U.S. patent application number 12/795246 was filed with the patent office on 2010-09-23 for sustained release of microcrystalline peptide suspensions.
This patent application is currently assigned to Ardana Bioscience Limited. Invention is credited to Francois Boutignon, Romano Deghenghi.
Application Number | 20100239683 12/795246 |
Document ID | / |
Family ID | 23234486 |
Filed Date | 2010-09-23 |
United States Patent
Application |
20100239683 |
Kind Code |
A1 |
Deghenghi; Romano ; et
al. |
September 23, 2010 |
SUSTAINED RELEASE OF MICROCRYSTALLINE PEPTIDE SUSPENSIONS
Abstract
The invention relates to a fluid, milky microcrystalline aqueous
suspension of a peptide or peptidomimetic and a counter-ion of a
strong proton donor in water, wherein the peptide or peptidomimetic
and counter-ion are present in amounts and at a molar ratio
sufficient to form the suspension upon mixing and without formation
of a gel. The invention also relates to lyophilized compositions
that include a dried suspension, methods of making the lyophilized
composition, methods of preparing the suspension, and sustained
release formulations prepared by the methods.
Inventors: |
Deghenghi; Romano; (St.
Cergue, CH) ; Boutignon; Francois; (Ermont,
FR) |
Correspondence
Address: |
WINSTON & STRAWN LLP;PATENT DEPARTMENT
1700 K STREET, N.W.
WASHINGTON
DC
20006
US
|
Assignee: |
Ardana Bioscience Limited
|
Family ID: |
23234486 |
Appl. No.: |
12/795246 |
Filed: |
June 7, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11450292 |
Jun 12, 2006 |
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12795246 |
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10080130 |
Feb 19, 2002 |
7098305 |
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11450292 |
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60317616 |
Sep 6, 2001 |
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Current U.S.
Class: |
424/499 ;
514/1.1; 514/10.3; 514/10.6; 514/11.1 |
Current CPC
Class: |
A61P 5/02 20180101; A61K
38/09 20130101; A61K 47/20 20130101; A61K 9/10 20130101; A61K
9/0024 20130101; A61P 5/04 20180101; A61K 47/12 20130101; A61K
47/26 20130101; A61P 43/00 20180101; A61K 38/31 20130101; A61K
9/0019 20130101; A61K 9/19 20130101; A61K 47/02 20130101 |
Class at
Publication: |
424/499 ;
514/1.1; 514/10.3; 514/10.6; 514/11.1 |
International
Class: |
A61K 9/19 20060101
A61K009/19; A61K 9/14 20060101 A61K009/14; A61P 5/04 20060101
A61P005/04; A61K 38/02 20060101 A61K038/02; A61K 38/24 20060101
A61K038/24; A61K 38/31 20060101 A61K038/31; A61P 5/02 20060101
A61P005/02 |
Claims
1. A method of preventing gel formation of a hydrophobic peptide
which comprises contacting the hydrophobic peptide with a
counter-ion derived from a strong acid in an amount and at a molar
ratio sufficient to provide a fluid, milky microcrystalline aqueous
suspension of the peptide without formation of a gel.
2. The method of claim 1 wherein the counter-ion is derived from
trifluoroacetic acid or sulfuric acid.
3. The method of claim 1 in which the hydrophobic peptide is a GnRH
analogue.
4. The method of claim 3 in which the GnRH analogue is a GnRH
antagonist.
5. The method of claim 4 in which the GnRH antagonist is selected
from the groups of Azaline B, Abarelix, Antide, Ganirelix,
Cetrorelix, or FE200486 in the form of their trifluoroacetate or
sulfate salts.
6. The method of claim 4 in which the GnRH antagonist is either
Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH.sub.2
trifluoroacetate or
Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH.sub.2
sulfate.
7. The method of claim 1 in which the hydrophobic peptide is a
somatostatin analogue.
8. The method of claim 1 in which the hydrophobic peptide salt is
suspended in the aqueous medium at a concentration of equal to or
high than 25 mg/ml.
9. The method of claim 1 in which the aqueous suspension contains
an isotonic agent.
10. The method of claim 9 in which the isotonic agent is
mannitol.
11. The method of claim 1 in which the aqueous suspension contains
a pharmaceutically acceptable excipient.
12. The method of claim 1 in which the aqueous suspension is
obtained extemporaneously from a lyophilized peptide salt.
13. A fluid, milky microcrystalline aqueous suspension of a
hydrophobic peptide and a counter-ion derived from a strong acid in
water, wherein the peptide and counter-ion are present in amounts
and at a molar ratio sufficient to form, upon mixing, the
suspension without formation of a gel.
14. The suspension of claim 13 wherein the counter-ion is derived
from trifluoroacetic acid or sulfuric acid.
15. The suspension of claim 13 in which the hydrophobic peptide is
a GnRH analogue.
16. The suspension of claim 15 in which the GnRH analogue is a GnRH
antagonist.
17. The suspension of claim 16 in which the GnRH antagonist is
selected from the groups of Azaline B, Abarelix, Antide, Ganirelix,
Cetrorelix, or FE200486 in the form of their trifluoroacetate or
sulfate salts.
18. The suspension of claim 16 in which the GnRH antagonist is
either
Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH.sub.2
trifluoroacetate or
Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH.sub.2
sulfate.
19. The suspension of claim 13 in which the hydrophobic peptide is
a somatostatin analogue.
20. The suspension of claim 13 in which the hydrophobic peptide
salt is suspended in the aqueous medium at a concentration of equal
to or high than 25 mg/ml.
21. The suspension of claim 13 in which the aqueous suspension
contains an isotonic agent.
22. The suspension of claim 21 in which the isotonic agent is
mannitol.
23. The suspension of claim 13 in which the aqueous suspension
contains a pharmaceutically acceptable excipient.
24. The suspension of claim 13 wherein the microcrystals are in the
form of needles having a particle size of between about 5 and 150
.mu.m.
25. A lyophilized composition comprising the dried suspension of
claim 13.
26. A method of preparing a lyophilized composition according to
claim 25 which comprises a method as claimed in claim 1 followed by
freeze-drying or spray-drying to obtain the composition.
27. A method of preparing an injectable fluid, milky,
microcrystalline aqueous suspension of a hydrophobic peptide which
comprises reconstituting with water or a buffer solution the
lyophilized composition of claim 25.
28. A method of preparing a sustained release formulation of a
hydrophobic peptide which comprises contacting the hydrophobic
peptide with a counter-ion derived from a strong acid, wherein the
peptide and counter-ion are present in amounts and at a molar ratio
sufficient to form, upon mixing, the suspension without formation
of a gel.
29. The method of claim 28 wherein the counter-ion is derived from
trifluoroacetic acid or sulfuric acid.
30. The method of claim 28 in which the hydrophobic peptide is a
GnRH analogue.
31. The method of claim 30 in which the GnRH analogue is a GnRH
antagonist.
32. The method of claim 31 in which the GnRH antagonist is selected
from the groups of Azaline B, Abarelix, Antide, Ganirelix,
Cetrorelix, or FE200486 in the form of their trifluoroacetate or
sulfate salts.
33. The method of claim 31 in which the GnRH antagonist is either
Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-llys-Pro-D-Ala-NH.sub.2
trifluoroacetate or
Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-llys-Pro-D-Ala-NH.sub.2
sulfate.
34. The method of claim 28 in which the hydrophobic peptide is a
somatostatin analogue.
35. The method of claim 28 in which the hydrophobic peptide salt is
suspended in the aqueous medium at a concentration of equal to or
high than 25 mg/ml.
36. The method of claim 28 in which the aqueous suspension contains
an isotonic agent.
37. The method of claim 36 in which the isotonic agent is
mannitol.
38. The method of claim 28 in which the aqueous suspension contains
a pharmaceutically acceptable excipient.
39. The method of claim 28 in which the aqueous suspension is
obtained extemporaneously from a lyophilized peptide salt.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 11/450,292, filed Jun. 12, 2006, which is a continuation of
U.S. application Ser. No. 10/080,130, filed Feb. 19, 2002, which
claims priority to U.S. Provisional Application No. 60/317,616,
filed Sep. 6, 2001, the entire disclosure of each of which is
incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] There is frequently a need to deliver biologically active
peptides to animals and humans in formulations providing a
sustained release of the active principle. Such formulations may be
provided by incorporating the active principle in biodegradable and
biocompatible polymers in the form of microcapsules, microgranules
or implantable rods, or alternatively using mechanical devices such
as micropumps or non-biodegradable containers. If the peptide is
highly soluble in aqueous media, it can be formulated as a complex
with non-degradable polymers such as cellulose derivatives, or
mixed with polymer solutions, which form a gel upon parenteral
injection, from which the active peptide is slowly released.
[0003] All the above-mentioned formulations have drawbacks and
limitations, such as the large volume of suspending fluids or the
need to remove the non-degradable device. In the case of gel
forming peptides, there is frequently a problem of bioavailability,
which interferes with the desired sustained action of the active
principle.
[0004] Some of the problems due to physico-chemical aspects of
peptides have been described in an article by R. Deghenghi
"Antarelix" in Treatment with GnRH Analogs: Controversies and
Perspectives", edited by M. Filicori and C. Flamigni, The Parthenon
Publishing Group, New York and London 1996, pages 89-91. Additional
problems were illustrated by J. Rivier "GnRH analogues towards the
next millennium" in GnRH Analogues, edited by B. Lunenfeld, The
Parthenon Publishing Group, New York and London 1999, pages 31-45
and by other workers such as M. F. Powell et al. "Parenteral
Peptide Formulations: Chemical and Physical Properties of Native
LHRH and Hydrophobic Analogues in Aqueous Solution" in
Pharmaceutical Research, Vol. 8, 1258-1263 (1991).
[0005] Accordingly, there is a need for new formulations and
methods of administration that avoid these problems, and this need
is addressed by the present invention.
SUMMARY OF THE INVENTION
[0006] The present invention relates to a fluid, milky
microcrystalline aqueous suspension of a peptide or peptidomimetic
and a counter-ion of a strong proton donor in water. The peptide or
peptidomimetic and counter-ion are present in amounts and at a
molar ratio sufficient to form the suspension of the peptide or
peptidomimetic upon mixing without formation of a gel.
[0007] In one embodiment, the counter-ion is
trifluoromethanesulfonic acid, benzenesulfonic acid,
trifluoroacetic acid, or sulfuric acid. Generally, the counter-ion
is a strong acid and the peptide is a GnRH analogue. The GnRH
analogue is preferably a GnRH antagonist.
[0008] In another embodiment, the GnRH antagonist is
Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH.sub.2. In
yet another embodiment, the GnRH antagonist is Azaline B, Abarelix,
Antide, Ganirelix, Cetrorelix, or FE200486 and is in the form of an
alkylsulfonate, arylsulfonate, trifluoroacetate or sulfate
salt.
[0009] The peptide may also be a somatostatin analogue. The
somatostatin analogue may be, for example, Vapreotide, Octreotide,
Lanreotide or SOM 230.
[0010] Generally, the peptide or peptidomimetic forms a salt with
the counter-ion, and the salt is suspended in the aqueous medium at
a concentration of equal to or higher than 25 mg/mL. The aqueous
suspension usually contains an isotonic agent, such as
mannitol.
[0011] Typically, the suspension also includes a pharmaceutically
acceptable excipient. The amount of peptide or peptidomimetic
generally ranges from about 0.1 to 5 mg per kg body weight of a
mammal or human to which the suspension is to be administered. The
peptide is preferably at least partially in the form of
microcrystals having a particle size of from about 1 .mu.m to 150
.mu.m.
[0012] The present invention also relates to a lyophilized
composition that includes a dried suspension. In addition, the
present invention relates to a method of making the lyophilized
composition by associating the peptide or peptidomimetic with a
counter-ion of a strong proton donor in an amount and at a molar
ratio that are sufficient to provide the suspension without
formation of a gel, and lyophilizing the suspension to obtain the
composition.
[0013] The present invention further relates to a method of
preparing a fluid, milky microcrystalline aqueous suspension of a
peptide or peptidomimetic that includes adding water or a buffer
solution to the lyophilized composition with mixing to obtain the
suspension.
[0014] A method of preparing a fluid, milky microcrystalline
aqueous suspension of a peptide or peptidomimetic is also
encompassed by the present invention. The method includes
associating the peptide or peptidomimetic with the counter-ion in
an amount and at a molar ratio with the peptide that are sufficient
to provide the fluid, milky microcrystalline aqueous suspension
without formation of a gel; lyophilizing the suspension to form a
lyophilized composition; and adding water or a buffer solution to
the lyophilized composition with mixing to obtain the
suspension.
[0015] Furthermore, the present invention relates to a method of
preparing a fluid, milky microcrystalline aqueous suspension of a
peptide or peptidomimetic that includes associating the peptide or
peptidomimetic with the counter-ion in an amount and at a molar
ratio that are sufficient to provide the fluid, milky
microcrystalline aqueous suspension without formation of a gel.
[0016] The suspension is generally prepared to provide a sustained
release formulation of the peptide or peptidomimetic such that,
when administered to a subject, the peptide or peptidomimetic is
released in vivo over a period of at least two weeks. Preferably,
the counter-ion is a trifluoromethanesulfonic acid, benzenesulfonic
acid, trifluoroacetic acid or sulfuric acid. Typically, the
counter-ion is a strong acid and the peptide is a GnRH analogue.
The GnRH analogue is, for example, a GnRH antagonist. The GnRH
antagonist is preferably
Ac-D-Nal-DCpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH.sub.2. The
GnRH antagonist is typically Azaline B, Abarelix, Antide,
Ganirelix, Cetrorelix, or FE200486 and is in the form of an
alkylsulfonate, arylsulfonate, trifluoroacetate or sulfate
salt.
[0017] The peptide is typically a somatostatin analogue.
Preferably, the somatostatin analogue is Vapreotide, Octreotide,
Lanreotide, or SOM 230. The peptide or peptidomimetic usually forms
a salt with the counter-ion, and the salt is suspended in the
aqueous medium at a concentration of at least 25 mg/mL.
[0018] In one embodiment, the aqueous suspension is injected
parenterally into a mammal or human subject to obtain a sustained
release of the peptide or peptidomimetic over at least one month.
The amount of peptide or peptidomimetic in the suspension to be
injected generally ranges from about 0.1 to 5 mg per kg body weight
of the mammal or human subject.
[0019] A sustained release formulation of a peptide or
peptidomimetic prepared by the method of the present invention,
when administered to a subject, generally releases the peptide or
peptidomimetic in vivo over a period of at least two weeks.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] FIG. 1 is a graph which illustrates the pharmacodynamic
effect (testosterone suppression) obtained by subcutaneous
injection in rats of a suspension of Teverelix trifluoroacetate
according to the invention; and
[0021] FIG. 2 is a graph which illustrates the sustained release of
the peptide Teverelix for several weeks in rats injected with the
suspension of Teverelix trifluoroacetate according to the
invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0022] The present invention is directed to the unexpected
discovery that certain peptides can be prepared or associated with
various counter-ions and simply formulated to provide desirable
suspensions of the peptide, which suspensions are highly useful for
administering the suspension by injection. In particular, a fluid,
milky, stable microcrystalline suspension of the peptide is
obtained without formation of a gel that would interfere with the
handling of the suspension or the bioavailability of the peptide
after injection.
[0023] The peptide that is to be utilized in the present suspension
can be any one of a variety of well known bioactive peptides or
peptide analogues which mimic such peptides. Advantageously, these
peptides are formulated to obtain a delayed and sustained release
of the peptide after injection. While any peptide can be utilized
in this invention, those peptides or peptidomimetics having between
3 and 45 amino acids have been found to be the most suitable. In
particular, representative peptides or peptidomimetics are well
known to those of ordinary skill in the art and need not be
exhaustively mentioned here. Typical examples include GnRH
analogues and antagonists, as well as somatostatin and analogues
thereof. Specific peptides include Azaline B, Abarelix, Antide,
Ganirelix, Cetrorelix, FE 200486, Vapreotide, Octreotide,
Lanreotide and SOM-230. These peptides have between 6 and 12 amino
acids and are synthetically made to mimic the biological activity
of GnRH or somatostatin. The examples mention further preferred
peptides.
[0024] It has been found that certain counter-ions are highly
preferred for obtaining sustained release of the peptide. Suitable
counter-ions are those which are strong proton donors. While many
compounds are well known to provide this function, the most
preferred are strong acids. Sulfuric acid, a well known commodity,
is quite useful for this purpose, as are other strong inorganic
acids. Sulfuric is preferred due to its ready formation of suitable
sulfate salts with the peptides of the invention. Strong organic
acids can also be used as counter-ions. These acids include
sulfonic acids, such as trifluoromethanesulfonic acid and benzene
sulfonic acid. Others, such as trifluoroacetic acid or other
fluorinated acids can be used if desired.
[0025] The amount of counter-ion is preferably that which is in
excess of what is necessary to form a stoichiometric salt of the
peptide. The amount of counter-ion is typically at least 1.6 mol
acid/mole peptide and preferably 2 mol/mol or greater. While no
upper limit has been determined, the amount can be as high as 10
mol/mol. In addition, the injectable suspension should be
concentrated to obtained the most desirable release profiles. By
concentrated, we mean that the amount of peptide should be above
2.5% by weight of the overall formulation. This is conveniently
achieved by adding to water or a buffer solution at least 25 mg/mL
of the peptide. Amounts of as high as 100 mg/mL can be used, and
these suspensions can also contain other additives. In addition to
conventional pharmaceutically acceptable excipients, an isotonic
agent, such as mannitol, can be included for its known purpose.
Other usual pharmaceutical additives can be included, as
desired.
[0026] The suspensions can be dried by freeze-drying or spray
drying to form lyophilized compositions that can be stored as is
and later reconstituted with sterile water or buffer solutions when
an injectable formulation is to be prepared. These lyophilized
compositions can be stored for relatively long periods of time
prior to use. Also they can be easily sterilized and handled until
the time when they are to be reconstituted.
[0027] An additional advantage of this discovery is the small
volume of such suspensions, allowing parenteral injections through
a fine needle and thus improving the local tolerance of the
injected material. Furthermore, the material can also be used for
the local treatment of diseased tissues, e.g., brachytherapy. The
peptide is partially or totally in the microcystalline form having
a particle size of between about 1 and 150 .mu.m, and preferably
between about 5 and 25 .mu.m. These small particles easily pass
through the injection needle. In such injections, the amount of
peptide ranges from about 0.1 to 5 mg per kg body weight of the
mammal or human to which the suspension is to be administered.
[0028] A specific discovery was that a highly concentrated aqueous
suspension of the peptide of the formula
Ac-D-Nal-D-pClPhe-D-Pal-Ser-Tyr-D-Hci-Leu-Lys(iPr)-Pro-D-Ala-NH.sub.2
(Teverelix, a GnRH antagonist) as a trifluoroacetate (TFA) or
sulfate salt does not, as might be expected by its hydrophobic
character, form a gel but instead forms a microcrystalline milky
suspension which is easy to inject parenterally in animals or
humans, and which releases the active principle over several weeks
(see FIGS. 1 and 2). Such behavior is not elicited by other salts
such as the acetate, which result in the expected, but unwanted,
formation of gels with poor bioavailability in vivo.
[0029] The invention thus represents a simple and elegant solution
to the problem of how to suppress gelation of peptide salts while
obtaining a prolonged sustained delivery of peptides in the form of
highly concentrated suspensions.
EXAMPLES
Example 1
[0030] 200 .mu.L of 5% mannitol were added to approximately 15 mg
of the LHRH antagonist Teverelix trifluoroacetate. The mixture was
stirred using vortex during one minute and a flowing milky pearly
suspension was obtained. The suspension is made of microcrystals of
about 10 .mu.m length. Microcrystals may clump together to form
urchin like structures. The suspension was injected in rats (1 mg)
sub-cutaneously and provided the pharmacodynamic effect of
testosterone suppression for more than 45 days (FIG. 1). The
pharmacokinetic analysis showed a sustained release of the peptide
for several weeks (FIG. 2).
Example 2
[0031] 200 .mu.L of water were added to approximately 15 mg of the
LHRH antagonist Teverelix trifluoroacetate. The mixture was stirred
using vortex during one minute and a flowing milky pearly
suspension was obtained.
Example 3
[0032] 200 .mu.L of water were added to approximately 15 mg of the
LHRH antagonist Teverelix acetate. The mixture was stirred using
vortex during one minute and a transparent gel was obtained. The
addition of 20 .mu.L of TFA (3 mols/mol) to the gel resulted in the
formation of a fluid, flowing milky pearly suspension.
Example 4
[0033] 200 .mu.L of 100 mM TFA were added to approximately 15 mg of
the LHRH antagonist Teverelix acetate (2 mols/mol) to obtain a
flowing milky suspension. In addition, mixing 200 .mu.L of 75 mM
TFA with approximately 15 mg of the LHRH antagonist Teverelix
acetate (1.5 mol/mol) resulted in a transparent gel being obtained
after mixing. In another study, 100 .mu.L of TFA of various
concentrations were added to 7.5 mg of the LHRH antagonist
Teverelix acetate, with the TFA/Teverelix molar ratio ranging from
1 to 3. A flowing milky suspension was obtained with molar ratios
of 1.6, whereas gels were obtained at other molar ratios.
Example 5
[0034] 200 .mu.L of 150 mM TFA were added to amounts of the LHRH
antagonist Teverelix acetate ranging from 5 to 30 mg (concentration
ranging from 25 to 150 mg/mL). A flowing milky suspension was
obtained with concentrations up to 100 mg/mL.
Example 6
[0035] 200 .mu.L of 150 mM TFA were added to approximately 15 mg of
the LHRH antagonist Teverelix acetate (3 mols/mol) and a flowing
milky suspension was obtained after mixing. The suspension was
freeze-dried overnight. 200 .mu.L of water or 5% mannitol were
added to the lyophilisate and a flowing milky suspension was
obtained after mixing and reconstitution.
Example 7
[0036] 1 mL of 150 mM TFA were added to approximately 75 mg of the
LHRH antagonist Teverelix acetate (3 mols/mol) and a flowing milky
suspension was obtained after mixing. The suspension was
freeze-dried overnight. 1 mL of water and 0.2 M acetate buffer pH
4.0 were added to the lyophilisate and a flowing milky suspension
was obtained after mixing and reconstitution. These suspensions
were stable for at least 3 days at room temperature.
Example 8
[0037] 100 .mu.L of a 250 mM H.sub.2SO.sub.4 were added to 7.5 mg
of the LHRH antagonist Teverelix acetate (5 mols/mol) and a flowing
milky suspension was obtained after several hours.
[0038] The suspension is made of microcrystals of about 100 .mu.m
length. Microcrystals may assemble together to form urchin like
structures. The suspension was freeze-dried overnight. 100 .mu.L of
water or 5% mannitol were added to the lyophilisate and a flowing
milky suspension was obtained after mixing and reconstitution.
Example 9
[0039] 100 .mu.L of a 150 mM trifluoromethane sulfonic acid
solution were added to 7.5 mg of Teverelix acetate to obtain a free
flowing milky suspension after mixing.
Example 10
[0040] 100 .mu.L of a 150 mM solution of benzenesulfonic acid were
added to 7.5 mg Teverelix hydrochloride to give after a mixing a
free flowing suspension.
Example 11
[0041] 100 .mu.L of a 200 mM solution of trifluoroacetic acid
solution were added to 2.5 mg of Cetrorelix acetate to obtain a
milky free flowing suspension.
Example 12
[0042] Free flowing suspensions were obtained by adding 100 .mu.L
of a 150 mM trifluoroacetic acid solution to 7.5 mg each of the
following somatostatin analogues: [0043]
D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH.sub.2 [0044]
D-2Me-Trp-c[Cys-Phe-D-Trp-Lys-Thr-Cys]-Trp(2Me)-NH.sub.2 [0045]
D-Nal-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp(2Me)-NH.sub.2 [0046]
D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp(2Me)-NH.sub.2
Example 13
[0047] 100 .mu.L of a 5% mannitol--water solution were added to
approximately 5 mg of the somatostatin analog known under the
designation SOM 230, i.e.,
ETD-carboxy-c[Hyp-Phg-D-Trp-Lys-Tyr(Bzl)-Phe], as the
trifluoroacetate salt. A milky free flowing suspension was thus
obtained.
* * * * *