048] It is especially preferred that the active ingredient in the
invention's compositions is bendamustine or a pharmaceutically
acceptable salt thereof. It is most preferred that the active
ingredient is bendamustine hydrochloride.
[0049] The dose of the active ingredient in the pharmaceutical
composition may readily be determined by the skilled artisan
depending on the patient's condition, sex, body weight, body
surface area (m.sup.2; average approximately 2 m.sup.2 per person),
or age, especially depending on the patient's body weight and body
surface area. It is preferred that the daily dosage ranges from
about 50 to about 1000 mg, preferably from about 100 to about 500
mg of the active ingredient, more preferably from about 200 to
about 400 mg and most preferably about 280 mg. The daily dosage may
be taken as a single dose or as multiple doses such as twice or
three-times daily, most preferably as a single daily dose. The
daily dose may be taken once a week or several times a week. The
minimum oral single dose is 50 mg. The above doses relate to
bendamustine and may easily be recalculated in relation to a
pharmaceutically acceptable ester, salt or solvate thereof. The
dose can be expressed in absolute amounts (mg), but in oncology
normally the dose is expressed in mg/m.sup.2, taking into account
the patient's body surface area.
[0050] The maximum tolerated dose (MTD) and the effective dose of
bendamustine is dependent on the cumulative amount given per cycle.
Based on the reproducible BA of bendamustine the MTD is reached at
a cumulative dose of 1000 mg per cycle. The lower limit of
effective cumulative dose is between 350 mg and 500 mg per cycle.
Therefore a cumulative dose per cycle of 350 mg to 1000 mg needs to
be given orally. The preferred cumulative oral dose per cycle is
500 mg to 700 mg. Bendamustine can be given in effective single
doses from 50 mg to 900 mg. The preferred range of a single oral
dose is 200-300 mg.
[0051] The maximum tolerated dose (cumulative) is about 1000 mg
bendamustine within one cycle (3-4 week cycle). In
sensitive/compromised patients the cumulative dose is about 350-500
mg bendamustine within one cycle (3-4 weeks), preferably about 365
mg within 4 weeks.
[0052] Possible and preferred oral dosage regimens are:
[0053] 200-300 mg bendamustine on day 1 and day 2, optionally
followed by a maintenance low dose of 50 mg once a day
[0054] 50 mg bendamustine each day from day 1 up till and including
day 14
[0055] about 150 mg bendamustine once a week for 3 weeks.
[0056] Generally, the treatment with bendamustine is effected in
therapeutic cycles, wherein bendamustine and optional additional
agents are dosed for 1 to 5 days and then the treatment is repeated
after an interruption of 2 to 4 weeks. The repetitions of the
therapeutic cycle are continued until the respective condition to
be treated has improved. Basically, the number of repetitions is
within the discretion of a medical doctor. Generally, the
therapeutic cycle is repeated 4 to 15 times, preferably 4 to 12
times, more preferably 4 to 6 times.
[0057] In the following approved (intravenous application) and
preferred oral dosage regimens for specific indications within the
scope of the present invention are given:
[0058] Monotherapy for chronic lymphocytic leukaemia:
[0059] 100 mg/m.sup.2 body surface area bendamustine hydrochloride
on days 1 and 2; every 4 weeks (intravenous application).
[0060] Oral: 145 mg/m.sup.2 or 261 mg (1.8 m.sup.2): range 100-200
mg/m.sup.2 or 150-350 mg per day.
[0061] Monotherapy for indolent non-Hodgkin's lymphomas refractory
to rituximab:
[0062] 120 mg/m.sup.2 body surface area bendamustine hydrochloride
on days 1 and 2; every 3 weeks (intravenous application).
[0063] Oral: 174 mg/m.sup.2 or 313 mg (1.8 m.sup.2): range 100-250
mg/m.sup.2 or 150-400 mg per day.
[0064] Preferably bendamustine is combined with vincristine and
prednisone in first line non-Hodgkin's lymphoma.
[0065] Multiple Myeloma:
[0066] 120-150 mg/m.sup.2 body surface area bendamustine
hydrochloride on days 1 and 2 (intravenous application), 60
mg/m.sup.2 body surface area prednisone i.v. or per os on days 1 to
4; every 4 weeks.
[0067] Oral: 174-217 mg/m.sup.2 or 313-391 mg (1.8 m.sup.2): range
100-250 mg/m.sup.2 or 150-400 mg per day.
[0068] Combination treatment for first-line therapy for patients
with follicular (FL), indolent and mantle cell lymphomas (MCL):
[0069] Rituximab 375 mg/m.sup.2 (day 1) plus either bendamustine 90
mg/m.sup.2 (days 1+2) every 28 days (intravenous application).
[0070] Oral: 130 mg/m.sup.2 or 235 mg (1.8 m.sup.2): range 100-200
mg/m.sup.2 or 150-350 mg per day.
[0071] The invention thus relates to a pharmaceutical composition
as defined above for use for the oral treatment of a medical
condition which is selected from chronic lymphocytic leukaemia,
acute lymphocytic leukaemia, chronic myelocytic leukaemia, acute
myelocytic leukaemia, Hodgkin's disease, non-Hodgkin's lymphoma,
multiple lymphoma, breast cancer, ovarian cancer, small cell lung
cancer and non-small cell lung cancer, wherein the dosage regimen
comprises at least the administration of a dose of 100 to 600
mg/m.sup.2/per person of bendamustine on day 1 and day 2,
optionally a dose of 50 to 150 mg/m.sup.2 i.v. or orally of a
corticosteroid on days 1 to 5, and optionally a suitable dose of a
further active agent selected from the group consisting of an
antibody specific for CD20, an anthracyclin derivative, a vinca
alkaloid or a platin derivative; and the repetition of said dosage
regimen 4 to 15 times after intervals of two to four weeks.
Moreover, the invention relates to the pharmaceutical composition
as defined above for the use as defined above, wherein the active
ingredient bendamustine is administered in a dosage regimen
selected from 200-300 mg on day 1 and day 2, optionally followed by
a maintenance dose of 50 mg once a day, 50 mg each day from day 1
up till and including day 14, or 150 mg once a week for 3
weeks.
[0072] The invention further relates to the pharmaceutical
composition as defined above for the use as defined above, wherein
the patient is one having non-Hodgkin's lymphoma and the dosage
regimen comprises administering a total amount of 200 mg/person/day
of active ingredient bendamustine on days 1 to 5, 2 mg i.v. of
vincristine on day 1 and 100 mg/m.sup.2 i.v. of prednisone on days
1 to 5 and repeating said treatment every three weeks until the
non-Hodgkin's lymphoma has improved.
[0073] The invention further relates to the pharmaceutical
composition as defined above for the use as defined above wherein
the patient is one having multiple myeloma and the dosage regimen
comprises administering an amount of 100-250, preferably 174 to 217
mg/m.sup.2 body surface area bendamustine hydrochloride on days 1
and 2, 60 mg/m.sup.2 i.v. or orally of prednisone on days 1 to 4
and repeating said treatment every four weeks until the multiple
myeloma has improved.
[0074] The invention further relates to the pharmaceutical
composition as defined above for the use as defined above, wherein
the patient is one having chronic lymphocytic leukaemia and the
dosage regimen comprises administering an amount of 100 to 200,
preferably 145 mg/m.sup.2 body surface area bendamustine
hydrochloride on days 1 and 2 and 60 mg/m.sup.2 i.v. or orally of
prednisone on days 1 to 4 and repeating said treatment every four
weeks until the chronic lymphocytic leukaemia has improved.
[0075] The invention moreover relates to the pharmaceutical
composition as defined above for the use as defined above, wherein
the patient is one having follicular, indolent or mantle cell
lymphoma and the dosage regimen comprises administering a dose of
375 mg/m.sup.2 rituximab on day 1 plus 100 to 200, preferably 130
mg/m.sup.2 oral bendamustine on days 1 and 2 every 28 days until
the respective lymphoma has improved.
[0076] The dosage form may contain the amount of a single daily
dose or parts thereof. It is preferred that the dosage form of the
present invention comprises about 10 to about 1000 mg, preferably
about 25 to about 600 mg, more preferably about 50 to about 200 mg
and most preferably about 50 mg or about 100 mg of the active
ingredient.
[0077] As used herein, the term "non-ionic surfactant" refers to an
amphiphilic compound having a polar, hydrophilic group and a
non-polar, lipophilic group or chain and wherein the hydrophilic
and lipophylic properties of the compound are characterised by the
so-called Hydrophilic-Lipophilic Balance (HLB) value. The non-ionic
surfactant to be used for preparing the compositions of the present
invention preferably has an HLB-value between 10 and 20 and
preferably between 12 and 18. The non-ionic surfactant further has
a melting point, pour point or melting range between 5.degree. C.
and body temperature (37.degree. C.) and preferably between just
below room temperature (20.degree. C.) and body temperature. The
material can be in a liquid or a semi-solid state at room
temperature. The amphiphilic material is a carrier for the
bendamustine active ingredient, which can be present in a dissolved
form, a suspended form or partly in a dissolved and partly in a
suspended form.
[0078] The non-ionic surfactants that are advantageously used for
the preparation of the compositions according to the first
embodiment of the present invention are selected from the group
consisting of a polyethoxylated castor oil or derivative thereof
and a block copolymer of ethylene oxide/propylene oxide, provided
the materials have the afore-mentioned HLB-value and melting point,
pour point or melting range.
[0079] In one embodiment, the non-ionic surfactant is a
polyethoxylated castor oil. One example of a polyethoxylated castor
oil is sold under the tradename Cremophor.RTM.. Cremophor.RTM.
products of various purities and viscosities are produced and may
be used in the present invention. In particular macrogol glycerol
hydroxystearate (Cremophor.RTM. RH 40) and polyoxyl-35-castor oil
(Cremophor.RTM. EL or Cremophor.RTM. ELP) can be used.
Cremophor.RTM.ELP and Cremophor.RTM. EL are known as nonionic
solubilizers and emulsifiers, produced by reacting castor oil with
ethylene oxide in a molar ratio of 1 to 35. They have an HLB-value
of 12-14 and a melting point of 26.degree. C. Depending on the
ambient temperature these products can be characterised as either
semi-solid or as a medium viscosity liquid. Macrogol glycerol
hydroxystearate (commercially available as Cremophor.RTM. RH 40) is
a semi-solid material at 25.degree. C., having a viscosity range at
the same temperature of 20-40 cps (as a 30% aqueous solution). It
is known as a nonionic solubiliser and emulsifier. It is produced
by reacting castor oil with ethylene oxide in a molar ratio of 1 to
45. Its HLB-value ranges from 14-16 and the melting range is from
20-28.degree. C. In experiments it was shown that macrogol glycerol
hydroxystearate can advantageously be used on its own for the
preparation of compositions according to the present invention.
[0080] Pluronic.RTM. block copolymers consist of ethylene oxide and
propylene oxide blocks. The ethylene oxide units have a hydrophilic
character whereas the propylene oxide units have a lipophilic
character Variations in the number of hydrophilic ethylene oxide
units and lipophilic propylene oxide units results in copolymers
with a different molecular mass and different
hydrophilic-lipophilic-balance (HLB). Examples of block copolymers
of propylene oxide ("PEO")-polypropylene oxide ("PPO") meeting the
requirements of the HLB-value and the melting point or pour point
or melting range for making the compositions according to the
present invention include the commercially available types
Pluronic.RTM. L35, Pluronic.RTM. L 44, Pluronic.RTM. L64,
Pluronic.RTM. P85 and Pluronic.RTM. P105. Pluronic.RTM. L44 or
Poloxamer.RTM. 124, but not Pluronic.RTM. 68 or Poloxamer.RTM. 188
and Pluronic.RTM. 127 or Poloxamer.RTM. 407. Pluronic.RTM. L44 is a
preferred non-ionic surfactant.
[0081] Except for macrogol glycerol hydroxystearate the
above-mentioned non-ionic surfactants are all liquids having a
viscosity value which may be too low to avoid sedimentation of the
bendamustine hydrochloride. The additional problem to be solved was
to find an excipient or a combination of excipients that would
allow for a total value for the viscosity of the mixture that would
be high enough to avoid segregation of the bendamustine chloride
when added to the mixture.
[0082] Therefore the compositions according to the first embodiment
of the present invention, that contain a liquid non-ionic
surfactant, advantageously further contain a viscosity improving
agent. Suitable viscosity-improving agents include a powder such as
colloidal silicon dioxide (commercially available under the
trademark Aerosil.RTM.) or a semi-solidwaxy material, such as
lauroyl macrogol glycerides (commercially available under the
trademark Gelucire.RTM. 44/14). The amount of the powder or the
semi-solid material to be added to the liquid non-ionic surfactant
depends on the viscosity of the liquid non-ionic surfactant.
Different concentrations have been tested in order to find the
minimum suitable amount of viscosity improving agent to be added to
visually avoid sedimentation of the active ingredient. Typical
relative concentrations of colloidal silicon dioxide to be added
range from about 1% to about 8%, but are preferably as low as 1.7%
or 2.0% in order not to have a negative impact on the dissolution
characteristics of the active ingredient. Typical relative
concentrations of lauroyl macrogol glycerides range from 5 to 50%,
and are preferably about 10% and about 45%.
[0083] Preferred compositions according to the first embodiment of
the present invention, are disclosed in example 4 and comprise
bendamustine hydrochloride in combination with: [0084] macrogol
glycerol hydroxystearate; [0085] ethylene oxide/propylene oxide
block copolymer (Pluronic.RTM. L44 NF or Poloxamer.RTM. 124),
optionally in combination with colloidal silicon dioxide or lauroyl
macrogol glycerides (Gelucire.RTM. 44/14) and [0086]
polyoxyl-35-castor oil, optionally in combination with lauroyl
macrogol glycerides (Gelucire.RTM. 44/14).
[0087] The pharmaceutical compositions according to the first
embodiment of the present invention are advantageously filled into
a capsule, which can then easily be taken by the patient.
[0088] Two types of capsule are commonly used and are classified
according to the nature and flexibility of the capsule shell: soft
and hard capsules.
Soft capsules are single unit solid dosage forms comprising a
liquid or semi-solid fill. They are formed, filled and sealed in
one operation using a rotary die process. They have been used as
unit dose containers for liquids for many years, whereas hard
capsules have conventionally been used for the delivery of solids
in the form of powders, granulates and pellets. Hard capsules are
single unit dosage forms, consisting of a cap and a body, which are
manufactured separately and which are supplied empty for
filling.
[0089] Soft capsules are most commonly manufactured from gelatine,
to which a plasticiser, usually glycerine or sorbitol, is added in
addition to water. Also for hard capsules the most commonly used
polymer is gelatine. An additional component is water, which acts
as a plasticiser. This component however may be responsible for
degradation of active ingredients, such as bendamustine
hydrochloride. Therefore as an alternative hard capsules may be
manufactured from hydroxypropylmethyl cellulose.
[0090] Both soft and hard capsules in addition can include
colouring agents and opacifiers.
[0091] The preferred type of capsule for the compositions according
to the present invention is the hard capsule and more in particular
the hard gelatine capsule. Ideally, the materials to be filled into
the capsule are fluid at room temperature, which would avoid
heating during the filling operation. Generally, heating could
result in an easy degradation of the active component.
[0092] In principle numerous excipients are available for filling
into hard capsules, but in addition to biopharmaceutical
considerations, the chemical and physical stability of the final
dosage-form are also important to consider, as well as the
dissolution profile to produce a safe, effective and stable
dosage-form.
[0093] Generally, fill formulations for hard capsules may be
Newtonian liquids, such as oils, thixotropic or shear thinning gels
or semi-solid matrix products that are filled at elevated
temperatures and in which the active ingredient is either dissolved
or suspended as a fine dispersion. In principle any excipient or
mixture of excipients can be used provided that the viscosity of
the fill material confirms to the requirements of the filling
process. The uniformity of capsule fill weights is important.
Further fill formulations should not show stringing and should
allow for a clean break from the dosing nozzle.
[0094] It has surprisingly been found that the compositions
according to the first embodiment of the present invention can be
advantageously administered in hard gelatine capsules. The
particular non-ionic surfactants, selected from the group
consisting of a polyethoxylated castor oil or derivative thereof
and a block copolymer of ethylene oxide/propylene oxide, and in
particular from the group consisting of macrogol glycerol
hydroxystearate, polyoxyl-35-castor oil and Pluronic.RTM. L44 or
Poloxamer.RTM. 124, if incorporating bendamustine or a
pharmaceutically acceptable ester, salt, or solvate thereof, and
after incorporation into hard gelatine capsules result in achieving
a good stability, a good dissolution profile and a good
bioavailability. To the contrary, if macrogol glycerol
hydroxystearate is used in combination with a liquid material, such
as bis-diglyceryl polyacyladipate-1 (commercially available as
Softisan.RTM. 645) and ethylene oxide/propylene oxide block
copolymer (commercially available under the names Pluronic.RTM. L44
NF or Poloxamer 124), the dissolution profile of bendamustine is
deteriorated as compared to compositions containing macrogol
glycerol hydroxystearate only. Further it is to be noted that
Cremophor.RTM. A 25 (ceteareth-25 or macrogol (25) cetostearyl
ether) and Cremophor.RTM. A 6 (ceteareth-6 and stearylalcohol or
macrogol (6) cetostearyl ether) cannot be used as the non-ionic
surfactant. Also other commonly used excipients for the preparation
of liquid filled capsule preparations were shown to provide no
satisfactory results.
[0095] Further, the compositions of the present invention can
include additional excipients, in particular protective agents,
such as anti-oxidants and antimicrobial preservatives, e.g.
methyl-, ethyl- and propylparaben, as illustrated in examples 1-3.
The antioxidant may be d-alpha tocopherol acetate, dl-alpha
tocopherol, ascorbyl palmitate, butylated hydroxyanidole, ascorbic
acid, butylated hydroxyanisole, butylatedhydroxyquinone,
butylhydroxyanisol, hydroxycoumarin, butylated hydroxytoluene,
ethyl gallate, propyl gallate, octyl gallate, lauryl gallate, or
mixtures thereof. The anti-oxidant is preferably added to
compositions containing macrogol glycerol hydroxystearate or
polyoxyl-35-castor oil.
[0096] The saccharides are present in the compositions according to
the second embodiment of the invention in a substantial amount,
preferably in an amount ranging from 2 to 5 times the weight of the
active substance. The saccharides when incorporated into the
compositions of the present invention, have shown to have a
positive effect on the stability of the active compound. In
addition to that it was surprisingly found that these excipients
result in an increased bio-availability of the active compound, in
particular bendamustine hydrochloride, when compared to the
reference capsule.
[0097] Preferred examples of the saccharides include mannitol,
maltitol, erythritol, xylitol, lactose, sucrose, glucose, sorbitol,
maltose, trehalose, lactitol and dextrose (anhydrous or
monohydrate).
[0098] In addition to these saccharide excipients the
pharmaceutical composition according to the present invention may
comprise further excipients as described in more detail below for
lubricants, glidants, fillers (or diluents), binders and
disintegrants.
[0099] Lubricants are substances which may have one or more of the
following functions in pharmaceutical compositions and especially
in tablet manufacture: preventing adhesion of the tablet material
to the surface of parts of the tabletting machine (hopper, dies and
punches), reducing interparticle friction, facilitating ejection of
the tablets from the dies and improving the flow rate of the
mixture (to be tabletted). Said lubricant is typically selected
from a group consisting of stearic acid, salts or esters of stearic
acid, hydrogenated vegetable oils, magnesium oxide, polyethylene
glycol, sodium lauryl sulphate and talc, and mixtures thereof.
Preferably said lubricant is selected from magnesium stearate,
calcium stearate, zinc stearate, glyceryl palmitostearate and
sodium stearyl fumarate, and mixtures thereof. Stearic acid is the
most preferred alternative.
[0100] The term glidant in this application is to be understood as
a substance which improves the flow characteristics of the mixture
to be tabletted. With respect to glidants, any suitable glidant
such as talc, silicon dioxide and silicagel (Cab-O-Sil.RTM.,
Syloid.RTM., Aerosil.RTM.), starch and calcium silicate may be
used. Typically, silicon dioxide is used.
[0101] Generally, the terms filler (or diluent) represent
excipients which are used to increase the bulk of the materials to
be tabletted. This increase in size improves the handling of the
solid compositions. Fillers are usually necessary if the dose of
drug per solid composition is low and the solid composition would
otherwise be too small. Examples of suitable fillers are lactose,
sucrose, mannitol, sorbitol, saccharose, starch, pregelatinized
starch, microcrystalline cellulose, powdered cellulose, calcium
hydrogen phosphate, calcium carbonate and any combinations thereof.
In a preferred embodiment the filler is selected from the group
consisting of lactose, starch, microcrystalline cellulose,
microfine cellulose and any combinations thereof, most preferably
anhydrous lactose and microcrystalline cellulose.
[0102] Generally, the term binder is used for agents that impart
cohesiveness to the pharmaceutical formulation, which cohesiveness
ensures that the composition remains intact especially in case of
tablets after compression. Dependent on the compaction technique
used (direct compression, dry granulation or wet granulation)
different binders are used. For dry compaction techniques (direct
compression and dry granulation) suitable binders are lactose,
sucrose, mannitol, sorbitol, saccharose, starch, pregelatinized
starch, microcrystalline cellulose, powdered cellulose, calcium
hydrogen phosphate, calcium carbonate and any combinations thereof.
In a preferred embodiment the binder is selected from the group
consisting of lactose, starch, microcrystalline cellulose,
microfine cellulose and any combinations thereof, most preferably
anhydrous lactose and microcrystalline cellulose. In wet
granulation processes binders can be used both as a solution and in
a dry form. As suitable binders, there may be mentioned, for
example, polyvinylpyrrolidone, dispersible cellulose, hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, methylcellulose, starch,
pregelatinized starch, partly pregelatinized starch, gum arabic,
dextrin, pullulan and the like. Among these binders, dispersible
cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose and
hydroxypropylmethyl cellulose are more preferred.
[0103] A disintegrant can be included in a pharmaceutical
composition and especially a tablet composition to facilitate its
breakup or disintegration after the tablet comes into contact with
a physiological aqueous liquid. When the tablet is swallowed, the
disintegrant often is responsible for the quick disintegration of
the tablet when it comes into contact with body fluids, such as
saliva, gastric and intestinal fluids. Materials serving as
disintegrants have been classified chemically as starches,
celluloses, cross-linked polymers, etc. As a result of
investigations concerning the disintegrator species to be used in
the practice of this invention and the level of addition thereof,
it was found that starch, a modified starch such as sodium starch
glycolate (Primojel.RTM.), sodium carboxymethyl cellulose,
crosslinked carboxymethylcellulose sodium (Ac-Di-Sol.RTM.),
cross-linked polyvinylpyrrolidone, polacrilin potassium
(Amberlite.RTM. IRP88) and low-substituted hydroxypropyl cellulose
can produce a very good disintegrating effect.
[0104] The stability of an aqueous solution of bendamustine is
strongly influenced by the pH. A significant hydrolytic
decomposition of this compound is observed at pH values higher than
about 5. At pH>5, the decomposition proceeds rapidly and the
resulting content of by-products is high in this pH range. The main
hydrolysis products are
4-[5-[(2-Chloroethyl)-(2-hydroxy-ethyl)amino]-1-methyl-benzimidazo-2-yl]--
butanoic acid (HP1),
4-[5-[Bis(2-hydroxyethyl)amino]-1-methyl-benzimidazo-2-yl]-butanoic
acid (HP2) and 4-(5-Morpholino-1-methylbenzimidazol-2-yl)-butanoic
acid (HP3):
##STR00002##
[0105] Absorption of an orally administered drug usually happens
from the stomach, the small intestine and/or the large intestine.
The pH in the stomach is about 1 to 3.5, in the small intestine
about 6.5 to 7.6, and in the large intestine about 7.5 to 8.0.
Accordingly, for a compound like bendamustine which is prone to
degradation in aqueous environments with a pH higher than 5, it is
highly preferable that it is absorbed in the stomach, and does not
pass through to the small or even the large intestine, in order to
avoid decomposition. Hence there is a need for a pharmaceutical
composition from which the bendamustine is absorbed completely or
at least to a high extent in the stomach, thereby avoiding or
reducing the degradation of the bendamustine in the small or large
intestine.
[0106] It has surprisingly been found that it is possible to solve
this problem by using the present pharmaceutical compositions.
These compositions comprising bendamustine hydrochloride in a
pharmaceutically acceptable excipient, which is a non-ionic
surfactant, selected from the group consisting of a polyethoxylated
castor oil or derivative thereof and a block copolymer of ethylene
oxide and propylene oxide, or one of the above saccharides
surprisingly show a fast dissolution, and in particular a
dissolution of the bendamustine of at least 60% in 20 minutes, 70%
in 40 minutes and 80% in 60 minutes, and preferably of at least 60%
in 10 minutes, 70% in 20 minutes and 80% in 30 minutes, as measured
with a paddle apparatus at 50 rpm according to the European
Pharmacopoeia in an artificial gastric fluid. The artificial
gastric fluid as used herein refers to a solution prepared by
dissolving 2 g of sodium chloride in 1000 ml of water and then
adjusting the pH to 1.5.+-.0.05 with 5 N hydrochloric acid.
[0107] Further they have shown to be stable, when put in
accelerated stability testing. This is surprising since it has been
shown that: [0108] in a reference capsule formulation (see
reference example 1) containing bendamustine hydrochloride only in
a hard gelatine capsule, when stored at 40.degree. C./75% RH (glass
vial open) and 50.degree. C., degradation products were formed
within one month of storage. In the case of open vials with
40.degree. C. and 75% RH (relative humidity) the amount of
hydrolysis product HP1 was increased by a factor of 4 after one
month of storage. For the closed vials the HP1 content is even
higher; [0109] in the capsule formulations of reference examples 2,
3 and 4, when stored at 40.degree. C./75% RH (closed glass vial),
degradation products were formed within one month of storage and
increased upon further storage.
[0110] The total time of a drug to pass the stomach to the small
intestine is between about 20 minutes to 5 hours, usually between
about 30 minutes to 3 hours. Thus pharmaceutical compositions
according to this invention advantageously should reduce the
degradation of bendamustine in the patient since the bendamustine
is released and dissolved to a major extent while in the stomach.
Thus even an improved bioavailability of the bendamustine
containing compositions according to the invention may be
expected.
[0111] In a further aspect of this invention the oral
pharmaceutical compositions may be used for the treatment or
prevention of relapse of a medical condition in a human or animal,
preferably a human, which medical condition is selected from
chronic lymphocytic leukemia (abbreviated as CLL), acute
lymphocytic leukaemia (abbreviated as ALL), chronic myelocytic
leukaemia (abbreviated as CML), acute myelocytic leukaemiam
(abbreviated as AML), Hodgkin's disease, non-Hodgkin's lymphoma
(abbreviated as NHL), multiple myeloma, breast cancer, ovarian
cancer, small cell lung cancer, non-small cell lung cancer, and an
autoimmune disease.
[0112] In a further aspect of this invention the pharmaceutical
compositions in a solid dosage form may be used for the treatment,
induction, salvage therapy, conditioning prior to stem cell
transplantation, maintenance therapy, treatment of residual disease
of a medical condition in a human or animal, preferably a human,
which medical condition is selected from chronic lymphocytic
leukemia (CLL), acute lymphocytic leukaemia (ALL), chronic
myelocytic leukaemia (CML), acute myelocytic leukaemia (AML),
Hodgkin's disease, non-Hodgkin's lymphoma (NHL), multiple myeloma,
breast cancer, ovarian cancer, small cell lung cancer, non-small
cell lung cancer, and an autoimmune disease.
[0113] The present invention also comprises a method of treatment
or prevention of relapse of a medical condition selected from
chronic lymphocytic leukemia, acute lymphocytic leukaemia, chronic
myelocytic leukaemia acute myelocytic leukaemia, Hodgkin's disease,
non-Hodgkin's lymphoma, multiple myeloma, breast cancer, ovarian
cancer, small cell lung cancer, non-small cell lung cancer, and an
autoimmune disease, in a human or animal body comprising
administering to the human or animal body in need thereof an
effective amount of the pharmaceutical preparation of this
invention. Preferably the medical condition is non-Hodgkin's
lymphoma.
[0114] In another aspect the of this invention the pharmaceutical
composition may be administered in combination with at least one
further active agent, wherein said further active agent is given
prior, concurrently, or subsequently to the administration of the
pharmaceutical composition. This at least one further active agent
is preferably an antibody specific for CD20 (an examples is
rituximab or ofatumumab), an anthracyclin derivative (an example is
doxorubicin or daunorubicin), a vinca alkaloid (an example is
vincristine), a platin derivative (an example is cisplatin or
carboplatin), daporinad (FK866), YM155, thalidomide and analogues
thereof (an example is lenalidomide), or a proteasome inhibitor (an
example is bortezumib).
[0115] The pharmaceutical composition of this invention may also be
administered in combination with at least one corticosteroid,
wherein said corticosteroid is given prior, concurrently, or
subsequently to the administration of the pharmaceutical
composition. Examples of the corticosteroids are prednisone,
prednisolone and dexamethasone.
[0116] Several dosing regimens are possible. For example
bendamustine can be administered as an oral formulation in a total
amount of 200 mg/person/day on days 1-5+vincristine 2 mg i.v. on
day 1+prednisone 100 mg/m.sup.2 i.v. on days 1-5 every 3 weeks in
patients with NHL. In patients with MM bendamustine can be
administered as an oral formulation in a total amount of 400-500
mg/person/day on days 1 and 2+prednisone 60 mg/m.sup.2 i.v. or
orally on days 1-4 every 4 weeks. In patients with CCL bendamustine
can be administered as an oral formulation in a total amount of 200
mg-300 mg/person/day on days 1 and 2) every 4 weeks+prednisone 60
mg/m.sup.2 i.v. or orally on days 1-4 every 4 weeks.
[0117] The advantage of the liquid filled hard gelatine capsule
compositions according to the present invention further is, that
the active ingredient(s), optionally in admixture with one or more
excipients, do not need to be provided with a coating in order to
further mask the taste of such ingredient and/or to protect the
same against possible harmful effects by light and/or moisture such
as oxidation, degradation, or to prevent that the subject may
experience damage of the oral mucosa, due to the interaction with
the active ingredient.
[0118] The following examples further illustrate the invention. It
will be apparent to the skilled person that these examples are
solely for illustrative purposes and must not be considered to
limit the invention.
EXAMPLES
A) Examples Relating to the First Embodiment of the Invention
1. Capsule Formulations
Reference Example 1
Bendamustine Capsule Formulation (Prior Art)
[0119] 20.0.+-.1 mg of bendamustine hydrochloride were weighed into
the body of an empty hard gelatine capsule, and put into a clear
glass HPLC vial (6 ml) of Agilent. Capsules were closed by placing
the cap on top of the body and slight pushing.
[0120] Capsules were stored at 40.degree. C./75% RH (glass vial
open) or 50.degree. C. (glass vial closed). The amount of
bendamustine hydrochloride and of related substances was measured
with HPLC (column: Zorbax Bonus-RP, 5 .mu.m; temperature of column
oven: 30.degree. C.; temperature of autosampler: 5.degree. C.;
detector: 254 nm). The results are shown in Table 1:
TABLE-US-00001 TABLE 1 Related substances and assay of bendamustine
HCl (residual content) in bendamustine capsules Bendamustine HCl
Storage Related T = 1 [% area] condition substances T = 0 month T =
0 T = 1 month 40.degree. C./ HP1 0.10 0.45 99.64 98.83 75% RH
NP1*.sup.1 0.02 0.02 (open vial) BM1Dimer*.sup.1 0.06 0.42
BM1EE*.sup.1 0.13 0.11 HP2 n.d.*.sup.2 n.d. HP3 n.d. n.d.
50.degree. C. (closed HP1 0.10 1.46 99.64 97.51 vial) NP1 0.02 0.02
BM1Dimer 0.06 0.24 BM1EE 0.13 0.12 HP2 n.d. n.d. HP3 n.d. n.d.
*.sup.1NP1:
4-[6-(2-Chloroethyl)-3,6,7,8-tetra-hydro-3-methyl-imidazo[4,5-h]-[1,4]ben-
zothiazin-2-yl] butanoic acid BM1Dimer:
4-{5-[N-(2-Chloroethyl)-N-(2-{4-[5-bis(2-chloroethyl)amino-1-methylbenzim-
idazol-2-yl]butanoyloxy}ethyl)amino]-1-methylbenzimidazol-2-yl}butanoic
acid BM1EE:
4-[5-[Bis(2-chloroethyl)amino]-1-methyl-benzimidazo-2-yl] butanoic
ethyl ester *.sup.2n.d.: not detectable, i.e. beyond detection
limit (area percentage less than 0.05%)
Reference Example 2
TABLE-US-00002 [0121] TABLE 2a Bendamustine powder mixture for
capsules Component mg/dosage-form Relative Content % bendamustine
hydrochloride 55.1 21.09 Mannitol 141.4 54.11 Microcrystalline
cellulose 25.0 9.57 (Avicel .RTM. PH101) Crosscarmellose sodium
12.5 4.78 (Ac-Di-Sol .RTM.) Colloidal silicon dioxide 1.0 0.38
(Aerosil .RTM. 200) Talc 18.8 7.19 Stearic acid 7.5 2.87 Sum 261.3
100
[0122] For a batch size of 1000 capsules all excipients except for
colloidal silicon dioxide and stearic acid were loaded into a
Somakon vessel (5 L). Bendamustine was added and blending was
conducted for 4 minutes at 1000 rpm (wiper 10 rpm). The resulting
blend was sieved through a 0.5 mm sieve. The vessel was reloaded
with the blend and colloidal silicon dioxide was added. Blending
was conducted for 2 minutes at the afore-mentioned conditions.
Thereafter stearic acid was added and blending was continued for 1
minute. The blend was subsequently sieved through a 0.5 mm sieve,
reloaded into the vessel and blended for another 30 seconds, all at
the same conditions.
[0123] The blend was transferred to a capsule filling machine
(Zanassi AZ 5) and filled into hard gelatine capsules (size 2)
(mean mass: 259.5 mg (begin)-255.3 mg (end)) and hypromellose
capsules (size 2) (mean mass: 255.8 (begin)-253.4 mg (end))
respectively. Capsules were stored at 40.degree. C./75% RH in a
closed glass vial. The amount of bendamustine hydrochloride as well
as of related substances, like degradation products, by-products of
synthesis were measured with HPLC (column: Zorbax Bonus-RP, 5
.mu.m; temperature of column oven: 30.degree. C.; temperature of
autosampler: 5.degree. C.; detector: 254 nm). The results are shown
in Table 2b (filled in hypromellose capsules) and 2c (filled in
gelatine capsules).
TABLE-US-00003 TABLE 2b Bendamustine powder mixture in hypromellose
capsules: Related substances and assay of bendamustine HCl
(residual content) Bendamustine HCl Storage Related T = 2 [% area]
condition substances T = 0 months T = 0 T = 2 months 40.degree. C./
HP1 0.18 0.87 99.49 97.92 75% RH HP2 n.d. 0.38 (closed HP3 n.d.
0.08 vials) NP1 n.d. n.d. BM1Dimer 0.09 0.14 BM1EE 0.16 0.14 Unid
RRT 0.65*.sup.3 n.d. 0.05 Unid RRT 0.68 n.d. 0.06 Unid RRT 0.70
n.d. 0.19 Unid RRT 0.77 n.d. 0.05 Unid RRT 0.93 n.d. 0.05
*.sup.3Unidentified compound peak at relative retention time of
0.65 as compared to main peak
TABLE-US-00004 TABLE 2c Bendamustine powder mixture in gelatine
capsules: Related substances and assay of bendamustine HCl
(residual content) Bendamustine HCl Storage Related T = 2 [% area]
condition substances T = 0 months T = 0 T = 2 months 40.degree. C./
HP1 0.25 1.25 99.30 97.79 75% RH HP2 n.d. 0.11 (closed vials) HP3
n.d. <0.05 NP1 n.d. n.d. BM1Dimer 0.14 0.14 BM1EE 0.16 0.14 Unid
RRT 0.65 n.d. 0.05 Unid RRT 0.68 0.07 0.05 Unid RRT 0.70 n.d. 0.30
Unid RRT 0.77 n.d. n.d. Unid RRT 0.93 n.d. n.d.
Reference Example 3
TABLE-US-00005 [0124] TABLE 3a Bendamustine powder mixture for
capsules Component mg/dosage-form Relative Content % bendamustine
hydrochloride 55.1 21.09 Lactose anhydrous 141.4 54.11
Microcrystalline cellulose 25.0 9.57 (Avicel .RTM. PH112)
Crosscarmellose sodium 12.5 4.78 (Ac-Di-Sol .RTM.) Colloidal
silicon dioxide 1.0 0.38 (Aerosil .RTM. 200) Talc 18.8 7.19 Stearic
acid 7.5 2.87 Sum 261.3 100
[0125] For 1000 capsules all excipients except for colloidal
silicon dioxide and stearic acid were loaded into a Somakon vessel
(5 L). Bendamustine was added and blending was conducted for 4
minutes at 1000 rpm (wiper 10 rpm). The resulting blend was sieved
through a 0.5 mm sieve. The vessel was reloaded with the blend and
colloidal silicon dioxide was added. Blending was conducted for 2
minutes at the afore-mentioned conditions. Thereafter stearic acid
was added and blending was continued for 1 minute. The blend was
subsequently sieved through a 0.5 mm sieve, reloaded into the
vessel and blended for another 30 seconds, all at the same
conditions.
[0126] The blend was transferred to a capsule filling machine
(Zanassi AZ 5) and filled into hard gelatine capsules (size 2)
(mean mass: 257.9 mg (begin)-255.2 mg (end)) and hypromellose
capsules (size 2) (mean mass: 261.1 (begin)-257.8 mg (end))
respectively. Capsules were stored at 40.degree. C./75% RH in a
closed glass vial. The amount of bendamustine hydrochloride and of
related substances was measured with HPLC, as described above. The
results are shown in Table 3b (filled in hypromellose capsules) and
3c (filled in gelatine capsules).
TABLE-US-00006 TABLE 3b Bendamustine powder mixture in hypromellose
capsules: Related substances and assay of bendamustine HCl
(residual content) Bendamustine HCl [% area] Storage Related T = 2
T = 2 condition substances T = 0 months T = 0 months 40.degree.
C./75% RH HP1 0.18 0.86 99.50 98.17 (closed vials) HP2 n.d. 0.25
HP3 n.d. 0.06 NP1 n.d. n.d. BM1Dimer 0.08 0.10 BM1EE 0.15 0.14 Unit
RRT 0.68 n.d. <0.05 Unit RRT 0.70 n.d. 0.19
TABLE-US-00007 TABLE 3c Bendamustine powder mixture in gelatin
capsules: Related substances and assay of bendamustine HCl
(residual content) Bendamustine HCl [% area] Storage Related T = 2
T = 2 condition substances T = 0 months T = 0 months 40.degree.
C./75% RH HP1 0.23 1.35 99.38 97.74 (closed vials) HP2 n.d. 0.06
HP3 n.d. n.d. NP1 n.d. n.d. BM1Dimer 0.13 0.10 BM1EE 0.16 0.14 Unit
RRT 0.68 n.d. 0.05 Unit RRT 0.70 n.d. 0.32
Reference Example 4
TABLE-US-00008 [0127] TABLE 4a Bendamustine powder composition for
capsules Component mg/dosage-form Relative Content % Bendamustine
hydrochloride 55.1 22.04 Lactose anhydrous 145.15 58.06
Microcrystalline cellulose 31.25 12.50 (Avicel .RTM. PH112)
Ac-Di-Sol .RTM. 12.5 5.00 Colloidal silicon dioxide 1.0 0.40
(Aerosil .RTM. 200) Magnesium stearate 2.5 1.00 Ascorbic acid 2.5
1.00 Sum 250 100.0
[0128] For 1000 capsules all excipients except for colloidal
silicon dioxide and magnesium stearate were loaded into a Somakon
vessel (2.5 L). Bendamustine was added and blending was conducted
for 4 minutes at 1000 rpm (wiper 10 rpm). The resulting blend was
sieved through a 0.5 mm sieve. The vessel was reloaded with the
blend and colloidal silicon dioxide was added. Blending was
conducted for 2 minutes at the afore-mentioned conditions.
Thereafter magnesium stearate was added and blending was continued
for 1 minute. The blend was subsequently sieved through a 0.5 mm
sieve, reloaded into the vessel and blended for another 30 seconds,
all at the same conditions.
[0129] The blend was transferred to a capsule filling machine
(Zanassi AZ 5) and filled into hard gelatine capsules (size 2)
(mean mass: 241.3 mg (begin)-244. mg (end)) and hypromellose
capsules (size 2) (mean mass: 243.5 (begin)-243. mg (end))
respectively. Capsules were stored at 40.degree. C./75% RH in a
closed glass vial. The amount of bendamustine hydrochloride and of
related substances was measured with HPLC, as described above. The
results are shown in Table 4b (filled into hypromellose capsules)
and 4c (filled in gelatine capsules).
TABLE-US-00009 TABLE 4b Bendamustine powder composition in
hypromellose capsules: Related substances and assay of bendamustine
HCl (residual content) Bendamustine HCl [% area] Storage Related T
= 2 T = 2 condition substances T = 0 months T = 0 months 40.degree.
C./75% RH HP1 0.18 0.86 99.49 98.29 (closed vials) HP2 n.d. 0.25
HP3 n.d. 0.06 NP1 n.d. n.d. BM1Dimer 0.08 0.10 BM1EE 0.15 0.14 Unid
RRT 0.57 n.d. 0.07 Unid RRT 0.63 n.d. 0.05 Unid RRT 0.64 n.d. n.d.
Unid RRT 0.68 n.d. n.d. Unid RRT 0.69 n.d. n.d. Unid RRT 0.70 n.d.
0.19 Unid RRT 0.75 n.d. 0.07 Unid RRT 0.77 n.d. 0.05 Unid RRT 0.93
n.d. 0.07
TABLE-US-00010 TABLE 4c Bendamustine powder composition in gelatin
capsules: Related substances and assay of bendamustine HCl
(residual content) Bendamustine HCl [% area] Storage Related T = 2
T = 2 condition substances T = 0 months T = 0 months 40.degree.
C./75% RH HP1 0.29 1.10 99.26 96.38 (closed vials) HP2 n.d. 0.55
HP3 n.d. n.d. NP1 n.d. n.d. BM1Dimer 0.12 0.17 BM1EE 0.15 0.15 Unid
RRT 0.58 n.d. 0.44 Unid RRT 0.62 n.d. 0.23 Unid RRT 0.65 n.d. 0.10
Unid RRT 0.68 0.07 0.07 Unid RRT 0.69 n.d. 0.06 Unid RRT 0.70 0.05
0.25 Unid RRT 0.76 n.d. 0.17 Unid RRT 0.77 n.d. 0.07 Unid RRT 0.77
n.d. 0.08 Unid RRT 0.78 n.d. 0.09 Unid RRT 0.79 n.d. 0.06 Unid RRT
0.91 n.d. n.d. Unid RRT 0.94 n.d. 0.06 Unid RRT 1.11 n.d. n.d. Unid
RRT 1.18 n.d. n.d.
Example 1
TABLE-US-00011 [0130] TABLE 5a Liquid filled hard capsule Component
mg/dosage-form Relative Content % bendamustine hydrochloride 55.1
9.18 Pluronic .RTM. L44 NF 450.70 75.12 Cremophor .RTM. RH 40 81.85
13.64 Softisan .RTM. 645 -- -- Methyl paraben 1.20 0.20 Propyl
paraben 0.12 0.02 Butyl hydroxytoluene 0.12 0.02 Ethanol 10.91
1.82
[0131] 0.68 g of methylparaben, 0.068 g of propylparaben and 0.068
g of butylhydroxytoluene were weighed and dissolved in 6.14 g of
ethanol. Cremophor.RTM. RH 40 was melted at 40.degree. C. in a
sufficient amount. 5.56 g of the ethanolic solution obtained, 36.83
g of the melted Cremophor.RTM. RH 40 and 202.82 g of Pluronic.RTM.
L44 NF were weighed and mixed at 800 rpm using a mechanical stirrer
until the mixture became transparent. The mixture was allowed to
solidify by placing it at 10.degree. C. 24.80 g of bendamustine
hydrochloride was subsequently added to the solidified blend by
manual stirring and then distributed over the blend by
homogenisation using an Ultraturrax T18 high speed homogeniser at
15500 rpm for 10 minutes. The homogenised suspension was filled
into hard gelatine capsules with a CFS 1200 capsule filling and
sealing machine, operated at 25.degree. C. The capsules were closed
and sealed. The liquid filled capsules were stored in closed amber
glass bottles with screw plugs at 40.degree. C./75% RH, at
30.degree. C./65% RH, at 25.degree. C./60% RH and at 5.degree. C.
The amount of bendamustine hydrochloride as well as of related
substances, like degradation products, by-products of synthesis was
measured with HPLC (column: Zorbax Bonus-RP, 5 .mu.m; temperature
of column oven: 30.degree. C.; temperature of autosampler:
5.degree. C.; detector: 254 nm). The results are shown in Table
5b.
TABLE-US-00012 TABLE 5b Related substances and assay of
bendamustine HCl (residual content) Bendamustine HCl [% area]
Storage T = T = 3 condition Related substances T = 0 3 months T = 0
months 40.degree. C./ HP1 0.09 0.07 98.8 98.5 75% RH NP1 n.d. n.d.
(closed vial) BM1Dimer 0.02 0.03 BM1EE 0.15 0.15 Individual unknown
0.01 0.08 impurity 30.degree. C./ HP1 0.09 0.06 98.8 98.9 65% RH
NP1 n.d. n.d. (closed vial) BM1Dimer 0.02 0.03 BM1EE 0.15 0.15
Individual unknown 0.01 0.03 impurity 25.degree. C./ HP1 0.09 0.07
98.8 99.0 60% RH NP1 n.d. n.d. (closed vial) BM1Dimer 0.02 0.03
BM1EE 0.15 0.15 Individual unknown 0.01 0.03 impurity 5.degree. C.
HP1 0.09 0.07 98.8 99.8 (closed vial) NP1 n.d. n.d. BM1Dimer 0.02
0.02 BM1EE 0.15 0.15 Individual unknown 0.01 n.d. impurity
Example 2
TABLE-US-00013 [0132] TABLE 6a Liquid filled hard capsule Component
mg/dosage-form Relative Content % bendamustine hydrochloride 55.1
9.18 Pluronic .RTM. L44 NF -- Cremophor .RTM. RH 40 532.55 88.76
Softisan .RTM. 645 -- Methyl paraben 1.20 0.20 Propyl paraben 0.12
0.02 Butyl hydroxytoluene 0.12 0.02 Ethanol 10.91 1.82
[0133] 0.68 g of methylparaben, 0.068 g of propylparaben and 0.068
g of butylhydroxytoluene were weighed and dissolved in 6.14 g of
ethanol. Cremophor.RTM. RH 40 was melted at 40.degree. C. in a
sufficient amount. 5.56 g of the ethanolic solution obtained and
239.65 g of the melted Cremophor.RTM. RH 40 were weighed and mixed
at 800 rpm using a mechanical stirrer until the mixture became
transparent. The mixture was allowed to solidify and cool to room
temperature. 24.80 g of bendamustine hydrochloride was subsequently
added to the solidified blend by manual stirring and then
distributed over the blend by homogenisation using an Ultraturrax
T18 high speed homogeniser at 15500 rpm for 10 minutes. The
homogenised suspension was filled into hard gelatine capsules with
a CFS 1200 capsule filling and sealing machine, operated at
40.degree. C. The capsules were closed and sealed.
[0134] The liquid filled capsules so obtained were stored in closed
amber glass bottles with screw plugs at 40.degree. C./75% RH, at
30.degree. C./65% RH, at 25.degree. C./60% RH and at 5.degree. C.
The amount of bendamustine hydrochloride as well as of related
substances, like degradation products, by-products of synthesis was
measured with HPLC, as described above.
[0135] The results are shown in Table 6b:
TABLE-US-00014 TABLE 6b Related substances and assay of
bendamustine HCl (residual content) Bendamustine HCl Storage
Related T = 3 [% area] condition substances*.sup.1 T = 0 months T =
0 T = 3 months 40.degree. C./75% HP1 0.08 0.07 100.10 99.0 RH
(closed NP1 0.01 0.02 vial) BM1Dimer 0.03 0.09 BM1EE 0.16 0.17
Individual 0.02 0.09 unknown impurity 30.degree. C./65% HP1 0.08
0.06 100.1 100.4 RH (closed NP1 0.01 n.d. vial) BM1Dimer 0.03 0.04
BM1EE 0.16 0.13 Individual 0.02 0.03 unknown impurity 25.degree.
C./60% HP1 0.08 0.10 100.1 100.3 RH (closed NP1 0.01 n.d. vial)
BM1Dimer 0.03 0.03 BM1EE 0.16 0.14 Individual 0.02 0.02 unknown
impurity 5.degree. C. (closed HP1 0.08 0.09 100.1 99.5 vial) NP1
0.01 0.01 BM1Dimer 0.03 0.03 BM1EE 0.16 0.15 Individual 0.02 0.02
unknown impurity
Example 3
TABLE-US-00015 [0136] TABLE 7a Liquid filled hard capsule Component
mg/dosage-form Relative Content % Bendamustine hydrochloride 55.1
9.18 Pluronic .RTM. L44 NF -- Cremophor .RTM. RH 40 81.85 13.64
Softisan .RTM. 645 450.70 75.12 Methyl paraben 1.20 0.20 Propyl
paraben 0.12 0.02 Butyl hydroxytoluene 0.12 0.02 Ethanol 10.91
1.82
[0137] 0.68 g of methylparaben, 0.068 g of propylparaben and 0.068
g of butylhydroxytoluene were weighed and dissolved in 6.14 g of
ethanol. Cremophor.RTM. RH 40 was melted at 40.degree. C. in a
sufficient amount. 5.56 g of the ethanolic solution obtained, 36.83
g of the melted Cremophor.RTM. RH 40 and 202.82 g of Softisan.RTM.
645 were weighed and mixed at 800 rpm using a mechanical stirrer
until the mixture became transparent. The mixture was allowed to
solidify by placing it at 10.degree. C. 24.80 g of bendamustine
hydrochloride was subsequently added to the solidified blend by
manual stirring and then distributed over the blend by
homogenisation using an Ultraturrax T18 high speed homogeniser at
15500 rpm for 10 minutes. The homogenised suspension was filled
into hard gelatine capsules with a CFS 1200 capsule filling and
sealing machine, operated at 30.degree. C. The capsules were closed
and sealed. The liquid filled capsules were stored in closed amber
glass bottles with screw plugs at 40.degree. C./75% RH, at
30.degree. C./65% RH, at 25.degree. C./60% RH and at 5.degree. C.
The amount of bendamustine hydrochloride as well as of related
substances, like degradation products, by-products of synthesis was
measured with HPLC, as described above. The results are shown in
Table 7b:
TABLE-US-00016 TABLE 7b Related substances and assay of
bendamustine HCl (residual content) Bendamustine HCl Storage
Related T = 3 [% area] condition substances*.sup.1 T = 0*.sup.2
months T = 0 T = 3 months 40.degree. C./75% HP1 0.08 0.06 99.6 99.5
RH (closed NP1 n.d. 0.01 vial) BM1Dimer 0.03 0.36 BM1EE 0.15 0.26
Individual 0.03 0.13 unknown impurity 30.degree. C./65% HP1 0.08
0.11 99.6 99.9 RH (closed NP1 n.d. n.d. vial) BM1Dimer 0.03 0.09
BM1EE 0.15 0.17 Individual 0.03 0.04 unknown impurity 25.degree.
C./60% HP1 0.08 0.11 99.6 100.0 RH (closed NP1 n.d. n.d. vial)
BM1Dimer 0.03 0.09 BM1EE 0.15 0.17 Individual 0.03 0.04 unknown
impurity 5.degree. C. (closed HP1 0.08 0.07 99.60 100.1 vial) NP1
n.d. 0.01 BM1Dimer 0.03 0.03 BM1EE 0.15 0.15 Individual 0.03 0.02
unknown impurity
Example 4
TABLE-US-00017 [0138] TABLE 8 further Liquid filled hard capsule
formulations Relative content (%) Ex Ex Ex Ex Ex Ex Ex Component
4.1 4.2 4.3 4.4 4.5 4.6 4.7 Pluronic .RTM. L44 -- 88.2 -- 45.4 90.8
-- Cremophor .RTM. -- -- 80.7 -- 90.8 -- 88.4 EL Cremophor .RTM.
90.8 -- -- -- -- -- -- RH 40 Gelucire .RTM. -- -- 10.0 45.4 -- --
-- 44/14 Colloidal silicon -- 2.0 -- -- -- -- 1.7 dioxide
Bendamustine 9.2 9.8 9.3 9.2 9.2 9.2 9.9 HCl
2. Disintegration and Dissolution Tests
Example 5
[0139] Disintegration tests for the liquid filled capsule
formulations of examples 1, 2 and 3 were carried out in 1000.0 ml
of buffer solution pH=1.0.+-.0.05, using disintegration Apparatus
A, operated at 37.0.degree. C..+-.0.5.degree. C. The results are
listed in Tables 8a, 8b and 8c.
Example 6
[0140] Dissolution tests for the liquid filled capsule formulations
of examples 1, 2 and 3 were carried out in artificial gastric acid
solution at pH 1.5 (see Ph Eur: 2.9.3: Dissolution test for solid
dosage forms in Recommended Dissolution Media).
[0141] The dissolution samples were tested for assay by HPLC
(column: Zorbax Bonus-RP, 5 .mu.m; temperature of column oven:
30.degree. C.; temperature of autosampler: 5.degree. C.; detector:
254 nm). Artificial gastric fluid pH 1.5 was prepared by placing
250.0 mL of 0.2M potassium chloride 0.2M into a 1000 mL volumetric
flask, adding 207.0 mL of 0.2 M hydrochloric acid, then diluting to
1000 mL with Milli-Q water. The pH was measured and adjusted, if
necessary, with 2N hydrochloric acid or 2N potassium hydroxide to a
pH of 1.5.+-.0.05.
[0142] The dissolution test was conducted according to Chapter
2.9.3. of European Pharmacopoeia 6.0, using Apparatus 2
(Paddle-apparatus). The rotation speed of the paddle was 50 rpm,
the temperature was 37.degree. C..+-.0.5.degree. C., the amount of
dissolution medium was 500 ml.
[0143] The results for the liquid filled hard capsules of examples
1, 2 and 3 are shown in Tables 9a, 9b and 9c:
TABLE-US-00018 TABLE 9a Liquid filled hard capsules of example 1
Time Test T = 0 months T = 3 months Temperature 40.degree. C. 75%
RH Disintegration (minute:second) 03:23 03:30 Dissolution (%) pH
1.5 Not tested 10' 10.4 20' 35.1 30' 51.1 Temperature 30.degree. C.
65% RH Disintegration (minute:second) 03:23 03:26 Dissolution (%)
pH 1.5 Not tested 10' 7.0 20' 24.0 30' 54.6 Temperature 25.degree.
C. 60% RH Disintegration (minute:second) 03:23 03:33 Dissolution
(%) pH 1.5 Not tested 10' 37.4 20' 52.4 30' 71.6 Temperature
5.degree. C. Disintegration (minute:second) 03:23 03:23 Dissolution
(%) pH 1.5 Not tested 10' 57.0 20' 76.7 30' 83.1
TABLE-US-00019 TABLE 9b Liquid filled hard capsule of example 2
Time Test T = 0 months T = 3 months Temperature 40.degree. C. 75%
RH Disintegration (minute:second) 03:52 02:58 Dissolution (%) pH
1.5 Not tested 10' 65.2 20' 88.7 30' 102.0 Temperature 30.degree.
C. 65% RH Disintegration (minute:second) 03:52 03:09 Dissolution
(%) pH 1.5 Not tested 10' 48.1 20' 80.9 30' 93.7 Temperature
25.degree. C. 60% RH Disintegration (minute:second) 03:52 02:53
Dissolution (%) pH 1.5 Not tested 10' 54.5 20' 80.7 30' 94.4
Temperature 5.degree. C. Disintegration (minute:second) 03:52 02:56
Dissolution (%) pH 1.5 Not tested 10' 57.9 20' 90.0 30' 98.0
TABLE-US-00020 TABLE 9c Liquid filled hard capsule of example 3
Time Test T = 0 months T = 3 months Temperature 40.degree. C. 75%
RH Disintegration (minute:second) 03:59 03:36 Dissolution (%) pH
1.5 Not tested 10' 28.5 20' 49.1 30' 62.9 Temperature 30.degree. C.
65% RH Disintegration (minute:second) 03:59 03:34 Dissolution (%)
pH 1.5 Not tested 10' 17.5 20' 35.2 30' 58.1 Temperature 25.degree.
C. 60% RH Disintegration (minute:second) 03:59 03:27 Dissolution
(%) pH 1.5 Not tested 10' 25.9 20' 44.2 30' 62.1 Temperature
5.degree. C. Disintegration (minute:second) 03:59 03:18 Dissolution
(%) pH 1.5 Not tested 10' 15.9 20' 31.1 30' 46.6
[0144] As may be taken from the above Tables 9a, 9b and 9c, only
the liquid filled hard capsule formulation of example 2 according
to the invention shows the preferred fast dissolution profile of
bendamustine, which is at least 60% in 10 minutes, 70% in 20
minutes and 80% in 30 minutes, as measured with a paddle apparatus
at 50 rpm according to the European Pharmacopoeia in 500 ml of an
artificial gastric fluid.
Example 7
TABLE-US-00021 [0145] TABLE 10 results of analytical tests on
formulations of example 4 Analytical Ex. Ex. Ex Ex Ex Ex. Ex Test
Limits 4.2 4.7 4.3 4.5 4.6 4.4 4.1 Identification (HPLC) Positive
Positive Positive Positive Positive Positive Positive Positive
Content uniformity Complies N/A N/A N/A Complies Complies Complies
Complies (RSD 4.40) (RSD 2.66) Assay (HPLC) 95.0%- 98.2 101.0 117.9
98.6 103.3 95.8 98.0 105.0% Related substances (HPLC) HP1 =0.50%
0.30 0.30 0.11 0.13 0.07 0.07 0.05 BM1 Dimer =0.20% 0.05 0.04 0.04
0.05 0.04 0.04 0.04 BM1EE =0.50% 0.14 0.15 0.15 0.14 0.15 0.14 0.14
NP1 =0.20% 0.01 0.01 0.01 0.01 0.01 0.01 0.01 Ind. Unknown impurity
=0.10% 0.04 0.14 0.04 0.05 0.02 0.01 0.03 Total impurities =1.50%
0.54 0.68* 0.35 0.38 0.29 0.27 0.29 Total impurities after 3
months' 0.35 1.12 1.12 storage at 40.degree./75% RH Dissolution
Test (Medium: buffer pH = 1.5) (% 10 min) 80% in 96.9 25.6 67.3
46.8 95.7 65.3 56.9 30 min (% 20 min) 97.1 46.5 96.2 74.3 96.7
102.5 80.4 (% 30 min) 96.7 72.4 104.5 88.9 95.0 109.5 93.8
Dissolution test after 3 months' 91 72 92 storage at 40.degree./75%
RH; (% 30 min)
3. In Vivo Tests
Example 8
[0146] The liquid filled hard capsules of example 2, containing 50
mg of bendamustine, were orally administered to male and female
beagle dogs in comparison with the capsules of reference example 1
in order to determine the bioavailability of 1 dose (i.e. 50 mg) of
bendamustine (AUC and Cmax) and to determine the level of
variability in bioavailability of these capsule formulations: (i.e.
% CV on AUC and Cmax). A further formulation (formulation X) was
also included in the test but since this formulation was outside
the scope of the present invention no details are provided. The
total number of animals required was 16. The basic study design was
a cross-over design with 8 animals per arm.
Period 1 (Single Dose of Capsule, Day 1):
TABLE-US-00022 [0147] Number Group Treatment Composition Dose #
(mg) of animals 1 Bendamustine Reference 50 4 Male + Capsule 4
Female 2 Bendamustine Reference 50 4 Male + Capsule 4 Female
[0148] There was a one week wash-out period.
Period 2 (1 Week after Period 1, Single Dose of Either of the
Following Formulations, Day 8):
TABLE-US-00023 Number Group Treatment Composition Dose # (mg) of
animals 1 Bendamustine Formulation 50 4 Male + example 2 4 Female 2
Bendamustine Formulation X 50 4 Male + 4 Female
[0149] The mean plasma profiles vs. time for both the capsule
formulation (reference example 1) and the liquid filled capsule
formulation of Example 2 are shown in FIG. 1.
Example 9
[0150] An open label, randomized two-way crossover study to assess
the absolute bioavailability of oral bendamustine in patients with
cancer was conducted to assess the absolute bioavailability of
bendamustine administered as an oral formulation (example 2).
Besides assessing the pharmacokinetics of bendamustine in plasma
following oral and i.v. administration, a further objective was to
evaluate the safety and tolerability of bendamustine following i.v.
and especially oral administration of the formulation of example 2.
6 Patients resided in hospital for 2 periods; Day -1 to 2 (period
1) and Day 7-9 (period 2). Patients were enrolled to receive in a
random order one of the following two treatments on Day 1 and 8:
[0151] a single oral dose of 110.2 mg (2.times.55.1 mg)
bendamustine hydrochloride (HCl), being equivalent to about 100 mg
bendamustine free base and [0152] a single i.v. dose of 100 mg
bendamustine HCl, equivalent to 90.7 mg bendamustine free base.
[0153] The dose of bendamustine HCl (100 mg intravenous, 110.2 mg
orally) was selected based on the safety of the oral formulation in
preclinical studies and based on the safety of the registered i.v.
formulation.
[0154] Blood samples were taken on days 1 and 2 and 8 and 9 to
determine the pharmacokinetics of bendamustine and its metabolites
in plasma after oral and i.v. administration of bendamustine. The
time-points were chosen based on data from the literature (Preiss
1985) following i.v. administration of bendamustine. Preiss and
co-workers reported a mean bioavailability of bendamustine of 57%
(range: 25-94%; % CV=44%) after oral administration of bendamustine
as capsule at doses of 250-350 mg in patients with cancer.
Bendamustine was administered on days 1 and 8 in the morning either
orally or intravenously as a single dose (as bendamustine
hydrochloride 100 mg i.v. or 110.2 mg orally).
[0155] Bendamustine was administered orally as two liquid-filled
hard-shell capsules with 250 mL of water or as i.v. infusion over
30 minutes.
[0156] Patients had to fast overnight for at least 8 hours before
oral and i.v. administration of bendamustine in the morning, except
for drinking water which is allowed up to 2 hours prior to
administration of study medication. Patients are allowed to have a
light breakfast 2 hours after each administration.
[0157] The total duration of the admission period was 6 days (day
-1 to 2 and day 7-9) excluding screening and a post study
visit.
[0158] Certain medication was prohibited from 2 weeks before the
first administration of the first study drug.
[0159] The blood concentration-time curve as obtained after
evaluating 6 patients is shown in FIG. 2. The mean value for the
absolute bioavailability, calculated as
AUC.sub.oral/dose/AUC.sub.iv/dose*100% was 58.5%, with a standard
deviation of 9.3 and an interindividual variation (expressed as %
CV) of 15.9.
[0160] Therefore the bioavailability of bendamustine hydrochloride
from the oral formulation of example 2 was found to be in
accordance with that previously reported for
bendamustine-containing capsules in the literature (Preiss), but
the interpatient variability is much lower.
B) Examples Relating to the Second Embodiment of the Invention
1. Compatibility Tests
Example 10a
[0161] For compatibility testing mixtures containing bendamustine
hydrochloride and an excipient at a ratio of 1:1 (m/m) were
prepared. The excipients were selected from mannitol and lactose.
After preparation the mixtures were packed in clear glass
HPLC-Vials (6 ml) Agilent and stored at different storage
conditions as shown in Table 11 below. At defined time points
samples were removed from storage and tested for purity (HPLC;
column: Zorbax Bonus-RP, 5 .mu.m; temperature of column oven:
30.degree. C.; temperature of autosampler: 5.degree. C.; detector:
254 nm) and appearance.
TABLE-US-00024 TABLE 11 Storage Conditions Bendamustine
hydrochloride and excipients for oral formulation Tested time
points Storage condition T = 0 T = 1 month (1) 50.degree. C., Vials
closed n = 2 n = 1 (2) 70.degree. C., Vials closed* n = 2 n = 2 (3)
40.degree. C./75% r.h., Vials open** n = 2 n = 2 *stored at
50.degree. C. for one month before storage at 70.degree. C.
**stored at 25.degree. C./60% r.h. for one month before storage at
40.degree. C./75%
[0162] In all these mixtures, the bendamustine hydrochloride
content (measured by HPLC) barely changed and always remained above
99% for all three storage conditions. The hydrolysis product HP 1
was barely detectable (Area %<0.2) for all three storage
conditions.
[0163] Appearance tests of the named bendamustine hydrochloride
mixtures were carried out with the naked eye. All the investigated
mixtures complied with the specifications and gave white to
off-white powder both immediately after preparation and after one
month of storage under all three storage conditions.
Example 10b
[0164] For further compatibility testing in accordance with the
methods of example 1a, mixtures containing bendamustine
hydrochloride and an excipient at a ratio of 1:1 (m/m) were
prepared. The excipients were selected from Opadry.RTM.,
Eudragit.RTM. E PO, sodium carboxymethylcellulose (Avicel.RTM. RC
591) and cross-linked polyvinylpyrrolidone (Crospovidone).
[0165] In the case of Eudragit.RTM. E PO the initial amounts of the
impurities HP1 (hydrolysis product) and BM1DIMER were significantly
increased (HP1: 1.5%, BM1DIMER: 1%) but during storage a decrease
of these impurities could be detected at all storage conditions
independent of the influence of humidity. In the case of
cross-linked polyvinylpyrrolidone a significant increase of HP1
from 0.1% to 0.4% could be detected at the storage condition
40.degree./75% R.H./vials open. At all other storage conditions
(vials closed) no increase of HP1 could be detected.
[0166] The appearance of the mixtures containing Eudragit.RTM. E PO
and cross-linked polyvinylpyrrolidone changed at the storage
condition 70.degree. C./vials closed. Both mixtures got lightly
sticky. Additionally the colour of the mixture with cross-linked
polyvinylpyrrolidone changed from white too cream-coloured.
[0167] In case of the mixtures containing Opadry.RTM. and
Avicel.RTM. RC591 the colour also changed to cream-coloured at the
storage condition 70.degree. C./vials closed.
2. Tablet Formulations
Example 11
[0168] 253 g of a mixture comprising mannitol as the main excipient
and microcrystalline cellulose, Ac-Di-Sol.RTM., colloidal silicon
dioxide, talc and stearic acid in the relative quantities mentioned
in the following table 2a was prepared by mixing in a 1 liter cube
blender (Erweka) for 15 minutes. Thereafter 10.612 g of the mixture
and 3.0 g of bendamustine hydrochloride were sieved through a 0.425
mm sieve and then transferred into a Turbula mixer T2A, equipped
with a glass vial of 50 ml and subsequently mixed for 10 minutes at
60 rpm.
[0169] From this mixture round tablets were compressed having the
following characteristics:
[0170] Mean value diameter: 9.1 mm; mean value mass: 247.7 mg; mean
value hardness: 81N.
TABLE-US-00025 TABLE 12a Tablet mg/dosage- Relative Component form
Content % bendamustine hydrochloride 55.1 22.04 Mannitol 141.4
56.56 Microcrystalline cellulose (Avicel .RTM. PH112) 25.0 10.00
Ac-Di-Sol .RTM. 12.5 5.00 Colloidal silicon dioxide (Aerosil .RTM.
200) 1.0 0.40 Talc 12.5 5.00 Stearic acid 2.5 1.00
[0171] Tablets were stored at 40.degree. C./75% RH (glass vial
open) or 50.degree. C. (glass vial closed). The amount of
bendamustine hydrochloride as well as of related substances, like
degradation products, by-products of synthesis were measured with
HPLC (column: Zorbax Bonus-RP, 5 .mu.m; temperature of column oven:
30.degree. C.; temperature of autosampler: 5.degree. C.; detector:
254 nm). The results are shown in Table 12b.
TABLE-US-00026 TABLE 12b Related substances and assay of
bendamustine HCl (residual content) Bendamustine HCl Storage
Related [% area] condition substances*.sup.1 T = 0*.sup.2 T = 1
month T = 0 T = 1 month 40.degree. C./75% HP1 0.13 0.22 99.60 99.13
RH (open NP1 0.02 0.02 vial) BM1Dimer 0.06 0.25 BM1EE 0.13 0.12 HP2
n.d. 0.13 HP3 n.d. 0.03 50.degree. C. HP1 0.13 0.53 99.60 98.94
(closed vial) NP1 0.02 0.02 BM1Dimer 0.06 0.14 BM1EE 0.13 0.11 HP2
n.d. 0.05 HP3 n.d. n.d. *.sup.1NP1:
4-[6-(2-Chloroethyl)-3,6,7,8-tetra-hydro-3-methyl-imidazo[4,5-h]-[1,4]ben-
zothiazin-2-yl] butanoic acid BM1Dimer:
4-{5-[N-(2-Chloroethyl)-N-(2-{4-[5-bis(2-chloroethyl)amino-1-met-
hylbenzimidazol-2-yl]butanoyloxy}ethyl)amino]-1-methylbenzimidazol-2-yl}bu-
tanoic acid BM1EE:
4-[5-[Bis(2-chloroethyl)amino]-1-methyl-benzimidazo-2-yl] butanoic
ethyl ester *.sup.2n.d.: not detectable, i.e. beyond detection
limit (area percentage less than 0.05%)
Example 12
[0172] A mixture and tablets were prepared in the same way as
described in Example 11, but using the compounds and relative
amounts as indicated in the following Table 3a.
[0173] The tablets had the following characteristics:
[0174] Mean value diameter: 9.1 mm; mean value mass: 248.9 mg.
TABLE-US-00027 TABLE 13a Tablet mg/dosage- Relative Component form
Content % bendamustine hydrochloride 55.1 22.04 Lactose anhydrous
141.4 56.56 Microcrystalline cellulose (Avicel .RTM. PH112) 25.0
10.00 Ac-Di-Sol .RTM. 12.5 5.00 Colloidal silicon dioxide (Aerosil
.RTM. 200) 1.0 0.40 Talc 12.5 5.00 Stearic acid 2.5 1.00
[0175] Tablets were stored at 40.degree. C./75% RH (glass vial
open) or 50.degree. C. (glass vial closed). The amount of
bendamustine hydrochloride and of related substances was measured
with HPLC as mentioned above. The results are shown in Table
13b:
TABLE-US-00028 TABLE 13b Related substances and assay of
bendamustine HCl (residual content) Bendamustine HCl Storage
Related T = 1 [% area] condition substances T = 0 month T = 0 T = 1
month 40.degree. C./75% RH HP1 0.12 0.22 99.60 99.13 (open vial)
NP1 0.02 0.02 BM1Dimer 0.06 0.26 BM1EE 0.13 0.13 HP2 n.d. 0.11 HP3
n.d. 0.03 50.degree. C. (closed HP1 0.12 0.57 99.61 98.88 vial) NP1
0.02 0.02 BM1Dimer 0.06 0.13 BM1EE 0.13 0.11 HP2 n.d. 0.05 HP3 n.d.
n.d.
Example 13
[0176] Tablets were prepared in the same way as described in
Example 11, but using the compounds and relative amounts as
indicated in the following Table 14a.
[0177] The tablets had the following characteristics:
[0178] Mean value diameter: 9.1 mm; mean value mass: 247.8 mg.
TABLE-US-00029 TABLE 14a Tablet mg/dosage- Relative Component form
Content % Bendamustine hydrochloride 55.1 22.04 Lactose anhydrous
145.15 58.06 Microcrystalline cellulose (Avicel .RTM. PH112) 31.25
12.50 Ac-Di-Sol .RTM. 12.5 5.00 Colloidal silicon dioxide (Aerosil
.RTM. 200) 1.0 0.40 Magnesium stearate 2.5 1.00 Ascorbic acid 2.5
1.00
[0179] Tablets were stored at 40.degree. C./75% RH (glass vial
open) or 50.degree. C. (glass vial closed). The amount of
bendamustine hydrochloride and of related substances was measured
with HPLC as mentioned above. The results are shown in Table
14b:
TABLE-US-00030 TABLE 14b Related substances and assay of
bendamustine HCl (residual content) Bendamustine HCl Storage
Related T = 1 [% area] condition substances T = 0 month T = 0 T = 1
month 40.degree. C./75% RH HP1 0.13 0.24 99.58 99.05 (open vial)
NP1 0.02 0.02 BM1Dimer 0.06 0.27 BM1EE 0.14 0.13 HP2 n.d. 0.13 HP3
n.d. 0.06 50.degree. C. (closed HP1 0.13 0.63 99.58 98.32 vial) NP1
0.02 0.02 BM1Dimer 0.06 0.18 BM1EE 0.14 0.12 HP2 n.d. n.d. HP3 n.d.
n.d.
Prior Art Reference Example
[0180] 20.0.+-.1 mg of bendamustine hydrochloride were weighed into
the body of an empty hard gelatine capsule, and put into a clear
glass HPLC vial (6 ml) of Agilent. Capsules were closed by placing
the cap on top of the body and slight pushing. Capsules were stored
at 40.degree. C./75% RH (glass vial open) or 50.degree. C. (glass
vial closed). The amount of bendamustine hydrochloride and of
related substances was measured with HPLC as mentioned above. The
results are shown in Table 15:
TABLE-US-00031 TABLE 15 Related substances and assay of
bendamustine HCl (residual content) Bendamustine HCl Storage
Related T = 1 [% area] condition substances T = 0 month T = 0 T = 1
month 40.degree. C./75% RH HP1 0.10 0.45 99.64 98.83 (open vial)
NP1 0.02 0.02 BM1Dimer 0.06 0.42 BM1EE 0.13 0.11 HP2 n.d. n.d. HP3
n.d. n.d. 50.degree. C. (closed HP1 0.10 1.46 99.64 97.51 vial) NP1
0.02 0.02 BM1Dimer 0.06 0.24 BM1EE 0.13 0.12 HP2 n.d. n.d. HP3 n.d.
n.d.
[0181] As is immediately apparent, the capsule formulations were a
lot less stable than the tablet formulations according to the
invention although the capsule formulations were prepared from pure
bendamustine hydrochloride without any further processing steps.
Both at 40.degree. C./75% RH (glass vial open) and 50.degree. C.
(closed vial) more degradation products are formed within one month
of storage. In the case of open vial with 40.degree. C. and 75% RH
(relative humidity) the amount of hydrolysis product HP1 is
increased by a factor of 4 after one month of storage. For the
closed vials the HP1 content is even higher, which might be due to
reaction with the capsules. Summarising, tablets provide a much
more stable solid dosage form than the capsules.
Example 14
[0182] 8.0 g of hydroxypropylmethyl cellulose and 1.5 g PEG 6000
are dissolved in 88.5 g purified water. Thereafter 2.0 g yellow
ferric oxide and 0.5 g titanium oxide are dispersed therein
yielding a coating liquid. Tablets as obtained in Example 11 are
coated with 3% of this solution per tablet mass using a film
coating device.
Example 15
TABLE-US-00032 [0183] TABLE 16a Coated Tablet Relative Content
Component mg/dosage-form % Tablet cores bendamustine hydrochloride
55.1 21.09 Mannitol 141.4 54.11 Microcrystalline cellulose (Avicel
.RTM. PH101) 25.0 9.57 Crosscarmellose sodium (Ac-Di-Sol .RTM.)
12.5 4.78 Colloidal silicon dioxide (Aerosil .RTM. 200) 1.0 0.38
Talc 18.8 7.19 Stearic acid 7.5 2.87 Sum 261.3 100 Film-coating
Opadry .RTM. 12.5 10 Purified water -- 90 Target mass gain
(mg/tablet)/Sum 12.5 100 Manufacturing method for 1000 tablets
[0184] All tablet-core components except for colloidal silicon
dioxide and stearic acid were loaded into a Somakon vessel (5 L).
Bendamustine was added and blending was conducted for 4 minutes at
1000 rpm (wiper 10 rpm). The resulting blend was sieved through a
0.5 mm sieve. The vessel was reloaded with the blend and colloidal
silicon dioxide was added. Blending was conducted for 2 minutes at
the afore-mentioned conditions. Thereafter stearic acid was added
and blending was continued for 1 minute. The blend was subsequently
sieved through a 0.5 mm sieve, reloaded into the vessel and blended
for another 30 seconds, all at the same conditions.
[0185] From this mixture round tablets were compressed having the
following characteristics:
[0186] Mean value diameter: 9.5 mm; mean value mass: 254.6 mg
(begin)-257.2 mg (end); friability 0.1%; mean value hardness: 122N
(begin)-128 (end).
[0187] The tablets were subsequently film-coated with the
Opadry.RTM. dispersion until a mass increase of 5% had been
achieved.
[0188] The mean mass of the film-coated tablets was 268.4 mg.
[0189] Both the tablet cores and film-coated tablets were stored at
40.degree. C./75% RH in closed amber glass vials. The amount of
bendamustine hydrochloride as well as of related substances, like
degradation products, by-products of synthesis were measured with
HPLC as mentioned above. The results are shown in Tables 16b.1 and
16b.2.
TABLE-US-00033 TABLE 16b.1 Related substances and assay of
bendamustine HCl (residual content) in tablet cores Bendamustine
HCl Storage Related T = 2 [% area] condition substances T = 0
months T = 0 T = 2 months 40.degree. C./75% HP1 0.15 0.13 99.49
99.49 RH (closed NP1 n.d. n.d. vials) BM1Dimer 0.09 0.17 BM1EE 0.15
0.13 Unid RRT 0.69*.sup.3 0.08 0.05 *.sup.3Unidentified compound
peak at relative retention time of 0.69 as compared to main
peak
TABLE-US-00034 TABLE 16b.2 Related substances and assay of
bendamustine HCl (residual content) in coated tablet Bendamustine
HCl Storage Related T = 2 [% area] condition substances T = 0
months T = 0 T = 2 months 40.degree. C./75% HP1 0.16 0.17 99.46
99.29 RH (closed HP2 n.d. 0.08 vials) HP3 n.d. <0.05 NP1 n.d.
n.d. BM1Dimer 0.09 0.18 BM1EE 0.15 0.14 Unid RRT 0.69 0.10 0.05
Example 16
TABLE-US-00035 [0190] TABLE 17a Tablet Relative Component
mg/dosage-form Content % Tablet cores bendamustine hydrochloride
55.1 21.09 Lactose anhydrous 141.4 54.11 Microcrystalline cellulose
25.0 9.57 (Avicel .RTM. PH112) Crosscarmellose sodium (Ac-Di-Sol
.RTM.) 12.5 4.78 Colloidal silicon dioxide (Aerosil .RTM. 200) 1.0
0.38 Talc 18.8 7.19 Stearic acid 7.5 2.87 Sum 261.3 100
Film-coating Eudragit .RTM. E PO 7.5 7.5 Sodium laurylsulphate 0.8
0.8 Stearic acid 1.2 1.2 Iron oxide 1.0 1.0 Titanium dioxide 1.0
1.0 Talc 3.5 3.5 Purified water -- 85.0 Target mass gain
(mg/tablet)/Sum 15.0 100.0 Manufacturing method for 1000
tablets
[0191] All tablet-core components except for colloidal silicon
dioxide and stearic acid were loaded into a Somakon vessel (5 L).
Bendamustine was added and blending was conducted for 4 minutes at
1000 rpm (wiper 10 rpm). The resulting blend was sieved through a
0.5 mm sieve. The vessel was reloaded with the blend and colloidal
silicon dioxide was added. Blending was conducted for 2 minutes at
the afore-mentioned conditions. Thereafter stearic acid was added
and blending was continued for 1 minute. The blend was subsequently
sieved through a 0.5 mm sieve, reloaded into the vessel and blended
for another 30 seconds, all at the same conditions.
[0192] From this mixture round tablets were compressed having the
following characteristics: mean value diameter: 9.5 mm; mean value
mass: 262.4 mg (begin)-254.4 mg (end); friability: 0.1%
(begin)-0.2% (end); mean hardness value: 98N (begin)-91N (end).
[0193] The tablets were subsequently film-coated with the
Eudragit.RTM. dispersion until a mass increase of 3% had been
achieved.
[0194] The mean mass of the film-coated tablets was 273.5 mg.
[0195] Both the tablet cores and the film-coated tablets were
stored at 40.degree. C./75% RH in closed amber glass vials. The
amount of bendamustine hydrochloride and of related substances was
measured with HPLC, as mentioned above. The results are shown in
Tables 17b.1 and 17.b2:
TABLE-US-00036 TABLE 17b.1 Related substances and assay of
bendamustine HCl (residual content) in tablet core Bendamustine HCl
Storage Related T = 2 [% area] condition substances T = 0 months T
= 0 T = 2 months 40.degree. C./75% RH HP1 0.17 0.12 99.50 99.55
(closed vials) NP1 n.d. n.d. BM1Dimer 0.09 0.14 BM1EE 0.15 0.14
Unid RRT 0.06 <0.05 0.69
TABLE-US-00037 TABLE 17b.2 Related substances and assay of
bendamustine HCl (residual content) in coated tablet Bendamustine
HCl Storage Related T = 2 [% area] condition substances T = 0
months T = 0 T = 2 months 40.degree. C./75% RH HP1 0.18 0.20 99.43
98.93 (closed vials) HP2 n.d. 0.35 HP3 n.d. 0.07 NP1 n.d. n.d.
BM1Dimer 0.12 0.20 BM1EE 0.15 0.13 Unid RRT 0.05 <0.05 0.69
Example 17
TABLE-US-00038 [0196] TABLE 18a Tablet Relative Component
mg/dosage-form Content % Tablet cores Bendamustine hydrochloride
55.1 22.04 Lactose anhydrous 145.15 58.06 Microcrystalline
cellulose 31.25 12.50 (Avicel .RTM. PH112) Ac-Di-Sol .RTM. 12.5
5.00 Colloidal silicon dioxide (Aerosil .RTM. 200) 1.0 0.40
Magnesium stearate 2.5 1.00 Ascorbic acid 2.5 1.00 Sum 250 100.0
Film-coating Eudragit .RTM. E PO 7.5 7.5 Sodium laurylsulphate 0.8
0.8 Stearic acid 1.2 1.2 Iron oxide 1.0 1.0 Titanium dioxide 1.0
1.0 Talc 3.5 3.5 Purified water -- 85.0 Target mass gain
(mg/tablet)/Sum 15.0 100.0 Manufacturing method for 1000
tablets
[0197] All tablet-core components except for colloidal silicon
dioxide and stearic acid were loaded into a Somakon vessel (2.5 L).
Bendamustine was added and blending was conducted for 4 minutes at
1000 rpm (wiper 10 rpm). The resulting blend was sieved through a
0.5 mm sieve. The vessel was reloaded with the blend and colloidal
silicon dioxide was added. Blending was conducted for 2 minutes at
the afore-mentioned conditions. Thereafter stearic acid was added
and blending was continued for 1 minute. The blend was subsequently
sieved through a 0.5 mm sieve, reloaded into the vessel and blended
for another 30 seconds, all at the same conditions.
[0198] From this mixture round tablets were compressed having the
following characteristics: Mean value diameter: 9.5 mm; mean value
mass: 252.2 mg (begin)-250.7 mg (end); friability: 0.1%
(begin)-0.2% (end); mean hardness value: 65N (begin)-73N (end).
[0199] The tablets were subsequently film-coated with the
Eudragit.RTM. dispersion until a mass increase of 3% had been
achieved.
[0200] The mean mass of the film-coated tablets was 253.6 mg. Both
the tablet cores and the film-coated tablets were stored at
40.degree. C./75% RH in closed amber glass vials. The amount of
bendamustine hydrochloride and of related substances was measured
with HPLC, as described above. The results are shown in Tables
18b.1 and 18b.2:
TABLE-US-00039 TABLE 18b.1 Related substances and assay of
bendamustine HCl (residual content) in tablet core Bendamustine HCl
Storage Related T = 2 [% area] condition substances T = 0 months T
= 0 T = 2 months 40.degree. C./75% RH HP1 0.17 0.14 99.47 99.45
(closed vials) HP3 n.d. 0.07 NP1 n.d. n.d. BM1Dimer 0.10 0.19 BM1EE
0.15 0.14 Unid RRT 0.05 n.d. 0.69
TABLE-US-00040 TABLE 18b.2 Related substances and assay of
bendamustine HCl (residual content) in coated tablet Bendamustine
HCl Storage Related T = 2 [% area] condition substances T = 0
months T = 0 T = 2 months 40.degree. C./75% RH HP1 0.19 0.16 99.46
99.36 (closed vials) HP2 n.d. 0.06 HP3 n.d. 0.05 NP1 n.d. n.d.
BM1Dimer 0.09 0.18 BM1EE 0.15 0.14 Unid RRT <0.05 <0.05
0.69
Example 18
TABLE-US-00041 [0201] TABLE 9a composition coated tablets
Composition PF1 PF2 PF3 component mg/tablet mg/tablet mg/tablet
Bendamustine HCl 55.1 55.1 55.1 Anhydrous dextrose -- -- 205.8
Dextrose monohydrate 186.0 -- -- Trehalose -- 66.0 -- sorbitol --
-- 43.9 Lactose DCL 21 68.2 185.7 -- Avicel .RTM. PH 112 18.7 --
23.0 Crospovidone -- 21.0 -- Magnesium stearate 2.0 2.2 2.2 Opadry
8.0 8.0 8.0 Total 338.0 338.0 338.0
Manufacturing Method for Formulations PF1 for 600 Tablets:
[0202] 33.06 g of bendamustine, 111.60 g of dextrose, 40.92 g of
lactose, 11.22 g of microcrystalline cellulose and 1.20 g of
magnesium stearate were weighed and transferred into a double
polyethylene bag and mixed for 5 minutes. Thereafter the powder
blend was transferred to the hopper of an eccentric tabletting
machine (Korsch EK0) and compressed into round tablets having the
following characteristics: mean value diameter: 10.0 mm; mean value
mass: 336.9 mg (begin)-335.98 (end); friability: 0.15%; mean
hardness value: 69.25N (begin)-68.60N (end).
[0203] The tablet cores were subsequently coated in a coating pan
(4M8 ForMate PanCoat) using a 9% Opadry.RTM. TM White aqueous
suspension and dried. The mean mass of the tablets was 342.42 mg.
Thereafter the tablets were packed into amber glass bottles closed
with screw plugs and stored at 40.degree. C./75% RH.
Manufacturing Method for Formulations PF2 for 600 Tablets:
[0204] 33.06 g of bendamustine, 111.42 g of lactose, 39.60 g of
trehalose, 12.60 g of cross-linked polyvinylpyrrolidone and 1.32 g
of magnesium stearate were weighed and transferred into a double
polyethylene bag and mixed for 5 minutes. Thereafter the powder
blend was transferred to the hopper of an eccentric tabletting
machine (Korsch EK0) and compressed into round tablets having the
following characteristics: mean value diameter: 10.0 mm; mean value
mass: 332.95 mg (begin)-332.12 (end); friability: 0.3%; mean
hardness value: 65.9 N (begin)-59.0 N (end).
[0205] The tablet cores were subsequently coated in a coating pan
(4M8 ForMate PanCoat) using a 9% Opadry.RTM. TM White aqueous
suspension and dried. The mean mass of the tablets was 340.1 mg.
Thereafter the tablets were packed into amber glass bottles closed
with screw plugs and stored at 40.degree. C./75% RH.
Manufacturing Method for Formulation PF3:
[0206] Sorbitol and anhydrous dextrose were weighed. 140.64 g of
Sorbitol was dissolved in 105.48 g of purified water and the
solution obtained was subsequently used to granulate 659.36 g of
dextrose in a Fluid Bed Granulator (4M8ForMate FluidBed).
Thereafter the granulate was dried at 60.degree. C. and sieved
through a 850 .mu.m sieve.
[0207] 33.06 g of bendamustine hydrochloride, 149.82 g of the
sorbitol/dextrose granulate, 13.8 g of microcrystalline cellulose
and 1.32 g of magnesium stearate were weighed into a double
polyethylene bag and mixed for 5 minutes. Thereafter the powder
blend was transferred to the hopper of an eccentric tabletting
machine (Korsch EK0O and compressed into round tablets having a
mean diameter of 10.0 mm The tablets had a mean value for mass of
335.99 mg (begin)-339.50 mg (end); friability: 0%; mean hardness
value: 125.60N (begin)-129.7N (end). The tablets were then
subjected to a conditioning process according to the following two
steps (performed only on selected batches): placing them at
25.degree. C./60% R.H. for two hours and subsequently at 40.degree.
C. for two hours.
[0208] The tablets were subsequently coated in a coating pan (4M8
ForMate PanCoat) using a 9% Opadry.RTM. TM White aqueous
suspension. Mean mass of the tablets: 341.43 mg. Thereafter the
tablets were packed into amber glass bottles closed with screw
plugs and stored at 40.degree. C./75% RH.
[0209] The amount of bendamustine hydrochloride and of related
substances in the stored film-coated tablets was measured with
HPLC, as described above. The results are shown in Tables 19b.1-19b
0.3:
TABLE-US-00042 TABLE 19b.1 Related substances and assay of
bendamustine HCl (residual content) in coated tablet (formulation
1; Opadry .RTM.) PF1 Bendamustine HCl Storage Related T = 3 [%
area] condition substances T = 0 months T = 0 T = 3 months
40.degree. C./75% RH HP1 0.03 0.08 99.5 98.7 (closed vials) NP1
n.d. n.d. BM1Dimer 0.05 0.16 BM1EE 0.15 0.13 Individual 0.01 0.06
unknown impurity
TABLE-US-00043 TABLE 19b.2 Related substances and assay of
bendamustine HCl (residual content) in coated tablet (formulation
2; Opadry .RTM.) PF2 Bendamustine HCl Storage Related T = 3 [%
area] condition substances T = 0 months T = 0 T = 3 months
40.degree. C./75% RH HP1 0.02 0.23 98.5 98.3 (closed vials) NP1
0.01 0.01 BM1Dimer 0.03 0.23 BM1EE 0.15 0.11 Individual 0.01 0.05
unknown impurity
TABLE-US-00044 TABLE 19b.3 Related substances and assay of
bendamustine HCl (residual content) in coated tablet (formulation
3; Opadry .RTM.) PF3 Bendamustine HCl Storage Related T = 3 [%
area] condition substances T = 0 months T = 0 T = 3 months
40.degree. C./75% RH HP1 0.05 0.09 98.1 98.4 (closed vials) NP1
n.d. n.d. BM1Dimer 0.06 0.19 BM1EE 0.15 0.14 Individual 0.03 0.11
unknown impurity
3. Dissolution Tests
Example 19
[0210] Dissolution tests for the tablet formulations of Examples 11
and 12 were carried out in artificial gastric fluid at T=0. The
dissolution samples are tested for assay by HPLC (column: Zorbax
Bonus-RP, 5 .mu.m; temperature of column oven: 30.degree. C.;
temperature of autosampler: 5.degree. C.; detector: 254 nm).
Artificial gastric fluid pH 1.5 was prepared by dissolving 2 g of
sodium chloride p.A. in 1000 ml of water and adjusting the pH to
1.5.+-.0.05 with 5 N hydrochloric acid. The dissolution test was
conducted according to Chapter 2.9.3. of European Pharmacopoeia
6.0, using Apparatus 2 (Paddle-apparatus). The rotation speed of
the paddle was 50 rpm, the temperature was 37.degree.
C..+-.0.5.degree. C., the amount of dissolution medium was 500
ml.
[0211] The results for the tablet formulations of Example 11
(tablet formulation 1) and Example 12 (tablet formulation 2) are
shown in the following Table 20a:
TABLE-US-00045 TABLE 20.a Tablet Tablet formulation 1 formulation 2
Dissolution Dissolution: Single Mean Single Mean Dissolution value
value value value after: [%] [%] [%] [%] 10 min 85.3 84 80.9 88
77.4 87.8 87.2 88.7 90.6 94.3 79.6 87.9 84.1 90.8 20 min 94.7 95
96.5 96 95.7 98.7 96.6 95.7 96.4 94.3 93.0 93.8 93.9 97.0 30 min
93.3 94 95.3 95 94.3 96.4 95.4 94.4 95.4 93.1 91.8 92.9 93.0
95.3
[0212] The results of the same dissolution tests carried out on the
coated tablet formulations of Example 15, Example 16 and Example 17
at T=0 are shown in the following Table 20b:
TABLE-US-00046 TABLE 20b Tablet Tablet formulation Tablet
formulation formulation Dissolution example 15 example 16 example
17 after Mean value Mean value Mean value 10 minutes 77 47 83 20
minutes 88 76 90 30 minutes 87 87 88
[0213] Corresponding dissolution data for the tablets of example 18
were:
TABLE-US-00047 Tablet Tablet formulation formulation Tablet
formulation example 18 (PF1) example 18 (PF2) example 18 (PF3) Mean
value after Mean value after Mean value after 3 Dissolution 3
months at 3 months at months storage at after 40.degree. C./75% RH
40.degree. C./75% RH 40.degree. C./75% RH 10 minutes 89.7 96.3 60.1
20 minutes 93.7 95.2 88.8 30 minutes 93.2 93.3 94.0
[0214] As may be taken from the above all tablet formulations of
the invention show a fast dissolution of bendamustine. In
particular the inventive formulations show a dissolution profile of
the bendamustine as defined hereinbefore.
4. In Vivo Tests
[0215] Animal Bioavailability Studies of Bendamustine were
Performed in Beagle Dogs: PK Study Outlines
Study 1
[0216] The objective was to determine the bioavailability of 1 dose
(i.e. 50 mg) of bendamustine in 3 tablet formulations (T1-3) and 1
capsule formulation (C) with a total of 4 oral formulations: AUC
and Cmax
[0217] Total number of animals required: 16
Basic Design:
[0218] Cross-over design, 8 animals per arm:
TABLE-US-00048 TABLE 21a Period 1 (single dose of tablet, or
capsule, day 1): Dose # Number of Animal Group Treatment Dose route
(mg) animals numbers 1 Bendamustine Capsule 50 2 Male + 37, 39 2
Female 38, 40 2 Bendamustine Tablet T1 50 2 Male + 41, 43 2 Female
42, 44 3 Bendamustine Capsule 50 1 Male + 45 1 Female 46 4
Bendamustine Tablet T2 50 2 Male + 47, 49 1 Female 48 5
Bendamustine Tablet T3 50 1 Male + 51 2 Female 50, 52
One Week Wash-Out
TABLE-US-00049 [0219] TABLE 21b Period 2 (1 week after period 1,
single dose of any of the following, day 8): Dose # Number of
Animal Group Treatment Dose route (mg) animals numbers 1
Bendamustine Tablet T1 50 2 Male + 37, 39 2 Female 38, 40 2
Bendamustine Capsule 50 2 Male + 41, 43 2 Female 42, 44 3
Bendamustine Tablet T3 50 1 Male + 45 1 Female 46 4 Bendamustine
Capsule 50 2 Male + 47, 49 1 Female 48 5 Bendamustine Tablet T2 50
1 Male + 51 2 Female 50, 52 One week wash-out
TABLE-US-00050 TABLE 21c Period 3 (1 week after period 2, single
dose of any of the following, day 15): Dose Dose # Number of Animal
Group Treatment route (mg) animals numbers 3 Bendamustine Tablet T2
50 1 Male + 45 1 Female 46 4 Bendamustine Tablet T3 50 2 Male + 47,
49 1 Female 48 5 Bendamustine Capsule 50 1 Male + 51 2 Female 50,
52
Study 2
[0220] The objective was to determine the bioavailability of 1 dose
(i.e. 50 mg) of bendamustine in 1 tablet formulation T4, and 1
capsule formulation (C) with a total of 3 oral formulations: AUC
and Cmax
[0221] Total number of animals required: 16
Basic Design:
[0222] Cross-over design, 8 animals per arm:
TABLE-US-00051 TABLE 22a Period 1 (single dose of capsule, day 1):
Dose # Number of Animal Group Treatment Dose (mg) animals numbers 1
Bendamustine Capsule 50 4 Male + 4 Female 2 Bendamustine Capsule 50
4 Male + 4 Female
One Week Wash-Out
TABLE-US-00052 [0223] TABLE 22b Period 2 (1 week after period 1,
single dose of either of the following formulations, day 8): Dose #
Number of Animal Group Treatment Dose route (mg) animals numbers 1
Bendamustine Formulation 50 4 Male + X 4 Female 2 Bendamustine T4
50 4 Male + 4 Female
Example 20
[0224] The coated tablets of Example 18 (formulation 3, coated with
Opadry.RTM. Tablets T4), containing 50 mg of bendamustine, were
orally administered to male and female dogs in comparison with the
capsules of the reference example.
[0225] The mean plasma profiles vs. time for both the capsule
formulation and the coated tablet of Example 18 are shown in FIG.
3.
Example 21
[0226] The coated tablets of Examples 15, 16, or 17 (Tablets T1 to
T3), containing 50 mg of bendamustine, were orally administered to
male and female dogs in comparison with the capsules of the
reference example.
[0227] The mean plasma profiles vs. time of the capsule formulation
and the coated tablets of Examples 15 to 17 are shown in FIG.
3.
[0228] Experiments were conducted in order to: [0229] assess which
saccharides or saccharide mixtures are suitable to obtain
chemically stable tablets, with fast dissolution profile and
hardness values suitable for coating; [0230] evaluate the
compatibility between API and excipients; [0231] develop placebo
and API-containing batches by investigating different manufacturing
processes: dry granulation, direct compression and wet granulation;
[0232] evaluate different bendamustine hydrochloride/saccharide
weight ratios; [0233] evaluate the impact of saccharide purity on
the formation of bendamustine hydrochloride purities; [0234]
investigate the influence of moisture content on the technological
properties and stability of the manufactured tablets; [0235]
manufacture tablets using the commercially available freeze dried
bendamustine hydrochloride product (Ribomustin.RTM.) and to compare
the properties of these tablets with tablets produced using
corresponding amounts of mannitol and bendamustine
hydrochloride.
[0236] The following saccharidests were used for the manufacturing
of tablets in accordance with the invention, the tablets containing
50 mg of bendamustine (55 mg as bendamustine hydrochloride)
TABLE-US-00053 TABLE 23 Product name/ Chemical name Manufacturer
Class Dextrose anhydrous Dextrose anhydrous Monosaccharide
C/Roquette Dextrose anhydrous Dextrose anhydrous ST Monosaccharide
0.5/Roquette Dextrose monohydrate Dextrose monohydrate
Monosaccharide G/Roquette Dextrose monohydrate Dextrose monohydrate
Monosaccharide M/Roquette Lactitol monohydrate Lacty-M/Purac
Biochem Disaccharide Lactitol MC/Danisco Trehalose Treha
16400/Cargill Disaccharide Sorbitol Neosorb P60W/Roquette
Monosaccharide Erythritol Zerose (TM) Erythritol Monosaccharide
16954/Cargill Maltose Monohydrate Sunmalt S/Hayashibara
Disaccharide Mannitol Pearlitol 200 Monosaccharide SD/Roquette
Lactose anhydrous SuperTab 21 AN/DMV- Disaccharide Fonterra
Excipients Lactose monohydrate SuperTab 14 SD/DMV- Disaccharide
Fonterra Excipients Fructose Fructose MS/Galam Monosaccharide
Maltitol Sweetpearl Disaccharide P200/Roquette Xylitol Xylisorb
300/Roquette Monosaccharide Sucrose Sucrose Comprizucker
Disaccharide S/Suedzucher Sucrose Sucrose RFS/Suedzucker
Disaccharide Sucrose EV saccharide DC 3,75 Disaccharide 97% +
Maltodextrin 3% MD/ Vibar Nord SPA .beta.-Cyclodextrin Kleptose
DC/Roquette Cyclic eptasaccharide D-Raffinose Pentahydrate n/a/Senn
Chemicals Trisaccharide D-Melezitose n/a/Biosynth Trisaccharide
monohydrate Microcrystalline Cellulose Avicel PH112/FMC
Polysaccharide Biopolymer Microcrystalline Cellulose Avicel
pH101/FMC Polysaccharide Biopolymer
[0237] The quality of the batches made was assessed by observation
of the physical appearance, identification test (HPLC), dissolution
test, content and related substances assay (HPLC), content
uniformity test (HPLC), hardness test and water content (Karl
Fischer method). Batches were submitted to accelerated stability
studies packaged in amber glass bottles under the storage
conditions detailed in the following table. For each manufactured
API-containing batch some tablets were stored at 5.degree. C. as
back-up samples.
[0238] In the following, the various excipients in relation to
their manufacturing process were investigated. By using these
excipients several placebo manufacturing trials were carried out by
dry granulation to obtain preliminary information about the
manufacturing method suitable to obtain tablets with good
quality.
[0239] Two types of disintegrants were used: microcrystalline
cellulose (Avicel.RTM.PH 112), as a standard disintegrant, and
cross-linked polyvinylpyrrolidone (Crospovidone.RTM.), used just
for batch D001T/002. The choice of Crospovidone.RTM. for batch
D001T/002 (filler: anhydrous lactose) was based on the similarity
between this formulation and the prototype formulation of example
9. Magnesium stearate was used as lubricant for all the batches
produced. the dry granulation manufacturing process for placebo
trials consisted in the following steps: [0240] 1. The saccharide
and a partial quantity of lubricant (83.3%.sub.w/w of the total
amount) were accurately weighed and then mixed in a polyethylene
bag for 2 minutes. [0241] 2. The obtained mixture was compacted by
using the tabletting machine equipped with a 18 mm diameter punch.
[0242] 3. The obtained slugs were sieved by using a 850 micron net.
[0243] 4. The granulate was weighed and mixed with the disintegrant
and the remaining amount of the lubricant (16.7%.sub.w/w) in a
polyethylene bag for 2 minutes and then tabletted by using a 10 mm
diameter punch.
[0244] Table 24 and Table 25 summarize the composition of each
Placebo formulation and the results of the analytical tests
performed on both the final mixtures and the tablets. In Table 16,
observations made during the manufacturing process of placebo
batches and/or during their analytical characterization are
reported.
[0245] The analytical and physical test results carried out on
placebo batches D001T/001-D001T/002-D001T/004-D001T/013-D001T/015
showed that these formulations are suitable to be manufactured by
dry granulation and further investigated by the addition of the
API. All the other formulations are characterized by a powder
difficult to compact and, when obtained, tablets with high
friability.
[0246] Batch D001T/005 (filler: .beta.-cyclodextrin) showed good
behaviour in dry manufacturing process, high hardness, low
friability but long disintegration time. This formulation was
further investigated by employing a super disintegrant
(Crospovidone.RTM.) and adding the API (see following
paragraph).
TABLE-US-00054 TABLE 24 Dry granulation--Placebo batches
composition and analytical results (batches D001T/001 / D001T/010).
Placebo Batches manufactured by Dry Granulation Com- D001T/001
D001T/002 D001T/003 D001T/004 D001T/005 D001T/006 D001T/007
D001T/008 D001T/009 D001T/010 ponents (%.sub.w/w) (%.sub.w/w)
(%.sub.w/w) (%.sub.w/w) (%.sub.w/w) (%.sub.w/w) (%.sub.w/w)
(%.sub.w/w) (%.sub.w/w) (%.sub.w/w) Lactose 93.7 -- -- -- -- -- --
-- -- -- Mono- hydrate (SuperTab 14 SD) Lactose -- 93.7 -- -- -- --
-- -- -- -- Anhydrous (SuperTab 21 AN) Mannitol -- -- 93.7 -- -- --
-- -- -- -- (Pearlitol 200 SD) Sorbitol -- -- -- 93.7 -- -- -- --
-- -- (Neosorb P60 W) .beta.-Cyclo- -- -- -- -- 93.7 -- -- -- -- --
dextrin (Kleptose DC) Dextrose -- -- -- -- -- 93.7 -- -- -- --
Anhydrous (Dextrose Anhy- drous C) Dextrose -- -- -- -- -- -- 93.7
-- -- -- Mono- hydrate (Dextrose Mono- hydrate G) D- -- -- -- -- --
-- -- 93.7 -- -- Raffinose Penta- hydrate Trehalose -- -- -- -- --
-- -- -- 93.7 -- (Treha 16400) Erythritol 99.5 (Zerose Erythritol
16954) Avicel 5.7 -- 5.7 5.7 5.7 5.7 5.7 5.7 5.7 -- PH 112 Cros- --
5.7 -- -- -- -- -- -- -- -- povidone Mag- 0.6 0.6 0.6 0.6 0.6 0.6
0.6 0.6 0.6 0.5 nesium Stearate Results of analytical tests
performed on final mixtures Water 5.26 0.85 0.47 0.93 12.62 0.47
8.47 14.59 9.36 N.A. Content (%) Flowability 24.68 4.66 9.91 13.70
15.61 27.70 25.37 19.43 20.85 N.A. (seconds) (Nozzle 1, (Nozzle 3,
(Nozzle 2, (Nozzle 1, (Nozzle 1, (Nozzle 1, (Nozzle 1, (Nozzle 1,
(Nozzle 1, (Test diameter = diameter = diameter = diameter =
diameter = diameter = diameter = diameter = diameter = performed
10.0 mm) 25.0 mm) 15.0 mm) 10.0 mm) 10.0 mm) 10.0 mm) 10.0 mm) 10.0
mm) 10.0 mm) according to EP 6.0, par. 2.9.16) Results of
analytical tests performed on tablets Hardness 70 99 86 148 127
N.A. 54 46 61 N.A. (N) Friability 0.1 0.1 0.6 0.2 0.2 N.A. Test
Test Test N.A. (%) (Test failure failure failure performed (39.4)
(31.7) (44.9) according to EP 6.0, par. 2.9.7) Mean 360 365 319 332
327 N.A 365 337 335 N.A. Weight (mg/tablet) Disinte- 5'07'' 1'24''
2'51'' 4'56'' 20'59'' N.A. 4'18'' 1'22'' 3'59'' N.A. gration (min.
sec) (medium: buffer pH = 1.5) N.A. = not available because the
mixture is not suitable for tabletting process (see the
observations reported in table 5a)
TABLE-US-00055 TABLE 25 Dry granulation--Placebo batches
composition and analytical results (batches D001T/011 / D001T/025).
Placebo Batches manufactured by Dry Granulation D001T/011 D001T/012
D001T/013 D001T/014 D001T/015 D001T/016 D001T/017 D001T/018
D001T/019 D001T/025 Components (% .sub.w/w) (% .sub.w/w) (%
.sub.w/w) (% .sub.w/w) (% .sub.w/w) (% .sub.w/w) (% .sub.w/w) (%
.sub.w/w) (% .sub.w/w) (% .sub.w/w) Fructose 93.7 -- -- -- -- -- --
-- -- -- (Fructose MS) Maltitol -- 93.7 -- -- -- -- -- -- -- --
(Sweetpearl P200) Maltose -- -- 93.7 -- -- -- -- -- -- --
Monohydrate (Sunmalt S) Lactitol -- -- -- 93.7 -- -- -- -- -- --
Monohydrate (Lacty M) Sucrose 97% + -- -- -- -- 93.7 -- -- -- -- --
Maltodextrin 3% (EV Saccharide DC 3.75 MD) Sucrose -- -- -- -- --
99.5 (Sucrose Comprizuker S) Sucrose -- -- -- -- -- -- 93.7
(Sucrose grandular RFS) Xylitol -- -- -- -- -- -- -- 99.5 (Xylisorb
300) .beta.-Cyclodextrin -- -- -- -- -- -- -- -- 93.8 (Kleptose DC)
D-Melezitose 93.8 monohydrate Avicel PH 112 -- 5.7 5.7 5.7 5.7 --
5.7 -- -- -- Crospovidone 5.7 -- -- -- -- -- -- -- 5.6 5.6
Magnesium 0.6 0.6 0.6 0.6 0.6 0.5 0.6 0.5 0.6 0.5 Stearate Results
of analytical tests performed on final mixtures Water Content 0.42
0.38 5.71 5.45 0.78 N/A 0.32 N/A 12.30 (%) Flowability 19.09 22.54
16.57 23.41 5.37 N/A 17.38 N/A 18.64 Not flow (seconds) (Nozzle 1,
(Nozzle 1, (Nozzle 1, (Nozzle 1, (Nozzle 3, (Nozzle 1, (Nozzle 1,
(Nozzle 3, (Test performed diameter = diameter = diameter =
diameter = diameter = diameter = diameter = diameter = according to
10.0 mm) 10.0 mm) 10.0 mm) 10.0 mm) 25.0 mm) 10.0 mm) 10.0 mm) 25.0
mm) EP 6.0, par. 2.9.16) Results of analytical tests performed on
tablets Hardness (N) 17 33 130 69 69 N/A 19 N/A 62 56 Friability
(%) Test failure Test failure 0.2 Test failure 0.4 N/A Test failure
N/A 0.2 Test failure (Test performed (100.0) (100.0) (19.6) (78.0)
(20.7) according to EP 6.0, par. 2.9.7) (39.4) (31.7) (44.9) Mean
Weight 380 388 328 338 349 N/A 383 N/A 338 328 (mg/tablet)
Disintegration 5'52'' 6'40'' 5'09'' 6'32'' 5'47'' N/A 4'50'' N/A
4'01'' 3'30'' (min.) (medium: buffer pH = 1.5) N/A = not available
because the mixture is not suitable for tabletting process (see the
observations reported in table 5a)
TABLE-US-00056 TABLE 26 Observations about manufacturing process,
product technological properties and analytical tests for each
manufactured placebo batch Placebo Dry Granulation Batches
process/obtained slugs Tabletting Process/obtained tablets
Analytical tests on tablets D001T/001 Excellent slugs; easy to be
sieved Easy to be tabletted; good tablets obtained Fast
disintegration; low friability; medium hardness D001T/002 Good
slugs; easy to be sieved Easy to be tabletted; good tablets
obtained Fast disintegration; low friability; high hardness
D001T/003 Difficult to compact; high pressure Difficult to be
tabletted; Fast disintegration; high friability; high hardness
needed to obtain slugs The powder adheres to punches; tabletting
process was interrupted after a few tablets D001T/004 Excellent
slugs; easy to be sieved Fairly good to be tabletted; good tablets
obtained Fast disintegration; low friability; very high hardness
D001T/005 Excellent slugs; easy to be sieved Easy to be tabletted;
good tablets obtained Slow disintegration; low friability; high
hardness D001T/006 Poor slugs, high friability Impossible to be
tabletted; tabletting No tablets available for analytical testing
process interrupted D001T/007 Poor slugs, high friability Good to
be tabletted; fairly good tablets obtained Fast disintegration;
very high friability, above acceptance limit; medium hardness
D001T/008 Poor slugs, high friability Good to be tabletted; fairly
good tablets obtained Fast disintegration; very high friability,
above acceptance limit; medium hardness D001T/009 Good slugs; easy
to be sieved Good to be tabletted; fairly good tablets obtained
Fast disintegration; very high friability, above acceptance limit;
medium hardness D001T/010 Impossible to obtain slugs; not -- --
further processed D001T/011 Poor slugs, high friability Poor
tablets obtained (many tablets break during Fast disintegration;
very high friability, above tabletting process) acceptance limit
(all tablets broken after test); very low hardness D001T/012 Poor
slugs, high friability Poor tablets obtained (many tablets break
during Fast disintegration; very high friability, above tabletting
process) acceptance limit (all tablets broken after test); low
hardness D001T/013 Excellent slugs; easy to be sieved Easy to be
tabletted; good tablets obtained Fast disintegration; low
friability; very high hardness D001T/014 Good slugs; easy to be
sieved Good to be tabletted; fairly good tablets obtained Fast
disintegration; high friability, above acceptance limit; medium
hardness D001T/015 Good slugs; easy to be sieved Good to be
tabletted; good tablets obtained Fast disintegration; medium
friability; medium hardness D001T/016 Impossible to obtain slugs;
not -- -- further processed D001T/017 Poor slugs, high friability
Poor tablets obtained (many tablets break during Fast
disintegration; high friability, tabletting process) above
acceptance limit; low hardness D001T/018 Impossible to obtain
slugs; not -- -- further processed D001T/019 Excellent slugs; easy
to be sieved Easy to be tabletted; good tablets obtained Fast
disintegration; low friability; medium hardness D001T/025 Good
slugs; easy to be sieved Good to be tabletted; fairly good tablets
obtained Fast disintegration; very high friability, above
acceptance limit; medium hardness
Batches Manufactured by Dry Granulation with a 1:5 Bendamustine
Hydrochloride/Saccharide Weight Ratio
[0247] The placebo formulations, evaluated as more suitable to
manufacture tablets containing the active pharmaceutical ingredient
(API) by dry granulation, were modified to include the API and two
API/saccharide weight ratios were explored: 1:5 and 1:2.
[0248] In this paragraph, formulations with a 1:5 API/saccharide
weight ratios are described.
[0249] Two types of disintegrant were used: microcrystalline
cellulose (Avicel.RTM.PH 112), as a standard disintegrant, and
crosslinked polyvivylpyrrolidone (Crospovidone), used just for the
batch D001T/022. Magnesium stearate was used as lubricant for all
the batches produced.
[0250] The manufacturing process of the API-containing batches by
dry granulation consisted in the following steps: [0251] 1. The
saccharide, a partial quantity of lubricant (83.3%.sub.w/w of the
total amount) and Bendamustine Hydrochloride were accurately
weighed and mixed in a double polyethylene bag for 5 minutes.
[0252] 2. The powder blend was pressed by using the tabletting
machine equipped with 18 mm diameter punch. [0253] 3. To obtain a
granulate, the produced slugs were sieved by using a 850 micron
net. [0254] 4. The granulate was weighed and mixed with the
disintegrant and the remaining amount of the lubricant
(16.7%.sub.w/w) in a double polyethylene bag for 5 minutes. [0255]
5. The obtained mixture was tabletted by using a 10 mm diameter
punch.
[0256] Table 27 summarizes the composition of each API-containing
formulation manufactured and the results of the analytical tests
performed on the API-containing final mixtures; table 28 summarizes
the results of the analytical tests performed on the obtained
products.
TABLE-US-00057 TABLE 27 Dry granulation - API/Saccharide weight
ratio 1:5. API-containing batches final mixture composition and
analytical results. API-containing batches manufactured by Dry
granulation API/Saccharide ratio 1:5 D001T/020 D001T/021 D001T/022
D001T/023 D001T/024 Components (%.sub.w/w) (%.sub.w/w) (%.sub.w/w)
(%.sub.w/w) (%.sub.w/w) Bendamustine HCL 15.3 16.6 16.6 16.6 15.7
Lactose Monohydrate 78.4 -- -- -- -- (SuperTab 14 SD) Sorbitol --
77.1 -- -- (Neosorb P60W) .beta.-Cyclodextrin -- -- 77.1 --
(Kleptose DC) Maltose (Food grade) -- -- -- 77.1 -- (Sunmalt S)
Sucrose 97% + Maltodextrin 3%) -- -- -- -- 78.0 (EV Saccharide DC
3.75 MD) Avicel PH 112 5.7 5.7 5.7 5.7 Crospovidone -- 5.7 -- --
Magnesium Stearate 0.6 0.6 0.6 0.6 0.6 Result of analytical tests
performed on final mixture Flowability (seconds) 7.31 19.91 3.89
23.00 7.99 (Test performed according to EP 6.0, (Nozzle 2, (Nozzle
1, (Nozzle 3, (Nozzle 1, (Nozzle 3, par. 2.9.16) diameter =
diameter = diameter = diameter = diameter = 15 mm) 10 mm) 25 mm) 10
mm) 25 mm)
TABLE-US-00058 TABLE 28 Dry granulation--API/Saccharide weight
ratio 1:5. API-containing batches tablets analytical results.
Specification Results of analytical tests performed on tablets
Analytical Test Limits D001T/020 D001T/021 D001T/022 D001T/023
D001T/024 Identification Positive Positive Positive Positive
Positive Positive (HPLC) Mean Weight Specific for 359.43 336.27
334.67 333.19 349.72 (mg/tablet) each Limits: Limits: Limits:
Limits: Limits: formulation 342 / 378 315.4 / 348.6 315.4 / 348.6
315.4 / 348.6 332.5 / 367.5 Content Uniformity Complies Complies
Complies Complies Complies Complies (Test performed RSD 1.26 RSD
1.42 RSD 0.84 RSD 0.58 RSD 2.02 according to EP 6.0) Assay (%)
95.0%-105.0% 96.9 93.5 97.4 93.8 97.7 (HPLC) Related substances (%)
(HPLC) HP1 .ltoreq.0.5% 0.12 0.10 0.08 0.11 0.14 BM1 Dimer
.ltoreq.0.2% 0.04 0.05 0.05 0.05 0.04 BM1EE .ltoreq.0.5% 0.14 0.13
0.13 0.13 0.15 NP1 .ltoreq.0.2% n.d. n.d. 0.01 n.d. 0.1 Individual
unknown impurity .ltoreq.0.1% 0.01 n.d. n.d. n.d. n.d. Total
impurities .ltoreq.1.5% 0.31 0.28 0.27 0.29 0.34 Dissolution Test
(Medium: buffer pH = 1.5) (% 10 min) 80% in 30 72.9 72.1 88.0 60.0
75.5 minutes ( % 20 min) 87.6 85.9 88.9 79.2 89.6 ( % 30 min) 87.2
84.7 87.4 84.7 90.3 Moisture content (%) -- 4.72 1.00 11.3 5.13
0.88 Hardness (N) .gtoreq.40N 67 89 77 151 55 Friability (%)
.ltoreq.1.0% 0.2 0.2 0.1 0.2 0.4 (Test performed according to EP
6.0, par. 2.9.7)
[0257] The results of analytical tests performed both on final
mixtures and finished products were in most cases good, mainly for
Content Uniformity and Purity. All API-containing batches showed
satisfactory mass uniformity, homogeneity of API content, and a low
impurities content. The impurity profile of all formulations was in
compliance with the specifications of API (see specification limits
in the tables), thus no degradation occurs during manufacturing
process.
[0258] Two API-containing batches showed low values in API assay;
this result could be due to the small batch size and to the losses
during the manufacturing process and the samples for IPCs on the
final mixtures.
API-Containing Batches Manufactured by Dry Granulation with a 1:2
API/Saccharide Weight Ratio
[0259] All the saccharide previously investigated by dry
granulation to manufacture tablets with a 1:5 API/Saccharide weight
ratio were also evaluated at a ratio of 1:2.
[0260] For the manufacturing process see above. In this case, the
obtained mixture was tabletted by using a 8 mm diameter punch.
[0261] Two types of disintegrant were used: microcrystalline
cellulose (Avicel.RTM. PH 112), as a standard disintegrant, and
crosslinked polyvinylpyrrolidone (Ccrospovidone.RTM.', used just
for the batch D001T/105. For this batch we have explored the use of
Avicel.RTM. PH 112 and of Crospovidone.RTM.. The Crospovidone.RTM.
was chosen according to the previous cyclodextrin based formulation
manufactured by dry granulation with a 1:5 API/Saccharide (see
previous results).
[0262] Table 29 and Table 30 summarize the composition of each
API-containing formulation manufactured by dry granulation with an
API/Saccharide weight ratio of 1:2 and the results of the
analytical tests performed on both, the final mixtures and the
tablets. All API-containing batches showed suitable uniformity of
mass, homogeneity of API content and low impurities content.
Friability and hardness values are, in the most of the cases, in
compliance with the specifications. In the case of batches
D001T/093, D001T/095 and D001T/096, the results of the dissolution
test performed on 6 tablets showed out of specifications values
with a high RSD and the test was extended to a sample of 12
tablets.
[0263] Cyclodextrin based tablets show good properties with both
disintegrants (Avicel.RTM. PH 112 and Crospovidone.RTM.).
TABLE-US-00059 TABLE 29 Dry granulation--API/Saccharide weight
ratio 1:2. API-containing batches final mixture composition and
analytical results. API-containing Batches manufactured by Dry
Granulation API/SaccharideSaccharide ratio 1:2 D001T/091 D001T/092
D001T/093 D001T/094 D001T/105 D001T/095 D001T/096 Components (%
.sub.w/w) (% .sub.w/w) (% .sub.w/w) (% .sub.w/w) (% .sub.w/w) (%
.sub.w/w) (% .sub.w/w) Bendamustine HCl 31.1 31.1 31.1 31.1 31.1
31.1 31.1 Lactose 62.3 -- -- -- -- -- Monohydrate (Supertab 14 SD)
Lactose Anhydrous -- 62.3 -- -- -- -- (Supertab 21 AN) Sorbitol --
-- 62.3 -- -- -- (Neosorb P60W) .beta.-Ciclodextrine -- -- -- 62.3
62.3 -- -- (Kleptose DC) Sucrose 97% + -- -- -- -- 62.3 --
Maltodextrine 3% (EV SaccharideSaccharide DC 3.75 MD) Maltose (Food
grade) -- -- -- -- -- -- 62.3 (Sunmalt S) Avicel PH 112 5.9 5.9 5.9
5.9 5.9 5.9 Crospovidone 5.9 Magnesium Stearate 0.7 0.7 0.7 0.7 0.7
0.7 0.7 Results of analytical tests performed on final mixtures
Flowability (seconds) Not flow Not flow Not flow Not flow Not flow
Not flow Not flow (Test performed (Nozzle 3, (Nozzle 3, (Nozzle 3,
(Nozzle 3, (Nozzle 3, (Nozzle 3, (Nozzle 3, according to EP 6.0,
diameter = diameter = diameter = diameter = diameter = diameter =
diameter = par. 2.9.16) 25.0 mm) 25.0 mm) 25.0 mm) 25.0 mm) 25.0
mm) 25.0 mm) 25.0 mm)
TABLE-US-00060 TABLE 30 Dry granulation--API/Saccharide weight
ratio 1:2. API-containing batches tablets analytical results.
Analytical Specification Results of analytical tests performed on
tablets Test Limits D001T/091 D001T/092 D001T/093 D00IT/094
D001T/105 D001T/095 D001T/096 Identification Positive Positive
Positive Positive Positive Positive Positive Positive (HPLC) Mean
Weight Specific for 175.01 178.85 176.90 176.06 176.40 175.81
180.81 (mg/tablet) each Limits: Limits: RSD 2.3 Limits: Limits: RSD
6.1 RSD 1.3 formulation 168.2 / 185.9 168.2 / 185.9 Limits: 168.2 /
185.9 168.2 / 185.9 Limits: Limits: 168.2 / 185.9 168.2 / 185.9
168.2 / 18.9 Content Complies Complies Complies Complies Complies
Complies Complies Complies Uniformity RSD 2.43 RSD 2.41 RSD 3.34
RSD 3.84 RSD 2.69 RSD 2.86 RSD 3.41 (Test performed according to EP
6.0) Assay (%) 95.0%- 96.0 96.8 96.6 96.6 97.2 97.7 99.3 (HPLC)
105.0% Related substances (%) (HPLC) HP1 .ltoreq.0.50% 0.08 0.28
0.11 0.11 0.19 0.12 0.08 BM1 Dimer .ltoreq.0.20% 0.04 0.03 0.04
0.04 0.05 0.04 0.04 BM1EE .ltoreq.0.50% 0.13 0.13 0.13 0.14 0.13
0.12 0.13 NP1 .ltoreq.0.20% 0.01 0.01 0.01 0.01 0.01 0.01 0.02
Individual un- .ltoreq.0.10% n.d. 0.04 0.06 0.05 0.02 0.05 0.03
known impurity Total impurities .ltoreq.1.50% 0.27 0.54 0.36 0.35
0.40 0.37 0.31 Total impurities 0.29 0.31 0.31 0.32 0.35 0.35 after
storage at 40.degree. C./75% RH for 3 months Dissolution Test n =
12 n = 12 n = 12 (Medium: buffer pH = 1.5) (% 10 min) 80% in 30 min
49.2 84.7 36.2 (RSD 15.7) 68.8 75.0 58.2 (RSD 24.3) 57.5 (RSD 22.2)
(% 20 min) 75.2 92.4 54.6 (RSD 14.0) 88.8 92.1 73.8 (RSD 19.1) 75.1
(RSD 17.5) (% 30 min) 84.7 93.0 65.2 (RSD 10.4) 92.4 92.8 82.5 (RSD
20.5) 84.6 (RSD 19.7) Dissolution after 89 92 86 92 75 89 storage
at 40.degree. C./75% RH for 3 months Moisture -- 4.02 0.62 0.70
8.30 8.70 0.71 4.06 content (%) Hardness (N) .gtoreq.40N 95 49 118
110 100 75 125 Friability (%) (Test performed .ltoreq.1.0% 0.5 0.7
0.3 0.5 0.5 1.5 0.1 according to EP 6.0) n.d. = not detected
API-Containing Batches Manufactured by Direct Compression with a
1:5 API/SaccharideSaccharide Weight Ratio
[0264] The saccharides with suitable characteristics to be
manufactured by dry granulation were also explored by using direct
compression developing tablets with a 1:5 API/Saccharide ratio.
[0265] Two types of disintegrant were used: microcrystalline
cellulose (Avicel.RTM. PH 112), as a standard disintegrant, and
crosslinked polyvinylpyrrolidone (Crospovidone.RTM.), used just for
batch D001T/029.
[0266] This manufacturing process consisted of the following steps:
[0267] 1. Weighing the API and the excipients. [0268] 2.
Transferring the raw materials in a double polyethylene bag and
mixing for about 5 minutes until a homogeneous powder blend is
obtained. [0269] 3. Transferring of the powder blend in the hopper
of the tabletting machine. [0270] 4. Compression of the powder
blend using an eccentric tablet machine equipped with a 10 mm
diameter punch.
[0271] The characteristics of the API-containing batches
manufactured by direct compression are presented in the following
table.
TABLE-US-00061 TABLE 31 Direct Compression - API/Saccharide weight
ratio 1:5. API-containing batches final mixture composition and
analytical results. API-containing batches manufactured by Direct
Compression D001T/026 D001T/027 D001T/028 D001T/029 D001T/030
(%.sub.w/w) (%.sub.w/w) (%.sub.w/w) (%.sub.w/w) (%.sub.w/w)
Bendamustine HCL 16.6 16.6 15.3 16.6 15.7 Lactose Monohydrate -- --
78.4 -- -- (Supertab 14 SD) Sorbitol 77.1 -- -- -- (Neosorb P60W)
.beta.-Cyclodextrin -- -- -- 77.1 (Kleptose DC) Maltose (Food
grade) 77.1 -- -- -- -- (Sunmalt S) Sucrose 97% + Maltodextrin 3%
-- -- -- -- 78.0 (EV Saccharide DC 3.75 MD) Avicel PH 112 5.7 5.7
5.7 5.7 Crospovidone -- -- 5.7 -- Magnesium Stearate 0.6 0.6 0.6
0.6 0.6 Flowability (seconds) 4.78 4.01 Not flow Not flow 4.12
(Test performed according to EP (Nozzle 3, (Nozzle 3, (Nozzle 3,
(Nozzle 3, (Nozzle 3, 6.0, par. 2.9.16) diameter = diameter = 25
mm) diameter = 25 mm) diameter = 25 mm) diameter = 25 mm) 25
mm)
[0272] The obtained results of the analytical tests are listed in
table 32.
TABLE-US-00062 TABLE 32 Direct Compression-API/Saccharide weight
ratio 1:5. API-containing batches tablets analytical results.
Specification Result of analytical Tests performed on tablets
Analytical Test Limits D001T/026 D001T/027 D001T/028 D001T/029
D001T/030 Identification Positive Positive Positive Positive
Positive Positive (HPLC) Mean Weight Specific for 333.80 332.25
363.86 331.41 356.61 (mg/tablet) each Limits: Limits: Limits:
Limits: Limits: formulation 315.4 / 348.6 315.4 / 348.6 342.0 /
378.0 315.4 / 348.6 332.5 / 367.5 Content Uniformity Complies
Complies Complies Complies Complies Not (Test performed RSD 3.51
RSD 3.60 RSD 0.88 RSD 1.57 Complies according to EP 6.0) RSD 10.84
Assay (%) 95.0%-105.0% 94.5 97.2 100.8 100.1 99.6 (HPLC) Related
substances (%) (HPLC) HP1 .ltoreq.0.5% 0.10 0.11 0.12 0.13 0.11 BM1
Dimer .ltoreq.0.2% 0.04 0.04 0.04 0.04 0.04 BM1EE .ltoreq.0.5% 0.13
0.15 0.14 0.14 0.14 NP1 .ltoreq.0.2% 0.01 0.01 0.02 0.01 0.02
Individual unknown .ltoreq.0.1% 0.03 0.03 0.03 0.03 0.03 impurity
Total impurities .ltoreq.1.5% 0.31 0.34 0.35 0.35 0.34 Dissolution
Test (Medium: buffer pH = 1.5) (% 10 min) 80% in 30 45.5 71.5 54.7
83.3 73.5 (% 20 min) minutes 69.7 89.7 88.6 89.5 90.9 (% 30 min)
83.3 89.3 91.1 91.5 91.3 Moisture content (%) -- 5.04 0.71 4.40
11.26 0.83 Hardness (N) .gtoreq.40N 106 108 74 99 92 Friability (%)
.ltoreq.1.0% 0.2 0.2 0.2 0.1 0.8 (Test performed according to EP
6.0, par. 2.9.7)
[0273] As reported in the above table the API-containing tablets
manufactured by direct compression showed no critical differences
from the ones produced by dry granulation except for batch
D001T/030 (filler: Sucrose 97%+Maltodextrin 3%) that showed a non
homogeneous API content and a slight increase in the value of
friability.
Wet Granulation:
Placebo Exploratory Trials
[0274] Based on the results obtained in the first and second part
of the project, the saccharides not suitable for dry granulation or
direct compression were investigated by wet granulation.
[0275] The present approach to investigate the wet granulation
technology is shown below.
[0276] Each saccharide was granulated according to the steps
described in the flow-sheet of FIG. 4. At the end of each step the
wet granulated saccharide was dried and a compression trial was
performed to evaluate if the granulate was suitable for tabletting.
Placebo batches were manufactured only for the granulated
saccharides with doubtful results of the compression test. The
compositions and the relevant analytical results of the placebo
trials are reported in Table 33.
[0277] Placebo batches were manufactured according to the following
steps: [0278] 1. Wet granulation of the saccharide with water or
sorbitol solution using Fluid Bed or High Shear granulator (see
above Flow-sheet of wet granulation manufacturing trials, and table
23) [0279] 2. Drying of the wet granulated saccharide in the Fluid
Bed granulator or in oven. [0280] 3. Sieving the granulated
saccharide by using 850 and 710 micron nets. [0281] 4. Weighing of
all components of the formulation and mixing in a polyethylene bag
for 2 minutes. [0282] 5. Compression of the powder blend using an
eccentric tablet machine equipped with a 10 mm diameter punch.
[0283] Avicel PH 112 and magnesium stearate were used as
disintegrant and as lubricant, respectively, for all the batches
produced.
TABLE-US-00063 TABLE 33 Wet granulation. Placebo batches
composition and IPC results. Placebo Batches manufactured by Wet
Granulation D001T/032 D001T/034 D001T/035 D001T/045 D001T/051
D001T/054 Components (%.sub.w/w) (%.sub.w/w) (%.sub.w/w)
(%.sub.w/w) (%.sub.w/w) (%.sub.w/w) Dextrose Anhydrous 93.66 -- --
-- -- -- (Dextrose Anhydrous ST 0.5) Dextrose Monohydrate -- 93.66
-- -- -- -- (Dextrose Monohydrate) Mannitol -- -- 93.67 -- -- --
(Pearlitol 200 SD) D-Melezitose monohydrate -- -- -- 93.55 -- --
Maltitol -- -- -- -- 93.70 (Sweetpearl P200) Trehalose (Food grade)
-- -- -- -- -- 93.72 (Treha 16400) D-Raffinose Pentahydrate -- --
-- -- -- -- Erythritol (Food grade) -- -- -- -- -- -- (Zerose
Erythritol 16954) Fructose (Fructose MS) Xylitol (Xyilisorb 300)
Avicel PH 112 5.7 5.7 5.7 5.7 5.7 5.7 Magnesium Stearate 0.6 0.6
0.6 0.8 0.6 0.6 Equipment and Binder Fluid Bed High Shear Fluid Bed
Fluid Bed Fluid Bed Fluid Bed Solution utilized Water Water Water
Water Sorbitol Sorbitol for saccharide granulation solution
solution Percentage of sorbitol in the n/a n/a n/a n/a 1.2 1.1
granulate (%.sub.w/w) Percentage of water in the granulate
(%.sub.w/w) 1.03 7.93 0.20 5.08 0.20 0.22 Results of analytical
tests performed on tablets Appearance Complies Complies Complies
Complies Complies Complies Hardness (N) 98 82 277 96 76 60 Placebo
Batches manufactured by Wet Granulation D001T/055 D001T/057
D001T/058 D001T/070 D001T/075 Components (%.sub.w/w) (%.sub.w/w)
(%.sub.w/w) (%.sub.w/w) (%.sub.w/w) Dextrose Anhydrous -- -- -- --
(Dextrose Anhydrous ST 0.5) Dextrose Monohydrate -- -- -- --
(Dextrose Monohydrate) Mannitol -- -- -- -- (Pearlitol 200 SD)
D-Melezitose monohydrate -- -- -- -- Maltitol (Sweetpearl P200)
Trehalose (Food grade) (Treha 16400) D-Raffinose Pentahydrate 93.72
Erythritol (Food grade) -- 93.52 93.56 (Zerose Erythritol 16954)
Fructose 93.66 (Fructose MS) Xylitol 93.71 (Xyilisorb 300) Avicel
PH 112 5.7 5.8 5.7 5.8 5.7 Magnesium Stearate 0.6 0.7 0.6 0.7 0.6
Equipment and Binder Fluid Bed Fluid Bed High Shear High Shear High
Shear Solution utilized Sorbitol Sorbitol Water Water Water for
saccharide granulation solution solution Percentage of sorbitol in
1.1 1.1 N/A N/A N/A the granulate (%.sub.w/w) Percentage of water
in the granulate (%.sub.w/w) 15.40 0.22 0.13 0.40 0.19 Results of
analytical tests performed on tablets Appearance Complies Complies
Complies Not Not Complies Complies Hardness (N) 64 15 30 N/A
N/A
API-Containing Batches Manufactured by Wet Granulation with a 1:5
API/Saccharide Weight Ratio
[0284] Manufacturing trials including a wet granulation process
were carried out on all saccharides that turned out to be not
suitable for tablet manufacturing by dry granulation or direct
compression technologies.
[0285] The manufacturing process of these trials performed at
laboratory scale is summarized as follow: [0286] 1. Wet granulation
of the saccharide with water or sorbitol solution using Fluid Bed
or High Shear granulator (see above Flow-sheet of wet granulation
manufacturing trials, and table 34) [0287] 2. Drying of the wet
granulated saccharide in the Fluid Bed granulator or in oven [0288]
3. Sieving by using 850 and 710 micron nets. [0289] 4. Weighing of
the API and excipients and mixing in a double polyethylene bag for
5 minutes. [0290] 5. Compression of the powder blend using an
eccentric tablet machine equipped with a 10 mm diameter punch.
[0291] Avicel PH 112 and magnesium stearate were used as
disintegrant and as lubricant, respectively, for all the batches
produced.
[0292] Table 33 and Table 34 list the composition of each
API-containing formulation manufactured by wet granulation and the
results of the analytical tests performed on both, the final
mixtures and the tablets.
[0293] The results of the analytical tests performed on the final
mixtures and on the finished products are, in the most of the
cases, in compliance with the specifications. No degradation occurs
during the manufacturing process.
[0294] Among the saccharides investigated, only Fructose MS (Galam)
is not suitable to be processed by wet granulation: the
API-containing batch D001T/047 has a high friability and the batch
D001T/082 shows friability and hardness values out of
specifications.
[0295] The batches D001T/060, D001T/061, D001T/082, D001T/086 have
low values in API assay and for the batches D001T/082 and D001T/086
the Uniformity of Content does not comply, though the granulate was
sieved by using 850 micron and 710 micron nets. This result is
probably due to poor powders mixing.
TABLE-US-00064 TABLE 34 Wet granulation-API/Saccharide weight ratio
1:5. API-containing batches final mixture composition and
analytical results. API-containing Batches manufactured by Wet
Granulation D001T/033 D001T/036 D001T/037 D001T/040 D001T/047
D001T/059 Components (%.sub.w/w) (%.sub.w/w) (%.sub.w/w)
(%.sub.w/w) (%.sub.w/w) (*) (%.sub.w/w) Bendamustine HCl 15.7 15.7
15.7 15.7 14.9 15.7 Dextrose Anhydrous 78 -- -- -- -- -- (Anhydrous
Dextrose ST 0.5) Dextrose Monohydrate G -- 78 -- -- -- -- Mannitol
-- -- 78 -- -- -- (Pearlitol 200 SD) Lactitol Monohydrate -- -- --
78 -- -- (Lacty M)(Food grade) D-Melezitose monohydrate -- -- -- --
78.8 -- Maltitol -- -- -- -- -- 78 (Sweetpearl P200) Trehalose
(Food grade) -- -- -- -- -- -- (Treha 16400) D-Raffinose
Pentahydrate -- -- -- -- -- -- Erythritol (Food grade) -- -- -- --
-- -- (Zerose Erythritol 16954) Xylitol (Xyilisorb 300) (**)
Fructose MS (**) Avicel PH 112 5.7 5.7 5.7 5.7 5.7 5.7 Magnesium
Stearate 0.6 0.6 0.6 0.6 0.6 0.6 Equipment and Binder Fluid Bed
High Shear Fluid Bed Fluid Bed Fluid Bed Fluid Bed Solution
utilized Water Water Water Water Water Sorbitol for saccharide
granulation solution Percentage of sorbitol in the N/A N/A N/A N/A
N/A 1.2 granulate (%.sub.w/w) Results of analytical tests performed
on final mixtures Flowability (seconds) Not flow 18.95 11.14 6.12
Not flow 5.12 (Test performed according to (Nozzle 3, (Nozzle 1,
(Nozzle 2, (Nozzle 2, (Nozzle 3, (Nozzle 2, EP 6.0, par. 2.9.16)
diameter = diameter = diameter = diameter = diameter = diameter =
25.0 mm) 10.0 mm) 15.0 mm) 15.0 mm) 25.0 mm) 15.0 mm) Observations
on manufactured tablets Appearance Complies Complies Complies
Complies Complies Complies Stability Study Suitable for Suitable
for Suitable for Suitable for Suitable for Suitable for Stability
Stability Stability Stability Stability Stability Study Study Study
Study Study Study API-containing Batches manufactured by Wet
Granulation D001T/060 D001T/061 D001T/082 D001T/086 D001T/087
Components (%.sub.w/w) (%.sub.w/w) (%.sub.w/w) (%.sub.w/w)
(%.sub.w/w) Bendamustine HCl 15.7 15.7 15.7 15.7 15.7 Dextrose
Anhydrous -- -- -- -- (Anhydrous Dextrose ST 0.5) Dextrose
Monohydrate G -- -- -- -- Mannitol -- -- -- -- (Pearlitol 200 SD)
Lactitol Monohydrate -- -- -- -- (Lacty M)(Food grade) D-Melezitose
monohydrate -- -- -- -- Maltitol (Sweetpearl P200) Trehalose (Food
grade) 78 (Treha 16400) D-Raffinose Pentahydrate -- 78 Erythritol
(Food grade) -- -- 78 (Zerose Erythritol 16954) Xylitol 78
(Xyilisorb 300) (**) Fructose MS (**) 78 Avicel PH 112 5.7 5.7 5.7
5.7 5.7 Magnesium Stearate 0.6 0.6 0.6 0.6 0.6 Equipment and Binder
Fluid Bed Fluid Bed High Shear High Shear High Shear Solution
utilized Sorbitol Sorbitol Sorbitol Sorbitol Sorbitol for
saccharide granulation solution solution solution solution solution
Percentage of sorbitol in the 1.1 1.1 3.4 4.8 3.0 granulate
(%.sub.w/w) Results of analytical tests performed on final mixtures
Flowability (seconds) 6.46 5.35 Not flow 4.23 Not flow (Test
performed according to (Nozzle 2, (Nozzle 2, (Nozzle 3, (Nozzle 2,
(Nozzle 3, EP 6.0, par. 2.9.16) diameter = diameter = diameter =
diameter = diameter = 15.0 mm) 15.0 mm) 25.0 mm) 15.0 mm) 25.0 mm)
Observations on manufactured tablets Appearance Complies Complies
Complies Complies Not Complies (***) Stability Study Suitable for
Suitable for Suitable for Suitable for Not Suitable Stability
Stability Stability Stability for Stability Study Study Study Study
Study (*) This batch contains an excess of A.P.I (5.9%) ; (**) It
was not possible to investigate granulation step using fluid bed
with saccharide solution because these saccharides are not
fluidized with air stream; (***) The final mixture is not suitable
for tabletting
TABLE-US-00065 TABLE 35 Wet granulation-API/Saccharide weight ratio
1:5. API-containing batches tablets analytical results.
Specification Results of analytical tests performed on tablets
Analytical Test Limits D001T/033 D001T/036 D001T/037 D001T/040
D001T/047 Identification Positive Positive Positive Positive
Positive Positive (HPLC) Mean Weight Specific for 348.52 351.56
354.06 351.98 368.66 (mg/tablet) each Limits: Limits: Limits:
Limits: Limits: formulation 332.5 / 367.5 332.5 / 367.5 332.5 /
367.5 332.5 / 367.5 351.5 / 388.5 Content Uniformity Complies
Complies Complies Complies Complies Complies (Test performed RSD
1.50 RSD 3.64 RSD 1.35 RSD 2.82 RSD 1.11 according to EP 6.0) Assay
(%) 95.0%-105.0% 101.0 98.2 98.4 98.6 101.2 (HPLC) Related
substances (%) (HPLC) HP1 .ltoreq.0.5% 0.08 0.08 0.09 0.08 0.10 BM1
Dimer .ltoreq.0.2% 0.04 0.04 0.04 0.04 0.04 BM1EE .ltoreq.0.5% 0.13
0.13 0.13 0.14 0.16 NP1 .ltoreq.0.2% 0.01 0.01 0.01 0.01 0.01
Individual unknown impurity .ltoreq.0.1% 0.02 0.02 0.02 0.03 0.03
Total impurities .ltoreq.1.5% 0.30 0.30 0.31 0.30 0.34 Dissolution
Test (Medium: buffer pH = 1.5) (% 10 min) 80% in 30 91.9 73.9 97.1
77.0 80.9 (% 20 min) minutes 93.3 90.5 95.5 88.4 93.5 (% 30 min)
91.8 89.5 93.7 87.8 92.3 Moisture content (%) -- 1.15 6.58 0.59
4.48 4.14 Hardness (N) .gtoreq.40N 68 66 140 46 73 Friability (%)
(Test performed .ltoreq.1.0% 0.5 0.5 0.2 0.6 Test failure according
to (28.3) EP 6.0, par. 2.9.7) Results of analytical tests performed
on tablets Analytical Test D001T/059 D001T/060 D001T/061 D001T/082
D001T/086 D001T/087 Identification Positive Positive Positive
Positive Positive N/A (HPLC) Mean Weight 347.49 350.37 349.04
352.09 351.78 N/A (mg/tablet) Limits: Limits: Limits: Limits:
Limits: 332.5 / 367.5 332.5 / 367.5 332.5 / 367.5 332.5 / 367.5
332.5 / 367.5 Content Uniformity Complies Complies Complies Not Not
N/A (Test performed RSD 3.36 RSD 3.38 RSD 2.99 complies complies
according to RSD 31.06 RSD 8.39 EP 6.0) Assay (%) 96.7 91.3 92.7
90.6 94.0 N/A (HPLC) Related substances (%) (HPLC) HP1 0.07 0.07
0.13 0.05 0.21 N/A BM1 Dimer 0.04 0.04 0.04 0.04 0.04 BM1EE 0.14
0.13 0.13 0.12 0.15 NP1 0.01 0.01 0.01 0.01 0.02 Individual unknown
impurity n.d. 0.01 0.02 0.02 0.04 Total impurities 0.26 0.26 0.33
0.24 0.49 Dissolution Test (Medium: buffer pH = 1.5) (% 10 min)
77.5 86.3 71.4 90.5 87.2 N/A (% 20 min) 87.2 99.7 88.4 89.0 92.2 (%
30 min) 86.9 99.9 87.9 87.2 89.2 Moisture content (%) 0.49 7.81
12.12 0.51 0.56 0.90 Hardness (N) 81 48 71 26 56 N/A Friability (%)
(Test performed 0.4 0.4 0.3 Test failure 0.3 N/A according to (74)
EP 6.0, par. 2.9.7)
API-Containing Batches Manufactured by Wet Granulation with a 1:2
API/Saccharide Weight Ratio
[0296] All saccharides previously investigated by wet granulation
to manufacture tablets with a 1:5 API/Saccharide weight ratio were
also evaluated at a ratio of 1:2.
[0297] The fructose was not evaluated at a ratio of 1:2 because the
obtained granulate is not suitable for tabletting.
[0298] Avicel PH 112 and magnesium stearate were used as
disintegrant and as lubricant, respectively, for all the batches
produced.
[0299] To improve the uniformity of the API content, these
API-containing batches were manufactured by applying the following
approach: [0300] 1. Wet granulation of the saccharide by using
procedures previously optimized [0301] 2. Preparation of the
API-containing mixture [0302] 3. Dry granulation of the mixture
(Slugs production.fwdarw.Slugs sieving) [0303] 4. Tabletting of the
obtained mixture by using a 8 mm diameter punch.
[0304] For the step 3 (Dry granulation of the mixture) see
above.
[0305] Table 36 and table 37 report the compositions and the
analytical results of the API-containing batches manufactured by
using wet granulated saccharides with an API/Saccharide weight
ratio of 1:2. Friability is, in the most of the cases, out of
specifications. The API/Saccharide weight change does not
compromise the technological properties of the D001T/084 batch
(Filler: granulated mannitol).
TABLE-US-00066 TABLE 36 Wet granulation-A.P.I./Saccharide weight
ratio 1:2. API-containing batches final mixture composition and
analytical results. API-containing Batches manufactured by Wet
Granulation API/Saccharide ratio 1:2 D001T/114 D001T/115 D001T/084
D001T/116 D001T/117 Components (%.sub.w/w) (%.sub.w/w) (%.sub.w/w)
(%.sub.w/w) (%.sub.w/w) Bendamustine HCl 31.1 31.1 31.1 31.1 31.1
Dextrose Monohydrate G 62.3 Dextrose Anhydrous -- 62.3 -- -- --
(Anhydrous Dextrose ST 0.5) Mannitol -- -- 62.3 -- -- (Pearlitol
200 SD) D-Melezitose monohydrate -- -- -- 62.3 -- Maltitol -- -- --
-- 62.3 (Sweetpearl P200) Trehalose (Food grade) -- -- -- -- --
(Treha 16400) D-Raffinose Pentahydrate -- -- -- -- -- Erythritol
(Food grade) -- -- -- -- -- (Zerose Erythritol 16954) Lactitol
monohydrate .sup.(*.sup.) -- -- -- -- -- Xylitol (Xyilisorb 300)
(**) Avicel PH 112 5.9 5.9 5.9 5.9 5.9 Magnesium Stearate 0.7 0.7
0.7 0.7 0.7 Equipment and Binder Solution High Shear Fluid Bed
Fluid Bed Fluid Bed Fluid Bed utilized Water Water Water Water
Sorbitol for saccharide granulation solution Percentage of sorbitol
in the N/A N/A N/A N/A 1.2 granulate (%.sub.w/w) Results of
analytical Tests performed on final mixtures Flowability (seconds)
Not flow Not flow Not flow Not flow Not flow (Test performed
according to (Nozzle 3, (Nozzle 3, (Nozzle 3, (Nozzle 3, (Nozzle 3,
EP 6.0, par. 2.9.16) diameter = diameter = diameter = diameter =
diameter = 25.0 mm) 25.0 mm) 25.0 mm) 25.0 mm) 25.0 mm) D001T/118
D001T/119 D001T/120 D001T/123 D001T/124 Components (%.sub.w/w)
(%.sub.w/w) (%.sub.w/w) (%.sub.w/w) (%.sub.w/w) Bendamustine HCl
31.1 31.1 31.1 31.1 31.1 Dextrose Monohydrate G Dextrose Anhydrous
-- -- -- -- -- (Anhydrous Dextrose ST 0.5) Mannitol -- -- -- -- --
(Pearlitol 200 SD) D-Melezitose monohydrate -- -- -- -- -- Maltitol
-- -- -- -- -- (Sweetpearl P200) Trehalose (Food grade) 62.3 (Treha
16400) D-Raffinose Pentahydrate -- 62.3 Erythritol (Food grade) --
-- 62.3 (Zerose Erythritol 16954) Lactitol monohydrate
.sup.(*.sup.) -- -- -- 62.3 Xylitol 62.3 (Xyilisorb 300) (**)
Avicel PH 112 5.9 5.9 5.9 5.9 5.9 Magnesium Stearate 0.7 0.7 0.7
0.7 0.7 Equipment and Binder Solution Fluid Bed Fluid Bed High
Shear Fluid Bed High Shear utilized Sorbitol Sorbitol Sorbitol
Water Sorbitol for saccharide granulation solution solution
solution solution Percentage of sorbitol in the 1.1 1.1 3.4 N/A 4.8
granulate (%.sub.w/w) Results of analytical Tests performed on
final mixtures Flowability (seconds) Not flow Not flow Not flow Not
flow Not flow (Test performed according to (Nozzle 3, (Nozzle 3,
(Nozzle 3, (Nozzle 3, (Nozzle 3, EP 6.0, par. 2.9.16) diameter =
25.0 diameter = diameter = diameter = diameter = mm) 25.0 mm) 25.0
mm) 25.0 mm) 25.0 mm) .sup.(*.sup.) As the lactitol used to develop
the previous formulation (API/Saccharide weight ratio 1:5) is no
longer commercially available, this batch was manufactured by using
lactitol purchased by new manufacturer (Lactitol MC by
Danisco).
TABLE-US-00067 TABLE 37 Wet granulation-A.P.I./Saccharide weight
ratio 1:2. API-containing batches tablets analytical results.
Specification Results of analytical tests performed on tablets
Analytical Test Limits D001T/114 D001T/115 D001T/084 D001T/116
D001T/117 Identification Positive Positive Positive Positive
Positive Positive (HPLC) Mean Weight Specific for 178.67 184.41
177.14 174.81 178.70 (mg/tablet) each Limits: Limits: Limits:
Limits: Limits: formulation 168.2 / 185.9 168.2 / 185.9 168.2 /
185.9 168.2 / 185.9 168.2 / 185.9 Content Uniformity Complies
Complies Complies Complies Complies Complies (Test performed RSD
2.3 RSD 2.9 RSD 2.40 RSD 3.4 RSD 4.0 according to EP 6.0) Assay (%)
95.0%-105.0% 96.9 103.5 98.8 94.8 98.5 (HPLC) Related substances
(%) (HPLC) HP1 .ltoreq.0.50% 0.07 0.14 0.09 0.07 0.08 BM1 Dimer
.ltoreq.0.20% 0.03 0.04 0.04 0.04 0.04 BM1EE .ltoreq.0.50% 0.14
0.16 0.13 0.13 0.15 NP1 .ltoreq.0.20% 0.01 0.01 0.01 0.01 0.01
Individual unknown impurity .ltoreq.0.10% n.d. n.d. n.d. 0.01 0.02
Total impurities .ltoreq.1.50% 0.25 0.35 0.27 0.27 0.33 Dissolution
Test (Medium: buffer pH = 1.5) (% 10 min) 80% in 30 71.7 85.3 94.4
65.6 49.8 (% 20 min) min 93.5 91.7 93.8 83.6 69.2 (% 30 min) 94.5
91.8 92.6 88.8 88.8 Moisture content (%) -- 5.4 1.1 1.5 3.2 0.5
Hardness (N) .gtoreq.40N 47 46 67 49 41 Friability (%) .ltoreq.1.0%
Test failure Test failure 0.4 Test failure 1.2 (Test performed
(9.0) (41.3) (60.0) according to EP 6.0) Results of analytical
tests performed on tablets Analytical Test D001T/118 D001T/119
D001T/120 D001T/123 D001T/124 Identification Positive Positive
Positive Positive Positive (HPLC) Mean Weight 179.86 177.30 183.26
180.33 173.38 (mg/tablet) Limits: Limits: Limits: Limits: Limits:
168.2 / 185.9 168.2 / 185.9 168.2 / 185.9 168.2 / 185.9 168.2 /
185.9 Content Uniformity Complies Complies Not Not Complies (Test
performed RSD 1.7 RSD 1.4 Complies Complies RSD 2.7 according to EP
6.0) RSD 7.4 RSD 11.3 Assay (%) 98.0 96.9 100.4 98.0 96.7 (HPLC)
Related substances (%) (HPLC) HP1 0.06 0.11 0.09 0.05 0.06 BM1
Dimer 0.04 0.04 0.04 0.04 0.03 BM1EE 0.15 0.14 0.14 0.15 0.13 NP1
0.01 0.01 0.01 0.01 0.01 Individual unknown impurity 0.02 0.02 0.04
0.03 0.03 Total impurities 0.32 0.34 0.37 0.32 0.29 Dissolution
Test (Medium: buffer pH = 1.5) (% 10 min) 48.2 68.2 81.9 51.4 58.2
(% 20 min) 74.5 92.5 84.4 71.9 80.4 (% 30 min) 84.8 92.5 84.5 82.2
86.3 Moisture content (%) 6.3 9.4 0.8 3.6 0.5 Hardness (N) 44 50 18
43 45 Friability (%) Test failure Test failure Test failure Test
failure 0.8 (Test performed (41.1) (16.8) (97.4) (16.0) according
to EP 6.0)
Effect of the API/Mannitol Weight Ratio
[0306] Mannitol based tablets were manufactured investigating the
following API/mannitol ratios: (1:0.01, 1:0.1, 1:0.5, 1:1.7, 1:4,
1:5, 1:6 and 1:10). The formulation with a 1:5 API/mannitol weight
ratio (standard formulation) was reported above.
[0307] For the production of these batches Avicel PH 112 and
magnesium stearate were used as disintegrant and as lubricant
respectively. Regarding the manufacturing process, for the 1:1.7,
1:4, and 1:6 ratios, wet granulated mannitol, Bendamustine
Hydrochloride and excipients were accurately weighed and mixed in a
double polyethylene bag for 5 minutes. For batch D001T/110 (1:10
ratio) a premix was performed. In this case, Bendamustine
Hydrochloride was mixed, for 5 min, with half quantity of the
excipients mixture. Then, the obtained mixture was added to the
remaining quantity of the excipients and mixed for additional 5
minutes. The final mixture was tabletted using the tabletting
machine equipped with a suitable punch (8 mm diameter punch for
1:1, 1:1.7 and 1:2 ratios, 10 mm in the case of 1:4 and 1:6 ratios,
12 mm for 1:7 ratio and 14 mm for 1:10 ratio).
[0308] With regard to the 1:0.01, 1:0.1, 1:0.5 ratios, we have
applied the manufacturing process reported above (wet granulation
of the saccharide and subsequent dry granulation), to improve the
API content uniformity. The obtained mixture was tabletted using a
6 mm diameter punch.
[0309] The following tables (Table 38 and Table 39) summarize the
compositions and the analytical results of the API-containing
formulations manufactured to study the effects of the different
API/Mannitol ratios. The batches D001T/111, D001T/083 and D001T/106
showed high friability and for the batches D001T/106, D001T/108 and
D001T/109 the Uniformity of Content did not comply deviating from
data trends previously obtained. This result may be due to the fact
that these batches were produced using a new lot of Bendamustine
HCl (Lot number: F08-05873) that may have different physical
properties.
TABLE-US-00068 TABLE 38 Effect of theA.P.I./Mannitol weight ratio.
API-containing batches final mixture composition A.P.I./Mannitol
Ratio Study D001T/113 D001T/112 D001T/111 D001T/083 D001T/106
D001T/084 (%.sub.w/w) (%.sub.w/w) (%.sub.w/w) (%.sub.w/w)
(%.sub.w/w) (%.sub.w/w) A.P.I./Saccharide 1:0.01 (*) 1:0.1 (*)
1:0.5 (*) 1:1 1:1.7 1:2 Ratio Bendamustine HCl 55.1 55.1 55.1 44.1
34.4 31.1 Mannitol 0.55 5.51 27.6 44.1 58.5 62.3 Granulated
(Pearlitol 200 SD) Avicel PH 112 43.7 38.7 16.6 11.1 6.4 5.9
Magnesium Stearate 0.7 0.7 0.7 0.7 0.7 0.7 Batch number of
F08-03755 F08-03755 F08-03755 F08-03755 F08-05873 F08-03755
Bendamustine HCl Results of analytical tests performed on final
mixtures Flowability (seconds) Not flow Not flow Not flow Not flow
Not flow Not flow (Test performed (Nozzle 3, (Nozzle 3, (Nozzle 3,
(Nozzle 3, (Nozzle 3, (Nozzle 3, according to EP 6.0, diameter =
diameter = diameter = diameter = diameter = diameter = par. 2.9.16)
25.0 mm) 25.0 mm) 25.0 mm) 25.0 mm) 25.0 mm) 25.0 mm)
A.P.I./Mannitol Ratio Study D001T/108 D001T/037 D001T/109 D001T/085
D001T/110 (%.sub.w/w) (%.sub.w/w) (%.sub.w/w) (%.sub.w/w)
(%.sub.w/w) A.P.I./Saccharide 1:4 1:5 1:6 1:7 1:10 Ratio
Bendamustine HCl 18.7 15.7 13.4 11.9 8.6 Mannitol 74.7 78.0 80.7
82.9 86.1 Granulated (Pearlitol 200 SD) Avicel PH 112 5.9 5.7 5.3
4.6 4.6 Magnesium Stearate 0.7 0.6 0.6 0.6 0.7 Batch number of
F8-05873 F08-03755 F8-05873 F08-03755 F08-03755 Bendamustine HCl
Results of analytical tests performed on final mixtures Flowability
(seconds) 5.20 11.14 2.59 10.90 10.06 (Test performed (Nozzle 3,
(Nozzle 2, (Nozzle 3, (Nozzle 2, (Nozzle 2, according to EP 6.0,
diameter = diameter = diameter = diameter = diameter = par. 2.9.16)
25.0 mm) 15.0 mm) 25.0 mm) 15.0 mm) 15.0 mm) (*) Batches
manufactured by using the experimental approach reported above
Standard formulation 1:5 API/Saccharide weight ratio
TABLE-US-00069 TABLE 39 Effect of the A.P.I./Mannitol weight ratio
study. API-containing batches tablets analytical results.
Specification Results of analytical tests performed on tablets
Analytical Test Limits D001T/113 D001T/112 D001T/111 D001T/083
D001T/106 Identification Positive Positive Positive Positive
Positive Positive (HPLC) Mean Weight Specific for 100.28 104.51
95.95 126.76 163.85 (mg/tablet) each Limits: Limits: Limits:
Limits: Limits: formulation 95 / 105 95 / 105 95 / 105 118.75 /
131.3 152.0 / 168.0 Content Uniformity Complies Complies Complies
Complies Complies Not (Test performed RSD 2.7 RSD 3.2 RSD 3.7 RSD
2.77 Complies according to EP 6.0) RSD 14.24 Assay (%) 95.0%-105.0%
101.6 104.1 95.4 99.3 96.8 (HPLC) Related substances (%) (HPLC) HP1
.ltoreq.0.50% 0.07 0.11 0.06 0.09 0.09 BM1 Dimer .ltoreq.0.20% 0.04
0.04 0.04 0.04 0.04 BM1EE .ltoreq.0.50% 0.15 0.16 0.15 0.14 0.12
NP1 .ltoreq.0.20% 0.01 0.01 0.01 0.01 0.01 Individual unknown
impurity .ltoreq.0.10% n.d. n.d. n.d. 0.02 n.d. Total impurities
.ltoreq.1.50% 0.27 0.32 0.26 0.31 0.26 Dissolution Test (Medium:
buffer pH = 1.5) (% 10 min) 80% in 30 71.8 81.3 86.7 80.6 75.7 (%
20 min) min 77.5 88.0 92.1 83.1 81.8 (% 30 min) 80.0 87.5 95.2 81.3
84.1 Moisture content (%) -- 2.3 2.1 1.1 0.8 0.5 Hardness (N)
.gtoreq.40N 88 85 67 63 70 Friability (%) .ltoreq.1.0% 0.7 0.9 Test
failure Test failure Test failure (Test performed (6.1) (5.2)
(18.8) according to EP 6.0) Results of analytical tests performed
on tablets Analytical Test D001T/084 D001T/108 D001T/037 D001T/109
D001T/085 D001T/110 Identification Positive Positive Positive
Positive Positive Positive (HPLC) Mean Weight 177.14 299.05 354.06
410.0 469.55 646.24 (mg/tablet) Limits: Limits: Limits: Limits:
Limits: Limits: 168.2 / 185.9 280.3 / 309.8 332.5 / 367.5 389.5 /
430.5 441.8 / 488.3 608 / 672 Content Uniformity Complies Not
Complies Not Complies Complies (Test performed RSD 2.40 Complies
1.35 Complies RSD 2.79 RSD 2.6 according to EP 6.0) RSD 8.63 RSD
8.33 Assay (%) 98.8 97.1 98.4 97.1 95.1 99.4 (HPLC) Related
substances (%) (HPLC) HP1 0.09 0.09 0.09 0.06 0.12 0.07 BM1 Dimer
0.04 0.04 0.04 0.04 0.03 0.04 BM1EE 0.13 0.13 0.13 0.13 0.14 0.14
NP1 0.01 0.01 0.01 0.05 0.01 0.01 Individual unknown impurity n.d.
n.d. 0.02 n.d. 0.03 n.d. Total impurities 0.27 0.27 0.31 0.28 0.33
0.26 Dissolution Test (Medium: buffer pH = 1.5) (% 10 min) 94.4
90.1 97.1 91.4 96.7 97.7 (% 20 min) 93.8 89.8 95.5 91.1 94.6 97.2
(% 30 min) 92.6 88.4 93.7 90.6 92.8 96.3 Moisture content (%) 1.5
0.4 0.6 0.5 0.4 0.6 Hardness (N) 67 226 140 227 181 91 Friability
(%) 0.4 0.3 0.2 0.5 0.3 0.9 (Test performed according to EP 6.0)
Standard formulation 1:5 API/Saccharide weight ratio
Saccharides Combination Study
[0310] Table 40 and Table 41 report the results concerning the
saccharide combination study.
[0311] The following combinations were investigated:
[0312] Monosaccharide/Disaccharide 1:1 [0313] .sup.(*)Mannitol
(Pearlitol 200 SD)/Lactose Anhydrous (SuperTab 21 AN) Sorbitol
(Neosorb P60W)/Maltose (Sunmalt S)
[0314] Oligosaccharide/Monosaccharide 1:1 [0315]
.sup.(*)D-Melezitose monohydrate/.sup.(*)Dextrose anhydrous ST 0.5
[0316] .sup.(*)Raffinose Pentahydrate granulated/.sup.(*)Mannitol
granulated (Pearlitol 200 SD)
[0317] Oligosaccharide/Disaccharide 1:1 [0318] .sup.(*)Raffinose
Pentahydrate granulated/Lactose Monohydrate (Supertab 14SD)
.beta.-Ciclodextrine (Kleptose DC)/Sucrose (EV Saccharide) (*)
These saccharides were granulated by wet granulation
[0319] The manufacturing process consisted in direct compression of
the unprocessed or granulated saccharide.
[0320] By using Avicel PH 112 and magnesium stearate as
disintegrant and as lubricant, respectively, these batches were
manufactured performing the following steps: [0321] 1. The
saccharides (or the granulated saccharide), Bendamustine
Hydrochloride and excipients were accurately weighed and mixed in a
double polyethylene bag for 5 minutes. [0322] 2. The obtained
mixture was tabletted by using a 10 mm diameter punch.
TABLE-US-00070 [0322] TABLE 40 Saccharides Combination Study.
API-containing batches final mixture composition and analytical
results. Saccharide Combination Study API-containing Batches
D001T/049 D001T/074 D001T/100 D001T/101 D001T/102 D001T/103
Components (%.sub.w/w) (%.sub.w/w) (%.sub.w/w) (%.sub.w/w)
(%.sub.w/w) (%.sub.w/w) Bendamustine HCl 14.89 15.74 15.74 15.74
15.74 15.74 Saccharide combination Oligosaccharide/Monosaccharide
1:1 D-Melezitose monohydrate/Dextrose 78.81 -- -- -- -- --
anhydrous ST 0.5 Raffinose Pentahydrate/Mannitol -- -- -- -- 77.96
-- (Pearlitol 200 SD) Saccharide combination
Oligosaccharide/Disaccharide 1:1 Raffinose Pentahydrate/Lactose --
-- -- -- -- 77.96 Monohydrate (Supertab 14SD) .beta.-Ciclodextrine
(Kleptose DC)/Sucrose -- -- -- 77.96 -- -- (EV Saccharide)
Saccharide combination Monosaccharide/Disaccharide 1:1 Sorbitol
(Neosorb P60W)/Maltose -- -- 77.96 -- -- -- (Sunmalt S) Mannitol
(Pearlitol 200 SD)/Anhydrous -- 77.96 -- -- -- Lactose (SuperTab 21
AN) Avicel PH 112 5.70 5.70 5.70 5.70 5.70 5.70 Magnesium Stearate
0.60 0.60 0.60 0.60 0.60 0.60 Results of analytical tests performed
on final mixtures Flowability (seconds) Not flow Not flow 5.24 5.25
Not flow Not flow (Test performed (Nozzle 3, (Nozzle 3, (Nozzle 3,
(Nozzle 3, (Nozzle 3, (Nozzle 3, according to EP 6.0, diameter =
diameter = diameter = diameter = diameter = diameter = par. 2.9.16)
25.0 mm) 25.0 mm) 25.0 mm) 25.0 mm 25.0 mm 25.0 mm
TABLE-US-00071 TABLE 41 Saccharide Combination Study.
API-containing batches tablets analytical results. Specification
Results of analytical tests performed on tablets Analytical Test
Limits D001T/049 D001T/074 D001T/100 D001T/101 D001T/102 D001T/103
Identification (HPLC) Positive Positive Positive Positive Positive
Positive Positive Mean Weight Specific for 365.96 346.06 351.56
349.60 354.13 348.83 (mg/tablet) each 351.5 / 388.5 332.5 / 367.5
332.5 / 36.5 332.5 / 367.5 332.5 / 367.5 332.5 / 367.5 formulation
Content Uniformity Complies Not Complies Not Complies Complies
Complies (Test performed according complies RSD 1.41 Complies RSD
1.51 RSD 4.73 RSD 1.46 to EP 6.0) RSD 5.55 RSD 4.50 Assay (%)
95.0%-105.0% 96.7 95.1 97.5 97.6 97.9 98.9 (HPLC) Related
substances (%) (HPLC) HP1 .ltoreq.0.50% 0.10 0.06 0.06 0.12 0.09
0.09 BM1 Dimer .ltoreq.0.20% 0.04 0.03 0.04 0.04 0.04 0.04 BM1EE
.ltoreq.0.50% 0.15 0.13 0.12 0.12 0.12 0.12 NP1 .ltoreq.0.20% 0.01
0.01 0.01 0.01 0.01 0.01 Individual unknown impurity .ltoreq.0.10%
0.03 n.d. 0.01 0.02 n.d. 0.02 Total impurities .ltoreq.1.50% 0.33
0.23 0.24 0.31 0.26 0.28 Dissolution Test (Medium: buffer pH = 1.5)
(% 10 min) 80% in 30 min 76.3 73.1 62.9 65.4 89.6 55.7 (% 20 min)
93.8 97.4 86.1 89.4 91.1 87.6 (% 30 min) 92.7 99.2 91.7 93.4 89.8
88.9 Moisture content (%) -- 2.70 0.60 2.77 5.66 5.38 8.12 Hardness
(N) .gtoreq.40 N 73 147 216 144 93 118 Friability (%) .ltoreq.1.0%
0.4 0.1 0.1 0.2 Test failure 0.2 (Test performed according (26.4)
to EP 6,0)
[0323] In general, the tablets manufactured for the saccharides
combination studies show good properties. However, the batch
D001T/102 (Raffinose Pentahydrate/Mannitol (Pearlitol 200 SD)),
show high friability and the batches D001T/100 and D001T/049 are
non homogeneous in API content.
Example 22
Freeze Dried Bendamustine HCl (Ribomustin) and Bendamustine
HCl/Mannitol Tablets (Api/Saccharide Weight Ratio 1:1.2)
[0324] Tablets containing bendamustine hydrochloride/mannitol in a
weight ratio of 1:1.2 were prepared by using either freeze dried
material obtained from the commercially available product for
intravenous application (Ribomustin.RTM.) or using wet granulated
mannitol and Bendamustine HCl.
[0325] The manufacturing processes were performed according to the
following experimental operations: the freeze dried powder was
removed from the Ribomustin.RTM. vials and was sieved using a 850
micron net. The obtained powder and the lubricant (magnesium
stearate) were accurately weighed and mixed in a polyethylene bag
for 5 minutes. The mixture was slowly transferred in the pressing
chamber of the tabletting machine and was manually pressed by using
an 8 mm diameter punch in order to obtain small slugs. The slugs
were sieved using a 850 micron net and the obtained granulate was
manually pressed using a 8 mm diameter punch.
[0326] Bendamustine HCl/mannitol tablets were manufactured applying
the same operating procedures as described above in this
example.
[0327] The composition of the formulations is reported in table
42.
TABLE-US-00072 TABLE 42 Ribomustin and bendamustine/mannitol
tablets. API-containing batches final mixture composition.
Ribomustin and bendamustine/ mannitol tablets D001T/125 D001T/126
(%.sub.w/w) (%.sub.w/w) A.P.I./Saccharide 1:1.2 1:1.2 Ratio
Ribomustin Freeze- 99.36 dried(*) Bendamustine HCl 45.16 Mannitol
54.20 Granulated (Pearlitol 200 SD) Magnesium 0.64 0.64 Stearate
Batch number of F08-03755 Bendamustine HCl Flowability N/A N/A
(seconds) (Test performed according to EP 6.0, par. 2.9.16)
(*)Corresponding to 45.16% of Bendamustine HCl and 54.20% of
Mannitol
[0328] Table 43 reports the data concerning the comparison between
the tablets obtained using the freeze dried bendamustine
hydrochloride/mannitol mixture and the non freeze-dried
bendamustine hydrochloride/mannitol mixture.
TABLE-US-00073 TABLE 43 Ribomustin and bendamustine/mannitol
tablets. API-containing batches tablets analytical results. Results
of analytical tests Specification performed on tablets Analytical
Test Limits D001T/125 D001T/126 Identification Positive Positive
Positive (HPLC) Mean Weight Specific for 123.45 121.79 (mg/tablet)
each Limits: Limits: formulation 115.9 / 128.1 115.9 / 128.1 RSD
6.02 RSD 2.88 Content Uniformity Complies Complies Complies (Test
performed RSD 4.05 RSD 3.35 according to EP 6.0) Assay (%)
95.0%-105.0% 98.6 99.5 (HPLC) Related substances (%) (HPLC) HP1
.ltoreq.0.50% 1.03 0.08 BM1 Dimer .ltoreq.0.20% 0.19 0.04 BM1EE
.ltoreq.0.50% 0.19 0.14 NP1 .ltoreq.0.20% 0.01 0.01 Individual
unknown .ltoreq.0.10% 0.03 n.d. impurity Total impurities
.ltoreq.1.50% 1.50 0.27 Dissolution Test (Medium: buffer pH = 1.5)
(% 10 min) 80% in 30 min 93.3 57.7 (% 20 min) 94.6 80.0 (% 30 min)
93.0 89.9 Moisture content (%) -- 1.61 0.21 Hardness (N) .gtoreq.40
N 61 44 Friability (%) .ltoreq.1.0% N/A Test failure (Test
performed (15.6) according to EP 6.0)
[0329] Taking as reference target the impurity profile of the
Bendamustine Hydrochloride API (see specification limits in the
table), batch D001T/125 showed an out of specification value for
HP1 impurity. The results of the dissolution test highlight that,
although after 10 minutes the dissolution profile of the tablets,
containing the freeze-dried bendamustine hydrochloride/mannitol
mixture is faster, for both formulations, after 30 minutes the
dissolution is in compliance with the current specifications. The
friability is out of specification for batch D001T/126, whereas the
test was not performed for batch D001T/125 due to lack of
sufficient amounts of material.
Example 23
Absolute Bioavailability of Oral Bendamustine in Patients with
Cancer
[0330] A total of 12 patients was planned for a phase 1,
open-label, randomised, 2-way crossover study to investigate the
bioavailability of bendamustine after oral administration of a
liquid-filled hard capsule formulation of bendamustine
hydrochloride. 14 patients who were suffering from multiple
myeloma, B-cell type chronic lymphocytic leukemia or advanced
indolent non-Hodgkin's lymphoma were enrolled and were treated with
bendamustine. Patients were allowed to be previously treated with
intravenous bendamustine, but should have received their last
intravenous cycle at least 7 days before the first administration
of study drug. After signing the informed consent form and
following the screening period (days -21 to -2), eligible patients
were assigned a patient number which was specific for each study
site. Patients were randomized to receive one of the following on
day 1 followed by the other on day 8: [0331] a single oral dose of
110.2 mg (2.times.55.1 mg) bendamustine HCl [0332] a single
intravenous dose of 100 mg bendamustine HCl
[0333] Bendamustine was provided a) orally as capsules, a LFHC
formulation (liquid-filled, hard-shell capsule) and b)
intravenously as a solution after reconstituting a powder for the
preparation of a solution for injection. The LFHC formulation (per
capsule) was prepared from 55.1 mg bendamustine hydrochloride, 1.2
mg methylparaben, 0.12 mg polyparaben, 0.12 mg butylated
hydroxytoluene, 10.9 mg ethanol and 532.56 mg Cremophor.RTM. RH40.
The vial with powder for concentrate for solution was the marketed
product in Germany (Ribomustine.RTM.) which contains per vial 100
mg of bendamustine hydrochloride and mannitol as an excipient. This
product was reconstituted with water for injection to a final
concentration of 2.5 mg/ml of bendamustine HCl and was further
diluted with 0.9% NaCl until about 500 ml before administration to
the patient, in accordance with the instructions of the package
insert.
[0334] Patients were admitted to the study site for 2 periods; days
-1 to 2 (period 1) and days 7 to 9 (period 2). A total of 12
patients was to be randomized to receive treatment. Six patients
were to receive treatment with a single oral dose of 110.2 mg
(2.times.55.1 mg) bendamustine HCl (day 1) followed by a single
intravenous dose of 100 mg bendamustine HCl (day 8) while 6 other
patients were to receive treatment in the alternate order. Patients
underwent a washout period of at least 7 days between
treatments.
[0335] Bendamustine is metabolized via hydrolysis to the inactive
metabolites monohydroxybendamustine (HP 1) and
dihydroxybendamustine (HP2) and via cytochrome P450 (CYP 1A2) to
the active metabolites .gamma.-hydroxybendamustine (M3) and
N-desmethylbendamustine (M4).
[0336] After oral and intravenous administration of bendamustine
the concentration of bendamustine, as well as that of the active
metabolites of bendamustine (M3 and M4), were determined in plasma
and urine samples on day 1 and day 8. Patients returned to the
study site for an end-of-study visit 7 to 14 days after completion
of the second treatment period, or after early
discharge/withdrawal. Subsequently the pharmacokinetic parameters
of bendamustine and its metabolites were calculated.
[0337] No interim analyses were planned or conducted.
[0338] The following results were obtained:
Population:
[0339] Of the 23 patients screened for this study, 14 patients were
randomly assigned to treatment and received at least 1 dose of
study medication. These included 6 patients receiving the
oral/intravenous sequence and 8 patients receiving the
intravenous/oral sequence. Of these 14 patients:
[0340] 1 was excluded due to a protocol violation (concomitant
medication) and received oral medication only, so no intravenous
administration;
[0341] 1 was excluded from the oral analysis due to vomiting and di
not qualify for the bioavailability assessment and
[0342] 1 was excluded from the intravenous administration due to an
adverse event. This patient received oral dosing only, no
intravenous.
[0343] Ten (71%) of the 14 patients were male, and all were white.
Patient ages ranged from 54 to 82, with a mean of approximately 70
years. Seven of the patients had multiple myeloma, 4 had indolent
non-Hodgkin's lymphoma and 3 had chronic lymphocytic leukemia.
Pharmacokinetic Results:
[0344] Plasma pharmacokinetic parameters of bendamustine (base), M3
and M4 are shown in Table 44, Table 45 and Table 46, respectively.
Based on statistical analysis, the absolute bioavailability (oral
versus intravenous ratio of AUC.sub.inf) of bendamustine was 66%
(geometric mean; 90% CI: 55%, 78%). C.sub.max after oral dosing was
42% of C.sub.max after intravenous dosing (90% CI: 32%, 54%).
TABLE-US-00074 TABLE 44 Plasma Pharmacokinetic Parameters for
Bendamustine t.sub.max C.sub.max AUC.sub.last AUC.sub.inf Treatment
Statistic (h) (ng/mL) (ng h/mL) (ng h/mL) Bendamustine n 12 12 12
12 HCl, Mean 0.946 3173.dagger-dbl. 3893 3901 110.2 mg SD 0.4833
1767 1929 1930 orally t.sub.1/2 CL/F V.sub.z/F F (h) (L/h) (L) (%)
n 12 12 12 11 Mean 0.461 31.7 20.2 69.0.dagger. SD 0.107 14.5 7.9
17.9 t.sub.max C.sub.max AUC.sub.last AUC.sub.inf Statistic (h)
(ng/mL) (ng h/mL) (ng h/mL) Bendamustine n 11 11 11 11 HCl, 100 mg
Mean 0.524 5900.dagger-dbl. 4785 4793 intravenously SD 0.119 1823
1689 1691 t.sub.1/2 CL V.sub.z V.sub.ss (h) (L/h) (L) (L) n 11 11
11 10 Mean 0.504 21.2 14.7 10.3 SD 0.143 7.4 4.1 3.2 Notes: All
patients who received at least 1 dose of study drug and who had
sufficient plasma concentration data available to derive at least 1
pharmacokinetic parameter, excluding 1 patient whose
pharmacokinetic data were considered unreliable due to an AE of
vomiting (modified pharmacokinetic analysis set).
.dagger.Arithmetic mean. Geometric mean was 66% (90% CI: 55%, 78%).
.dagger-dbl.C.sub.max after oral dosing was 42% of C.sub.max after
intravenous dosing (90% CI: 32%, 54%).
TABLE-US-00075 TABLE 45 Plasma Pharmacokinetic Parameters for M3
AUC.sub.last AUC.sub.inf t.sub.max C.sub.max (ng h/ (ng h/
t.sub.1/2 Treatment Statistic (h) (ng/mL) mL) mL) (h) Bendamustine
n 11 11 11 11 11 HCl, Mean 1.27 243 367 369 0.643 110.2 mg orally
SD 0.45 149 194 194 0.285 Bendamustine n 11 11 11 11 11 HCl, 100 mg
Mean 0.823 344 370 372 0.727 intravenously SD 0.221 193 178 179
0.426 Notes: All patients who received at least 1 dose of study
drug and who had sufficient plasma concentration data available to
derive at least 1 pharmacokinetic parameter, excluding 1 patient
whose pharmacokinetic data were considered unreliable due to an AE
of vomiting (modified pharmacokinetic analysis set).
TABLE-US-00076 TABLE 46 Plasma Pharmacokinetic Parameters for M4
C.sub.max AUC.sub.last AUC.sub.inf t.sub.max (ng/ (ng h/ (ng h/
t.sub.1/2 Treatment Statistic (h) mL) mL) mL) (h) Bendamustine n 11
11 11 11 11 HCl, Mean 1.325 26.9 42.8 44.4 0.515 110.2 mg orally SD
0.449 19.9 29.6 29.6 0.134 Bendamustine n 11 11 11 11 11 HCl, 100
mg Mean 0.935 33.6 40.8 42.5 0.543 intravenously SD 0.198 20.0 22.9
22.6 0.097 Notes: All patients who received at least 1 dose of
study drug and who had sufficient plasma concentration data
available to derive at least 1 pharmacokinetic parameter, excluding
1 patient whose pharmacokinetic data were considered unreliable due
to an AE of vomiting (modified pharmacokinetic analysis set).
[0345] After oral administration, bendamustine was absorbed with a
t.sub.max of approximately 0.95 hours, with individual values
ranging between 15 minutes and 1.8 hours. Mean CL after intravenous
administration was 21.2 L/h. Mean t.sub.1/2 was approximately 30
minutes, both after oral intake and after intravenous
administration. Mean V.sub.Z and V.sub.SS after intravenous
administration were 14.7 L and 10.3 L respectively.
[0346] M3 and M4 exposure in plasma was considerably lower than for
bendamustine. Mean AUC.sub.inf of bendamustine was 10.6 and 88
times higher than for M3 and M4, respectively, after oral
administration. In contrast to bendamustine, M3 and M4 AUC.sub.inf
values were similar for oral and intravenous administration. Based
on statistical analysis, after oral administration AUC.sub.inf of
M3 was 86% of AUC.sub.inf after intravenous administration (90% CI:
76%, 98%). For M4 this was 88% (90% CI: 77%, 102%).
[0347] Urine pharmacokinetic parameters of bendamustine, M3 and M4
are presented in Table 47, Table 48 and Table 49, respectively. The
percentage of the dose excreted in urine unchanged was low (2.6%
and 2.1% for oral and intravenous bendamustine, respectively).
TABLE-US-00077 TABLE 47 Urine Pharmacokinetic Parameters for
Bendamustine Ae.sub.last % Ae.sub.last Ae.sub.inf % Ae.sub.inf
CL.sub.R Treatment Statistic (mg) (%) (mg) (%) (L/h) Bendamustine n
11 11 11 11 11 HCl, 110.2 mg Mean 2.66 2.66 2.64 2.64 0.788 orally
SD, 1.64, 62 1.64, 62 1.63, 62 1.63, 62 0.573, 73 CV % Min-
0.40-5.9 0.40-5.9 0.40-5.8 0.40-5.8 0.18-2.0 max Median 2.23 2.23
2.23 2.23 0.782 Bendamustine n 11 11 11 11 11 HCl, 100 mg Mean 1.88
2.07 1.874 2.07 0.385 intravenously SD, 2.29, 122 2.52, 122 2.28,
122 2.52, 122 0.414, 108 CV % Min- 0.24-8.0 0.27-8.8 0.24-8.0
0.27-8.8 0.06-1.4 max Median 1.12 1.23 1.11 1.22 0.202 Notes: All
patients who received at least 1 dose of study drug and who had
sufficient plasma concentration data available to derive at least 1
pharmacokinetic parameter, excluding 1 patient whose
pharmacokinetic data were considered unreliable due to an AE of
vomiting (modified pharmacokinetic analysis set).
TABLE-US-00078 TABLE 48 Urine Pharmacokinetic Parameters for M3
Ae.sub.last % Ae.sub.last Ae.sub.inf % Ae.sub.inf CL.sub.R
Treatment Statistic (mg) (%) (mg) (%) (L/h) Bendamustine n 10 10 10
10 10 HCl, Mean 0.635 0.61 0.636 0.611 2.14 110.2 mg SD, 0.409, 64
0.393, 64 0.407, 64 0.391, 64 2.08, 97 orally CV % Min- 0.13-1.7
0.12-1.6 0.13-1.6 0.13-1.5 0.45-7.4 max Median 0.576 0.553 0.558
0.537 1.49 Bendamustine n 11 11 11 11 11 HCl, 100 mg Mean 0.433
0.457 0.435 0.459 1.29 intravenously SD, 0.435, 100 0.459, 100
0.441, 101 0.466, 101 1.44, 112 CV % Min- 0.017-1.5 0.018-1.6
0.017-1.6 0.018-1.6 0.082-5.2 max Median 0.334 0.353 0.336 0.354
0.856 Notes: All patients who received at least 1 dose of study
drug and who had sufficient plasma concentration data available to
derive at least 1 pharmacokinetic parameter, excluding 1 patient
whose pharmacokinetic data were considered unreliable due to an AE
of vomiting (modified pharmacokinetic analysis set).
TABLE-US-00079 TABLE 49 Urine Pharmacokinetic Parameters for M4
Ae.sub.last % Ae.sub.last Ae.sub.inf % Ae.sub.inf CL.sub.R
Treatment Statistic (mg) (%) (mg) (%) (L/h) Bendamustine n 10 10 10
10 10 HCl, Mean 0.109 0.113 0.105 0.109 2.83 110.2 mg SD, 0.058, 54
0.060, 54 0.052, 50 0.054, 50 1.96, 69 orally CV % Min- 0.019-0.21
0.019-0.21 0.033-0.21 0.034-0.22 0.78-7.1 max Median 0.1 0.104 0.1
0.104 2.24 Bendamustine n 11 11 11 11 11 HCl, 100 mg Mean 0.075
0.086 0.071 0.081 1.74 intravenously SD, 0.067, 89 0.077, 89 0.057,
81 0.066, 81 1.44, 83 CV % Min- 0.0025-0.18 0.0028-0.21 0.0034-0.15
0.0039-0.17 0.18-5.3 max Median 0.038 0.043 0.039 0.045 1.66 Notes:
All patients who received at least 1 dose of study drug and who had
sufficient plasma concentration data available to derive at least 1
pharmacokinetic parameter, excluding 1 patient whose
pharmacokinetic data were considered unreliable due to an AE of
vomiting (modified pharmacokinetic analysis set).
Safety Results:
[0348] Both oral and intravenous administrations of bendamustine
were safe and well tolerated. Overall, 6 patients (43%) experienced
treatment-emergent adverse events during oral treatment and 3
patients (25%) experienced treatment-emergent adverse events during
intravenous treatment. Four patients (29%) receiving the oral dose
and no patients receiving the intravenous dose experienced at least
1 adverse event that was considered by the investigator to be
related to study drug; these included headache in 1 patient, both
headache and fatigue in 1 patient, nausea in 1 patient and vomiting
in 1 patient. These events were Grade 1 in severity except for
vomiting, which was Grade 2 in severity.
[0349] Most adverse events were Grade 1 or Grade 2 in severity. One
patient receiving the oral dose experienced Grade 3 increased serum
creatinine, hypokalemia, and acute renal failure, and Grade 4
thrombocytopenia, all considered by the investigator to be related
to the patient's multiple myeloma and unrelated to study drug. The
increased serum creatinine and acute renal failure were severe
adverse events, leading to the patient's premature discontinuation
from the study. No deaths occurred during the study.
[0350] No clinically meaningful trends were observed in mean
changes from baseline or categorical shifts for any hematology,
biochemistry, urinalysis, or vital sign parameter. A few patients
had abnormal hematology or biochemistry findings that were reported
as adverse events; none of these were considered to be related to
study drug by the investigator.
[0351] Mean changes from baseline in heart rate were small and
similar between treatment groups. Due to the age and medical
history of the patients in this study, most had at least 1
electrocardiogram finding of "abnormal, not clinically significant"
at screening and/or during the study. In 1 patient in the
intravenous/oral group, abnormal, clinically significant atrial
fibrillation, nonspecific ST depression and left axis deviation was
observed at screening and following both the intravenous and oral
doses.
CONCLUSIONS
[0352] Absolute bioavailability of bendamustine after single oral
administration using the capsule was 66% (geometric mean; 90% CI:
55%, 78%). [0353] Mean bendamustine CL, Vz and Vss after
intravenous administration were 21.2 L/h, 14.7 L and 10.3 L,
respectively. [0354] Bendamustine was quickly absorbed after oral
administration (median t.sub.max approximately 0.95 hours). Mean
t.sub.1/2 was approximately 30 minutes. Approximately 2.6% of the
dose was excreted in urine unchanged after oral administration,
while 0.6% was excreted as M3 and 0.1% was excreted as M4. M3 and
M4 exposure were approximately 9% and 1% that of bendamustine,
respectively, after oral administration.
[0355] Based on adverse events reporting, clinical laboratory
evaluations, vital signs, physical examinations and
electrocardiograms, single doses of both the oral (110.2 mg) and
intravenous (100 mg) forms of bendamustine were shown to be safe
and well tolerated in this mostly elderly population of patients
with indolent non-Hodgkin's lymphoma, multiple myeloma or B-cell
type chronic lymphocytic leukemia.
INDUSTRIAL APPLICABILITY
[0356] The compositions according to the present invention show
many advantages. They can be easily used by the patient without
assistance of supervisory medical staff. Hence the time-consuming
trips to the hospital may become obsolete, thereby increasing the
patient compliance.
[0357] Since the dosage forms are solid, they can be swallowed as
such, which means that the patient does not need to wait until
dissolution of the active ingredient has been achieved. Further due
to the good stability of the dosage forms they can be easily stored
at room temperature and without the need of any special storage
conditions.
[0358] By using the dosage forms according to the present
invention, a considerable reduction of the volume of the dosage
form may be achieved. The reduced size is desirable both from a
manufacturing and handling standpoint and patient compliance.
[0359] Pharmaceutical compositions show a high dissolution in vitro
reducing the degradation of bendamustine in vivo, thus resulting in
an improved bioavailability of the bendamustine in vivo.
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