U.S. patent application number 12/600740 was filed with the patent office on 2010-07-15 for extended-release composition comprising a somatostatin derivative in microparticles.
This patent application is currently assigned to NOVARTIS AG. Invention is credited to Olivier Lambert, Marc Riemenschnitter, Vitomir Vucenovic.
Application Number | 20100178344 12/600740 |
Document ID | / |
Family ID | 38222465 |
Filed Date | 2010-07-15 |
United States Patent
Application |
20100178344 |
Kind Code |
A1 |
Lambert; Olivier ; et
al. |
July 15, 2010 |
Extended-Release Composition Comprising a Somatostatin Derivative
in Microparticles
Abstract
The present invention relates to improved microparticles
comprising a somatostatin analogue, a process of making said
microparticles and to pharmaceutical compositions comprising the
same.
Inventors: |
Lambert; Olivier; (Spechbach
le Haut, FR) ; Riemenschnitter; Marc; (Freiburg,
DE) ; Vucenovic; Vitomir; (Loerrach, DE) |
Correspondence
Address: |
NOVARTIS;CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 104/3
EAST HANOVER
NJ
07936-1080
US
|
Assignee: |
NOVARTIS AG
Basel
CH
|
Family ID: |
38222465 |
Appl. No.: |
12/600740 |
Filed: |
May 23, 2008 |
PCT Filed: |
May 23, 2008 |
PCT NO: |
PCT/EP2008/056347 |
371 Date: |
March 23, 2010 |
Current U.S.
Class: |
424/486 ;
424/400; 424/484; 514/11.1; 514/2.4 |
Current CPC
Class: |
A61P 1/00 20180101; A61P
29/00 20180101; A61P 1/12 20180101; A61P 35/02 20180101; A61P 27/02
20180101; A61P 3/04 20180101; A61P 13/12 20180101; A61P 35/00
20180101; A61P 9/00 20180101; A61P 19/02 20180101; A61K 9/0002
20130101; A61K 38/31 20130101; A61P 5/04 20180101; A61P 25/02
20180101; A61K 9/5031 20130101; A61P 5/02 20180101; A61P 37/00
20180101; A61P 3/10 20180101; A61P 7/10 20180101; A61P 3/00
20180101; A61P 5/00 20180101; A61P 1/18 20180101; A61P 9/14
20180101; A61P 9/10 20180101 |
Class at
Publication: |
424/486 ;
424/484; 514/11; 424/400 |
International
Class: |
A61K 38/12 20060101
A61K038/12; A61K 9/10 20060101 A61K009/10; A61P 35/00 20060101
A61P035/00; A61P 3/04 20060101 A61P003/04; A61P 13/12 20060101
A61P013/12; A61P 1/12 20060101 A61P001/12; A61P 35/02 20060101
A61P035/02; A61P 19/02 20060101 A61P019/02; A61P 29/00 20060101
A61P029/00; A61P 37/00 20060101 A61P037/00 |
Foreign Application Data
Date |
Code |
Application Number |
May 24, 2007 |
EP |
07108796.9 |
Claims
1. Pharmaceutical composition for extended release comprising
microparticles with a polymer matrix comprising of one or more
biodegradable polymers and Compound A pamoate as active ingredient
wherein the maximum plasma concentration of the active ingredient
in rabbits within the first 24 hours after administration of 4
mg/kg is below 15 ng/ml.
2. Pharmaceutical composition according to any one of claims 1
wherein the maximum plasma concentration (t.sub.max) of Compound A
is reached not before day 12 after administration.
3. Pharmaceutical composition according to any one of claims 1 to 2
wherein the plasma concentration of Compound A is above 2 ng/ml
between day 2 and day 35 after administration.
4. Pharmaceutical composition for extended release comprising
microparticles with a polymer matrix consisting of one or more
biodegradable polymers and Compound A pamoate as active ingredient
wherein the burst as % of Compound A content after 24 hours is
between 0.5%-1.2% as measured by the in vitro dissolution test as
described in Example 4.
5. Pharmaceutical composition according to claims 1 to 4 wherein
the active ingredient Compound A is released over a time period of
at least 4 weeks.
6. Pharmaceutical composition according to any one of claims 1 to 5
wherein the polymer matrix comprises a linear and a branched
polylactide-co-glycolide.
7. Pharmaceutical composition according to claim 6 wherein the
polymer matrix comprises a Resomer.RTM. RG and a star
polylactide-co-glycolide polymer having a weight average molecular
weight of between about 47,000 to about 63,000 Da.
8. Pharmaceutical composition according to claim 7 wherein the
ratio of linear to branched polylactide-co-glycolide is about 60:40
to 40:60.
9. Process of making microparticles comprising dissolving a mixture
of a linear polylactide-co-glycolide polymer and a branched
polylactide-co-glycolide polymer in methylene chloride, adding this
polymer solution to the active ingredient Compound A pamoate,
preparing an aqueous dispersion of phosphate salts and polyvinyl
alcohol mixing the polymer/active ingredient solution with the
polyvinyl alcohol/phosphate solution, evaporating the methylene
chloride and filtering off the obtained microparticles, wherein the
concentration of the polymer mixture in methylene chloride is
between 14.2% and 17.5% weight by weight.
10. Process according to claim 9 wherein the concentration of the
polymer mixture in methylene chloride about 15.9% weight by
weight.
11. Microparticles obtainable by the process of claim 9 or 10.
12. Microparticles according to claim 11 with a diameter from 10 to
200 microns.
13. Microparticles according to claim 11 with a particle size
distribution .times.10<15 microns, .times.50<40 microns and
.times.90<70 microns.
14. Microparticles according to any one of claims 11 to 13 further
comprising a surfactant, a porosity influencing agent and/or a
basic salt.
15. A pharmaceutical composition comprising microparticles
according to any one of claims 11 to 14 and a water-based
vehicle.
16. A kit comprising microparticles according to any one of claims
11 to 14 and a water-based vehicle.
17. A composition according to claim 15 or 16 wherein the
water-based vehicle comprises a wetting agent, a tonicity agent and
a viscosity increasing agent.
18. A composition according to claim 17 wherein the wetting agent
is selected from a poloxamer and/or a
polyoxyethylene-sorbitan-fatty acid ester.
19. A composition according to claim 17 wherein the tonicity agent
is selected from mannitol, sodium chloride, glucose, dextrose,
sucrose and glycerin.
20. A composition according to claim 17 wherein the viscosity
increasing agent is selected from carboxymethyl cellulose sodium
(CMC-Na), sorbitol, polyvinylpyrrolidone and aluminium
monostearate.
21. A composition according to claim 17 for use in vials wherein
the water-based vehicle comprises carboxymethyl cellulose sodium,
mannitol and Pluronic F68.
22. Use of microparticles according to any one of claims 11 to 14
or of a pharmaceutical composition according to any one of claims 1
to 8 for the preparation of a medicament for the treatment of a
disease or disorder with an aetiology comprising or associated with
excess GH- and/or IGF-1 secretion.
23. A method of treating a disease or disorder with an aetiology
comprising or associated with excess GH- and/or IGF-1 secretion in
a subject in need thereof which comprises administering
microparticles according to any one of claims 11 to 14 or of a
pharmaceutical composition according to any one of claims 1 to 8 to
the subject.
Description
[0001] The present invention relates to improved microparticles
comprising a somatostatin analogue, a process of making said
microparticles and to pharmaceutical compositions comprising the
same.
[0002] The preferred somatostatin analogue according to the present
invention is Compound A of formula
##STR00001##
also called
cyclo[{4-(NH.sub.2--C.sub.2H.sub.4--NH--CO--O--)Pro}-Phg-DTrp-Lys-Tyr(4-B-
zl)-Phe] or pasireotide, as well as diastereoisomers and mixtures
thereof, in free form, in salt or complex form or in protected
form. Phg means --HN--CH(C.sub.6H.sub.5)--CO-- and Bzl means
benzyl.
[0003] Preferred salts for Compound A are the lactate, aspartate,
benzoate, succinate and pamoate including mono- and di-salts, more
preferably the aspartate di-salt and the pamoate monosalt, most
preferred the pamoate monosalt.
[0004] The compounds of the invention, including its salts, may be
prepared in accordance with conventional methods. Compound A and
its synthesis have been described in detail e.g. in WO02/10192, the
contents of which are incorporated herein by reference.
[0005] WO05/046645, the contents of which are incorporated herein
by reference, describes that administration of microparticles
comprising a somatostatin analogue, for instance Compound A, e.g.
embedded in a biocompatible pharmacologically acceptable polymer,
suspended in a suitable vehicle gives release of all or of
substantially all of the active agent over an extended period of
time, e.g. several weeks up to 6 months, preferably over at least 4
weeks.
[0006] However, the microparticle formulations of Compound A as
described in WO05/046645 have sometimes a less favourable
pharmakokinetic release profile of the active ingredient (drug).
The duration of action sometimes is unsatisfactory, i.e. not long
lasting enough.
[0007] However, especially the relatively high initial release of
the drug within the first day(s) after administration (drug burst)
can lead to problems, such as for instance unwanted side effects
including e.g. nausea or temporarily too high blood glucose level.
This drug burst is even more concerning at repeated dosing when the
plasma concentration of the drug reaches steady state conditions at
higher levels.
[0008] Surprisingly, it has been found that keeping the overall
composition of the formulation constant but changing the
polymer/drug concentration during the process of making the
microparticles comprising Compound A results in microparticles with
improved properties.
[0009] Pharmaceutical compositions comprising the new
microparticels according to the present invention show a lower
initial release of the active ingredient and/or a longer duration
of action and/or a favourable pharmacokinetic release profile,
especially at repeated dosing, compared to pharmaceutical
compositions comprising the microparticles described in
WO05/046645.
[0010] The improved properties of pharmaceutical compositions
according to the present invention can, for instance, be documented
by results obtained in clinical studies in humans.
[0011] FIG. 1 shows comparative release profiles of Compound A in
healthy human volunteers following a single dose administration of
40 mg Compound A in microparticles either according to Example 1 or
according to Reference example (Example 8 of WO05/046645). The
microparticles were suspended in vehicle D and administered
intramuscular (i.m.). Blood samples were taken periodically and
plasma levels of Compound A were measured by Radioimmunoassay (RIA)
analysis. The obtained results show a significantly reduced drug
burst in the release profile of microparticles according to the
present invention compared to the pharmakokinetic profile of
microparticels according to the reference example.
[0012] The improved properties of pharmaceutical compositions
according to the present invention can, for instance, also be
determined by in vivo experiments in rabbits. The results obtained
in rabbits can easily and reliably be transferred to the
corresponding situation in humans, because the pharmacological
profile in rabbits and humans with regard to Compound A are closely
related.
[0013] The release profile of the pharmaceutical compositions
according to the present invention after single administration in
rabbits can be summarized as follows.
[0014] In one embodiment the present invention provides a
pharmaceutical composition for extended release comprising
microparticles with a polymer matrix comprising one or more
biodegradable polymers and Compound A pamoate as active ingredient
wherein the maximum plasma concentration (burst) of the active
ingredient in rabbits within the first 24 hours after
administration of 4 mg/kg is below 15, preferably 12 or 10
ng/ml.
[0015] In a preferred embodiment of the present invention, the
pharmaceutical compositions for extended release of the present
invention comprises microparticles with a polymer matrix consisting
of one or more biodegradable polymers and Compound A pamoate as
active ingredient.
[0016] In another embodiment the present invention provides a
pharmaceutical composition for extended release comprising
microparticles with a polymer matrix comprising one or more
biodegradable polymers and Compound A pamoate as active ingredient
wherein in rabbits the ratio of the maximum plasma concentration
(burst) of the active ingredient within the first 24 hours after
administration and the minimum plasma concentration of the active
ingredient between day 2 and 10 after administration is less than 5
or less than 4. Even more preferred is a ratio of the maximum
plasma concentration (burst) of the active ingredient within the
first 24 hours after administration and the minimum plasma
concentration of the active ingredient between day 2 and 10 after
administration of less than 3.7 or, preferably, less than 3.6.
[0017] In another embodiment the present invention provides a
pharmaceutical composition for extended release comprising
microparticles with a polymer matrix comprising one or more
biodegradable polymers and Compound A pamoate as active ingredient
wherein in rabbits the maximum plasma concentration (t.sub.max) of
Compound A is reached not before day 12 after administration.
[0018] In another embodiment the present invention provides a
pharmaceutical composition for extended release comprising
microparticles with a polymer matrix comprising one or more
biodegradable polymers and Compound A pamoate as active ingredient
wherein in rabbits the plasma concentration of Compound A is above
2 ng/ml between day 2 and day 35 after administration.
[0019] In another embodiment the present invention provides a
pharmaceutical composition for extended release comprising
microparticles with a polymer matrix comprising one or more
biodegradable polymers and Compound A pamoate as active ingredient
wherein the active ingredient Compound A is released over a time
period of at least 4 weeks.
[0020] In another embodiment the present invention provides also a
pharmaceutical depot formulation comprising the microparticles of
the present invention.
[0021] The burst release of Compound A can alternatively, or
additionally, be measured by an in vitro dissolution test, e.g., as
described in Example 4 of the present application. In one
embodiment, the present invention provides a pharmaceutical
composition for extended release comprising microparticles with a
polymer matrix comprising one or more biodegradable polymers and
Compound A pamoate as active ingredient wherein the burst measured
as % of Compound A content after 24 hours is less than 1.2%, less
than 1.0%, less than 0.9% or less than 0.8%. The burst measured by
the dissolution test as % of Compound A content after 24 hours is
conveniently between 0.5% to 1.2% or 0.6% to 1.0%.
[0022] In another embodiment the present invention provides a
method of treatment of a disease amendable to treatment with
Compound A in a patient in need of such treatment comprising
administering to the patient a dosage form for parenteral
administration of Compound A pamoate, said dosage form comprising
microparticles as described herein, wherein said dosage form
releases Compound A in rabbits such that a maximum plasma
concentration (burst) of the active ingredient in rabbits within
the first 24 hours after administration of 4 mg/kg is below 15,
preferably 12 or 10 ng/ml. In one embodiment of the method the
maximum plasma concentration (t.sub.max) of Compound A in rabbits
is reached not before day 12 after administration. In another
embodiment, the plasma concentration of Compound A in rabbits is
above 2 ng/ml between day 2 and day 35. Alternatively or
additionally, the burst release is measured with the method as
described in Example 4 and is less than 1.2% or 1% of Compound A
content. The administration can for instance be done at least every
2 weeks or at least every 4 weeks (including e.g. monthly) or at
least every 6 weeks or at least every 8 weeks (or e.g. every two
months). Diseases amenable to Compound A include diseases or
disorders with an aetiology comprising or associated with excess
GH- and/or IGF-1 secretion.
[0023] In one embodiment the present invention provides the use of
a formulation of compound Compound A obtainable by a process for
the preparation of microparticles as described hereinbelow in the
manufacture of a medicament for the treatment of disorders with an
aetiology comprising or associated with excess GH-secretion and/or
excess of IGF-1.
[0024] In another embodiment the present invention provides the use
of Compound A in the manufacture of a medicament for treating a
disease amendable to treatment with Compound A wherein Compound A
is in a dosage form for parenteral administration comprising
microparticles with a polymer matrix comprising one or more
biodegradable polymers and Compound A pamoate as active ingredient
characterized in that the microparticles release compound A in
rabbits is such that a maximum plasma concentration (burst) of the
active ingredient in rabbits within the first 24 hours after
administration of 4 mg/kg is below 15, preferably 12 or 10 ng/ml.
In one embodiment, the maximum plasma concentration (t.sub.max) of
Compound A in rabbits is reached not before day 12 after
administration. In another embodiment, the plasma concentration of
Compound A in rabbits is above 2 ng/ml between day 2 and day 35.
The burst release may alternatively or additionally be measured by
the dissolution test as described in Example 4 and is less than
1.2% or 1% of Compound A content.
[0025] In another embodiment the present invention provides the use
of a pharmaceutical composition for extended release comprising
microparticles with a polymer matrix comprising of one or more
biodegradable polymers, e.g. a mixture of a linear
polylactide-co-glycolide polymer and a branched
polylactide-co-glycolide polymer, and Compound A pamoate as active
ingredient, wherein the microparticles have been prepared by a
process for preparing microparticles as described hereinbelow
characterized in that methylene chloride in a concentration from
14.24% to 17.45%, preferably from 15.0% to 16.5%, even more
preferred about 15.9% (weight/weight) is used to dissolve the
polymer mixture. Such pharmaceutical compositions can for instance
be used in the manufacture of a medicament for the treatment of
Acromegaly, GEP tumors, Cushing and Tumors such as e.g.
Hepatocellular carcinoma, breast cancer. Such compositions have an
advantageous release profile for Compound A and in particular a
reduced initial burst, as described in the present application.
[0026] Compound A (free base) may be present in an amount of from
about 1 to about 35%, preferably from about 10 to about 35%, even
more preferably from about 20% to about 30%, by weight of the
microparticles dry weight.
[0027] Preferably, the compound of the invention used to prepare
the microparticles is in the form of an amorphous powder.
[0028] The particle size and/or the particle size distribution of
the compound of the invention may influence the release profile of
the drug from the microparticles.
[0029] Typically, the smaller the particle size, the lower is the
burst and the release during the first diffusion phase, e.g. the
first 20 days. Preferably, the particles of the compound of the
invention used to prepare the microparticles have a size of about
0.1 microns to about 15 microns, preferably less than about 5
microns, even more preferably less than about 3 microns.
[0030] The particle size distribution is preferably
.times.10<0.8 microns, i.e. 10% of the particles are smaller
than 0.8 microns; .times.50<3.0 microns i.e. 50% of the
particles are smaller than 3.0 microns; or .times.90<5.0
microns, i.e. 90% of the particles are smaller than 5.0
microns.
[0031] The polymer matrix of the microparticles comprises of one or
more biodegradable polymers. By "polymer" is meant an homopolymer
or a copolymer. In a preferred embodiment, the polymer matrix of
the microparticles consist of one or more biodegradable
polymers.
[0032] The polymer matrix is designed to degrade sufficiently to be
transported from the site of administration within one to 6 months
after release of all or substantially all the active agent.
[0033] The preferred polymers of this invention are linear
polyesters and branched chain polyesters (i.e. polyesters which
have linear chains radiating from a polyol moiety, e.g. glucose).
The linear polyesters may be prepared from .alpha.-hydroxy
carboxylic acids, e.g. lactic acid and/or glycolic acid, by
condensation of the lactone dimers, see e.g. U.S. Pat. No.
3,773,919, the contents of which are incorporated herein by
reference.
[0034] The preferred polyester chains in the linear or branched
(star) polymers are copolymers of the .alpha.-carboxylic acid
moieties, lactic acid and glycolic acid, or of the lactone dimers.
The molar ratio of lactide:glycolide of polylactide-co-glycolides
in the linear or branched polyesters is preferably from about 75:25
to 25:75, e.g. 60:40 to 40:60, with from 55:45 to 45:55, e.g. 52:48
to 48:52 the most preferred. Particularly preferred is about
50:50.
[0035] Linear polyesters, e.g. linear polylactide-co-glycolides
(PLG), preferably used according to the invention have a weight
average molecular weight (Mw) between about 10,000 and about
500,000 Da, e.g. between about 47,000 to about 63,000, e.g. about
50,000 Da. Such polymers have a polydispersity M.sub.W/M.sub.n e.g.
between 1.2 and 2. Suitable examples include e.g.
poly(D,L-lactide-co-glycolide), e.g. having a general formula
--[(C.sub.6H.sub.8O.sub.4)).sub.x(C.sub.4H.sub.4O.sub.4).sub.y].sub.n--
(each of x, y and n having a value so that the total sum gives the
above indicated Mws), e.g. those commercially available, e.g.
Resomers.RTM. from Boehringer Ingelheim, in particular
Resomers.RTM. RG, e.g. Resomer.RTM. RG 502, 502H, 503, 503H, 504,
504H.
[0036] Branched polyesters, e.g. branched
polylactide-co-glycolides, preferably used according to the
invention may be prepared using polyhydroxy compounds e.g. polyol
e.g. glucose or mannitol as the initiator. These esters of a polyol
are known and described e.g. in GB 2,145,422 B, the contents of
which are incorporated herein by reference. The polyol contains at
least 3 hydroxy groups and has a molecular weight of up to 20,000
Da, with at least 1, preferably at least 2, e.g. as a mean 3 of the
hydroxy groups of the polyol being in the form of ester groups,
which contain poly-lactide or co-poly-lactide chains. Typically
0.2% glucose is used to initiate polymerization. The branched
polyesters (Glu-PLG) have a central glucose moiety having rays of
linear polylactide chains, e.g. they have a star shaped
structure.
[0037] The branched polyesters having a central glucose moiety
having rays of linear polylactide-co-glycolide chains (Glu-PLG) may
be prepared by reacting a polyol with a lactide and preferably also
a glycolide at an elevated temperature in the presence of a
catalyst, which makes a ring opening polymerization feasible.
[0038] The branched polyesters having a central glucose moiety
having rays of linear polylactide-co-glycolide chains (Glu-PLG)
preferably have an weight average molecular weight M.sub.w in the
range of from about 10,000 to 200,000, preferably 25,000 to
100,000, especially 35,000 to 60,000 or 47,000 to 63,000, e.g.
about 50,000 Da, and a polydispersity e.g. of from 1.5 to 3.0, e.g.
1.7 to 2.5. The intrinsic viscosities of star polymers of M.sub.w
35,000 or K.sub.w 60,000 are from 0.20 dl/g to 0.70 dl/g, such as
e.g. 0.36 or 0.51 dl/g, respectively, in acetone or chloroform. A
star polymer having a M.sub.w 53,800 has a viscosity of 0.25 dl/g
to 0.50 dl/g in acetone or chloroform such as e.g. 0.34 dl/g in
acetone at room temperature.
[0039] Preferably, the polymer matrix comprises a linear and a
branched polylactide-co-glycolide. More preferably, the polymer
matrix comprises a Resomer.RTM. RG and a star
polylactide-co-glycolide polymer having a weight average molecular
weight of between about 47,000 to about 63,000, e.g. about 50,000
Da. The ratio of linear to branched polylactide-co-glycolide
preferably is 50:50 to 25:75. More preferably the ratio is about
50:50.
[0040] The polymer matrix may be present in a total amount of about
40 to 99% by weight of the microparticles.
[0041] The present invention in another embodiment provides a
process for the preparation of microparticles of the invention
comprising [0042] (i) preparation of an internal organic phase
comprising [0043] (ia) dissolving the polymers in methylene
chloride in a concentration from 14.24% to 17.45%, preferably from
15.0% to 16.5%, even more preferred about 15.9% (weight/weight)
[0044] and optionally [0045] dissolving/dispersing a
porosity-influencing agent in the solution obtained in step (ia),
or [0046] adding a basic salt to the solution obtained in step
(ia), [0047] adding a surfactant to the solution obtained by step
(ia); [0048] (ib) suspending the compound of the invention in the
polymer solution obtained in step (ia), or [0049] dissolving the
compound of the invention in a solvent miscible with the solvent
used in step (ia) and mixing said solution with the polymer
solution, or [0050] directly dissolving the compound of the
invention in the polymer solution, or [0051] dissolving the
compound of the invention in form of a water soluble salt in an
aqueous phase and emulsifying said aqueous solution with the
polymer solution (ia); [0052] (ii) preparation of an external
aqueous phase comprising [0053] (iia) preparing a buffer to adjust
the pH to 7-7.5, e.g. acetate or phosphate buffer, e.g.
Na.sub.2HPO.sub.4 and KH.sub.2PO.sub.4, and [0054] (iib) dissolving
a stabilizer in the solution obtained in step (iia); [0055] (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, or by applying ultrasound or by ultrasonic
homogenization to form an emulsion; and [0056] (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.
[0057] Suitable organic solvents for the polymers include
halogenated hydrocarbons, e.g. methylene chloride, chloroform or
hexafluoroisopropanol or ethyl acetate. The preferred organic
solvent is methylene chloride. The concentration of the polymer
mixture in methylene chloride is between 14.24% and 17.45% (weight
polymer per weight polymer solution), preferably from 15.0% to
16.5%, even more preferred about 15.9% (weight/weight).
[0058] Suitable examples of a stabilizer for step (iib) include
[0059] a) Polyvinyl alcohol (PVA), preferably having a weight
average molecular weight from about 10,000 to about 150,000 Da,
e.g. about 30,000 Da. Conveniently the polyvinyl alcohol has low
viscosity having a dynamic viscosity of from about 3 to about 9
mPas when measured as a 4% aqueous solution at 20.degree. C. or by
DIN 53015. Suitably the polyvinyl alcohol may be obtained from
hydrolyzing polyvinyl acetate. Preferably, the content of the
polyvinyl acetate is from about 10 to about 90% of the polyvinyl
alcohol. Conveniently the degree of hydrolysis is about 85 to about
89%. Typically the residual acetyl content is about 10 to 12%.
Preferred brands include Mowiol.RTM. 4-88, 8-88 and 18-88 available
from Clariant AG Switzerland. [0060] Preferably the polyvinyl
alcohol is present in an amount of from about 0.1 to about 5%, e.g.
about 0.5%, by weight of the volume of the external aqueous phase;
[0061] b) Hydroxyethyl cellulose (HEC) and/or hydroxypropyl
cellulose (HPC), e.g. formed by reaction of cellulose with ethylene
oxide and propylene oxide respectively. HEC and HPC are available
in a wide range of viscosity types; preferably the viscosity is
medium. Preferred brands include Natrosol.RTM. from Hercules Inc.,
e.g. Natrosol.RTM. 250MR, and Klucel.RTM. from Hercules Inc. [0062]
Preferably, HEC and/or HPC is present in a total amount of from
about 0.01 to about 5%, e.g. about 0.5%, by weight of the volume of
the external aqueous phase; [0063] c) Polyvinylpyrolidone, e.g.
suitably with a molecular weight of between about 2,000 and 20,000
Da. Suitable examples include those commonly known as Povidone K12
F with an average molecular weight of about 2,500 Da, Povidone K15
with an average molecular weight of about 8,000 Da, or Povidone K17
with an average molecular weight of about 10,000 Da. Preferably,
the polyvinylpyrolidone is present in an amount of from about 0.1
to about 50%, e.g. 10% by weight of the volume of the external
aqueous phase; [0064] d) Gelatin, preferably porcine or fish
gelatin. Conveniently, the gelatin has a viscosity of about 25 to
about 35 cps for a 10% solution at 20.degree. C. Typically pH of a
10% solution is from about 6 to about 7. A suitable brand has a
high molecular weight, e.g. Norland high molecular weight fish
gelatin obtainable from Norland Products Inc, Cranbury N.J. USA.
[0065] Preferably, the gelatin is present in an amount of from
about 0.01 to about 5%, e.g. about 0.5%, by weight of the volume of
the external aqueous phase.
[0066] Preferably, polyvinyl alcohol or gelatine is used. Most
preferred is polyvinyl alcohol, especially PVA 18-88.
[0067] In a preferred embodiment the process of making
microparticles comprises the steps of [0068] dissolving a mixture
of a linear polylactide-co-glycolide polymer and a branched
polylactide-co-glycolide polymer in methylene chloride, [0069]
adding this polymer solution to the active ingredient Compound A
pamoate, [0070] preparing an aqueous solution of phosphate salts
and polyvinyl alcohol [0071] mixing the polymer/active ingredient
solution with the polyvinyl alcohol/phosphate solution, [0072]
evaporating the methylene chloride and filtering off the obtained
microparticles, wherein the concentration of the polymer mixture in
methylene chloride is between 14.2% and 17.5% weight by weight.
[0073] Even more preferred is a concentration of the polymer
mixture in methylene chloride of about 15.9% weight by weight.
[0074] The resulting microparticles may have a diameter from a few
submicrons to a few millimeters; e.g. diameters of at most about
250 microns, e.g. 10 to 200 microns, preferably 10 to 130 microns,
more preferably 10 to 90 microns, even more preferably 10 to 60
microns, are strived for, e.g. in order to facilitate passage
through an injection needle. A narrow particle size distribution is
preferred. For example, the preferred particle size distribution is
.times.10<15 microns, .times.50<40 microns and
.times.90<70 microns.
[0075] Content uniformity of the microparticles and of a unit dose
is excellent. Unit doses may be produced which vary from about 75%
to about 125%, e.g. about 85 to about 115%, e.g. from about 90 to
about 110%, or from about 95 to about 105%, of the theoretical
dose.
[0076] The microparticles in dry state may e.g. be mixed, e.g.
coated, with an anti-agglomerating agent, or e.g. covered by a
layer of an anti-agglomerating agent e.g. in a prefilled syringe or
vial.
[0077] 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.
[0078] Preferably, an anti-agglomerating agent is present in an
amount of about 0.1 to about 10%, e.g. about 4% by weight of the
microparticles.
[0079] Prior to administration, the microparticles are suspended in
a vehicle suitable for injection.
[0080] Accordingly, the present invention further provides a
pharmaceutical composition comprising microparticles of the
invention in a vehicle. The vehicle may optionally further contain:
a) one or more wetting agents; and/or b) one or more tonicity
agent; and/or c) one or more viscosity increasing agents.
[0081] Preferably, the vehicle is water based, e.g. it may contain
water, e.g deionized, and optionally a buffer to adjust the pH to
7-7.5, e.g. a phosphate buffer such as a mixture of
Na.sub.2HPO.sub.4 and KH.sub.2PO.sub.4, and one or more of agents
a), b) and/or c) as indicated above.
[0082] However, when using water as a vehicle, the microparticles
of the invention may not suspend and may float on the top of the
aqueous phase. In order to improve the capacity of the
microparticles of the invention to be suspended in an aqueous
medium, the vehicle preferably comprises a wetting agent a). The
wetting agent is chosen to allow a quick and suitable
suspendibility of the microparticles in the vehicle. Preferably,
the microparticles are quickly wettened by the vehicle and quickly
form a suspension therein.
[0083] Suitable wetting agents for suspending the microparticles of
the invention in a water-based vehicle include non-ionic
surfactants such as poloxamers, or polyoxyethylene-sorbitan-fatty
acid esters, the characteristics of which have been described
above. A mixture of wetting agents may be used. Preferably, the
wetting agent comprises Pluronic F68, Tween 20 and/or Tween 80.
[0084] The wetting agent or agents may be present in about 0.01 to
about 1% by weight of the composition to be administered,
preferably from 0.01 to 0.5% and may be present in about 0.01 to 5
mg/ml of the vehicle, e.g. about 2 mg/ml.
[0085] Preferably, the vehicle further comprises a tonicity agent
b) such as mannitol, sodium chloride, glucose, dextrose, sucrose,
or glycerin. Preferably, the tonicity agent is mannitol.
[0086] The amount of tonicity agent is chosen to adjust the
isotonicity of the composition to be administered. In case a
tonicity agent is contained in the microparticles, e.g. to reduce
agglomeration as mentioned above, the amount of tonicity agent is
to be understood as the sum of both. For example, mannitol
preferably may be from about 1% to about 5% by weight of the
composition to be administered, preferably about 4.5%.
[0087] Preferably, the vehicle further comprises a viscosity
increasing agent c). Suitable viscosity increasing agents include
carboxymethyl cellulose sodium (CMC-Na), sorbitol,
polyvinyl-pyrrolidone, or aluminium monostearate.
[0088] CMC-Na with a low viscosity may conveniently be used.
Embodiments may be as described above. Typically, a CMC-Na with a
low molecular weight is used. The viscosity may be of from about 1
to about 30 mPa s, e.g. from about 10 to about 15 mPa s when
measured as a 1% (w/v) aqueous solution at 25.degree. C. in a
Brookfield LVT viscometer with a spindle 1 at 60 rpm, or a
viscosity of 1 to 15 mPa*s for a solution of NaCMC 7LF (low
molecular weight) as a 0.1 to 1% solution in water.
[0089] A polyvinylpyrrolidone having properties as described above
may be used.
[0090] A viscosity increasing agent, e.g. CMC-Na, may be present in
an amount of from about 0.1 to about 2%, e.g. about 0.7% or about
1.75% of the vehicle (by volume), e.g. in a concentration of about
1 to about 30 mg/ml in the vehicle, e.g. about 7 mg/ml or about
17.5 mg/ml.
[0091] In a further aspect, the present invention provides a kit
comprising microparticles of the invention and a vehicle of the
invention. For example, the kit may comprise microparticles
comprising the exact amount of compound of the invention to be
administered, e.g. as described below, and about 1 to about 5 ml,
e.g. about 2 ml of the vehicle of the invention.
[0092] In one embodiment, the dry microparticles, optionally in
admixture with an anti-agglomerating agent, may be filled into a
container, e.g. a vial or a syringe, and sterilized e.g. using
.gamma.-irradiation. Prior to administration, the microparticles
may be suspended in the container by adding a suitable vehicle,
e.g. the vehicle described above. For example, the microparticles,
optionally in admixture with an anti-agglomerating agent, a
viscosity increasing agent and/or a tonicity agent, and the vehicle
for suspension may be housed separately in a double chamber
syringe. A mixture of the microparticles with an anti-agglomerating
agent and/or a viscosity increasing agent and/or a tonicity agent,
also forms part of the invention.
[0093] In another embodiment, under sterile conditions dry
sterilized microparticles, optionally in admixture with an
anti-agglomerating agent, may be suspended in a suitable vehicle,
e.g. the vehicle described above, and filled into a container, e.g.
a vial or a syringe. The solvent of the vehicle, e.g. the water,
may then be removed, e.g. by freeze-drying or evaporation under
vacuum, leading to a mixture of the microparticles and the solid
components of the vehicle in the container. Prior to
administration, the microparticles and solid components of the
vehicle may be suspended in the container by adding a suitable
vehicle, e,g, water, e.g. water for infusion, or preferably a low
molarity phosphate buffer solution. For example, the mixture of the
microparticles, optionally the anti-agglomerating agent, and solid
components of the vehicle and the vehicle for suspension, e.g.
water, may be housed separately in a double chamber syringe.
[0094] The microparticles and the compositions of the invention are
useful [0095] a) for the prevention or treatment of disorders with
an aetiology comprising or associated with excess GH-secretion
and/or excess of IGF-1 e.g. in the treatment of acromegaly as well
as in the treatment of type I or type II diabetes mellitus,
especially complications thereof, e.g. angiopathy, diabetic
proliferative retinopathy, diabetic macular edema, nephropathy,
neuropathy and dawn phenomenon, and other metabolic disorders
related to insulin or glucagon release, e.g. obesity, e.g. morbid
obesity or hypothalamic or hyperinsulinemic obesity, [0096] b) in
the treatment of enterocutaneous and pancreaticocutaneous fistula,
irritable bowel syndrom, inflammatory diseases, e.g. Grave's
Disease, inflammatory bowel disease, psoriasis or rheumatoid
arthritis, polycystic kidney disease, dumping syndrom, watery
diarrhea syndrom, AIDS-related diarrhea, chemotherapy-induced
diarrhea, acute or chronic pancreatitis and gastrointestinal
hormone secreting tumors (e.g. GEP tumors, for example vipomas,
glucagonomas, insulinomas, carcinoids and the like), lymphocyte
malignancies, e.g. lymphomas or leukemias, hepatocellular carcinoma
as well as gastrointestinal bleeding, e.g variceal oesophagial
bleeding, [0097] c) for the prevention or treatment of
angiogenesis, inflammatory disorders as indicated above including
inflammatory eye diseases, macular edema, e.g. cystoid macular
edema, idiopathic cystoid macular edema, exudative age-related
macular degeneration, choroidal neovascularization related
disorders and proliferative retinopathy, [0098] d) for preventing
or combating graft vessel diseases, e.g. allo- or xenotransplant
vasculopathies, e.g. graft vessel atherosclerosis, e.g. in a
transplant of organ, e.g. heart, lung, combined heart-lung, liver,
kidney or pancreatic transplants, or for preventing or treating
vein graft stenosis, restenosis and/or vascular occlusion following
vascular injury, e.g. caused by catherization procedures or
vascular scraping procedures such as percutaneous transluminal
angioplasty, laser treatment or other invasive procedures which
disrupt the integrity of the vascular intima or endothelium, [0099]
e) for treating somatostatin receptor expressing or accumulating
tumors such as pituitary tumors, e.g. Cushing's Disease or
Syndrome, gastro-enteropancreatic, carcinoids, central nervous
system, breast, prostatic (including advanced hormone-refractory
prostate cancer), ovarian or colonic tumors, small cell lung
cancer, malignant bowel obstruction, paragangliomas, kidney cancer,
skin cancer, neuroblastomas, pheochromocytomas, medullary thyroid
carcinomas, myelomas, lymphomas, Hodgkins and non-Hodgkins
lymphomas, bone tumours and metastases thereof, as well as
autoimmune or inflammatory disorders, e.g. rheumatoid arthritis,
Graves disease or other inflammatory eye diseases.
[0100] Preferably, the microparticles and the compositions of the
invention are useful in the treatment of acromegaly and cancer,
e.g. Cushing's Disease or Syndrome, carcinoids.
[0101] The properties of the microparticles and the compositions of
the invention may be tested in standard animal tests or clinical
trials.
[0102] The microparticles and the compositions of the invention are
well-tolerated.
[0103] The compounds of the invention are released from the
microparticles of the invention and from the compositions of the
invention over a period of several weeks e.g. about 4 weeks to
about 8 weeks, preferably about 4 weeks to about 6 weeks.
[0104] Appropriate dosage of the composition of the invention will
of course vary, e.g. depending on the condition to be treated (for
example the disease type or the nature of resistance), the drug
used, the effect desired and the mode of administration.
[0105] In general, satisfactory results are obtained on
administration, e.g. parenteral administration, at dosages on the
order of from about 0.2 to about 100 mg, e.g. 0.2 to about 35 mg,
preferably from about 3 to about 100 mg of Compound A per injection
per month or about 0.03 to about 1.2 mg, e.g. 0.03 to 0.3 mg per kg
body weight per month. Suitable monthly dosages for patients are
thus in the order of about 0.3 mg to about 100 mg of Compound
A.
[0106] The following Examples serve to illustrate the invention,
without any limitation:
EXAMPLE 1
Microparticles
[0107] The polymers are dissolved in an amount of methylene
chloride as indicated in Table 1. The polymer solution is then
added to the Compound A pamoate. The resulting suspension is
treated with an Ultra-Turrax for 1 min.
[0108] 2 l of water are heated to 90.degree. C. During warming, the
phosphate salts in an amount as given in Table 1 are added one
after another. At 90.degree. C., PVA 18-88 in an amount as given in
Table 1 is added. The resulting solution is then cooled to
20.degree. C. and filled up with water to the required volume.
[0109] The polymer/drug suspension and the PVA/phosphate solution
are mixed at constant pump rates of 90 ml/min and 1800 ml/min at a
mixing speed of 3300 upm, methylene chloride is evaporated under
vacuum using a temperature program, which heats 2.degree. C. per 20
min over 300 min. Subsequently, the microparticles are filtered
off, washed with water (WBU) and dried under reduced pressure (0.1
mbar) at room temperature.
[0110] Dried microparticles are filled in vials, evacuated and
terminally sterilized. Terminal sterilization is performed by
gamma-irradiation applying irradiation dose of 27.7 to 34.1
kGy.
TABLE-US-00001 TABLE 1 (Amounts given in g) Reference Example
Example 1 (Ex. 8 of WO05/046645) Star polymer: Poly-(D,L-lactide-
1.30 1.278 co-glycolide) with a M.sub.w of about 50,000 Da Molar
Ratio lactide:glycolide 50:50 Resomer RG 502H 1.30 1.278 Molar
Ratio lactide:glycolide 50:50 Methylene chloride 13.780 16.926
Compound A pamoate 1.401 1.445 Polyvinyl alcohol (PVA) 18-88 15.00
15.00 KH.sub.2PO.sub.4 5.43 5.43 Na.sub.2HPO.sub.4 anhydrous 22.71
22.71 Water (WBU) Ad 3.0 l Ad 3.0 l
EXAMPLE 2
Vehicle Compositions A to G
[0111] CMC-Na, Mannitol and Pluronic F68 in an amount as given in
Table 2 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-00002 TABLE 2 (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 Vehicle D is
preferred for use with microparticles in vials Vehicle E is
preferred for use in double chamber syringe.
EXAMPLE 3
Release of Compound A from Microparticles
[0112] Microparticles of example 1 and of Reference Example in an
amount corresponding to 4 mg of Compound A per kg of the rabbit are
suspended in 1 ml of the vehicle composition D. The suspension is
homogenized by shaking for about 30 seconds and injected into the
left Musculus gastronemius of rabbits (Male Chinchilla bastard
rabbits, about 7 months old), weighing about 3 kg before onset of
the study, using an 19G needle.
[0113] Blood samples (about 1 ml) are collected over 55 days.
Plasma levels of Compound A are determined using an ELISA method.
Mean concentration of Compound A after administration is given in
Table 3. Mean AUC (0-55 d) is found to be 287 ng/ml d for example 1
and 227 ng/ml d for reference example.
TABLE-US-00003 TABLE 3 (mean concentration in ng/ml) Time after
administration [days] 0 0.021 0.042 0.083 0.167 0.25 1 2 3 6 9
Microparticles 0 2.20 3.64 6.66 8.33 8.04 3.69 2.87 2.34 3.83 6.46
of Ex. 1 Microparticles 0 12.40 11.51 17.61 17.13 13.09 5.73 4.58
4.58 13.32 9.15 of Reference Example Time after administration
[days] 13 16 20 23 27 30 34 37 41 44 49 Microparticles 8.30 8.95
12.50 10.31 7.46 7.76 6.45 3.20 1.03 1.01 0.53 of Ex. 1
Microparticles 4.82 4.93 6.89 6.22 7.71 3.30 1.39 0.88 0.47 0.0 0.0
of Reference Example
EXAMPLE 4
Burst Release of Compound A from Microparticles
[0114] The dissolution tests were performed in shaker bath set at
37.degree. C., 80 min-1 (n=3) for 24 h. The samples were weighted
into polyester bags of 4.times.4 cm and tightly sealed. The sample
bags were placed into 50 ml Schott bottles and 50 ml of pre-warmed
(37.degree. C.) medium was added.
[0115] Medium was prepared by dissolving e.g. 2.98 g di-sodium
hydrogen phosphate dihydrate, 8.0 g sodium chloride, 0.19 g
potassium dihydrogen phosphate, 0.01 g benzalkonium chloride and
0.2 g tween 80 in 1000 ml of water and adjusting the pH with
phosphoric acid 85% to 7.4
[0116] After 24 h the medium was aspirated. Data was normalized to
the sample weight within the individual bags. The burst can be
measured as % Drug Content which is the percentage of drug released
related to the before determined assay, i.e. if 100 mg MP contains
25 mg Compound A and 0.25 mg Compound A are released after 24 h
this means the burst is 1%.
TABLE-US-00004 TABLE 4 (burst as % of drug content) Burst 0 h 24 h
Microparticles of Ex. 1 0% 0.75% Microparticles of Reference
Example 0% 1.59%
* * * * *