U.S. patent application number 12/865145 was filed with the patent office on 2011-01-06 for sustained release formulation comprising octreotide and three linear polylactide-co-glycolide polymers.
Invention is credited to Markus Ahlheim, Holger Petersen.
Application Number | 20110003002 12/865145 |
Document ID | / |
Family ID | 39577789 |
Filed Date | 2011-01-06 |
United States Patent
Application |
20110003002 |
Kind Code |
A1 |
Petersen; Holger ; et
al. |
January 6, 2011 |
SUSTAINED RELEASE FORMULATION COMPRISING OCTREOTIDE AND THREE
LINEAR POLYLACTIDE-CO-GLYCOLIDE POLYMERS
Abstract
The present invention relates to sustained release formulations
comprising as active ingredient octreotide or a
pharmaceutically-acceptable salt thereof and three different linear
polylactide-co-glycolide polymers (PLGAs).
Inventors: |
Petersen; Holger;
(Eimeldingen, DE) ; Ahlheim; Markus; (Staufen,
DE) |
Correspondence
Address: |
NOVARTIS;CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 101/2
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
39577789 |
Appl. No.: |
12/865145 |
Filed: |
January 29, 2009 |
PCT Filed: |
January 29, 2009 |
PCT NO: |
PCT/EP2009/051026 |
371 Date: |
July 29, 2010 |
Current U.S.
Class: |
424/490 ;
424/501; 514/11.1 |
Current CPC
Class: |
A61P 1/04 20180101; A61P
1/14 20180101; A61K 9/0019 20130101; A61P 1/12 20180101; A61K
9/0024 20130101; A61K 9/06 20130101; A61P 5/08 20180101; A61K
9/1647 20130101; A61K 9/10 20130101; A61P 35/00 20180101; A61K
9/1694 20130101; A61P 17/00 20180101; A61P 5/00 20180101; A61K
38/31 20130101 |
Class at
Publication: |
424/490 ;
514/11.1; 424/501 |
International
Class: |
A61K 9/14 20060101
A61K009/14; A61K 38/12 20060101 A61K038/12; A61P 1/12 20060101
A61P001/12 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 30, 2008 |
EP |
08150826.9 |
Claims
1. A sustained release pharmaceutical composition comprising as
active ingredient octreotide or a pharmaceutically-acceptable salt
thereof and three different linear polylactide-co-glycolide
polymers (PLGAs).
2. The pharmaceutical composition according to claim 1 wherein the
PLGAs are present as polymer blend.
3. The pharmaceutical composition according to claim 1 wherein the
PLGAs have a lactide:glycolide monomer ratio of 90:10 to 40:60.
4. The pharmaceutical composition according to claim 3 wherein the
PLGAs have a lactide:glycolide monomer ratio of 85:15 to 65:35.
5. The pharmaceutical composition according to claim 1 wherein the
inherent viscosity of the PLGAs is below 0.9 dl/g in
CHCl.sub.3.
6. The pharmaceutical composition according to claim 5 wherein the
inherent viscosity of the PLGAs is below 0.8 dl/g in
CHCl.sub.3.
7. The pharmaceutical composition according to claim 1 comprising
the pamoate salt of octreotide.
8. The pharmaceutical composition according to claim 1 wherein the
release of the active ingredient is three or more months.
9. The pharmaceutical composition according to claim 8 wherein the
release of the active ingredient is between three and six
months.
10. The pharmaceutical composition according to claim 1 in form of
microparticles, a semisolid or an implant.
11. The pharmaceutical composition according to claim 10 in form of
microparticles.
12. The pharmaceutical composition according to claim 11 wherein
the microparticles have a diameter between 10 .mu.m and 90
.mu.m.
13. The pharmaceutical composition according to claim 11 wherein
the microparticles are additionally covered or coated with an
anti-agglomerating agent.
14. The pharmaceutical composition according to claim 13 wherein
the microparticles are coated with an anti-agglomerating agent and
the anti-agglomerating agent is present in an amount of less than
2% by weight of the microparticles.
15. The pharmaceutical composition according to claim 13 wherein
the anti-agglomerating agent is mannitol.
16. The pharmaceutical composition according to claim 1 sterilized
by gamma irradiation.
17. (canceled)
18. A method of administering octreotide or a
pharmaceutically-acceptable salt thereof for long-term maintenance
therapy in acromegalic patients, and treatment of severe diarrhea
and flushing associated with malignant carcinoid tumors and
vasoactive intestinal peptide tumors (vipoma tumors), said method
comprising administering to a patient in need of octreotide or a
pharmaceutically-acceptable salt thereof a pharmaceutical
composition according to claim 1.
19. A process of manufacturing microparticles according to claim 11
comprising (i) preparation of an internal organic phase comprising
(ia) dissolving the polymer or polymers in a suitable organic
solvent or solvent mixture; (ib)
dissolving/suspending/emulsification of the drug substance in the
polymer solution obtained in step (ia); (ii) preparation of an
external aqueous phase containing stabilizers; (iii) mixing the
internal organic phase with the external aqueous phase to form an
emulsion; and (iv) hardening the microparticles by solvent
evaporation or solvent extraction, washing the microparticles,
drying the microparticles and sieving the microparticles through
140 .mu.m.
20. An administration kit comprising the pharmaceutical composition
according to claim 1 in a vial, together with a water-based vehicle
in an ampoule, vial or prefilled syringe or as microparticles and
vehicle separated in a double chamber syringe.
Description
[0001] The present invention relates to sustained release
formulations comprising as active ingredient octreotide or a
pharmaceutically-acceptable salt thereof and three different linear
polylactide-co-glycolide polymers (PLGAs).
[0002] These pharmaceutical compositions according to the present
invention are indicated for inter alia long-term maintenance
therapy in acromegalic patients, and treatment of severe diarrhea
and flushing associated with malignant carcinoid tumors and
vasoactive intestinal peptide tumors (vipoma tumors).
[0003] Peptide drugs are usually administerd systemically, e.g.
parenterally. However, parenteral administration may be painful and
cause discomfort, especially for repeated daily administrations. In
order to minimize the number of injections to a patient, the drug
substance should be administered as a depot formulation. A common
drawback with injectable depot formulations is the fluctuation in
plasma levels such as high peak levels together with plasma levels
close to zero during the entire release periode.
[0004] Sustained release formulations comprising as active
ingredient octreotide or a pharmaceutically acceptable salt thereof
and two or more different polylactide-co-glycolide polymers (PLGAs)
have, for instance, been also disclosed in WO2007/071395.
[0005] The present invention discloses a sustained release
formulation comprising as active ingredient (drug substance)
octreotide or a pharmaceutically-acceptable salt thereof.
Octreotide is a somatostatin analog having the following
formula:
##STR00001##
[0006] The active ingredient may be in the form of a
pharmaceutically acceptable salt of octreotide, such as an acid
addition salt with e.g. inorganic acid, polymeric acid or organic
acid, for example with hydrochloric acid, acetic acid, lactic acid,
citric acid, fumaric acid, malonic acid, maleic acid, tartaric
acid, aspartic acid, benzoic acid, succinic acid or pamoic
(embonic) acid. Acid addition salts may exist as mono- or divalent
salts, e.g. depending whether 1 or 2 acid equivalents are added.
Preferred is the pamoate monosalt of octreotide.
[0007] The particle size distribution of the drug substance
influences the release profile of the drug from the depot form. The
drug substance which is used to prepare the depot formulation is
crystalline or in the form of an amorphous powder. Preferred is an
amorphous powder which has a particle of a size of about 0.1
microns to about 15 microns (99%>0.1 microns, 99%<15
microns), preferably from 1 to less than about 10 microns (90%>1
microns, 90%<10 microns). The drug substance preferentially
undergoes a micronization process to present the required particle
size distribution.
[0008] The present invention further provides a sustained release
pharmaceutical composition (depot) comprising as active ingredient
octreotide or a pharmaceutically-acceptable salt thereof
incorporated in blends or mixtures of poly(lactide-co-glycolide)s
(PLGAs), for instance in form of microparticles, implants or
semisolid formulations.
[0009] Alternatively to blends of PLGAs, in another aspect of the
present invention the pharmaceutical composition comprises a
mixture of PLGA polymers containing the active ingredient; i.e. the
active ingredient may be incorporated into one or more PLGAs in
form of microparticles, implants or semisolid formulations and is
then mixed with another microparticle or implant or semisolid
formulation also comprising the active ingredient and one or more
PLGAs.
[0010] The pharmaceutical composition according to the present
invention allows a sustained release of the active ingredient over
a period of more than three month, preferentially between three and
six months. During the release of the active ingredient the plasma
levels of octreotide are within the therapeutic range. It is
understood that the exact dose of octreotide will depend on a
number of factors, including the condition to be treated, the
severity of the condition to be treated, the weight of the subject
and the duration of therapy.
[0011] Surprisingly fluctuations in plasma levels can significantly
be reduced by using a suitable combination of three different
linear PLGAs in the pharmaceutical composition according to the
present invention.
[0012] The drug substance is incorporated into a biodegradable
polymer matrix consisting of three different linear
polylactide-co-glycolide polymers (PLGAs). The PLGAs have a
lactide: glycolide monomer ratio of 100:0 to 40:60, preferably
90:10 to 40:60, more preferably 85:15 to 65:35.
[0013] The PLGAs according to the present invention have a
molecular weight (Mw) ranging from 1,000 to 500,000 Da, preferably
from 5,000 to 100,000 Da. The architecture of the polymers is
linear.
[0014] The inherent viscosity (IV) of the PLGAs according to the
present invention is below 0.9 dl/g in CHCl.sub.3, preferentially
below 0.8 dl/g in CHCl.sub.3. The inherent viscosities can be
measured by the conventional methods of flow time measurement, as
described for example in "Pharmacopoee Europeenne", 1997, pages
17-18 (capillary tube method). Unless stated otherwise, these
viscosities have been measured in chloroform at a concentration of
0.5% at 25.degree. C. or in hexaisofluoropropanol at a
concentration of 0.5% at 30.degree. C.
[0015] End groups of the PLGAs according to the present invention
can be but are not limited to Hydroxy, carboxy, ester or the
like.
[0016] The drug substance content of the depot formulation (the
loading) is in a range of 1% to 30%, preferred 10% to 25%, more
preferred 15% to 20%. The loading is defined as the weight ratio of
drug substance as free base to the total mass of the PLGA
formulation.
[0017] Suitable polymers are commonly known but not limited to
those commercially available as RESOMER.RTM. by Boehringer
Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany, LACTEL.RTM.
by Absorbable Polymers International (API), Pelham, Ala., USA,
MEDISORB.RTM. by Alkermes, Inc., Cambridge, Mass., USA,
PURASORB.RTM. by PURAC biochem By, Gorinchem, The Netherlands.
Examples of suitable polymers are listed in Table 1.
TABLE-US-00001 TABLE 1 Examples of suitable polymers Inherent
Producer No Product name Polymer viscosity [dL/g] Supplier 1
Resomer .RTM. R 202 H Linear Poly(D,L-lactide) 0.16-0.24.sup.1)
Boehringer free carboxylic acid end group 2 Resomer .RTM. R 202 S
Linear Poly(D,L-lactide) 0.16-0.24.sup.1) Boehringer 3 Resomer
.RTM. R 203 S Linear Poly(D,L-lactide) 0.25-0.35.sup.1) Boehringer
4 Resomer .RTM. RG 752 H Linear Poly(D,L-lactide-co-
0.14-0.22.sup.1) Boehringer glycolide) 75:25 free carboxylic acid
end group 5 Resomer .RTM. RG 752 S Linear Poly(D,L-lactide-co-
0.16-0.24.sup.1) Boehringer glycolide) 75:25 6 Resomer .RTM. CR RG
Linear Poly(D,L-lactide-co- 0.32-0.44.sup.1) Boehringer 75:25 or
Resomer .RTM. glycolide) 75:25 RG Type 75:25 S/ Resomer .RTM. RG
753 S 7 Lactel .RTM. 100D020A Linear Poly(D,L-lactide)
0.15-0.25.sup.2) API/Durect free carboxylic acid end group 8 Lactel
.RTM. 100D040A Linear Poly(D,L-lactide) 0.26-0.54.sup.2) API/Durect
free carboxylic acid end group 9 Lactel .RTM. 100D040 Linear
Poly(D,L-lactide) 0.26-0.54.sup.2) API/Durect 10 Lactel .RTM.
100D065 Linear Poly(D,L-lactide) 0.55-0.75.sup.2) API/Durect 11
Lactel .RTM. 85DG040 Linear Poly(D,L-lactide-co- 0.26-0.54.sup.2)
API/Durect glycolide) 85:15 12 Lactel .RTM. 85DG065 Linear
Poly(D,L-lactide-co- 0.55-0.75.sup.2) API/Durect glycolide) 85:15
13 Lactel .RTM. 75DG065 Linear Poly(D,L-lactide-co-
0.55-0.75.sup.2) API/Durect glycolide) 75:25 14 Lactel .RTM.
65DG065 Linear Poly(D,L-lactide-co- 0.55-0.75.sup.3) API/Durect
glycolide) 65:35 15 Lactel .RTM. 50DG065 Linear
Poly(D,L-lactide-co- 0.55-0.75.sup.3) API/Durect glycolide) 50:50
16 Medisorb .RTM. Linear Poly(D,L-lactide) 0.66-0.80 Alkermes 100
DL HIGH IV 17 Medisorb .RTM. Linear Poly(D,L-lactide) 0.50-0.65
Alkermes 100 DL LOW IV 18 Medisorb .RTM. Linear
Poly(D,L-lactide-co- 0.66-0.80 Alkermes 8515 DL HIGH IV glycolide)
85:15 19 Medisorb .RTM. Linear Poly(D,L-lactide-co- 0.50-0.65
Alkermes 8515 DL LOW IV glycolide)85:15 20 Medisorb .RTM. Linear
Poly(D,L-lactide-co- 0.66-0.80 Alkermes 7525 DL HIGH IV glycolide)
75:25 21 Medisorb .RTM. Linear Poly(D,L-lactide-co- 0.50-0.65
Alkermes 7525 DL LOW IV glycolide) 75:25 22 Medisorb .RTM. Linear
Poly(D,L-lactide-co- 0.66-0.80 Alkermes 6535 DL HIGH IV glycolide)
65:35 23 Medisorb .RTM. Linear Poly(D,L-lactide-co- 0.50-0.65
Alkermes 6535 DL LOW IV glycolide) 65:35 24 Medisorb .RTM. Linear
Poly(D,L-lactide-co- 0.66-0.80 Alkermes 5050 DL HIGH IV glycolide)
50:50 25 Medisorb .RTM. Linear Poly(D,L-lactide-co- 0.50-0.65
Alkermes 5050 DL LOW IV glycolide) 50:50 .sup.1)IV has been
determined in chloroform at a concentration of 0.1% at 25.degree.
C. .sup.2)IV has been determined in chloroform at a concentration
of 0.5 g/dL at 30.degree. C. .sup.3)IV has been determined in
Hexafluoroisopropanol at a concentration of 0.5 g/dL at 30.degree.
C.
[0018] Plasma levels with low variability can be achieved over a
time period of more then three month, preferentially between three
and six month, only with pharmaceutical compositions according to
the present invention, not with formulations containing only one
single polymer from the table above.
[0019] In addition, the pharmaceutical composition according to the
present invention can be manufactured aseptically or
non-aseptically and sterilized terminally by gamma irradiation.
Preferred is terminal sterilization by gamma irradiation, resulting
in a product with the highest sterility assurance possible.
[0020] The pharmaceutical composition according to the present
invention may also contain one or more pharmaceutical excipients
modulating the release behavior in an amount of 0.1% to 50%.
Examples of such agents are: Poly(vinylpyrrolidone), carboxymethyl
cellulose sodium (CMC-Na), dextrin, poly(ethyleneglycol), suitable
surfactants such as poloxamers, also known as
poly(oxyethylene-block-oxypropylene),
Poly(oxyethylene)-sorbitan-fatty acid esters known and commercially
available under the trade name TWEEN.RTM. (e.g. Tween 20, Tween 40,
Tween 60, Tween 80, Tween 65 Tween 85, Tween 21, Tween 61, Tween
81), Sorbitan fatty acid esters e.g. of the type known and
commercially available under the trade name SPAN, Lecithins,
inorganic salts such as zinc carbonate, magnesium hydroxide,
magnesium carbonate, or protamine, e.g. human protamine or salmon
protamine, or natural or synthetic polymers bearing amine-residues
such as polylysine.
[0021] The pharmaceutical composition according to the present
invention can be a depot mixture or a polymer blend of different
polymers in terms of compositions, molecular weight and/or polymer
architectures. A polymer blend is defined herein as a solid
solution or suspension of three different linear polymers in one
implant or microparticle. A mixture of depots in contrast is
defined herein as a mixture of two or more depots like implants or
microparticles or semisolid formulations of different composition
with one or more PLGAs in each depot. Preferred is a pharmaceutical
composition wherein the three PLGAs are present as polymer
blend.
[0022] The pharmaceutical composition according to the present
invention can be in the form of implants, semisolids (gels), liquid
solutions or suspensions which solidify in situ once they are
injected or microparticles. Preferred are microparticles.
Preparation of microparticles comprising octreotide or a
pharmaceutically-acceptable salt thereof is know; and for instance
disclosed in U.S. Pat. No. 5,445,832 or U.S. Pat. No.
5,538,739.
[0023] The following part of the invention is focused on polymer
microparticles although the descriptions are applicable for
implants, semisolids and liquids as well.
[0024] The microparticles according to the present invention may
have a diameter from a few submicrons to a few millimeters, e.g.
from about 0.01 microns to about 2 mm, e.g. from about 0.1 microns
to about 500 microns. For pharmaceutical microparticles, diameters
of at most about 250 microns, e.g. 10 to 200 microns, preferably 10
to 130 microns, more preferably 10 to 90 microns.
[0025] The microparticles according to the present invention may be
mixed or coated with an anti-agglomerating agent or covered by a
layer of an anti-agglomerating agent, e.g. in a prefilled syringe
or vial. Suitable anti-agglomerating agents include, e.g. mannitol,
glucose, dextrose, sucrose, sodium chloride, or water soluble
polymers such as polyvinylpyrrolidone or polyethylene glycol, e.g.
with the properties described above. For microparticles according
to the present invention in dry state preferably an
anti-agglomerating agent is present in an amount of about 0.1 to
about 10%, preferentially about 3% to 5%, e.g. about 4% by weight
of the microparticles. A preferred anti-agglomerating agent in this
respect is mannitol.
[0026] Alternatively, an anti-agglomerating agent can be applied to
the microparticles during their manufacturing process. For example,
at the step of filtering/washing the microparticles they can be
additionally rinsed with an aqueous solution of an
anti-agglomerating agent. Thus, a layer of the anti-agglomerating
agent is formed on the surface of the microparticles. Preferably,
the anti-agglomerating agent is present in the microparticles at an
amount of less than 10%, more preferred less than 2%, most
preferred less than 0.5% by weight of the microparticles. A
preferred anti-agglomerating agent in this respect is mannitol.
[0027] The manufacturing process for the depot formulation of the
current invention is described in detail for microparticles:
[0028] The microparticles may be manufactured by several processes
known in the art, e.g., coacervation or phase separation, spray
drying, water-in-oil (W/O) or water-in-oil-in-water (W/O/W) or
solids-in-oil-in-water (S/O/W) emulsion/suspension methods followed
by solvent extraction or solvent evaporation. The
emulsion/suspension method is a preferred process, which comprises
the following steps: [0029] (i) preparation of an internal organic
phase comprising [0030] (ia) dissolving the polymer or polymers in
a suitable organic solvent or solvent mixture; optionally
dissolving/dispersing suitable additives; [0031] (ib)
dissolving/suspending/emulsification of the drug substance in the
polymer solution obtained in step (ia); [0032] (ii) preparation of
an external aqueous phase containing stabilizers and optionally but
preferably buffer salts; [0033] (iii) mixing the internal organic
phase with the external aqueous phase e.g. with a device creating
high shear forces, e.g. with a turbine or static mixer, to form an
emulsion; and [0034] (iv) hardening the microparticles by solvent
evaporation or solvent extraction, washing the microparticles, e.g.
with water, collecting and drying the microparticles, e.g.
freeze-drying or drying under vacuum, and sieving the
microparticles through 140 .mu.m.
[0035] Suitable organic solvents for the polymers include e.g.
ethyl acetate, acetone, THF, acetonitrile, or halogenated
hydrocarbons, e.g. methylene chloride, chloroform or
hexafluoroisopropanol.
[0036] Suitable examples of a stabilizer for step (iib) include
Poly(vinylalcohol) (PVA), in an amount of 0.1 to 5%, Hydroxyethyl
cellulose (HEC) and/or hydroxypropyl cellulose (HPC), in a total
amount of 0.01 to 5%, Poly(vinyl pyrolidone), Gelatin, preferably
porcine or fish gelatin.
[0037] The dry microparticles composition can be terminally
sterilized by gamma irradiation (overkill sterilization),
optionally in bulk or after filling in the final container
resulting in the highest sterility assurance possible.
Alternatively the bulk sterilized microparticles can be resuspended
in a suitable vehicle and filled as a suspension into a suitable
device such as double chamber syringe with subsequent freeze
drying.
[0038] The pharmaceutical composition according to the present
invention containing microparticles may also contain a vehicle to
facilitate reconstitution.
[0039] Prior to administration, the microparticles are suspended in
a suitable vehicle for injection. Preferably, said vehicle is water
based containing pharmaceutical excipients such as mannitol, sodium
chloride, glucose, dextrose, sucrose, or glycerins, non-ionic
surfactants (e.g. poloxamers, poly(oxyethylene)-sorbitan-fatty acid
esters, carboxymethyl cellulose sodium (CMC-Na), sorbitol,
poly(vinylpyrrolidone), or aluminium monostearate in order to
ensure isotonicity and to improve the wettability and sedimentation
properties of the microparticles. The wetting and viscosity
enhancing agents may be present in an amount of 0.01 to 1%; the
isotonicity agents are added in a suitable amount to ensure an
isotonic injectable suspension.
[0040] The invention further provides the use of a pharmaceutical
composition according to the present invention for inter alia
long-term maintenance therapy in acromegalic patients, and
treatment of severe diarrhea and flushing associated with malignant
carcinoid tumors and vasoactive intestinal peptide tumors (vipoma
tumors).
[0041] The utility of the pharmaceutical compositions according to
the present invention can be shown in standard clinical or animal
studies.
[0042] The invention further provides a kit comprising the depot
formulation in a vial, optionally equipped with a transfer set,
together with a water-based vehicle in an ampoule, vial or
prefilled syringe or as microparticles and vehicle separated in a
double chamber syringe.
EXPERIMENTAL PART
[0043] The following examples are illustrative, but do not serve to
limit the scope of the invention described herein. The examples are
meant only to suggest a method of practicing the present
invention.
Example 1
Microparticle Preparation
[0044] An appropriate amount of the PLGA polymers is dissolved in
an appropriate amount of dichloromethane to give an appropriate
polymer concentration as stated in column "PLGA conc." in Table 2.
An appropriate amount of drug substance is weight into a glass
beaker and the polymer solution is poured over the drug substance
so that the resulting microparticles have a drug load as stated in
column "drug load".
[0045] E.g. for microparticles with a drug load of 20% and a
polymer concentration of 20% the numbers are as the following:
3.547 g of the PLGA polymers are dissolved into 17.7 ml
dichloromethane to give a 20% (w/v) polymer solution. 1.453 g of
octreotide pamoate (corresponding to 1.00 g=20% octreotide free
base) is weight into a glass beaker and the polymer solution is
poured over the drug substance.
[0046] The suspension is homogenized with an Ultra-Turrax
rotor-stator mixer with 20'000 rpm for 1 min under cooling with an
ice/water mixture. This suspension is referred to as S/O
suspension.
[0047] 10.00 g of Polyvinylalcohol PVA 18-88, 3.62 g
KH.sub.2PO.sub.4 and 15.14 g Na.sub.2HPO.sub.4 are dissolved in
2.00 L deionized water to form a 0.5% PVA 18-88 solution buffered
to pH 7.4.
[0048] The S/O suspension is mixed with the 0.5% PVA18-88 solution
by pumping the S/O suspension with the help of a flexible tube pump
(Perpex, Viton tube) at a rate of 10 ml/min into a turbine and by
pumping the aqueous solution with a gear pump (Ismatec MV-Z/B with
pumping head P140) at a rate of 200 ml/min into the same turbine.
The two solutions are mixed in the turbine at 4'500 rpm. The
homogenized S/O/W emulsion is collected into a 2 L glass beaker
which is prefilled with 200 ml of the buffered PVA solution.
[0049] The S/O/W emulsion is then heated up to 52.degree. C. in 5
h. The temperature of 52.degree. C. is hold for further 30 min,
before the batch is cooled to room temperature again. During this
process escaping dichloromethane is removed by vacuum and the batch
is stirred by a 4 blade-propeller-stirrer at 250 rpm.
[0050] As a result, microparticles are formed out of the S/O/W
emulsion. The microparticles are collected by filtration (5 .mu.m).
They are washed 5 times with 200 ml water and dried for 36 h at
20.degree. C. and 0.030 mbar. The dried microparticles are sieved
through 140 .mu.m and filled under nitrogen into glass vials.
Prepared in that way, the microparticles are sterilized by
gamma-irradiation with a dose of 30 kGy.
[0051] The particle size of the microparticles is measured by laser
light diffraction. The microparticles are resuspended in white
spirit using ultra sound. Table 2 gives the diameter x.sub.90 (90%
of all particles are smaller than this value) after 120 seconds of
ultra sound treatment.
[0052] The assay of the microparticles is determined by HPLC after
dissolving the microparticles with ultra sound in a 3:2 mixture of
acetonitrile and methanol and further 1:1 dilution with a sodium
acetate buffer (pH 4). The solution is cleared from residual
particulate matter by centrifugation.
TABLE-US-00002 TABLE 2 Example 1-1: octreotide pamoate
microparticles prepared by blend of three linear PLGAs Drug PLGA
Pro- Assay Ex. Load conc. cess Particle size Batch ( % ) ( % ) A B
C info x.sub.90 (.mu.m) ( % ) 1-1 20 20 33 34 33 7/38 68.4 19.6 A:
PLGA 65:35 ester 0.6 dL/g ( % ) B: PLGA 75:25 ester 0.4 dL/g ( % )
C: PLGA 85:15 ester 0.6 dL/g ( % )
[0053] Process Info=Further Process Information:
7: 66 mM PBS pH 7.4
[0054] 38: Turbine speed 3800 rpm instead of 4500 rpm
Example 2
Vehicle Compositions A to G
[0055] CMC-Na, Mannitol and Pluronic F68 in an amount as given in
Table 3 are dissolved in about 15 ml hot deionized water of a
temperature of about 90.degree. C. under strong stirring with a
magnetic stirrer. The resulting clear solution is cooled to
20.degree. C. and filled up with deionized water to 20.0 ml.
TABLE-US-00003 TABLE 3 Suitable vehicles for the microparticles
(Amounts given in g) A B C D E F G CMC-Na 0 0 0.05 0.14 0.28 0.35
0.40 Mannitol 0 1.04 0.99 0.90 0.76 0.74 0.68 Pluronic F68 0.04
0.04 0.04 0.04 0.04 0.04 0.04
Example 3
Microparticle Suspension
[0056] 180 mg of microparticles of example 1-1 are suspended in 1.0
ml of a vehicle of composition D (Table 3) in a 6 R vials. The
suspensions are homogenized by shaking for about 30 seconds by
hand. The reconstituted suspension may be injected without any
issues using a 20 Gauge needle.
Example 4
Lyophilisation of the Microparticles
[0057] 180 mg of microparticles of example 1-1 are reconstituted in
1 ml of the vehicle composition F (Table 3), homogenized by
stirring for 1 to 12 hours and then freeze-dried in a
lyophilisator. Reconstitution of the lyophilized microparticles
with 1 ml pure water (aqua ad injectabilia) resulted in fast and
good wetting of the microparticles that may be injected without any
issues using a 20 Gauge needle.
Example 5
Release Profile In Vivo (Rabbits)
[0058] Microparticles containing octreotide are suspended in 1 ml
of a suitable aqueous vehicle and the resulting suspension is
injected intramusculary (i.m.) into male New Zealand White bastard
rabbits in a dose of 12 mg/kg. For each dosage form (test group) 4
animals are used. After defined time periods (indicated in the
table 4) plasma samples are taken and analyzed for octreotide
concentration.
TABLE-US-00004 TABLE 4 Plasma levels (dose corrected values);
concentration in ng/ml Ex. Time after Administration (days) Batch
0.021 0.042 0.083 0.167 0.250 1 2 3 5 8 12 1-1 20.250 18.621 7.534
2.320 0.966 0.159 0.303 0.799 1.235 1.534 1.999 Ex. Time after
Administration (days) Batch 19 27 33 40 47 54 61 68 75 82 89 96 1-1
1.557 1.404 0.947 0.903 1.224 3.204 2.381 1.887 2.142 1.511 0.512
0.284
* * * * *