U.S. patent application number 09/113532 was filed with the patent office on 2002-02-07 for cyclosporin a formulations as nanoparticles.
Invention is credited to FLOC'H, ROBERT, MERLE, CHRISTIAN.
Application Number | 20020016290 09/113532 |
Document ID | / |
Family ID | 24494467 |
Filed Date | 2002-02-07 |
United States Patent
Application |
20020016290 |
Kind Code |
A1 |
FLOC'H, ROBERT ; et
al. |
February 7, 2002 |
CYCLOSPORIN A FORMULATIONS AS NANOPARTICLES
Abstract
Cyclosporin A formulations are provided as amorphous
nanoparticle dispersions for physiologic absorption.. The
compositions have high bioavailability and patient acceptability.
By providing for concentrates comprising lower alkanols and a
polyoxyalkylene surfactant as a stable dispersion of cyclosporin A,
upon introducing the stable dispersion into an aqueous medium, the
subject formulation is produced comprising amorphous bioavailable
cyclosporin nanoparticles.
Inventors: |
FLOC'H, ROBERT; (NANTES,
FR) ; MERLE, CHRISTIAN; (POITIERS, FR) |
Correspondence
Address: |
RICHARD F TRECARTIN
FLEHR HOHBACH TEST ALBRITTON & HERBERT
SUITE 3400
FOUR EMBARCADERO CENTER
SAN FRANCISCO
CA
941114187
|
Family ID: |
24494467 |
Appl. No.: |
09/113532 |
Filed: |
July 10, 1998 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09113532 |
Jul 10, 1998 |
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08622516 |
Mar 25, 1996 |
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5827822 |
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Current U.S.
Class: |
514/20.5 ;
514/21.1; 530/317 |
Current CPC
Class: |
A61K 47/10 20130101;
A61K 47/14 20130101; Y10S 977/915 20130101; Y10S 977/928 20130101;
A61K 9/10 20130101; A61K 38/13 20130101; Y10S 514/938 20130101;
Y10S 977/773 20130101; A61K 47/26 20130101; A61K 9/4858 20130101;
Y10S 977/906 20130101 |
Class at
Publication: |
514/9 ; 514/11;
530/317 |
International
Class: |
A61K 038/12; C07K
017/00; C07K 016/00; C07K 007/00; C07K 005/00; A61K 038/00 |
Claims
What is claimed is:
1. An aqueous dispersion of cyclosporin nanoparticles, wherein at
least 50 weight percent of the cyclosporin present in the
dispersion is of particles less than about 1 .mu.m, said
cyclosporin being amorphous.
2. A dispersion according to claim 1, comprising in minor amounts
lower alkanol and at least one polyoxyethylene surfactant.
3. A dispersion according to claim 2, wherein said polyoxyethylene
surfactant is polysorbate 80.
4. A dispersion according to claim 2, wherein said lower alkanol is
at least one of ethanol and propylene glycol.
5. A dispersion according to claim 1, comprising a polyethylene
glycol of less than about 2000 Daltons.
6. In a method for orally administering cyclosporin to a patient,
the improvement which comprises: providing said cyclosporin,
wherein at least 50 weight % of said cyclosporin is as amorphous
particles of less than about 1000nm.
7. A method according to claim 6, wherein said providing comprises
adding to an aqueous medium a composition comprising cyclosporin
dispersed in a combination of lower alkanol consisting of at least
one of ethanol and propylene glycol and a polyoxyethylene
surfactant.
8. A method according to claim 7, wherein said polyoxyethylene
surfactant is polysorbate 80.
9. A method according to claim 7, wherein said lower alkanol is
present in from about 25 to 60 weight percent, said polyoxyalkylene
surfactant is present in from about 20 to 50 weight percent, and
said cyclosporin is present in from about 2.5 to 25 weight
percent.
10. A method according to claim 7, wherein said composition further
comprises polyoxyethylene cosolvent of less than 2000 Daltons.
11. A kit comprising cyclosporin, at least one of ethanol and
propylene glycol, and polysorbate 80.
12. A kit according to claim 11, further comprising PEG400.
13. A method for preparing a formulation according to claim 1
comprising: combining at least one of ethanol and propylene glycol
with cyclosporin A to from a solution; and combining said solution
with a polyethyleneoxy surfactant to form a second solution, which
upon dilution with water forms amorphous nanoparticles of said
cyclosporin A.
Description
BACKGROUND OF THE INVENTION
[0001] The drug cyclosporin A, despite its many shortcomings and
the difficulties in formulation, variations in bioavailability, and
side effects, has proven to be one of the great success stories of
the drug industry. Because of cyclosporin A's hydrophobicity,
formulations of cyclosporin A must take into account the need for a
stable dispersion of the cyclosporin A, as well as the manner of
administration of the formulation. For example, if it is intended
that the formulation be diluted with water prior to its being taken
orally, the resulting composition must provide the cyclosporin A in
a bioavailable form, where adverse effects are not enhanced,
preferably diminished. The cyclosporin A which will come out of
solution should be dispersable, so that the dosage is repeatable.
Alternatively, where the formulation is provided in a manner where
the cyclosporin A formulation becomes diluted with gastric juices,
such as the use of capsules, it is essential that the cyclosporin A
retains its bioavailability and activity in the environment of the
gastric juices. In all events, the cyclosporin A must be able to be
transported into the vascular system, where it can diminish the
immune response.
[0002] It is therefore of interest to develop formulations which
are organoleptically acceptable, provide for desirable levels of
bioavailability, do not introduce adverse effects associated with
cyclosporin A, and generally fulfill the requirements of
therapeutic formulations.
BRIEF SUMMARY OF THE INVENTION
[0003] Aqueous dispersions of cyclosporin are provided by
introducing a stable dispersion of cyclosporin in a formulation
comprising as co-solvents a lower alkanol and a polyoxyalkylene
surfactant, and desirably a polyethylene glycol, as co-solvent.
Upon dilution of the stable dispersion, an aqueous dispersion is
obtained comprising nanoparticles of cyclosporin in amorphous form
having good bioavailability.
DETAILED DESCRIPTION
[0004] Methods and compositions are provided for producing an
aqueous colloidal dispersion of cyclosporin nanoparticles having
good bioavailability. The nanoparticles are substantially spheric,
the cyclosporin is present in an amorphous form, and the average
size will generally be less than about 1000 nm, greater than about
50 nm, generally in the range of about 200-800 nm, usually in the
range of about 200-600 nm. Generally, at least about 50 weight
percent of the total weight of cyclosporin will be present as
particles in the indicated size range. Larger particles may be
present, particularly as aggregates of nanoparticles, where the
average diameter will usually be less than about 50 .mu.m, more
usually less than about 25 .mu.m, the aggregates usually not
exceeding 40 weight % of the total cyclosporin.
[0005] The amount of cyclosporin A amorphous particles in the
composition will be sufficient for therapeutic effect. Since the
formulation may be formed by introduction into an aqueous medium
prior to administration or directly into the gastric juices, the
particular concentration cannot be stated, since the dilution in
the stomach is uncertain. For preparation in an aqueous medium
prior to oral administration, generally, the cyclosporin will be
present at a weight percent of about 0.01-2.5, more usually from
about 0.01-0.5 weight percent. The temperature of mixing may be in
the range of about 10 to 50.degree. C., usually in the range of
about 20 to 40.degree. C. Usually the mixing will involve stirring
for sufficient time to provide the solution of the cyclosporin.
[0006] The colloidal amorphous suspension of the nanoparticles is
sufficiently stable to allow for some standing prior to
administration, frequently up to about 6 hours, more frequently up
to about 3 hours.
[0007] While cyclosporin A finds primary use, any of the
cyclosporins which are physiologically acceptable, e.g. A through
Z, may be employed.
[0008] The amorphous cyclosporin colloidal dispersion may be
produced by preparing a stable dispersion of cyclosporin in a lower
alkanol and a polyoxyalkylene compound, either ester or alcohol.
The alkanols will be ethanol or propylene glycol, individually or
in combination, particularly where ethanol will be present in the
range of about 25-75 volume percent, when the combination of
alkanols is employed. The particular manner in which the colloidal
dispersion is produced is not critical, so long as the materials
used in the stable dispersion are physiologically acceptable, do
not interfere with the activity of the cyclosporin, and are readily
available.
[0009] Various polyalkyleneoxy compounds may be employed which may
serve as surfactants and co-solvents with the lower alkanols. The
polyalkyleneoxy compounds are, therefore, liquids, soluble in both
water and lower alkanols, have low toxicity and in conjunction with
the lower alkanols are capable of maintaining a stable dispersion,
usually a solution of cyclosporin A. Exemplary of polyoxyethylene
surfactants are polyoxyethylene esters, such as polyoxyethylene
substituted sorbitan esterified with a fatty acid of from 12-18
carbon atoms, more usually from about 16-18 carbon atoms,
exemplified by polysorbate 80. The number of oxyethylene groups
will generally be from about from 10-30. Exemplary of
polyoxyalkylene compounds as cosolvents are polyethylene glycols of
an average molecular weight of less than about 2000, preferably
less than about 1000, at least about 300, more usually in the range
of about 300-700 particularly from about 350-500 kiloDaltons.
Generally, greater than 50% by weight of the polyethylene glycol
will be within 50% of the average molecular weight of the
polyethylene glycol.
[0010] In the formulation, the total amount of lower alkanol will
generally be in the range of about 25-60 weight percent, more
usually in the range of about 30-50 weight percent. The total
amount of alkenyloxy compound(s) will generally be in the range of
about 20-50 weight percent, more usually in the range of about
25-40 weight percent. Where combinations of polyoxyalkylene
compounds are employed, the amount of the fatty acid ester will
generally range from about 25-100% of the polyoxyalkylene
compounds.
[0011] The weight of cyclosporin in the formulation will be
sufficient to provide for a therapeutic dosage, generally in the
range of about 2.5 to 25 weight percent, more usually in the range
of about 5-15 weight percent.
[0012] The subject compositions may be prepared by first dissolving
the cyclosporin in the lower alkanol, where a small proportion of
the polyoxyalkylene compound may also be included, generally less
than about 50 weight percent of the composition used for dissolving
the cyclosporin. An elevated temperature may be employed, usually
in the range of about 60 to 90.degree. C. After dissolving the
cyclosporin, the major proportion of the polyalkyleneoxy compound
may be added and the total formulation brought to the desired
ratios by the addition of the appropriate components. Generally,
the cyclosporin can be dissolved in the lower alkanol (optionally
including a portion of the polyalkyleneoxy compound) at a weight
ratio of about 1:1.5-5, more usually 1:2-4.
[0013] The subject formulations may be used in accordance with
conventional ways already described in the literature. Oral
formulations have been reported in U.S. Pat. Nos. 4,388,307; and
5,342,625; and UK Patent No. 2,222,770B, whose disclosures are
incorporated herein by reference as describing the use of
cyclosporin in oral formulations. Thus, the subject compositions
may be administered as liquid solutions, capsules, or the like,
taken orally in single or multiple dosages, as therapeutically
required in accordance with conventional procedures. The
formulations are used with patients who require that they be
immunocompromised, as in the case of transplantation, autoimmune
diseases and the like.
[0014] For convenience of the user,kits may be provided having the
appropriate amount of cyclosporin, one or more dosage levels and
the cosolvents, namely the lower alkanol(s) and the polyalkyleneoxy
compound(s), e.g. at least one of ethanol and propylene glycol and
at least one of polysorbate 80 and PEG400.
[0015] The following examples are offered by way of illustration
and not by way of limitation.
EXAMPLE 1
[0016] 5 g of cyclosporin A was added to 5 mL of ethanol. The
mixture was stirred to complete dissolution of cyclosporin A. To
the resulting solution were added 25 g of polysorbate 80 and the
volume is completed to 50 mL by 1,2-propylene glycol. The mixture
was sufficiently stirred at room temperature until a homogeneous
solution was formed.
EXAMPLE 2
[0017] 5 g of cyclosporin A was added to 5 mL of ethanol. The
mixture was stirred until complete dissolution of cyclosporin A. To
the resulting solution were added 15 g of polysorbate 80 and the
volume is completed to 50 mL by a mixture of 1,2-propylene glycol
and polyethylene glycol 400. The mixture was sufficiently stirred
at room temperature until a homogeneous solution was formed.
EXAMPLE 3
[0018] 1 mL of the solution obtained in example 1 was added in 50
mL of water with a glass syringe as recommended for the oral
administration of concentrated emulsions or microemulsions in
human. The addition of the solution was followed by a quick
dissolution and a white suspension of fine particles was obtained
having a blue reflect as colloidal suspensions (Tyndall effect).
After centrifugation at 26,000 g during 5 hours, the sediment was
washed with water and then centrifuged at 26,000 g during 24 hours.
The washing and centrifugation processes were repeated twice under
the same conditions. After drying, an x-ray powder diagram was
performed. The solid was exclusively in amorphous form.
[0019] The sediment was examined by scanning electron microscopy.
The sediment was constituted of amorphous spheric nanoparticles
with a diameter between 200 and 400 nm with the presence of some
aggregates. 2 mL of the solution obtained in example 1 was added in
100 mL of water and the colloidal suspension was examined 10
minutes and 1 hour after the dilution by a diffraction/diffusion
laser granulometer (Malvern SB.OD).
[0020] After 1 hour, two particle populations were observed: one
representing 70% of the weight of cyclosporin A with an average
diameter of 300 nm and a second one representing 30% of the weight
of cyclosporin A with an average diameter of 20 .mu.m, probably
constituting aggregates of nanoparticles.
EXAMPLE 4
[0021] 1 mL of the solution obtained in example 1 was added to 50
mL of water and the colloidal suspension was stirred during 10
minutes.
[0022] The suspension was then added to 200 mL of artificial acidic
gastric juice and warmed at 37.degree. C. The homogeneous colloidal
suspension was examined by diffraction/diffusion laser granulometry
(Malvern SB.OD). The suspension was constituted exclusively of
nanoparticles with an average diameter of 600 nm.
EXAMPLE 5
[0023] 1 mL of the solution obtained in example 1 was added
directly to 200 mL of artificial acidic gastric juice.
[0024] The homogeneous suspension was warmed at 37.degree. C. and
examined rapidly by diffraction/diffusion laser granulometry
(Malvern SB.OD). The suspension was exclusively constituted of
nanoparticles with an average diameter of 350 nm.
[0025] The subject cyclosporin compositions provide for excellent
bioavailability in being amorphous particles, small, so as to have
high surface area, and without detrimental effects other than those
conventionally found with cyclosporin.
[0026] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated to be incorporated by
reference.
[0027] The invention now being fully described, it will be apparent
to one of ordinary skill in the art that many changes and
modifications can be made thereto without departing from the spirit
or scope of the appended claims.
* * * * *