U.S. patent application number 14/638647 was filed with the patent office on 2015-08-27 for cyclosporine emulsion.
This patent application is currently assigned to NEUROVIVE PHARMACEUTICAL AB. The applicant listed for this patent is NEUROVIVE PHARMACEUTICAL AB. Invention is credited to Eskil Elmer.
Application Number | 20150238563 14/638647 |
Document ID | / |
Family ID | 43733181 |
Filed Date | 2015-08-27 |
United States Patent
Application |
20150238563 |
Kind Code |
A1 |
Elmer; Eskil |
August 27, 2015 |
CYCLOSPORINE EMULSION
Abstract
The present invention relates to cyclosporine emulsions
containing: (i) a cyclosporine, (ii) a natural oil (long chain
triglyceride), (iii) a phosphatidylcholine, (iv) glycerol, (v) a
pharmaceutically tolerable alkali salt of a free fatty acid, (vi) a
medium chain triglyceride-oil, (vii) optionally, hydrochloric acid
or sodium hydroxide for pH adjustment and (viii) water, and to
therapeutic methods using them.
Inventors: |
Elmer; Eskil; (Lund,
SE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NEUROVIVE PHARMACEUTICAL AB |
Lund |
|
SE |
|
|
Assignee: |
NEUROVIVE PHARMACEUTICAL AB
Lund
SE
|
Family ID: |
43733181 |
Appl. No.: |
14/638647 |
Filed: |
March 4, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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13877326 |
Aug 23, 2013 |
9040487 |
|
|
PCT/EP2011/067117 |
Sep 30, 2011 |
|
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14638647 |
|
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61388633 |
Oct 1, 2010 |
|
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Current U.S.
Class: |
514/20.5 |
Current CPC
Class: |
A61K 47/44 20130101;
A61K 38/13 20130101; A61K 47/12 20130101; A61K 47/10 20130101; A61K
47/14 20130101; A61P 9/00 20180101; A61P 9/10 20180101; A61P 13/12
20180101; A61P 1/16 20180101; A61P 25/00 20180101; A61K 9/107
20130101; A61P 37/06 20180101; A61K 47/24 20130101 |
International
Class: |
A61K 38/13 20060101
A61K038/13; A61K 47/14 20060101 A61K047/14; A61K 47/10 20060101
A61K047/10; A61K 9/107 20060101 A61K009/107; A61K 47/24 20060101
A61K047/24 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 1, 2010 |
DK |
PA 2010 00891 |
Claims
1-18. (canceled)
19. A cyclosporine oil-in-water emulsion comprising: (i)
cyclosporine at a concentration of 1-15 g/L, (ii) long chain
triglyceride at a concentration of 50-150 g/L, (iii)
phosphatidylcholine at a concentration of 5-25 g/L, (iv) glycerol
at a concentration of 10-50 g/L, (v) pharmaceutically acceptable
alkali salt of a free fatty acid at a concentration of 0.1-1 g/L,
(vi) medium chain triglyceride-oil at a concentration of 5-140 g/L,
and (vii) water for injection, wherein the emulsion is isoosmolar
and has an osmolarity of from 280 to 305 mosm/l, and wherein the
composition does not contain polyethoxylated castor oil.
20. The cyclosporine emulsion according to claim 19, having an
osmolarity of from about 295 to about 300 mosm/1.
21. The cyclosporine emulsion of claim 19, wherein the pH of the
emulsion is from about 6 to about 8.8.
22. The cyclosporine emulsion of claim 21, further comprising
hydrochloric acid or sodium hydroxide at a concentration to provide
a pH of from about 6 to about 8.8.
23. The cyclosporine emulsion of claim 19, wherein the long chain
triglyceride comprises soy bean oil.
24. The cyclosporine emulsion of claim 19, wherein the
phosphatidylcholine comprises egg lecithin.
25. The cyclosporine emulsion of claim 19, wherein the
pharmaceutically acceptable alkali salt of a free fatty acid
comprises sodium oleate.
26. The cyclosporine emulsion of claim 19, wherein the medium chain
triglyceride-oil comprises one or more selected from the group
consisting of coconut oil and palm oil.
27. The cyclosporine emulsion of claim 19, wherein the emulsion is
stable for 12-36 months when stored at 25.degree. C. and 60%
relative humidity and protected from light.
28. The cyclosporine emulsion of claim 19, wherein the emulsion has
a shelf-life of 12 months when stored at 40.degree. C. and 75%
relative humidity.
29. The cyclosporine emulsion according to claim 19, wherein the
emulsion has a shelf-life of at least 30 months when stored below
25.degree. C. and protected from light.
30. A therapeutic method comprising administering the cyclosporine
emulsion according to claim 19 to a subject in need thereof.
31. The method of claim 30, wherein the cyclosporine emulsion
comprises 5 g/L cyclosporine, 100 g/L soya bean oil, 12 g/L egg
lecithin, 25 g/L water-free glycerol, 0.3 g/L sodium oleate, 100
g/L medium chain triglyceride-oil selected from the group
consisting of coconut oil, palm oil, and combinations thereof, and
water for injection.
32. The method of claim 30, wherein the cyclosporine emulsion is
administered without any premedication with corticosteroids.
33. A method for reducing the rate of anaphylactic reactions in
patients subjected to cyclosporine treatment, the method comprising
administering the cyclosporine emulsion of claim 19 to the
subject.
34. A method for providing immunosuppressive cyclosporine
treatment, comprising administering the cyclosporine emulsion of
claim 19 to a subject in need thereof.
35. A method of preventing cardiac reperfusion injury
(cardioprotection), comprising administering the cyclosporine
emulsion of claim 19 to a subject in need thereof.
36. A method of preventing brain damage (neuroprotection),
comprising administering the cyclosporine emulsion of claim 19 to a
subject in need thereof.
37. A method of preventing reperfusion injury (organ oprotection),
comprising administering the cyclosporine emulsion of claim 19 to a
subject in need thereof.
38. A method of preventing kidney reperfusion injury
(nephroprotection), comprising administering the cyclosporine
emulsion of claim 19 to a subject in need thereof.
39. A method of preventing liver reperfusion injury
(hepatoprotection), comprising administering the cyclosporine
emulsion of claim 19 to a subject in need thereof.
Description
CROSS-REFERENCE TO RELATED PATENT APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 13/877,326, filed on Aug. 23, 2013, which is a
continuation of U.S. patent application No. the U.S. national stage
of PCT/EP2011/067117, filed Sep. 30, 2011, and claims priority to
U.S. Provisional Application 61/388,633, filed Oct. 1, 2010, and
Denmark Application PA 2010 00891, filed Oct. 1, 2010.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to a novel cyclosporine
composition in the form of an emulsion with a content of medium
chain triglycerides. The emulsion is an oil-in-water emulsion, is
bioequivalent to the marketed product SANDIMMUNE.RTM. but has an
improved tolerability profile compared with SANDIMMUNE.RTM..
[0004] 2. Background of the Invention
[0005] Cyclosporine is a widely used immunosuppressant in organ and
tissue transplantation. Cyclosporine has poor solubility in water,
and a marketed product SANDIMMUNE.RTM. for infusion has been
formulated as a concentrate containing 50 mg/ml cyclosporine and
polyoxylated castor oil (CREMOPHOR EL.RTM.) in ethanol and must be
diluted with an isotonic solution of sodium chloride or a 5%
solution of glucose before administration. However, intravenous
administration of cyclosporine composition containing CREMOPHOR
EL.RTM. has been associated with hypersensitivity reactions, with
responses ranging from mild skin reactions to anaphylaxis and
cardiac collapse. Thus, there is a need for CREMOPHOR.RTM.-free
cyclosporine compositions as well as ready-to-use compositions.
[0006] CREMOPHOR EL.RTM. is the registered trademark of BASF Corp.
for its version of polyethoxylated castor oil. It is prepared by
reacting 35 moles of ethylene oxide with each mole of castor oil.
The resulting product is a mixture (CAS number 61791-12-6): the
major component is the material in which the hydroxyl groups of the
castor oil triglyceride have ethoxylated with ethylene oxide to
form polyethylene glycol ethers. Minor components are the
polyethylene glycol esters of ricinoleic acid, polyethylene glycols
and polyethylene glycol ethers of glycerol. Cremophor EL is a
synthetic, nonionic surfactant. Its utility comes from its ability
to stabilize emulsions of nonpolar materials in aqueous
systems.
[0007] A number of Cremophor products are available from BASF
(Cremophor RH 40 (polyoxyl-40 hydrogenated castor oil), Cremophor
EL (polyoxyl-35 castor oil), Cremophor ELP (extra pure grade of
EL), which all are grades of polyoxyl castor oil, and Cremophor A 6
(macrogol-6-cetostearyl ether) and Cremophor A 25
(macrogol-25-cetostearyl ether), which are grades of macrogol
cetostearyl ethers. To the best of our knowledge, at present only
CREMOPHOR EL.RTM. has been associated with hypersensitivity
reactions. However, it is likely that all the CREMOPHOR.RTM.
products from the polyoxyl castor oil series have the same
side-effect when administered to a subject.
SUMMARY OF THE INVENTION
[0008] Ready-to-use compositions of cyclosporine for parenteral
administration have been described in inter alia EP-B-0 570 829.
However, further developments of such compositions have been
necessary in order to obtain compositions that are bioequivalent to
the SANDIMMUNE.RTM. product and in order to ensure a proper
shelf-life.
[0009] Further developments are directed at ensuring formulations
which can both have sufficient stability and shelf-life as to
fulfill the requirements for marketing and distribution in
commercial pharmaceuticals business while being bioequivalent and
using ingredients which are beneficial to therapeutic targets such
as mitochondrial metabolism and being non-toxic.
[0010] In clinical practice, this also means that we can better
achieve the goal of e.g. SANDIMMUNE.RTM. and thereby ensure that in
clinical practice it is possible to avoid the adverse effect of
CREMOPHOR.RTM. and ethanol and avoid having to premedicate with
corticosteroids and/or antihistamines in cases where such
pretreatment or multi-pharmacy approach is contraindicated.
[0011] The present invention provides a CREMOPHOR.RTM..sup.-free
cyclosporine composition for parenteral administration, notably
intravenous administration.
A composition of the present invention contains: A cyclosporine A
natural oil (long chain triglyceride) (e.g. soy-bean oil) A
phosphatidylcholine (e.g. egg lecithin)
Glycerol
[0012] A pharmaceutically tolerable alkali salt of a free fatty
acid (e.g. sodium oleate) Medium chain triglyceride-oil (e.g.
coconut and/or palm oil) Optionally, hydrochloric acid or sodium
hydroxide for pH adjustment
Water.
[0013] A composition of the present invention has an osmolality in
the isoosmolar range, i.e. the osmolarity is in a range of from
about 280 mosm/l to about 305 mosm/l, preferably about 295-300
mosm/l, which correspond to the value of plasma, i.e. the
isoosmolar value. The use of a cyclosporine-containing compostion
with an isoosmolar osmolality is important in order to ensure a
good biocompatibility. Many of the known cyclosporine emulsions are
hyperosmolar in order to achieve a good penetration through the
blood-brain barrier when such compositions are used e.g. in the
treatment of stroke. However, cyclosporine emulsions of the
invention may also be used in other important therapeutic areas
such as, e.g., in connection with cardiac reperfusion injury and
immunosuppression, where the use of a hyperosmolar composition may
lead to unwanted entrance into the brain of specific metabolites,
substances, blood components etc., which in turn may lead to toxic
or adverse effects, all of which are unwanted.
[0014] The terms osmolarity, osmolality and tonicity are often used
interchangeably. For specific definitions see Remington's
Pharmaceutical Sciences, 18.sup.th Edition, Mack Publishing Company
1990, pages 1481-1498, which hereby is incorporated by
reference.
[0015] A composition of the present invention may also be used in
the treatment of traumatic brain injury, where the composition
crosses the blood-brain barrier due to breaches therein caused by
the brain injury itself and where there is thus no need for a
hyperosmolar composition to breach the blood-brain barrier. An
isoosmolar composition is highly preferable to a hyperosmolar
composition in such indications.
Cyclosporine
[0016] The cyclosporine may be any therapeutically active
cyclosporine or analogues and derivatives of cyclosporines. The
cyclosporine may have immunosuppressive properties or
non-immunosuppressive properties (NICAMs), or it may have any other
known or unknown effect (e.g. for cardioprotection or
neuroprotection of for treatment in cardiovascular diseases such as
myocardial infarction, reperfusion, or in neurodegenerative
diseases, brain injury, ischemia, trauma, etc. It is known that
cyclosporines have protective effects on mitochondria, Preferred
are cyclosporines that are suitable for use in immunosuppression.
The cyclosporine may be a natural or synthetic cyclosporine. As it
appears from the following several chiral carbon atoms are present.
Thus, any of these forms--either alone or in any combination--that
have therapeutic activity are encompassed by the term
"cyclosporine".
[0017] In the Examples, the following cyclosporine has been
employed:
INN: Ciclosporin
Chemical Names:
[0018] a)
Cyclo[[(2S,3R,4R,6E)-3-hydroxy-4-methyl-2-(methylamino)-oct-6-enoyl]-L-2--
aminobutanoyl-N-methylglycyl-N-methyl-L-leucyl-Lvalyl-N-methyl-L-leucyl-L--
alanyl-D-alanyl-N-methyl-L-leucyl-Nmethyl-L-leucyl-N-methyl-L-valyl]
[0019] b)
Cyclo[[(E)-(2S,3R,4R)-3-hydroxy-4-methyl-2-(methylamino)-6-octe-
noyl]-L-2-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-Lvalyl-N-methyl-L--
leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-Nmethyl-L-leucyl-N-methyl-L-val-
yl] [0020] c)
[R--[R*,R*-(E)]]-Cyclic(L-alanyl-D-alanyl-N-methyl-L-leucyl-Nmethyl-L-leu-
cyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-amino-6-octenoyl-L-.alpha.-
-aminobutyryl-N-methylglycyl-N-methyl-Lleucyl-L-valyl-N-methyl-L-leucyl)
Other names: Ciclosporine (DCI)
Ciclosporina (DCI-E)
[0021] Compendial names: Ciclosporin (Ciclosporinum) (Ph. Eur.)
Cyclosporine (USP)
[0022] CAS number: 59865-13-3 Structural formula (see FIG. 1)
Molecular formula: C.sub.62H.sub.111N.sub.11O.sub.12 Relative
molecular mass (Mr): 1202.61 Chirality: Ciclosporin is a molecule
of natural origin that possesses several chiral carbon atoms.
General Properties
[0023] Physical form: white or almost white powder Solubility:
soluble in acetone, ethanol, methanol, ether, chloroform and
methylene chloride; slightly soluble in saturated hydrocarbons;
practically insoluble in water Specific optical rotation:
-185.degree. to -193.degree. (methanol)
Phosphatidylcholine
[0024] Egg lecithin and/or soy lecithin, particularly egg lecithin,
are preferred as suppliers of phosphatidylcholine, notably
3-sn-phosphatidyl choline or hydrogenated 3-sn-phosphatidyl
choline. Lecithins with a content of more than 60% of
3-sn-phosphatidyl choline and/or partially hydrogenated
3-sn-phosphatidyl choline and/or hydrogenated 3-sn-phosphatidyl
choline are above all suited.
Pharmaceutically Tolerable Salts of Fatty Acids
[0025] An alkali salt of a free fatty acid with 6 to 26 carbon
atoms may be added to adjust the pH value or to facilitate the
emulsification and homogenization process. The sodium and potassium
salts of palmitic acid, palmitoleic acid, stearic acid, oleic acid,
linoleic acid and linolenic acid are especially preferred. In a
preferred embodiment sodium oleate is employed.
Isotonically/Isoosmolar Adjusting Substance
[0026] As seen from the examples herein, glycerol has been employed
to adjust the osmolarity of the composition to isoosmolar. However,
other substances like sorbitol, xylitol, sodium chloride, glucose
may also prove to be suitable.
Natural Oils (Long Chain Triglycerides)
[0027] Soy-bean oil or safflower oil or combinations thereof may be
employed as natural oils. In a preferred embodiment, soy-bean oil
is employed.
MCT-Oils (Medium-Chain Triglycerides)
[0028] As it appears from the following, it seems that the presence
of an MCT-oil is important in order to achieve the desired
stability of the emulsion, notably with respect to the physical
stability of the emulsion. Cyclosporine has a very good solubility
in MCT-oil and MCT-oil thus contributes to avoid undesired
precipitation of cyclosporine during storage.
[0029] Moreover, MCT-oils seem to have a beneficial effect on the
brain, e.g., there are indications that it may be beneficial in the
treatment of Alzheimer's disease and other condition where
stabilization protection and support of mitochondrial function is
important/needed. Mitochondria are present and produce energy in
almost all cells in the body. Mitochondrial collapse may be
associated with a variety of acute injuries, such as myocardial
infarctions and traumatic brain injury and chronic diseases like
amyothropic lateral sclerosis, multiple sclerosis, and other
neurological disorders. In myocardial infarctions, reperfusion of
the blocked artery can cause reperfusion injury and extra damage
and disability to the heart muscle, as well as increased mortality.
Mitochondrial protection in heart muscle tissue may moderate the
long-term impact of heart attacks.
[0030] A suitable MCT-oil is coconut oil, palm oil or a combination
thereof.
Water
[0031] The water employed must have a quality suitable for
parenteral products, such as water for injection (pharmacopoeia
standard).
Manufacturing Method
[0032] A suitable method for manufacturing a composition of the
invention appears in FIG. 2 and in the Examples herein.
Examples of Compositions According to the Invention
[0033] In all the compositions mentioned herein, the osmolarity is
adjusted to the isoosmolar value of about 285 to about 305 mosm/l,
preferably adjused to about 295 to about 300 mosm/1.
[0034] More specifically, a composition according to the invention
contains:
A cyclosporine in a concentration range of from 1 to 15 g/l, A
phosphatidylcholine (e.g. egg lecithin) in a concentration range of
from 5 to 25 g/l, A pharmaceutically tolerable alkali salt of a
free fatty acid (e.g. sodium oleate) in a concentration range of
from 0.1 to 1 g/l, Optionally, pH adjustment e.g. sodium hydroxide
1 M in a sufficient amount to reach a final pH value of the
composition of from about 6 to about 8.8, Glycerol in a
concentration range of from 10 to 50 g/l, A natural oil (long chain
triglyceride) (e.g. soy bean oil) in a concentration range of from
50 to 150 g/l, Medium chain triglyceride-oil in a concentration
range of from 50 to 150 g/l, and Water up to 1 liter.
[0035] In particular embodiments, a composition according to the
invention contains:
A cyclosporine in a concentration range of from 1 to 15 g/l, Egg
lecithin in a concentration range of from 5 to 25 g/l, A
pharmaceutically tolerable alkali salt of a free fatty acid (e.g.
sodium oleate) in a concentration range of from 0.1 to 1 g/l,
Optionally, pH adjustment e.g. sodium hydroxide 1 M in a sufficient
amount to reach a final pH value of the composition of from about 8
to about 8.8, Glycerol in a concentration range of from 10 to 50
g/l, A natural oil (long chain triglyceride) (e.g. soy bean oil) in
a concentration range of from 50 to 150 g/l, Medium chain
triglyceride-oil in a concentration range of from 50 to 150 g/l,
and Water up to 1 liter. A cyclosporine in a concentration range of
from 1 to 15 g/l, A phosphatidylcholin (e.g. egg lecithin) in a
concentration range of from 5 to 25 g/l, sodium oleate in a
concentration range of from 0.1 to 1 g/l, optionally, pH adjustment
e.g. sodium hydroxide 1 M in a sufficient amount to reach a final
pH value of the composition of from about 8 to about 8.8, Glycerol
in a concentration range of from 10 to 50 g/l, A natural oil (long
chain triglyceride) (e.g. soy bean oil) in a concentration range of
from 50 to 150 g/l, Medium chain triglyceride-oil in a
concentration range of from 50 to 150 g/l, and Water up to 1 liter.
A cyclosporine in a concentration range of from 1 to 15 g/l, egg
lecithin in a concentration range of from 5 to 25 g/l, sodium
oleate in a concentration range of from 0.1 to 1 g/l, optionally,
pH adjustment e.g. sodium hydroxide 1 M in a sufficient amount to
reach a final pH value of the composition of from about 8 to about
8.8, Glycerol in a concentration range of from 10 to 50 g/l, A
natural oil (long chain triglyceride) (e.g. soy bean oil) in a
concentration range of from 50 to 150 g/l, Medium chain
triglyceride-oil in a concentration range of from 50 to 150 g/l,
and Water up to 1 liter. A cyclosporine in a concentration range of
from 1 to 15 g/l, A phosphatidylcholin (e.g. egg lecithin) in a
concentration range of from 5 to 25 g/l, A pharmaceutically
tolerable alkali salt of a free fatty acid (e.g. sodium oleate) in
a concentration range of from 0.1 to 1 g/l, Optionally, pH
adjustment e.g. sodium hydroxide 1 M in a sufficient amount to
reach a final pH value of the composition of from about 8 to about
8.8, Glycerol in a concentration range of from 10 to 50 g/l, soy
bean oil in a concentration range of from 50 to 150 g/l, Medium
chain triglyceride-oil in a concentration range of from 50 to 150
g/l, and Water up to 1 liter. A cyclosporine in a concentration
range of from 1 to 15 g/l, egg lecithin in a concentration range of
from 5 to 25 g/l, A pharmaceutically tolerable alkali salt of a
free fatty acid (e.g. sodium oleate) in a concentration range of
from 0.1 to 1 g/l, Optionally, pH adjustment e.g. sodium hydroxide
1 M in a sufficient amount to reach a final pH value of the
composition of from about 8 to about 8.8, Glycerol in a
concentration range of from 10 to 50 g/l, soy bean oil in a
concentration range of from 50 to 150 g/l, Medium chain
triglyceride-oil in a concentration range of from 50 to 150 g/l,
and Water up to 1 liter. A cyclosporine in a concentration range of
from 1 to 15 g/l, A phosphatidylcholin (e.g. egg lecithin) in a
concentration range of from 5 to 25 g/l, sodium oleate in a
concentration range of from 0.1 to 1 g/l, optionally, pH adjustment
e.g. sodium hydroxide 1 M in a sufficient amount to reach a final
pH value of the composition of from about 8 to about 8.8, Glycerol
in a concentration range of from 10 to 50 g/l, soy bean oil in a
concentration range of from 50 to 150 g/l, Medium chain
triglyceride-oil in a concentration range of from 50 to 150 g/l,
and Water up to 1 liter. A cyclosporine in a concentration range of
from 1 to 15 g/l, egg lecithinin a concentration range of from 5 to
25 g/l, sodium oleate in a concentration range of from 0.1 to 1
g/l, optionally, pH adjustment e.g. sodium hydroxide 1 M in a
sufficient amount to reach a final pH value of the composition of
from about 8 to about 8.8, Glycerol in a concentration range of
from 10 to 50 g/l, soy bean oil in a concentration range of from 50
to 150 g/l, Medium chain triglyceride-oil in a concentration range
of from 50 to 150 g/l, and Water up to 1 liter. Moreover, the
invention relates to compositions having the following
compositions: A cyclosporine in a concentration of 5 g/l, A
phosphatidylcholin (e.g. egg lecithin) in a concentration of 12
g/l, A pharmaceutically tolerable alkali salt of a free fatty acid
(e.g. sodium oleate) in a concentration of 0.3 g/l, Optionally, pH
adjustment e.g. sodium hydroxide 1 M in a sufficient amount to
reach a final pH value of the composition of from about 8 to about
8.8, Glycerol in a concentration of 25 g/l, A natural oil (long
chain triglyceride) (e.g. soy bean oil) in a concentration of 100
g/l, Medium chain triglyceride-oil in a concentration range of 100
g/l, Water up to 1 liter. A cyclosporine in a concentration of 5
g/l, egg lecithin in a concentration of 12 g/l, A pharmaceutically
tolerable alkali salt of a free fatty acid (e.g. sodium oleate) in
a concentration of 0.3 g/l, Optionally, pH adjustment e.g. sodium
hydroxide 1 M in a sufficient amount to reach a final pH value of
the composition of from about 8 to about 8.8, Glycerol in a
concentration of 25 g/l, A natural oil (long chain triglyceride)
(e.g. soy bean oil) in a concentration of 100 g/l, Medium chain
triglyceride-oil in a concentration range of 100 g/l, Water up to 1
liter. A cyclosporine in a concentration of 5 g/l, A
phosphatidylcholin (e.g. egg lecithin) in a concentration of 12
g/l, sodium oleate in a concentration of 0.3 g/l, Optionally, pH
adjustment e.g. sodium hydroxide 1 M in a sufficient amount to
reach a final pH value of the composition of from about 8 to about
8.8, Glycerol in a concentration of 25 g/l, A natural oil (long
chain triglyceride) (e.g. soy bean oil) in a concentration of 100
g/l, Medium chain triglyceride-oil in a concentration range of 100
g/l, Water up to 1 liter. A cyclosporine in a concentration of 5
g/l, egg lecithin in a concentration of 12 g/l, sodium oleate in a
concentration of 0.3 g/l, Optionally, pH adjustment e.g. sodium
hydroxide 1 M in a sufficient amount to reach a final pH value of
the composition of from about 8 to about 8.8, Glycerol in a
concentration of 25 g/l, A natural oil (long chain triglyceride)
(e.g. soy bean oil) in a concentration of 100 g/l, Medium chain
triglyceride-oil in a concentration range of 100 g/l, Water up to 1
liter. A cyclosporine in a concentration of 5 g/l, A
phosphatidylcholin (e.g. egg lecithin) in a concentration of 12
g/l, A pharmaceutically tolerable alkali salt of a free fatty acid
(e.g. sodium oleate) in a concentration of 0.3 g/l, Optionally, pH
adjustment e.g. sodium hydroxide 1 M in a sufficient amount to
reach a final pH value of the composition of from about 8 to about
8.8, Glycerol in a concentration of 25 g/l, soy bean oil in a
concentration of 100 g/l, Medium chain triglyceride-oil in a
concentration range of 100 g/l, Water up to 1 liter. A cyclosporine
in a concentration of 5 g/l, egg lecithin in a concentration of 12
g/l, A pharmaceutically tolerable alkali salt of a free fatty acid
(e.g. sodium oleate) in a concentration of 0.3 g/l, Optionally, pH
adjustment e.g. sodium hydroxide 1 M in a sufficient amount to
reach a final pH value of the composition of from about 8 to about
8.8, Glycerol in a concentration of 25 g/l, soy bean oil in a
concentration of 100 g/l, Medium chain triglyceride-oil in a
concentration range of 100 g/l, Water up to 1 liter. A cyclosporine
in a concentration of 5 g/l, A phosphatidylcholin (e.g. egg
lecithin) in a concentration of 12 g/l, sodium oleate in a
concentration of 0.3 g/l, Optionally, pH adjustment e.g. sodium
hydroxide 1 M in a sufficient amount to reach a final pH value of
the composition of from about 8 to about 8.8, Glycerol in a
concentration of 25 g/l, soy bean oil in a concentration of 100
g/l, Medium chain triglyceride-oil in a concentration range of 100
g/l, Water up to 1 liter. A cyclosporine in a concentration of 5
g/l, egg lecithin in a concentration of 12 g/l, sodium oleate in a
concentration of 0.3 g/l, Optionally, pH adjustment e.g. sodium
hydroxide 1 M in a sufficient amount to reach a final pH value of
the composition of from about 8 to about 8.8, Glycerol in a
concentration of 25 g/l, soy bean oil in a concentration of 100
g/l, Medium chain triglyceride-oil in a concentration range of 100
g/l, Water up to 1 liter.
[0036] In all the above-mentioned compositions, the medium chain
triglycerides may be coconut oil, palm oil, or combinations
thereof.
[0037] The composition of the emulsion that has been tested in a
clinical study was produced according to the following formula (300
L batch size):
TABLE-US-00001 Ingredient Quantity (kg) Quality standard
Cyclosporine 1.50 R1-CEP 1999-034 Rev 02 Egg lecithin 3.60 Glycerol
(water free) 7.50 Ph. Eur. Sodium oleate 0.09 Sodium hydroxide 1M
q.s. Ph. Eur. Soya-bean oil 30.00 Ph. Eur. (long chain
triglyceride) MCT-oil 30.00 Ph. Eur. (medium chain triglyceride)
Water for injection Ad 300 L Ph. Eur. Nitrogen gas As required Ph.
Eur./USP
[0038] Thus, a preferred composition of the invention is the
following:
TABLE-US-00002 Concentration Ingredient g/L Cyclosporine 5 Egg
lecithin 12 Glycerol (water free) 25 Sodium oleate 0.3 Sodium
hydroxide 1M q.s. Soya-bean oil 100 (long chain triglyceride)
MCT-oil 100 (medium chain triglyceride) Water for injection Ad 1 L
Nitrogen gas As required (for production purposes)
[0039] The MCT-oil is coconut oil, palm oil or a combination
thereof.
[0040] As it appears from the experimental section a composition
according to the invention, notably, the above-mentioned
composition is bioequivalent to the SANDIMMUNE.RTM. product, i.e.
the concentrate diluted to a ready-to-use composition. The
bioequivalence study has been carried out according to
well-established guidelines (EMEA--European Medicines Agency,
London, January 2010. Guideline on the investigation of
bioequivalence, or US Department of Health and Human Services, Food
and Drug Administration, March 2003, Guidance for Industry,
Bioavailability and Bioequivalence Studies for Orally Administered
Drug Product--General Considerations).
[0041] The study also reveals that a composition according to the
invention has a much better safety profile than the SANDIMMUNE.RTM.
product. Thus, without premedication with corticosteroids, in 19
subjects two severe anaphylactic reactions were observed after
administration with SANDIMMUNE.RTM., whereas no such reactions were
observed after administration in 33 subjects with a composition
according to the invention. To sum up from the clinical study the
following table shows the adverse effects observed. Two serious
adverse events (SAEs) were reported. These were anaphylactic and
anaphylactoid reactions that occurred after administration of
SANDIMMUNE.RTM. injection. The proportion of overall adverse
effects was significantly higher in the SANDIMMUNE.RTM. injection
compared to the composition according to the invention.
TABLE-US-00003 Proportion Ciclo- Mulsion 95% Proportion (according
Mean Confidence Sandimmune to the Ratio Interval of McNemar's
injection invention) (%) Ratio (%) p-value Overall 0.800 0.350
-0.450 -0.668; 0.0027 -0.232 Eye 0.050 0.000 -0.050 -0.146; N/C
disorders 0.046 Gastro- 0.150 0.150 0.000 -0.139; 1.0000 intestinal
0.139 disorders Immune 0.200 0.050 -0.150 -0.306; 0.0833 system
0.006 disorders Anaphy- 0.050 0.000 -0.050 -0.146; N/C lactic 0.046
reaction Anaphy- 0.050 0.000 -0.050 -0.146; N/C lactoid 0.046
reaction Hyper- 0.100 0.050 -0.050 -0.146; 0.3173 sensitivity 0.046
Nervous 0.500 0.250 -0.250 -0.485; 0.0588 system -0.015 disorders
Psychiatric 0.050 0.000 -0.050 -0.146; N/C disorders 0.046 Repro-
0.050 0.000 -0.050 -0.146; N/C ductive 0.046 system and breast
disorders Respiratory, 0.050 0.050 0.000 0.000; N/C thoracic and
0.000 mediastinal disorders Vascular 0.400 0.100 -0.300 -0.544;
0.0339 Disorders -0.056
[0042] Another advantage of a composition of the invention (besides
bioequivalence with SANDIMMUNE.RTM. injection and better safety
profile than the SANDIMMUNE.RTM. injection) is the excellent
stability of the composition. It is currently believed that the
presence of medium-chain triglycerides plays an important role in
this respect. Thus, based on stability studies carried out
according to ICH guidelines and reported in the Examples, the
overall conclusion is that a shelf-life of 30-36 months when stored
below 25.degree. C. and protected from light is reasonable.
[0043] Other advantages are:
1. Ready-to-use solution. SANDIMMUNE.RTM. injection is marketed as
a 50 mg/ml infusion concentrate that has to be drawn up by a
syringe and then injected into a larger volume of saline or 5%
glucose. The concentrate solution is highly viscous, especially at
room temperature or below, which makes it more difficult to extract
and empty to the right amount than with a ready-to-use composition.
Further, following injection of the infusion concentrate into
saline, careful mixing is required to avoid injection of large
cyclosporine-containing CREMOPHOR.RTM. lumps into the circulation,
which also affects the concentration of cyclosporine given early
and late in a treatment. 2. No un-physiological emulsifier. The
contents of a composition of the invention are physiological fats
and phospho-lipids that can be metabolized by the human body. 3. No
risk of solvent-related severe hypersensitivity reactions,
including anaphylactic reactions and death. 4. No risk of
solvent-related cyto-, nephro- or cardiotoxicity. 5. Eliminates the
need for specialized IV tubing required for
CREMOPHOR.RTM.-containing products (to prevent leaching of
plasticizers). 6. Premedication with corticosteroids or
antihistamines is not necessary. 7. No risk of penetration of
unwanted substance over the blood-brain barrier.
[0044] The emulsions of the invention are suitable to use in the
treatment of disease where cyclosporine is indicated. Examples are
immunosuppresive disorders, reperfusion injury (organ damage),
cardiac reperfusion injuty (cardioprotection), kidney reperfusion
injury (nephroprotection), liver reperfusion injury
(hepatoprotection), prevention of brain damage
(neuroprotection).
BRIEF DESCRIPTION OF THE DRAWINGS
Legend to Figures
[0045] FIG. 1 shows the structure of cyclosporine
[0046] FIG. 2 shows a method for the manufacture of an emulsion
according to the invention
[0047] FIG. 3 shows arithmetic means with standard deviation of
blood Cyclosporine concentration in participants administered
CicloMulsion or Sandimmune. n=52
[0048] FIG. 4 shows mean blood Cyclosporine concentration with
standard deviation in participants administered CicloMulsion (A) or
Sandimmune (B) either with or without premedication consisting of
50 mg diphenhydramine orally, 10 mg dexamethasone intravenously and
50 mg ranitidine intravenously.
[0049] FIG. 5A shows results from combined individual graphs of
whole blood concentrations following infusion of 5 mg/kg
ciclosporin sampled over 48 hours in 52 healthy individuals, as
described in Example 4 (Top--Sandimmune Injection;
Bottom--CicloMulsion).
[0050] FIGS. 5A-5B show a summary of a clinical study to compare
the bioavailability and pharmacokinetics of cyclosporine (Example
4).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0051] The invention is further illustrated in the following
non-limiting examples.
EXAMPLES
Example 1
Manufacturing of a Composition According to the Invention
Preparation of the Emulsion
Preparation of Aqueous Suspension:
[0052] A mixing tank is provided with the appropriate quantity of
hot water for injection. All raw materials except the oil
components are ground and dispersed in water for injection at
55-70.degree. C. The suspension is dispersed by means of intense
mixing.
Preparation of Pre-Emulsion:
[0053] A solution of pre-heated oil components (50-60.degree. C.)
containing dissolved cyclosporine is added. Aqueous suspension and
oil phase are mixed at 55-70.degree. C. If necessary, pH
adjustment.
Homogenization:
[0054] The preparation of the final emulsion takes place by several
homogenization steps. Pressures of 400.+-.30 bar (stage 1) and
100.+-.30 bar (stage 2) are applied. The temperature of the
emulsion is between 55.degree. C. and 90.degree. C. Between the
homogenization steps the emulsion is stored in intermediate storage
tanks
Final Emulsion:
[0055] Depending on the capacity of the used equipment
(homogenizers and vessel) the emulsion has to be diluted under
stirring with the appropriate amount of water for injection. The
resulting emulsion is cooled down to a temperature of 15-25.degree.
C. A sample of the final concentration is taken for in-process
control and a pH-adjustment may be carried out.
Filtration of the Emulsion:
[0056] The emulsion is filtered through a 10 .mu.m absolute pore
size filter.
Filling and Closing:
[0057] The emulsion is filled under a nitrogen atmosphere into
suitable infusion bottles. Filled bottles are closed with rubber
stoppers and aluminium caps with transparent flip-off caps.
Sterilization:
[0058] The filled containers are sterilized in a rotating
autoclave.
Example 2
Composition According to the Invention
[0059] The composition of the emulsion that has been tested in a
clinical study was produced according to the following formula (300
L batch size):
TABLE-US-00004 Ingredient Quantity (kg) Quality standard
Cyclosporine 1.50 R1-CEP 1999-034 Rev 02 Egg lecithin 3.60 Glycerol
(water free) 7.50 Ph. Eur. Sodium oleate 0.09 Sodium hydroxide 1M
q.s. Ph. Eur. Soya-bean oil 30.00 Ph. Eur. (long chain
triglyceride) MCT-oil 30.00 Ph. Eur. (medium chain triglyceride)
Water for injection Ad 300 L Ph. Eur. Nitrogen gas As required Ph.
Eur./USP
Example 3
Stability of a Composition According to the Invention
[0060] The composition of Example 2 was subjected to stability
studies in accordance with the ICH guidelines.
[0061] The Ciclosporin 5 mg/ml Emulsion for Injection batch
PP0915013 is put on stability at 25.degree. C./60% RH and
40.degree. C./75% RH in accordance with ICH requirements. Currently
12 months data are available.
[0062] All results, at both temperatures, are well within
specifications. The cyclosporine appears very stable with no
decreasing trend. Only small amounts of degradation products are
found. The following tables summaries the results.
TABLE-US-00005 25.degree. C./60% RH Storage time (Months) Test item
0 3 6 9 12 Appearance White homogeneous emulsion conforms conforms
conforms conforms conforms pH 8.4 7.8 7.6 7.3 7.2 6.0-8.5 Particle
size distribution >1 .mu.m 100% .ltoreq. 5 .mu.m 98% .ltoreq.
1.5 .mu.m 100/100 100/98.6 100/99.2 100/99 100/98 Particle size
distribution <1 .mu.m z-average .ltoreq.350 nm 240 243 239 239
239 Polydispersion .ltoreq.0.25 0.09 0.06 0.08 0.09 0.08 Peroxide
value .ltoreq.2.5 mEq/L 0.02 0.04 0.05 0.10 0.0 Ciclosporin assay
95.0-105.0% 97.6 100.6 100.2 100.2 101.4 Degradation products
ciclosporin H (.ltoreq.1.4%) <DL 0.1 0.3 0.2 0.3
dihydrociclosporin A (.ltoreq.1.4%) 0.1 0.1 0.3 0.2 0.2
isociclosporin A (.ltoreq.1.4%) 0.1 0.2 0.1 0.2 0.1 single unknown
(.ltoreq.0.2%) 0.1 0.1 0.1 <DL 0.1 Total (.ltoreq.2.0%) <0.4
<0.5 <0.8 <0.7 <0.8 Free fatty acids .ltoreq.12 mEq/L 2
2 3 3 4 Lysophosphatidylcholine .ltoreq.16.7% 3 6 7 7 8 Sterility
sterile sterile -- -- -- --
TABLE-US-00006 40.degree. C./75% RH Storage time (Months) Test item
0 3 6 Appearance White homogeneous emulsion conforms conforms
conforms pH 8.4 7.2 6.5 6.0-8.5 Particle size distribution >1
.mu.m 100% .ltoreq. 5 .mu.m 98% .ltoreq. 1.5 .mu.m 100/100 100/99.6
100/99.6 Particle size distribution <1 .mu.m z-average
.ltoreq.350 nm 240 242 240 Polydispersion .ltoreq.0.25 0.09 0.05
0.05 Peroxide value .ltoreq.2.5 mEq/L 0.02 0.06 0.08 Ciclosporin
assay 95.0-105.0% 97.6 101.2 99.6 Degradation products ciclosporin
H (.ltoreq.1.4%) <DL 0.4 0.9 dihydrociclosporin A (.ltoreq.1.4%)
0.1 0.1 0.3 isociclosporin A (.ltoreq.1.4%) 0.1 0.2 0.1 single
unknown (.ltoreq.0.2%) 0.1 0.1 0.1 Total (.ltoreq.2.0%) <0.4
<0.7 <1.3 Free fatty acids .ltoreq.12 mEq/L 2 4 6
Lysophosphatidylcholine .ltoreq.16.7% 3 9 12 Sterility sterile
sterile -- --
Example 4
[0063] A clinical study to compare the bioavailability and
pharmacokinetics of cyclosporine
SUMMARY
[0064] Background: Ciclosporin is a widely used immunosuppressant
in organ and tissue transplantation. Ciclosporin has poor
solubility in water, and the concentrate for solution for infusion
has therefore been formulated in polyoxyethylated castor oil
(CREMOPHOR EL.RTM.). However, intravenous administration of
ciclosporin preparations containing cremophor has been associated
with hypersensitivity reactions, with responses ranging from mild
skin conditions to anaphylaxis and cardiac collapse. A
CREMOPHOR.RTM.-free, ready-to-use cidosporin lipid emulsion
(CICLOMULSION.RTM., ciclosporin 5 mg/ml) for intravenous use has
been developed. The objectives of the present study were to compare
the pharmacokinetics and tolerability profile of CICLOMULSION.RTM.
with the reference product SANDIMMUNE.RTM. Injection.
[0065] Methods: Healthy, male and female, Caucasian and
non-Caucasian volunteers (n=52), were investigated according to an
open-label, laboratory-blind, subject-blind, randomized,
single-dose, two-period cross-over design. Five mg/kg of each of
the two formulations was intravenously infused over 4 hours. Blood
concentrations of ciclosporin were determined by validated LC-MS/MS
analysis. FDA and EMA-compliant standard pharmacokinetic
comparisons were performed using analysis of variance. Point
estimates and 90% confidence intervals for the test/reference
geometric least square mean ratios of relevant variables were
calculated. Tolernbiliry and safety were evaluated by adverse event
monitoring, full blood count, vital signs measurements.
electrocardiogram and post-study physical examination.
[0066] Results: FIG. 5A shows the combined individual graphs of
whole blood concentrations following infosion of 5 mg/kg
ciclosporin sampled over 48 hours in 52 healthy individuals.
(Top--SANDIMMUNE.RTM. Injection; Bottom--CICLOMULSION.RTM.). Table
1 and FIG. 5B show the confidence interval (90%) for the mean
ratios (%) of CICLOMULSION.RTM./SANDIMMUNE.RTM.) and
intraindividual coefficient of variation (CV) of whole blood
ciclosporin pharmacokinetic variables. As reflected in Table 2, two
serious adverse events (SAEs) were reported. These were the
anaphylactic and anaphylactoid reactions that occurred after
administration of SANDIMMUNE.RTM. Injection. The proportion of
overall adverse events was significantly higher in the
SANDIMMUNE.RTM. Injection compared to CICLOMULSION.RTM..
TABLE-US-00007 TABLE 1 Intra- Mean 90% Confidence individual
Variable Ratio(%) Interval of Ratio CV (%) Power C.sub.max(ng/mL)
94.80 (92.43; 97.23) 7.70 >99% AUC(0-t.sub.last) 89.88 (87.92;
91.88) 6.71 >99% (hr*ng/mL) AUC(0-.sub.oo) 89.91 (87.71; 92.16)
7.53 >99% (hr*ng/mL) AUC(4-.sub.oo 86.90 (84.12; 89.77) 9.91
>99% (hr*ng/mL) AUC(0-4) 94.23 (92.37; 96.14) 6.08 >99%
(hr*ng/mL) AUC(4-t.sub.last) 86.52 (84.20; 88.90) 8.27 >99%
(hr*ng/mL) CL (mL/hr) 111.38 (108.67; 114.15) 7.49 >99% MRT (hr)
99.33 (92.08; 107.14) 23.36 >99% t/.sub.1/2z (hr) 101.19 (89.88;
113.93) 37.28 >93%
TABLE-US-00008 TABLE 2 95% Con- Proportion fidence SAND- Mean
Interval Mc- IMMUNE .RTM. CICLO- Ratio of Ratio Nemar's Injection
MULSION .RTM. (%) (%) p-value Overall 0.800 0.350 -0.450 -0.668;
0.0027 -0.232 Eye 0.050 0.000 -0.050 -0.146; N/C Disorders 0.046
Gastro- 0.150 0.150 0.000 -0.139; 1.0000 intestinal 0.139 disorders
Immune 0.200 0.050 -0.150 -0.306; 0.0833 system 0.006 disorders
Anaphy- 0.050 0.000 -0.050 -0.146; N/C lactic 0.046 reaction
Anaphy- 0.050 0.000 -0.050 -0.146; N/C lactoid 0.046 reaction
Hyper- 0.100 0.050 -0.050 -0.146; 0.3173 sensitivity 0.046 Nervous
0.500 0.250 -0.250 -0.485; 0.0588 system 0.015 disorders
Psychiatric 0.050 0.000 -0.050 -0.146; N/C disorders 0.046 Repro-
0.050 0.000 -0.050 -0.146; N/C ductive 0.046 system and breast
disorders Respiratory, 0.050 0.050 0.000 0.000; N/C thoracic 0.000
and mediastinal disorders Vascular 0.400 0.100 -0.300 -0.544;
0.0339 Disorders -0.056
Conclusions:
[0067] CICLOMULSION.RTM., a ready-to-use cremophor-free intravenous
formulation of ciclosporin, is bioequivalent to Sandimmune
Injection. [0068] CICLOMULSION.RTM. displays an improved safety and
tolerability profile. [0069] CREMOPHOR.RTM.-related severe
hypersensitivity reactions, including anaphylactic reactions and
death, can thus be avoided in patients requiring intravenous
ciclospurin. [0070] CICLOMULSION.RTM. has the following advantages
over i.v. SANDIMMUNE.RTM. Injection: [0071] 1. Ready-to-use
solution [0072] 2. Physiological emulsifier. The contents of
CICLOMULSION.RTM. are hysiological fats and phospholipids that can
be metabolized by the human body. [0073] 3. No risk of
CREMOPHOR.RTM.-related severe hypersensitivity reactions, including
anaphylactic reactions and death. [0074] 4. No risk of
CREMOPHOR.RTM.-relatecl cyto-, nephro- or cardiotoxicity. [0075] 5.
Eliminates need for specialized i.v. tubing required for
CREMOPHOR.RTM.-containing products (to prevent leaching of
plasticizers).
Details Regarding the Clinical Study
Introduction
[0076] Cyclosporine is widely used to prevent rejection of grafts
after transplantation. The intravenous formulation currently on the
market, SANDIMMUNE.RTM. Injection (SANDIMMUNE.RTM., uses
CREMOPHOR.RTM. EL (CrEL) as emulsifying excipient. CrEL is known to
cause hypersensitivity reactions in some patients, ranging from
skin reactions to anaphylactic shock and death. We have assessed
the pharmacokinetics and tolerability of a new, CrEL-free lipid
emulsion of cyclosporine, CICLOMULSION.RTM., compared to
SANDIMMUNE.RTM.. Fifty-two healthy subjects were treated with 5
mg/kg of each of the two formulations of cyclosporine as 4 h
intravenous infusion. Bioequivalence assessments according to
current guidelines were performed. The geometric mean ratios for
CICLOMULSION.RTM./SANDIMMUNE.RTM. (90% confidence interval) were
0.90 (0.88-0.92) for Area Under Curve (0 h to the last quantifiable
concentration) and 0.95 (0.92-0.97) for maximum blood cyclosporine
concentration. For all additional variables analyzed, the 90%
confidence intervals were also within the accepted bioequivalence
range of 0.80-1.25. One anaphylactoid and one anaphylactic
reaction, both classified as serious adverse events, were reported
after treatment with SANDIMMUNE.RTM.. No serious adverse events
were recorded after treatment with CICLOMULSION.RTM.. The
proportion of overall adverse events was significantly higher for
SANDIMMUNE.RTM.. We conclude that CICLOMULSION.RTM. is
bioequivalent to SANDIMMUNE.RTM. and exhibits fewer adverse
reactions.
LIST OF ABBREVIATIONS
[0077] AE Adverse Event [0078] ANOVA Analysis of variance [0079]
AUC Area Under Curve [0080] AUC.sub.0-4 Area Under Curve for time 0
to 4 hours [0081] AUC.sub.0-t Area Under Curve for time 0 to the
last quantifiable concentration [0082] AUC.sub.0-.infin. Area Under
Curve for time 0 hours extrapolated to infinity [0083] AUC.sub.4-t
Area Under Curve for time 4 to the last quantifiable concentration
[0084] AUC.sub.4-.infin. Area Under Curve for time 4 hours
extrapolated to infinity [0085] CI Confidence Interval [0086] CL
Clearance [0087] C.sub.max Maximum blood concentration [0088]
CICLOMULSION.RTM. CREMOPHOR EL.RTM.-free cyclosporine lipid
emulsion [0089] CrEL CREMOPHOR EL.RTM. [0090] CsA Cyclosporine,
Ciclosporin, Cyclosporin A [0091] CV Coefficient of variation
[0092] ECG Electrocardiogram [0093] EDTA Ethylenediaminetetraacetic
acid [0094] EMA European Medicines Agency [0095] FDA Food and Drug
Administration [0096] IV Intravenous [0097] LC-MS/MS Liquid
chromatography-mass spectrometry/mass spectrometry [0098] LLOQ
Lower level of quantification [0099] MedDRA Medical Dictionary for
Regulatory Activities [0100] MRT Mean Residence Time [0101] Ph Eur
European Pharmacopoeia [0102] PVC Polyvinyl chloride [0103] SAE
Serious Adverse Event [0104] Sandimmune SANDIMMUNE.RTM. Injection
[0105] SpO.sub.2 Peripheral Blood Oxygen Saturation [0106]
t.sub.1/2z Apparent terminal half-life [0107] USP United States
Pharmacopeia
[0108] Cyclosporine (CsA) is a potent immunosuppressant first
registered in 1983 that acts by reducing the function of
T-lymphocytes through inhibition of calcineurin. CsA is widely used
to prevent organ rejection and graft-versus-host disease after
solid organ or bone marrow transplantation, and to treat autoimmune
conditions such as psoriasis, atopic dermatitis, pyoderma
gangrenosum, ulcerative colitis, idiopathic nephrotic syndrome and
inflammatory uveitis (1-7). The molecule is highly hydrophobic and
requires a lipophilic solvent for administration. The intravenous
(IV) form of CsA currently on the market, SANDIMMUNE.RTM. Injection
(Novartis Pharma Stein AG, Switzerland) (Sandimmune), is a
preparation with ethanol and polyoxyethylated castor oil,
CREMOPHOR.RTM. EL (CrEL).
[0109] CrEL is not inert (8) and there have been a number of
reports of serious adverse effects after administration of IV CsA
due to reactions to this carrier medium (9-16). Hypersensitivity
reactions to CrEL have also been reported when used for other
intravenous preparations of drugs such as diazepam and
ALTHESIN.RTM. (17-21). In rodents, neurotoxicity, cardiotoxicity
and nefrotoxicity due to IV CsA dissolved in CrEL have been
demonstrated (22-25) and, in a canine model, CrEL has been shown to
reduce cardiac output and hepatic blood flow in a
non-dose-dependent fashion (26). The effects of CrEL include
complement activation, histamine release and severe
hypersensitivity reactions (8, 17, 19, 21).
[0110] CsA in CrEL requires a dilution step prior to
administration. Improper preparation of CrEL-containing
formulations has been reported to cause anaphylactoid reactions
(27, 28). An additional concern with the use of ethanol and CrEL is
the leaching of plasticizers from polyvinyl chloride (PVC) bags and
infusion sets used in routine clinical practice. Consequently,
preparation and administration should be done using glass or other
non-PVC infusion sets (29, 30).
[0111] Concern about the safety of CrEL as a carrier medium for IV
drugs has been raised on numerous occasions and several drugs that
previously were produced in preparations with CrEL are now
available only with other carrying media such as lipid emulsions.
Known examples are propofol (17, 31) and diazepam (32). Others,
such as the chemotherapeutic agent paclitaxel, are available both
with and without CrEL as solvent (33), and the anesthetic drug
ALTHESIN.RTM. that contained CrEL is no longer marketed for use in
humans (17, 21, 34).
[0112] In this study, the objective was to assess the
pharmacokinetics of a novel CrEL- and ethanol-free ready-to-use
preparation of CsA for IV administration, CICLOMULSION.RTM.
(NeuroVive Pharmaceutical AB, Lund, Sweden), in relation to the
CrEL-containing product currently on the market (SANDIMMUNE.RTM.
Injection) and to assess whether the two formulations are
bioequivalent. A ready-to-use preparation without CrEL potentially
offers increased patient safety with fewer adverse events due to
improper handling or immunological reactions to CrEL.
Study Design
[0113] This was a single-center, open-label, subject-blind,
laboratory-blind, single-dose, randomized, two-treatment,
two-period, two-sequence crossover study of the pharmacokinetics of
two formulations of IV CsA. The primary objective was to assess the
pharmacokinetics, and the secondary objective to compare the
tolerability profiles of the two preparations.
[0114] The study protocol, including amendments, subject
information sheets and informed consent documents, were reviewed by
the Ethics Committee of the Faculty of Health Sciences of the
University of the Free State (Reference number ETOVS 65/09), and by
the South African Medicines Control Council (Reference number BE
2009009), and written approval was acquired. The study was
performed in accordance with the declaration of Helsinki and
Guideline for Good Clinical Practice issued by the International
Conference on Harmonization. It was designed to comply with the
Guidance for Industry--Statistical Approaches to Establishing
Bioequivalence issued by the United States Department of Health and
Human Services, Food and Drug Administration (FDA) (35), and the
Note for Guidance on the Investigation of Bioavailability and
Bioequivalence by The European Medicines Agency (EMA) (36).
Cyclosporine Formulations
[0115] The reference formulation of CsA used was SANDIMMUNE.RTM.
Injection (Novartis Pharma Stein AG, Switzerland, 50 mg/mL CsA,
United States Pharmacopeia, USP) approved under U.S. New Drug
Application Number 050573) containing CREMOPHOR.RTM. EL (each 1 mL
infusion concentrate was diluted in 20 mL 0.9% saline solution
prior to use). The test product used was CICLOMULSION.RTM.
(NeuroVive Pharmaceutical AB, Lund, Sweden) 5 mg/mL ready-to-use
Cremophor- and ethanol-free cyclosporine Ph Eur/USP lipid emulsion.
Each mL of the lipid emulsion contains 100 mg of refined soya-bean
oil, 100 mg medium-chain triglycerides, 12 mg egg lecithin, 25 mg
glycerol, water, and sodium oleate and sodium hydroxide for pH
adjustment.
Participants
[0116] Healthy male and healthy, non-pregnant, non-lactating female
volunteers between 18 and 55 years of age with a body mass index
within the range of 19-33 kg/m.sup.2 were eligible. Further
inclusion criteria were body mass 60-100 kg, normal 12-lead
electrocardiogram (ECG) and vital signs, clinically acceptable
findings in medical history and physical examinations, laboratory
results within the reference ranges (unless the deviation was
considered irrelevant for the purpose of the study), willingness to
undergo pre-, interim- and post-study physical examinations and
laboratory investigations, ability to comprehend and willingness to
sign statement of informed consent, and abstinence from tobacco
during and three months prior to study. Female participants of
childbearing age underwent a pregnancy test prior to each CsA
dosing and, if positive, were excluded from the study. During the
study period, reliable, non-hormonal methods of contraception had
to be used.
[0117] Exclusion criteria included evidence of psychiatric
disorder, history of or current abuse of drugs (including alcohol),
use of any medication within two weeks prior to first
administration of study medication, participation in another study
with an experimental drug with administration within twelve weeks
prior to the current study, major illness during the last three
months, donation or loss of blood exceeding 500 mL during the eight
weeks before the first administration of the study drug, positive
test for Hepatitis B or C or HIV, positive urine drug screen,
vaccination of any kind within four weeks of first dose or planning
vaccination within three months of last dose, close family member
receiving live vaccine during study or within three months
post-study, and hypotension or hypertension during screening
period.
[0118] History of any of the following diseases was also criterion
for exclusion from the study: any type of malignancy,
immunodeficiency, tendency toward recurrent infections, known
untreated parasitic infection, allergy to any compound in the
reference and test product, or to egg or soybean, any
bronchiospastic diseases, epilepsy, porphyria, psoriasis, atopic
dermatitis, hypercholesterolemia, gout, rheumatoid arthritis or
kidney disease.
[0119] Care was taken to include both female and male participants
both of Caucasian and non-Caucasian race. Written informed consent
was obtained from all participants before study enrollment.
Sampling Period
[0120] Subjects were randomized into two treatment sequences: the
test product followed by the reference product or vice versa. There
was a washout period set to 14-21 days between the first and second
treatment period. Participants reported to the clinic the night
before treatment for laboratory testing, including blood samples,
pregnancy test and urine drug screen, The subjects were instructed
not to ingest any citrus fruits and/or apple or pineapple 72 h
prior to start of infusion and, within 24 h, no alcohol or any
caffeine-containing products were permitted. On the clinical day,
the only food served before drug administration was a standardized
breakfast. Through an indwelling IV cannula, the subjects received
either 5 mg/kg CicloMulsion (test) or 5 mg/kg Sandimmune
(reference), infused at a constant rate over 4 h with a syringe
pump. The dose recommended for induction of immunosuppression with
Sandimmune in clinical praxis is 3-6 mg/kg/day.
[0121] The same arm was used for administration during both
treatment periods. All infusion equipment were compatible with both
the reference and the test product. Through an IV cannula in the
contra-lateral arm, a total of 22 blood samples for CsA analysis
were obtained pre-dose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4,
4.5, 5, 6, 7, 8, 10, 14, 18, 24, 30, 36 and 48 h after start of
infusion. All samples were collected in vials containing
ethylenediaminetetraacetic acid (EDTA), labeled and stored at
-70.degree. C. until analysis. Whole blood CsA-concentration was
assayed with liquid chromatography-mass spectrometry/mass
spectrometry (LC-MS/MS). The method was validated according to
current FDA guidelines (37). The lower limit of quantification
(LLOQ) was 39.39 ng/mL and the mean CV was 3.5% for CsA. Complete
sets of calibration standards and quality controls were included
within each run.
[0122] Twenty-four hours after start of administration of study
medication, subjects were allowed to leave the clinic, provided
they returned for the subsequent collection of blood samples. Vital
signs were monitored during the infusion and measured 2 h after
completion of infusion and after the last blood sample was drawn.
Meals and drinks during clinic days were standardized. Water was
allowed ad libitum before and after infusion of study medication.
Alcohol, caffeine, citrus fruit, apple and pineapple were not
allowed until the last blood sample was drawn in each treatment
period.
Tolerability Assessment
[0123] Each subject was carefully monitored for adverse events
(AEs) during infusion, and was questioned on the study day for any
symptoms of such events. AEs were graded as mild, moderate or
severe according to the following definitions:
[0124] Mild: Causing no limitation of usual activities; the subject
may experience slight discomfort.
[0125] Moderate: Causing some limitation of usual activities; the
subject may experience annoying discomfort.
[0126] Severe: Causing inability to carry out usual activities; the
subject may experience intolerable discomfort or pain.
[0127] The investigator deemed each AE in regard of causality to
the administered medical product as "certain," "probable,"
"possible," "unlikely," "not related" or "not assessable." Every AE
was coded with the Medical Dictionary for Regulatory Activities
(MedDRA) and reported according to strict criteria.
[0128] The proportions of overall AEs and AEs per organ class were
compared between CicloMulsion and Sandimmune by means of 95%
confidence interval (CI) for the difference between paired
proportions and p-values from McNemar's test.
Pharmacokinetics and Bioequivalence Assessment
[0129] Pharmacokinetic variables for CsA were calculated by use of
non-compartmental methods using WINNONLIN.RTM. Professional Version
5.2 (Pharsight Corporation, Mountain View Calif., USA). Statistical
analysis was made using SAS.RTM. Software Version 9.1 (SAS
institute, Cary, N.C., USA). All values below LLOQ prior to first
positive sample were substituted with zero. For the pharmacokinetic
assessment, the terminal values below the LLOQ were ignored.
[0130] CICLOMULSION.RTM. was compared to SANDIMMUNE.RTM. with
respect to a number of pharmacokinetic variables using analysis of
variance (ANOVA) with sequence, subject within sequence, product
and period effects on log-transformed data. The parameters compared
were Area Under the CsA time-concentration Curves for time 0 to the
time of last quantifiable concentration (AUC.sub.0-t), time 0 h
extrapolated to infinity (AUC.sub.0-.infin.), time 4 h extrapolated
to infinity (AUC.sub.4-.infin.), time 0 to 4 h (AUC.sub.0-4) and
time 4 to the last quantifiable concentration (AUC.sub.4-t),
maximum blood CsA concentration (C.sub.max), apparent terminal CsA
half-life (t.sub.1/2z), blood CsA clearence (CL) and mean residence
time (MRT). C.sub.max, AUC.sub.0-.infin., AUC.sub.0-t and
AUC.sub.4-.infin. were considered primary variables and the
remaining secondary. Point estimates and 90% CI for the
CICLOMULSION.RTM./SANDIMMUNE.RTM. geometric mean ratios of all
variables were calculated. The two products were considered
bioequivalent if the 90% CI for the primary variables fell within
the limits of 0.8 and 1.25.
[0131] Based on the FDA and EMA recommended bioequivalence range of
0.80 to 1.25 for Cmax, AUC.sub.0-t and AUC.sub.0-.infin., an
estimated within-subject coefficient of variation (CV) of 35%, and
a "test/reference" mean ratio between 0.95 and 1.05, 52 subjects
were needed to achieve a power of 80% at an alpha level of 0.05 to
show bioequivalence (38).
Modifications in Study Design
[0132] The initial study design did not include any premedication,
but, due to an unexpectedly high incidence of Serious Adverse
Events (SAEs) to the reference product, the remainder of the study
was performed with premedication. An amendment to the study
protocol was written and approved by the ethical committees named
above. For the sake of consistency, premedication was used prior to
both CICLOMULSION.RTM. and SANDIMMUNE.RTM. even though the AEs
triggering the instatement of premedication were observed following
SANDIMMUNE.RTM. administration. Thirteen subjects completed both
treatment periods without premedication. Eighteen subjects received
the test product in the first treatment period without
premedication, and received the reference product with
premedication in second treatment period. The remainder (21
subjects) received premedication during both treatment periods, and
thus with both the test and reference product.
[0133] The premedication consisted of one 50 mg capsule of
diphenhydramine orally 1 h prior to commencement of infusion of
test or reference drug, 10 mg dexamethasone by slow IV injection,
and 50 mg ranitidine IV infusion over 5 minutes approximately 30
minutes prior to each dosing of study drug. The study was put on
hold for the protocol amendments to be approved. This caused the
washout period for the 18 subjects who received the test product in
the first treatment period without premedication and the reference
product with premedication in the second treatment period to be
prolonged to more than six weeks. None of the premedications are
known to change the pharmacokinetic properties of CsA or affect the
bioanalytical assay.
Results
[0134] Sixty-five volunteers were enrolled in the study and
randomized to a treatment sequence. Two subjects were withdrawn
before first dosing due to illness, and eleven more withdrew before
completion. Of these eleven, three were due to consent withdrawal,
two due to investigator/sponsor decision (uncertainty of dose
received due to problems with infusion), and six due to AEs. None
of these subjects were included in the bioequivalence analysis.
Fifty-two participants completed the study and were included in the
pharmacokinetic evaluation. The demographics of the subjects
completing the study are presented in Table 1.
TABLE-US-00009 TABLE 1 Demographics of subjects included in the
pharmacokinetic study n = 52 Gender male/female 33/19 Age (years)
mean (range) 24.4 (18-46) Race Caucasian/African/mixed heritage
35/16/1 Body Mass (kg) mean (range) 70.4 (60.0-99.8) BMI
(kg/m.sup.2) mean (range) 23.3 (18.8-28.3)
[0135] Sixty-three participants received at least one dose of study
medication and were included in the overall tolerability
assessment. Due to an unexpectedly high number of serious adverse
reactions to SANDIMMUNE.RTM., the study protocol was changed and
premedication as described above introduced. The statistical
analysis of incidence of AEs was performed solely including the
thirteen participants who received both the test and reference drug
without premedication.
Pharmacokinetics and Bioequivalence Assessment
[0136] For each time point, arithmetic means with standard
deviation were calculated for the whole blood CsA-concentrations
for the test drug CICLOMULSION.RTM. and the reference drug
SANDIMMUNE.RTM.. A graphical presentation of the CsA concentrations
over time is provided in FIG. 1. In FIGS. 4A and B,
time-concentration curves are presented separately for subjects
receiving and not receiving concomitant premedication. The
pharmacokinetic parameters are presented in Table 2.
TABLE-US-00010 TABLE 2 Pharmacokinetic parameters of Cyclosporine
in subjects treated with CICLOMULSION .RTM. OR SANDIMMUNE .RTM. as
a single intravenous infusion over 4 h in the dose 5 mg/kg.
Arithmetic means, standard deviation (SD) and coefficient of
variation (CV). CICLOMULSION .RTM. Injec- (n = 52) SANDIMMUNE .RTM.
tion Parameter CV (n = 52) CV (unit) Mean SD % Mean SD % C.sub.max
(ng/mL) 2972 381 12.8 3134 386 12.3 AUC.sub.0-t 19412 3202 16.5
21679 4165 19.2 (h*ng/mL) AUC.sub.0-.infin. 20519 3488 17.0 22904
4466 19.5 (h*ng/mL) AUC.sub.4-.infin. 11496 2569 22.3 13349 3626
27.2 (h*ng/mL) AUC.sub.0-4 9023 1232 13.7 9555 1148 12.0 (h*ng/mL)
AUC.sub.4-t 10389 2240 21.6 12124 3256 26.9 (h*ng/mL) CL (mL/h)
17446 2543 14.6 15746 2860 18.2 MRT (h) 8.8 3.2 36.1 9.1 5.8 63.5
t.sub.1/2z (h) 14.6 6.4 43.4 14.7 8.2 55.7 AUC Extrapola- 5.3 2.5
46.6 5.2 4.0 76.7 tion (%) T.sub.max (h) 3.7 0.4 11.4 3.7 0.4
10.1
[0137] The part of the AUC.sub.0-.infin., that was extrapolated was
approximately 5% for both of the study medications, indicating that
a reliable estimate of the AUC.sub.0-.infin. was obtained. No
values below LLOQ were present between positive samples.
[0138] The statistical analysis of bioequivalence after dosing with
CICLOMULSION.RTM. or SANDIMMUNE.RTM. is presented in Table 3. The
point estimates of the CICLOMULSION.RTM./SANDIMMUNE.RTM. geometric
mean ratios (90% CI) of the primary variables C.sub.max and
AUC.sub.0-t for CsA were 0.95 (0.92-0.97) and 0.90 (0.88-0.92),
respectively, and AUC.sub.0-.infin. and AUC.sub.4-.infin. for CsA
were 0.90 (0.88-0.92) and 0.87 (0.84-0.90), respectively. Thus, the
90% CI of all primary variables were within the range acceptable
for bioequivalence of 0.80 to 1.25. The 90% CI for all secondary
variables also met the criteria for bioequivalence.
TABLE-US-00011 TABLE 3 Assessment of bioequivalence of whole blood
Cyclosporine exposure after dosing with a single dose of
CICLOMULSION .RTM. (test) and SANDIMMUNE .RTM. Injection
(reference). Geometric means of log- transformed data, standard
deviation (SD), point estimates and 90% Confidence Interval (CI) of
the CICLOMULSION .RTM./SANDIMMUNE .RTM. Injection ratio and
intrasubject coefficient of variation (CV). Geometrical Mean and SD
SANDIMMUNE .RTM. Intra- Parameter CICLOMULSION .RTM. Injection
subject (unit) Mean SD Mean SD Ratio 90% CI CV (%) C.sub.max
(ng/mL) 2949 371 3111 382 0.95 (0.92-0.97) 7.7 AUC.sub.0-t 19157
3162 21315 3950 0.90 (0.88-0.92) 6.7 (h*ng/mL) AUC.sub.0-.infin.
20235 3431 22507 4247 0.90 (0.88-0.92) 7.5 (h*ng/mL)
AUC.sub.4-.infin. 11216 2562 12906 3417 0.87 (0.84-0.90) 9.9
(h*ng/mL) AUC.sub.0-4 8943 1200 9490 1113 0.94 (0.92-0.96) 6.1
(h*ng/mL) AUC.sub.4-t 10150 2253 11732 3061 0.87 (0.84-0.89) 8.3
(h*ng/mL) CL (mL/h) 17258 2608 15495 2837 1.11 (1.09-1.14) 7.5 MRT
(h) 8.3 2.8 8.3 3.2 0.99 (0.92-1.07) 23.4 t.sub.1/2z (h) 13.5 5.8
13.3 6.0 1.01 (0.90-1.14) 37.3
Tolerability
[0139] Out of 63 subjects, 55 reported one or more AEs. AEs graded
as at least "possibly" related to the study medication were
predominantly reported from the medDRA-coded organ classes of
nervous system disorders and vascular disorders (Table 4). The
nervous system disorders included headache, burning sensation,
paresthesia, dizziness and sensory loss. The vascular disorders
included events of hot flushes and orthostatic hypotension. When
subjects received--SANDIMMUNE.RTM. without premedication, 84%
(16/19) experienced AEs assessed as at least possibly related to
the study medication, compared to 64% (21/33) when they received
CICLOMULSION.RTM.. With premedication, the figures were 76% (31/41)
for SANDIMMUNE.RTM. and 67% (16/24) for CICLOMULSION.RTM..
Proportional analysis of AEs was performed for the subjects treated
with both CICLOMULSION.RTM. and SANDIMMUNE.RTM. without
premedication. There was a significantly higher proportion of
overall AEs (p=0.003) and vascular disorders (p=0.03) when subjects
were treated with SANDIMMUNE.RTM.. No other proportions were
significantly different between the two formulations.
TABLE-US-00012 TABLE 4 Summary of all adverse events at least
possibly related to study medication. Number of patients (n)
reporting adverse events and incidence in %. Presented with and
without premedication for CICLOMULSION .RTM. and SANDIMMUNE .RTM.
Injection. Without premedication With premedication All SANDIMMUNE
.RTM. SANDIMMUNE .RTM. Subjects Injection CICLOMULSION .RTM.
Injection CICLOMULSION .RTM. n % n % n % n % n % Number of subjects
63 19 33 41 24 exposed Total number of 54 86 16 84 21 64 31 76 16
67 subjects with adverse events System organ class: 40 63 9 47 16
48 16 39 12 50 Nervous system disorders Vascular disorders 32 51 8
42 8 24 19 46 2 8 Gastrointestinal 17 27 3 16 7 21 7 17 4 17
disorders Respiratory, thoracic 11 17 -- -- 1 3 7 17 3 13 and
mediastinal disorders Cardiac disorders 6 10 -- -- 1 3 3 7 3 13
Immune system 6 10 4 21 1 3 1 2 1 4 disorders General disorders 5 8
-- -- 1 3 4 10 1 4 and administrative site conditions Skin and 4 6
-- -- -- -- 3 7 1 4 subcutaneous tissue disorders Renal and urinary
3 5 -- -- -- -- 3 7 2 8 disorders Reproductive system 3 5 1 5 1 3 1
2 -- -- and breast disorders Musculoskeletal and 2 3 -- -- -- -- 2
5 -- -- connective tissue disorders Eye disorders 1 2 1 5 -- -- --
-- -- -- Psychiatric disorders 1 2 1 5 -- -- -- -- -- --
[0140] Two SAEs were recorded. The first affected a male, aged 21,
who in the first treatment period was randomized to receive the
reference medication, Sandimmune. Directly after start of infusion
he experienced shortness of breath and a flushing sensation.
Infusion was halted, treatment with 40% oxygen via Hudson mask was
initiated, and he received promethazine 25 mg and hydrocortisone
200 mg IV. Due to continuing dyspnea, inhalation with nebulized
salbutamol was commenced. Thirty-seven minutes after start of
infusion the event was considered resolved and oxygen therapy was
discontinued. The proceeding day, he left the clinic but reported
feeling tired for another three days. The event was diagnosed as an
anaphylactoid reaction.
[0141] The second of the two SAEs reported regarded a 42-year-old
male who also received the reference drug Sandimmune in the first
treatment period. Eleven minutes after infusion of the medication
commenced he presented with coughing, facial flushing and dyspnea.
Chest auscultation revealed wheezing sounds and the peripheral
blood oxygen saturation (SpO.sub.2) measured via pulse oxymeter was
95%. His condition quickly deteriorated, he became pale and sweaty,
and a systolic/diastolic blood pressure of 75/42 mmHg was recorded.
The infusion was stopped and therapy with 40% oxygen via Hudson
mask and IV infusion with Ringer lactate commenced. Blood pressure
was not rising and the SpO.sub.2 dropped to 91% after a couple of
minutes; he was treated with 0.5 mg adrenaline and 25 mg
promethazine intramuscularly and 5 mg salbutamol as nebulized
inhalation. An infusion of 200 mg hydrocortisone also commenced.
Five minutes after the first medical intervention his blood
pressure was normalized; within an hour all drug treatment could be
discontinued. After 24 hours, treatment with IV fluids was halted
and the subject could leave the clinic. He reported feeling
fatigued for another five days but could carry out all normal
activities. The event was diagnosed as an anaphylactic reaction.
Both subjects were excluded from the remainder of the study.
[0142] Due to the events described above, as well as an allergic
reaction considered moderate and possibly related to
SANDIMMUNE.RTM. that also caused withdrawal of the subject, the
study was put on hold and an amendment to the study protocol made
with the addition of premedication as described above.
[0143] Three other subjects did not complete the study due to AEs.
These were all moderate and possibly or probably related to the
study medication. Out of these, two participants received the test
product with premedication and one the reference product with
premedication. No subjects receiving the test drug
CICLOMULSION.RTM. without premedication were withdrawn due to
AEs.
[0144] A summary of all AEs at least possibly related to the study
medication is presented in Table 4. There were no clinically
significant or consistent changes in laboratory values or
ECG-findings due to CsA administration. Vital signs and clinical
findings remained essentially unchanged during the study for all
participants except for the two SAEs described above.
Discussion
[0145] After a single IV dose of 5 mg/kg, CICLOMULSION.RTM. and
SANDIMMUNE.RTM. met the conventional criteria for bioequivalence.
CICLOMULSION.RTM. was the better tolerated of the two CsA
formulations.
[0146] Three patients had to be excluded from the study due to
adverse reactions to SANDIMMUNE.RTM., hence the study design was
changed after a decision from local authorities. Due to this high
incidence of SAEs in subjects receiving SANDIMMUNE.RTM.,
premedication was introduced. The calculated pharmacokinetic
parameters between subjects who did and did not receive
premedication were similar, and bioequivalence could be established
with a low intrasubject CV (for most variables under 10%) including
premedicated and non-premedicated subjects. Thus, the changes in
protocol and the introduction of premedication did not affect the
pharmacokinetic profile of CsA.
[0147] In clinical practice, most CrEL-containing IV drugs (such as
the anti-cancer agent Paclitaxel) are administered with
premedication due to the known risk of hypersensitivity reactions
to CrEL or, in the case of SANDIMMUNE.RTM., is often given as a
part of a combined regime with corticosteroids. It is feasible to
assume that the actual incidence of adverse reactions to
SANDIMMUNE.RTM. is obscured by the protective effect of the
corticosteroids. A number of the reports of CrEL-reactions have
been explained by improper dilution of the SANDIMMUNE.RTM.
Injection concentrate. CrEL has a greater specific gravity than
water and a high viscosity and, unless properly mixed, will not be
equally partitioned in the infusion bottle. Concentrations of CrEL
and CsA up to nine times higher than the intended dose have been
reported during the first 10 minutes of infusion when mixed
improperly (15, 27, 28). With a stable, ready-to-use preparation
without the need for dilution, this would not be an issue.
[0148] When ALTHESIN.RTM. was withdrawn in the late 1980s because
of serious side effects due to CrEL, some authors argued that CrEL
should not be used as a solvent for future drugs (39). Until now,
CsA for IV administration has not been available with any other
emulsifying excipient; this is surprising considering the extensive
literature reporting serious or even fatal CrEL-related reactions
(27, 40)
[0149] There are several previous studies comparing
pharmacokinetics of orally administered CsA-formulations, but few
for IV administration. In its oral form, CsA has frequently been
found to have large variation in bioavailability between
individuals (41-45) due to a number of factors, such as rate of
gastric emptying, the rate of biliary, pancreatic and intestinal
secretion, polymorphism in cytochrome P4503A enzymes, and different
haplotypes of p-glycoprotein expressed in the gut wall mucosa. The
intraindividual differences are usually explained by dietary
factors and clinical condition (42-44, 46, 47).
[0150] There are examples of IV drugs in which the pharmacokinetic
profiles have been significantly altered when a lipid emulsion was
introduced as an emulsifier; known examples are Propofol and
Diazepam (17, 48-50). Taking this into account, the estimated
intraindividual coefficient of variation (CV) was estimated to 35%
when designing the study. It turned out to be under 10% for all
primary variables, supporting the view that most of the
intrasubject variation in bioavailability is due to factors
primarily relevant to the orally administered formulations of CsA.
The interindividual CV % in this study was between 10% and 20% for
Cmax, AUC.sub.0-t and AUC.sub.0-.infin., consistent with previous
reports for IV CsA (41, 51, 52). The ongoing debate about the
switchability of brand and generic formulations of orally
administered CsA for reasons of variability, should therefore not
be extrapolated to IV formulations of the drug.
[0151] From the study, we conclude that CicloMulsion is
bioequivalent to Sandimmune and that the ethanol- and CrE1-free,
ready-to-use IV CsA formulation CicloMulsion is better
tolerated
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