U.S. patent application number 12/888530 was filed with the patent office on 2011-03-17 for nanoparticulate and controlled release compositions comprising cyclosporine.
Invention is credited to Scott A. Jenkins, Gary Liversidge.
Application Number | 20110064800 12/888530 |
Document ID | / |
Family ID | 37087359 |
Filed Date | 2011-03-17 |
United States Patent
Application |
20110064800 |
Kind Code |
A1 |
Jenkins; Scott A. ; et
al. |
March 17, 2011 |
NANOPARTICULATE AND CONTROLLED RELEASE COMPOSITIONS COMPRISING
CYCLOSPORINE
Abstract
The present invention is directed to a composition comprising a
nanoparticulate cyclosporine having improved bioavailability. The
nanoparticulate cyclosporine particles of the composition have an
effective average particle size of less than about 2000 nm in
diameter and are useful in the prevention and treatment of organ
transplant rejection and autoimmune diseases such as psoriasis,
rheumatoid arthritis, and other related diseases. The invention
also relates to a controlled release composition comprising a
cyclosporine or a nanoparticulate cyclosporine that in operation
delivers the drug in a pulsed or bimodal manner for the prevention
and treatment of organ transplant rejection and autoimmune diseases
such as psoriasis, rheumatoid arthritis, and other related
diseases.
Inventors: |
Jenkins; Scott A.;
(Downingtown, PA) ; Liversidge; Gary; (West
Chester, PA) |
Family ID: |
37087359 |
Appl. No.: |
12/888530 |
Filed: |
September 23, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11568692 |
Aug 22, 2007 |
7825087 |
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PCT/US06/13631 |
Apr 12, 2006 |
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12888530 |
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60670836 |
Apr 13, 2005 |
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Current U.S.
Class: |
424/452 ;
424/465; 424/484; 424/490; 424/499; 424/649; 514/20.5; 977/795;
977/915; 977/918 |
Current CPC
Class: |
A61K 9/5078 20130101;
A61K 9/14 20130101; A61P 37/02 20180101; A61K 9/1676 20130101; A61K
31/395 20130101; A61P 37/06 20180101; A61K 9/5084 20130101 |
Class at
Publication: |
424/452 ;
424/499; 514/20.5; 424/465; 424/490; 424/649; 424/484; 977/795;
977/918; 977/915 |
International
Class: |
A61K 9/48 20060101
A61K009/48; A61K 9/14 20060101 A61K009/14; A61K 38/13 20060101
A61K038/13; A61K 9/20 20060101 A61K009/20; A61K 9/10 20060101
A61K009/10; A61K 9/08 20060101 A61K009/08; A61K 9/12 20060101
A61K009/12; A61K 33/24 20060101 A61K033/24; A61P 37/02 20060101
A61P037/02; A61P 37/06 20060101 A61P037/06 |
Claims
1. A stable nanoparticulate cyclosporine composition comprising:
(a) particles of a cyclosporine; and (b) associated with the
surface thereof at least one surface stabilizer, wherein the
cyclosporine particles have an effective average particle size of
less than about 2000 nm in diameter.
2. The composition of claim 1, wherein said nanoparticulate
cyclosporine particle is selected from the group consisting of a
crystalline phase, an amorphous phase, a semi-crystalline phase, a
semi amorphous phase, and mixtures thereof.
3. The composition of claim 1, wherein the composition is
formulated for administration in a form selected from the group
consisting of oral tablets, capsules, sachets, solutions,
dispersions and mixtures thereof.
4. The composition of claim 1, wherein the composition further
comprises one or more pharmaceutically acceptable excipients,
carriers, or a combination thereof.
5. The composition of claim 1, wherein cyclosporine is present in
an amount consisting of from about 99.5% to about 0.001% by weight,
based on the total combined weight of cyclosporine and at least one
surface stabilizer, not including other excipients.
6. The composition of claim 1, wherein at least one surface
stabilizer is present in an amount of from about 0.5% to about
99.999% by weight based on the total combined dry weight of
cyclosporine and at least one surface stabilizer, not including
other excipients.
7. The composition of claim 1, wherein the surface stabilizer is
selected from the group consisting of an anionic surface
stabilizer, a cationic surface stabilizer, a zwitterionic surface
stabilizer, and an ionic surface stabilizer.
8. A composition according to claim 1 which comprises: (a) about 50
to about 500 g/kg cyclosporine; (b) about 10 to about 70 g/kg
hypromellose; (c) about 1 to about 10 g/kg docusate sodium; (d)
about 100 to about 500 g/kg sucrose; (e) about 1 to about 40 g/kg
sodium lauryl sulfate; (f) about 50 to about 400 g/kg lactose
monohydrate; (g) about 50 to about 300 g/kg silicified
microcrystalline cellulose; (h) about 20 to about 300 g/kg
crospovidone; and (i) about 0.5 to about 5 g/kg magnesium
stearate.
9. The composition of claim 8, further comprising a coating
agent.
10. A composition according to claim 1 comprising the following
components: (a) about 100 to about 300 g/kg cyclosporine; (b) about
30 to about 50 g/kg hypromellose; (c) about 0.5 to about 10 g/kg
docusate sodium; (d) about 100 to about 300 g/kg sucrose; (e) about
1 to about 30 g/kg sodium lauryl sulfate; (f) about 100 to about
300 g/kg lactose monohydrate; (g) about 50 to about 200 g/kg
silicified microcrystalline cellulose; (h) about 50 to about 200
g/kg crospovidone; and (i) about 0.5 to about 5 g/kg magnesium
stearate.
11. The composition of claim 10, further comprising a coating
agent.
12. The composition of claim 1 formulated into a dosage form
selected from the group consisting of liquid dispersions, gels,
aerosols, ointments, creams, controlled release formulations, fast
melt formulations, lyophilized formulations, tablets, capsules,
delayed release formulations, extended release formulations,
pulsatile release formulations, and mixed immediate release and
controlled release formulations.
13. The composition of claim 1, additionally comprising one or more
active agents useful for the prevention and treatment of organ
transplant rejection and autoimmune diseases such as psoriasis,
rheumatoid arthritis, and other related diseases.
14. The composition of claim 13, wherein said one or more active
agents is selected from the group consisting of corticosteroids,
anthralin, calcipotriene, coal tar, siaclic acid, steroids,
tazarotene, methotrexate, oral retinoids, non-steroidal
anti-inflammatory drugs, azulfidine, corticosteroids, gold, and
hydroxychoroquine.
15. A method of preparing a nanoparticulate cyclosporine comprising
contacting particles of a cyclosporine with at least one surface
stabilizer for a time and under conditions sufficient to provide a
nanoparticulate cyclosporine composition having an effective
average particle size of less than about 2000 nm in diameter.
16. The method of claim 15, wherein said contacting comprises: (a)
dissolving the cyclosporine particles in a solvent; (b) adding at
least one surface stabilizer thereto; (c) precipitating the
solubilized cyclosporine with the at least one stabilizer absorbed
thereon by addition of a non-solvent.
17. A method of prevention and/or treatment of organ transplant
rejection and autoimmune diseases comprising the administration of
a stable nanoparticulate cyclosporine composition comprising
particles of a cyclosporine and, associated with the surface
thereof, at least one surface stabilizer, wherein the particles
have an effective particle size of less than about 2000 nm in
diameter
18. A controlled release composition comprising: (A) a first
population of cyclosporine-containing particles which allows for
the immediate or delayed immediate release of said cyclosporine
therefrom; and (B) at least one subsequent population of
cyclosporine-containing particles which allows for the modified
release of cyclosporine therefrom; said composition allowing the
delivery of cyclosporine in a pulsatile manner following oral
delivery.
19. A composition according to claim 18, wherein said modified
release is achieved using a modified release coating, a modified
release matrix material, or both.
20. The composition according to claim 18, wherein the amount of
active ingredient contained in is from about 0.1 mg to about 1
g.
21. The composition according to claim 18 wherein the composition
is contained in a hard gelatin or soft gelatin capsule.
22. A method for the prevention and/or treatment of organ
transplant rejection and autoimmune diseases comprising
administering to a patient a therapeutically effective amount of a
composition according to claim 18.
23. A composition comprising: (A) cyclosporine-containing particles
which allow for the modified release of cyclosporine therefrom; and
(B) a layer of cyclosporine coated on top of said particles which
allows for the immediate release of the cyclosporine.
24. A composition according to claim 1 which allows for the
modified release of said cyclosporine.
25. A composition according to claim 24 wherein said modified
release is achieved using a modified release coating, a modified
release matrix material, or both.
26. A composition according to claim 1 wherein said composition
comprises immediate release particles.
Description
FIELD OF INVENTION
[0001] The present invention relates to a novel composition for use
in prevention and treatment of organ transplant rejection and
autoimmune diseases such as psoriasis, rheumatoid arthritis, and
other related diseases and methods for making and using the
composition. The composition comprises cyclosporine. The
cyclosporine may exist in nanoparticulate form, that is in
particles having an effective average particle size of less than
2000 nm in diameter. The composition may be formulated to allow for
controlled release of the cyclosporine.
BACKGROUND OF INVENTION
A. Background Regarding Cyclosporine
[0002] The compositions of the invention comprise a cyclosporine.
Cyclosporines are a large class of peptide compounds having
pharmaceutical utility, for example immunosuppressant,
anti-inflammatory, and/or anti-parasitic activity and/or activity
in abrogating tumor resistance to anti-neoplastic or cytostatic
drug therapy. Cyclosporine is a cyclic non-ribosomal polypeptide
immunosuppressant agent consisting of 11 amino acids. It is
produced as a metabolite by the ascomycete fungus Beauveria nivea.
The cyclosporines include, for example, naturally occurring fungal
metabolites, such as the cyclosporine A, B, C, D and G, as well as
a wide variety of synthetic and semi-synthetic cyclosporines, for
example the dihydro- and iso-cyclosporines.
[0003] Cyclosporines have been described in, for example, U.S. Pat.
No. 5,756,450 for "Water Soluble Monoesters as Solubisers for
Pharmacologically Active Compounds and Pharmaceutical Excipients
and Novel Cyclosporine Galenic Forms;" U.S. Pat. No. 5,759,997 for
"Cyclosporin Galenic Forms; U.S. Pat. No. 5,977,066 for
"Cyclosporin Galenic Forms"; U.S. Pat. No. 6,239,124 for
"Pharmaceutical Compositions for the Treatment of Transplant
Rejection or Autoimmune or Inflammatory Conditions Comprising
Cyclosporin A and 40-0-(2-hydroxyethyl)-rapamycin;" U.S. Pat. No.
6,262,022 for "Pharmaceutical Compositions Containing Cyclosporin
as the Active Agent;" U.S. Pat. No. 6,306,825 for "Cyclosporin
Galenic Forms;" U.S. Pat. No. 6,432,445 for "Pharmaceutical
Capsules Comprising a Cyclosporin;" U.S. Pat. No. 6,455,518 for
"Pharmaceutical Compositions for the Treatment of Transplant
Rejection or Autoimmune or Inflammatory Conditions Comprising
Cyclosporin A and 40-0-(2-hydroxyethyl)-rapamycin;" U.S. Pat. No.
6,468,968 for "Cyclosporin Galenic Forms"; U.S. Pat. No. 6,475,519
for "Oil-free Pharmaceutical Compositions Containing Cyclosporin
A;" U.S. Pat. No. 6,486,124 for "Cyclosporin Compositions and
Processes Therefor;" U.S. Pat. No. 6,582,718 for "Cyclosporin
Compositions;` U.S. Pat. No. 6,620,325 for "Purification Process
for Cyclosporin;" and U.S. Pat. No. 6,723,339 for "Oil-free
Pharmaceutical Compositions Containing Cyclosporin A."
[0004] Cyclosporine has been demonstrated to suppress some humoral
immunity and, to a greater extent, cell-mediated reactions such as
allograft rejection, delayed hypersensitivity, experimental
allergic encephalomyelitis, Freund's adjuvant arthritis, and graft
versus host disease in many animal species for a variety of organs.
It has been used post-allogenic organ transplant to reduce the
activity of the patient's immune system to lower the risk of organ
rejection in the case of transplants of skin, heart, kidney, lung,
pancreas, bone marrow and small intestine.
[0005] Apart from transplant medicine, cyclosporine is also used in
treating psoriasis and rheumatoid arthritis and related diseases,
although only in severe cases, and has been investigated for use in
treating many other autoimmune disorders. It is often taken in
conjunction with corticosteroids. More recently, cyclosporine has
been used successfully in treating patients suffering from
ulcerative colitis.
[0006] Experimental evidence suggests that the effectiveness of
cyclosporine is due to specific and reversible inhibition of
immunocompetent lymphocytes in the G.sub.0- or G.sub.1-phase of the
cell cycle. T-lymphocytes are preferentially inhibited. The
T-helper cell is the main target, although the T-suppressor cell
may also be suppressed. Cyclosporine also inhibits lymphokine
production and release including interleukin-2 or T-cell growth
factor (TCGF). Cyclosporine is thought to bind to the cytosolic
protein cyclophilin (immunophilin) of immunocompetent lymphocytes,
especially T-lymphocytes. This complex of cyclosporin and
cyclophylin inhibits calcineurin, which under normal circumstances
is responsible for activating the transcription of interleukin-2.
It also inhibits lymphokine production and interleukin release and
therefore leads to a reduced function of effector T-cells. No
functional effects on phagocytic (changes in enzyme secretions not
altered, chemotactic migration of granulocytes, macrophage
migration, carbon clearance in vivo) or tumor cells (growth rate,
metastasis) can be detected in animals. Cyclosporine does not cause
bone marrow suppression in animal models or man.
[0007] Chemically, cyclosporine is designated as
[R--[R*,R*-(E)]]-cyclic
(L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl-3-
-hydroxy-N,4-dimethyl-L-2-amino-6-octenoyl-L-(alpha)-amino-butyryl-N-methy-
lglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl). The molecular
formula of cyclosporine is C.sub.62H.sub.111N.sub.11O.sub.12 with a
molecular weight of 1202.63. The chemical structure of cyclosporine
(also known as cyclosporin A) is:
##STR00001##
[0008] The drug is sold by Novartis under the brand names
SANDIMMUNE.RTM. and NEORAL.RTM.. NEORAL.RTM. and SANDIMMUNE.RTM.
differ in that NEORAL.RTM. has increased bioavailability compared
to SANDIMMUNE.RTM.. Adjunct therapy with adrenal corticosteroids is
recommended. Generic cyclosporine drugs have been produced by
companies such as Sangstat, Abbott Laboratories and Gengraf. A
topical emulsion of cyclosporine for treating keratoconjunctivitis
sicca has been marketed under the trade name RESTASIS.RTM..
[0009] The absorption of cyclosporine from the gastrointestinal
tract is incomplete and variable. Peak concentrations (C.sub.max)
in blood and plasma are achieved at about 3.5 hours. C.sub.max and
area under the plasma or blood concentration/time curve (AUC)
increase with the administered dose; for blood the relationship is
curvilinear (parabolic) between 0 and 1400 mg. C.sub.max is
approximately 1.0 ng/mL/mg of dose for plasma and 2.7-1.4 ng/mL/mg
of dose for blood (for low to high doses). Compared to an
intravenous infusion, the absolute bioavailability of the oral
solution is approximately 30% based upon the results in 2
patients.
[0010] Cyclosporine is distributed largely outside the blood
volume. In blood the distribution is concentration dependent.
Approximately 33%-47% is in plasma, 4%-9% in lymphocytes, 5%-12% in
granulocytes, and 41%-58% in erythrocytes. At high concentrations,
the uptake by leukocytes and erythrocytes becomes saturated. In
plasma, approximately 90% is bound to proteins, primarily
lipoproteins.
[0011] Cyclosporines are of high therapeutic value for the
prevention of organ transplant rejection, and the treatment of
autoimmune diseases, such as psoriasis and rheumatoid arthritis.
However, cyclosporines present highly specific difficulties in
relation to administration including in particular problems of
stability, drug bioavailability, and variability in inter- and
intra-patient dose response. In addition, because cyclosporine is
practically insoluble in water, conventional cyclosporine tablets
dissolve the drug in potentially toxic co-solvents, for example,
propylene glycol. The daily dose of cyclosporine must be given in
two divided doses, and should be administered on a consistent
schedule with regard to time of day and in relation to meals.
[0012] Thus, there is a need in the art for cyclosporine
compositions which overcome these and other problems associated
with their use. The present invention then relates to a composition
for the controlled release of a cyclosporine. The present invention
also relates to a nanoparticulate formulation of cyclosporine
having improved bioavailability. The present invention also relates
to a composition for the controlled release of a nanoparticulate
cyclosporine. In particular, the present invention relates to
controlled release compositions that in operation deliver a
cyclosporine in a pulsatile or in a constant zero order manner or
an immediate release nanoparticulate composition with improved
bioavailability. The present invention further relates to solid
oral dosage forms containing such a controlled release or immediate
release composition.
B. Background Regarding Nanoparticulate Compositions
[0013] Nanoparticulate compositions, first described in U.S. Pat.
No. 5,145,684 ("the '684 patent"), are particles consisting of a
poorly soluble therapeutic or diagnostic agent having adsorbed onto
the surface thereof a non-crosslinked surface stabilizer. The '684
patent does not describe nanoparticulate compositions of
cyclosporines.
[0014] Methods of making nanoparticulate compositions are described
in, for example, U.S. Pat. Nos. 5,518,187 and 5,862,999, both for
"Method of Grinding Pharmaceutical Substances;" U.S. Pat. No.
5,718,388, for "Continuous Method of Grinding Pharmaceutical
Substances;" and U.S. Pat. No. 5,510,118 for "Process of Preparing
Therapeutic Compositions Containing Nanoparticles."
[0015] Nanoparticulate compositions are also described, for
example, in U.S. Pat. No. 5,298,262 for "Use of Ionic Cloud Point
Modifiers to Prevent Particle Aggregation During Sterilization;"
U.S. Pat. No. 5,302,401 for "Method to Reduce Particle Size Growth
During Lyophilization;" U.S. Pat. No. 5,318,767 for "X-Ray Contrast
Compositions Useful in Medical Imaging;" U.S. Pat. No. 5,326,552
for "Novel Formulation For Nanoparticulate X-Ray Blood Pool
Contrast Agents Using High Molecular Weight Non-ionic Surfactants;"
U.S. Pat. No. 5,328,404 for "Method of X-Ray Imaging Using
Iodinated Aromatic Propanedioates;" U.S. Pat. No. 5,336,507 for
"Use of Charged Phospholipids to Reduce Nanoparticle Aggregation;"
U.S. Pat. No. 5,340,564 for "Formulations Comprising Olin 10-G to
Prevent Particle Aggregation and Increase Stability;" U.S. Pat. No.
5,346,702 for "Use of Non-Ionic Cloud Point Modifiers to Minimize
Nanoparticulate Aggregation During Sterilization;" U.S. Pat. No.
5,349,957 for "Preparation and Magnetic Properties of Very Small
Magnetic-Dextran Particles;" U.S. Pat. No. 5,352,459 for "Use of
Purified Surface Modifiers to Prevent Particle Aggregation During
Sterilization;" U.S. Pat. Nos. 5,399,363 and 5,494,683, both for
"Surface Modified Anticancer Nanoparticles;" U.S. Pat. No.
5,401,492 for "Water Insoluble Non-Magnetic Manganese Particles as
Magnetic Resonance Enhancement Agents;" U.S. Pat. No. 5,429,824 for
"Use of Tyloxapol as a Nanoparticulate Stabilizer;" U.S. Pat. No.
5,447,710 for "Method for Making Nanoparticulate X-Ray Blood Pool
Contrast Agents Using High Molecular Weight Non-ionic Surfactants;"
U.S. Pat. No. 5,451,393 for "X-Ray Contrast Compositions Useful in
Medical Imaging;" U.S. Pat. No. 5,466,440 for "Formulations of Oral
Gastrointestinal Diagnostic X-Ray Contrast Agents in Combination
with Pharmaceutically Acceptable Clays;" U.S. Pat. No. 5,470,583
for "Method of Preparing Nanoparticle Compositions Containing
Charged Phospholipids to Reduce Aggregation;" U.S. Pat. No.
5,472,683 for "Nanoparticulate Diagnostic Mixed Carbamic Anhydrides
as X-Ray Contrast Agents for Blood Pool and Lymphatic System
Imaging;" U.S. Pat. No. 5,500,204 for "Nanoparticulate Diagnostic
Dimers as X-Ray Contrast Agents for Blood Pool and Lymphatic System
Imaging;" U.S. Pat. No. 5,518,738 for "Nanoparticulate NSAID
Formulations;" U.S. Pat. No. 5,521,218 for "Nanoparticulate
Iododipamide Derivatives for Use as X-Ray Contrast Agents;" U.S.
Pat. No. 5,525,328 for "Nanoparticulate Diagnostic Diatrizoxy Ester
X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;"
U.S. Pat. No. 5,543,133 for "Process of Preparing X-Ray Contrast
Compositions Containing Nanoparticles;" U.S. Pat. No. 5,552,160 for
"Surface Modified NSAID Nanoparticles;" U.S. Pat. No. 5,560,931 for
"Formulations of Compounds as Nanoparticulate Dispersions in
Digestible Oils or Fatty Acids;" U.S. Pat. No. 5,565,188 for
"Polyalkylene Block Copolymers as Surface Modifiers for
Nanoparticles;" U.S. Pat. No. 5,569,448 for "Sulfated Non-ionic
Block Copolymer Surfactant as Stabilizer Coatings for Nanoparticle
Compositions;" U.S. Pat. No. 5,571,536 for "Formulations of
Compounds as Nanoparticulate Dispersions in Digestible Oils or
Fatty Acids;" U.S. Pat. No. 5,573,749 for "Nanoparticulate
Diagnostic Mixed Carboxylic Anydrides as X-Ray Contrast Agents for
Blood Pool and Lymphatic System Imaging;" U.S. Pat. No. 5,573,750
for "Diagnostic Imaging X-Ray Contrast Agents;" U.S. Pat. No.
5,573,783 for "Redispersible Nanoparticulate Film Matrices With
Protective Overcoats;" U.S. Pat. No. 5,580,579 for "Site-specific
Adhesion Within the GI Tract Using Nanoparticles Stabilized by High
Molecular Weight, Linear Poly(ethylene Oxide) Polymers;" U.S. Pat.
No. 5,585,108 for "Formulations of Oral Gastrointestinal
Therapeutic Agents in Combination with Pharmaceutically Acceptable
Clays;" U.S. Pat. No. 5,587,143 for "Butylene Oxide-Ethylene Oxide
Block Copolymers Surfactants as Stabilizer Coatings for
Nanoparticulate Compositions;" U.S. Pat. No. 5,591,456 for "Milled
Naproxen with Hydroxypropyl Cellulose as Dispersion Stabilizer;"
U.S. Pat. No. 5,593,657 for "Novel Barium Salt Formulations
Stabilized by Non-ionic and Anionic Stabilizers;" U.S. Pat. No.
5,622,938 for "Sugar Based Surfactant for Nanocrystals;" U.S. Pat.
No. 5,628,981 for "Improved Formulations of Oral Gastrointestinal
Diagnostic X-Ray Contrast Agents and Oral Gastrointestinal
Therapeutic Agents;" U.S. Pat. No. 5,643,552 for "Nanoparticulate
Diagnostic Mixed Carbonic Anhydrides as X-Ray Contrast Agents for
Blood Pool and Lymphatic System Imaging;" U.S. Pat. No. 5,718,388
for "Continuous Method of Grinding Pharmaceutical Substances;" U.S.
Pat. No. 5,718,919 for "Nanoparticles Containing the R(-)Enantiomer
of Ibuprofen;" U.S. Pat. No. 5,747,001 for "Aerosols Containing
Beclomethasone Nanoparticle Dispersions;" U.S. Pat. No. 5,834,025
for "Reduction of Intravenously Administered Nanoparticulate
Formulation Induced Adverse Physiological Reactions;" U.S. Pat. No.
6,045,829 "Nanocrystalline Formulations of Human Immunodeficiency
Virus (HIV) Protease Inhibitors Using Cellulosic Surface
Stabilizers;" U.S. Pat. No. 6,068,858 for "Methods of Making
Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV)
Protease Inhibitors Using Cellulosic Surface Stabilizers;" U.S.
Pat. No. 6,153,225 for "Injectable Formulations of Nanoparticulate
Naproxen;" U.S. Pat. No. 6,165,506 for "New Solid Dose Form of
Nanoparticulate Naproxen;" U.S. Pat. No. 6,221,400 for "Methods of
Treating Mammals Using Nanocrystalline Formulations of Human
Immunodeficiency Virus (HIV) Protease Inhibitors;" U.S. Pat. No.
6,264,922 for "Nebulized Aerosols Containing Nanoparticle
Dispersions;" U.S. Pat. No. 6,267,989 for "Methods for Preventing
Crystal Growth and Particle Aggregation in Nanoparticle
Compositions;" U.S. Pat. No. 6,270,806 for "Use of PEG-Derivatized
Lipids as Surface Stabilizers for Nanoparticulate Compositions;"
U.S. Pat. No. 6,316,029 for "Rapidly Disintegrating Solid Oral
Dosage Form," U.S. Pat. No. 6,375,986 for "Solid Dose
Nanoparticulate Compositions Comprising a Synergistic Combination
of a Polymeric Surface Stabilizer and Dioctyl Sodium
Sulfosuccinate;" U.S. Pat. No. 6,428,814 for "Bioadhesive
Nanoparticulate Compositions Having Cationic Surface Stabilizers;"
U.S. Pat. No. 6,431,478 for "Small Scale Mill;" and U.S. Pat. No.
6,432,381 for "Methods for Targeting Drug Delivery to the Upper
and/or Lower Gastrointestinal Tract," all of which are specifically
incorporated by reference. In addition, U.S. Patent Application No.
20020012675 A1, published on Jan. 31, 2002, for "Controlled Release
Nanoparticulate Compositions," describes nanoparticulate
compositions, and is specifically incorporated by reference.
[0016] Amorphous small particle compositions are described, for
example, in U.S. Pat. No. 4,783,484 for "Particulate Composition
and Use Thereof as Antimicrobial Agent;" U.S. Pat. No. 4,826,689
for "Method for Making Uniformly Sized Particles from
Water-Insoluble Organic Compounds;" U.S. Pat. No. 4,997,454 for
"Method for Making Uniformly-Sized Particles From Insoluble
Compounds;" U.S. Pat. No. 5,741,522 for "Ultrasmall, Non-aggregated
Porous Particles of Uniform Size for Entrapping Gas Bubbles Within
and Methods;" and U.S. Pat. No. 5,776,496, for "Ultrasmall Porous
Particles for Enhancing Ultrasound Back Scatter."
[0017] Because cyclosporine is practically insoluble in water,
significant bioavailability can be problematic. There is a need in
the art for nanoparticulate cyclosporine formulations which
overcome this and other problems associated with the use of
cyclosporine in the prevention and treatment of organ transplant
rejection and autoimmune diseases such as psoriasis, rheumatoid
arthritis, and other related diseases. The present invention
satisfies this need.
[0018] The present invention then, relates to a nanoparticulate
cyclosporine composition for the prevention and treatment of organ
transplant rejection and autoimmune diseases such as psoriasis,
rheumatoid arthritis, and other related diseases. As described
herein, the present invention further relates to controlled release
composition comprising such a nanoparticulate cyclosporine.
DESCRIPTION OF THE INVENTION
[0019] The present invention relates to a nanoparticulate
composition comprising cyclosporine. The composition comprises
nanoparticulate cyclosporine particles and at least one surface
stabilizer adsorbed on the surface of the cyclosporine particles.
The nanoparticulate cyclosporine particles have an effective
average particle size of less than about 2,000 nm in diameter.
[0020] A preferred dosage form of the invention is a solid dosage
form, although any pharmaceutically acceptable dosage form can be
utilized.
[0021] Another aspect of the invention is directed to a
pharmaceutical composition comprising nanoparticulate cyclosporine
particles and at least one surface stabilizer, a pharmaceutically
acceptable carrier, as well as any desired excipients.
[0022] Another aspect of the invention is directed to a
nanoparticulate cyclosporine composition, having an improved
pharmacokinetic profile as compared to conventional cyclosporine
formulations.
[0023] Another embodiment of the invention is directed to a
nanoparticulate cyclosporine composition comprising one or more
additional compounds useful in the prevention and treatment of
organ transplant rejection and autoimmune diseases such as
psoriasis, rheumatoid arthritis, and other related diseases.
[0024] This invention further discloses a method of making the
inventive nanoparticulate cyclosporine composition. Such a method
comprises contacting the nanoparticulate cyclosporine with at least
one surface stabilizer for a time and under conditions sufficient
to provide a stabilized nanoparticulate cyclosporine
composition.
[0025] The present invention is also directed to methods of
treatment including but not limited to, the prevention and
treatment of organ transplant rejection and autoimmune diseases
such as psoriasis, rheumatoid arthritis, and other related diseases
using the novel nanoparticulate cyclosporine composition disclosed
herein. Such methods comprise administering to a subject a
therapeutically effective amount of a nanoparticulate cyclosporine.
Other methods of treatment using the nanoparticulate compositions
of the invention are known to those of skill in the art.
[0026] The present invention further relates to a controlled
release composition comprising a cyclosporine or a nanoparticulate
cyclosporine which in operation produces a plasma profile
substantially similar to the plasma profile produced by the
administration of two or more immediate release (IR) dosage forms
given sequentially.
[0027] Conventional frequent dosage regimes in which an IR dosage
form is administered at periodic intervals typically give rise to a
pulsatile plasma profile. In this case, a peak in the plasma drug
concentration is observed after administration of each IR dose with
troughs (regions of low drug concentration) developing between
consecutive administration time points. Such dosage regimes (and
their resultant pulsatile plasma profiles) have particular
pharmacological and therapeutic effects associated with them. For
example, the wash out period provided by the fall off of the plasma
concentration of the active agent between peaks has been thought to
be a contributing factor in reducing or preventing patient
tolerance to various types of drugs.
[0028] The present invention further relates to a controlled
release composition comprising cyclosporine or a nanoparticulate
cyclosporine which in operation produces a plasma profile that
eliminates the "peaks" and "troughs" produced by the administration
of two or more IR dosage forms given sequentially if such a profile
is beneficial. This type of profile can be obtained using a
controlled release mechanism that allows for "zero-order"
delivery.
[0029] Multiparticulate modified controlled release compositions
similar to those disclosed herein are disclosed and claimed in the
U.S. Pat. Nos. 6,228,398 and 6,730,325 to Devane et al; both of
which are incorporated by reference herein. All of the relevant
prior art in this field may also be found therein.
[0030] It is a further object of the invention to provide a
controlled release composition which in operation delivers a
cyclosporine or a nanoparticulate cyclosporine in a pulsatile
manner or a zero-order manner.
[0031] Another object of the invention is to provide a controlled
release composition which substantially mimics the pharmacological
and therapeutic effects produced by the administration of two or
more IR dosage forms given sequentially.
[0032] Another object of the invention is to provide a controlled
release composition which substantially reduces or eliminates the
development of patient tolerance to, a cyclosporine or a
nanoparticulate cyclosporine present in the composition.
[0033] Another object of the invention is to provide a controlled
release composition in which a first portion of the composition,
i.e., a cyclosporine or a nanoparticulate cyclosporine, is released
immediately upon administration and a second portion of the active
ingredient is released rapidly after an initial delay period in a
bimodal manner.
[0034] Another object of the invention is to formulate the dosage
in the form of an erodable formulation, a diffusion controlled
formulation, or an osmotic controlled formulation.
[0035] Another object of the invention is to provide a controlled
release composition capable of releasing a cyclosporine or a
nanoparticulate cyclosporine, in a bimodal or multi-modal manner in
which a first portion of the active is released either immediately
or after a delay time to provide a pulse of drug release and one or
more additional portions of the cyclosporine or a nanoparticulate
cyclosporine is released, after a respective lag time, to provide
additional pulses of drug release during a period of up to
twenty-four hours.
[0036] Another object of the invention is to provide solid oral
dosage forms comprising a controlled release composition comprising
a cyclosporine or a nanoparticulate cyclosporine.
[0037] Other objects of the invention include provision of a once
daily dosage form of a cyclosporine or a nanoparticulate
cyclosporine which, in operation, produces a plasma profile
substantially similar to the plasma profile produced by the
administration of two immediate release dosage forms given
sequentially and a method for prevention and treatment of organ
transplant rejection and autoimmune diseases such as psoriasis,
rheumatoid arthritis, and other related diseases based on the
administration of such a dosage form.
[0038] The above objects are realized by a controlled release
composition having a first component comprising a first population
of a cyclosporine or a nanoparticulate cyclosporine, and at least
one subsequent component or formulation comprising a subsequent
population of cyclosporine or a nanoparticulate cyclosporine. The
ingredient-containing particles of the subsequent component further
comprises a modified release constituent comprising a release
coating or release matrix material, or both. Following oral
delivery, the composition in operation delivers a cyclosporine or a
nanoparticulate cyclosporine, in a pulsatile or zero order
manner.
[0039] The present invention utilizes controlled release delivery
of cyclosporine or a nanoparticulate cyclosporine, from a solid
oral dosage formulation to allow dosage less frequently than
before, and preferably once-a-day administration, increasing
patient convenience and compliance. The mechanism of controlled
release would preferably utilize, but not be limited to, an
erodable formulation, a diffusion controlled formulation and an
osmotic controlled formulation. A portion of the total dose may be
released immediately to allow for rapid onset of effect. The
invention would be useful in improving compliance and, therefore,
therapeutic outcome for all treatments requiring a cyclosporine or
a nanoparticulate cyclosporine, including but not limited to, the
prevention and treatment of organ transplant rejection and
autoimmune diseases such as psoriasis, rheumatoid arthritis, and
other related diseases. This approach would replace conventional
cyclosporine tablets and solution, which are administered two times
a day as adjunctive therapy in the prevention and treatment of
organ transplant rejection and autoimmune diseases such as
psoriasis, rheumatoid arthritis, and other related diseases.
[0040] The present invention also relates to a controlled modified
release composition for the controlled release of a cyclosporine or
a nanoparticulate cyclosporine. In particular, the present
invention relates to a controlled release composition that in
operation a cyclosporine or a nanoparticulate cyclosporine, in a
pulsatile or zero order manner, preferably during a period of up to
twenty-four hours. The present invention further relates to solid
oral dosage forms containing a controlled release composition.
[0041] Preferred controlled release formulations are erodable
formulations, diffusion controlled formulations and osmotic
controlled formulations. According to the invention, a portion of
the total dose may be released immediately to allow for rapid onset
of effect, with the remaining portion of the total dose released
over an extended time period. The invention would be useful in
improving compliance and, therefore, therapeutic outcome for all
treatments requiring a cyclosporine or a nanoparticulate
cyclosporine including but not limited to, prevention and treatment
of organ transplant rejection and autoimmune diseases such as
psoriasis, rheumatoid arthritis, and other related diseases.
[0042] Both the foregoing general description and the following
detailed description are exemplary and explanatory and are intended
to provide further explanation of the invention as claimed. Other
objects, advantages, and novel features will be readily apparent to
those skilled in the art from the following detailed description of
the invention.
DETAILED DESCRIPTION OF THE INVENTION
I. Nanoparticulate Cyclosporine Compositions
[0043] The present invention is directed to a nanoparticulate
composition comprising a cyclosporine. The composition comprises a
cyclosporine and preferably at least one surface stabilizer
adsorbed on the surface of the drug. The cyclosporine particles
have an effective average particle size of less than about 2000 nm
in diameter. By "effective average particle size" of less than a
specified amount, it is meant that at least 50% of the particles
have a particle size of less than about that amount.
[0044] As taught by the '684 patent, and as exemplified in the
examples below, not every combination of surface stabilizer and
active agent will result in a stable nanoparticulate composition.
It was surprisingly discovered that stable, nanoparticulate
cyclosporine formulations can be made.
[0045] Advantages of the nanoparticulate cyclosporine formulation
of the invention include, but are not limited to: (1) smaller
tablet or other solid dosage form size; (2) smaller doses of drug
required to obtain the same pharmacological effect as compared to
conventional microcrystalline forms of cyclosporine; (3) increased
bioavailability as compared to conventional microcrystalline forms
of cyclosporine; (4) improved pharmacokinetic profiles; (5) an
increased rate of dissolution for the cyclosporine compositions as
compared to conventional microcrystalline forms of the same
cyclosporine; and (6) the cyclosporine compositions can be used in
conjunction with other active agents useful in the prevention and
treatment of organ transplant rejection and autoimmune diseases
such as psoriasis, rheumatoid arthritis, and other related
diseases.
[0046] The present invention also includes a nanoparticulate
cyclosporine composition together with one or more non-toxic
physiologically acceptable carriers, adjuvants, or vehicles,
collectively referred to as carriers. The compositions can be
formulated for parental injection (e.g., intravenous,
intramuscular, or subcutaneous), oral administration in solid,
liquid, or aerosol form, vaginal, nasal, rectal, ocular, local
(powders, ointments, or drops), buccal, intracisternal,
intraperitoneal, or topical administrations, and the like.
[0047] A preferred dosage form of the invention is a solid dosage
form, although any pharmaceutically acceptable dosage form can be
utilized. Exemplary solid dosage forms include, but are not limited
to, tablets, capsules, sachets, lozenges, powders, pills, or
granules, and the solid dosage form can be, for example, a fast
melt dosage form, controlled release dosage form, lyophilized
dosage form, delayed release dosage form, extended release dosage
form, pulsatile release dosage form, mixed immediate release and
controlled release dosage form, or a combination thereof. A solid
dose tablet formulation is preferred.
A. Preferred Characteristics of the Nanoparticulate Cyclosporine
Compositions of the Invention
[0048] 1. Increased Bioavailability
[0049] The nanoparticulate cyclosporine formulation of the
invention is proposed to exhibit increased bioavailability, and
require smaller doses as compared to prior conventional
cyclosporine formulations.
[0050] 2. Dissolution Profiles of the Cyclosporine Composition of
the Invention
[0051] The nanoparticulate cyclosporine composition of the
invention is proposed to have an unexpectedly dramatic dissolution
profile. Rapid dissolution of an administered active agent is
preferable, as faster dissolution generally leads to faster onset
of action and greater bioavailability. To improve the dissolution
profile and bioavailability of the cyclosporine it would be useful
to increase the drug's dissolution so that it could attain a level
close to 100%.
[0052] The cyclosporine composition of the invention preferably
have a dissolution profile in which within about 5 minutes at least
about 20% of the composition is dissolved. In other embodiments of
the invention, at least about 30% or about 40% of the cyclosporine
composition is dissolved within about 5 minutes. In yet other
embodiments of the invention, preferably at least 40%, about 50%,
about 60%, about 70%, or about 80% of the cyclosporine composition
is dissolved within about 10 minutes. Finally, in another
embodiment of the invention, preferably at least about 70%, about
80%, about 90%, or about 100% of the cyclosporine composition is
dissolved within 20 minutes.
[0053] Dissolution is preferably measured in a medium which is
discriminating. Such a dissolution medium will produce two very
different dissolution curves for two products having very different
dissolution profiles in gastric juices; i.e., the dissolution
medium is predictive of in vivo dissolution of a composition. An
exemplary dissolution medium is an aqueous medium containing the
surfactant sodium lauryl sulfate at 0.025 M. Determination of the
amount dissolved can be carried out by spectrophotometry. The
rotating blade method (European Pharmacopoeia) can be used to
measure dissolution.
[0054] 3. Redispersability of the Cyclosporine Compositions of the
Invention
[0055] An additional feature of the cyclosporine composition of the
invention is that the composition redisperses such that the
effective average particle size of the redispersed cyclosporine
particles is less than about 2 microns in diameter. This is
significant, as if upon administration the cyclosporine
compositions of the invention did not redisperse to a substantially
nanoparticulate size, then the dosage form may lose the benefits
afforded by formulating the cyclosporine into a nanoparticulate
size.
[0056] This is because nanoparticulate active agent compositions
benefit from the small particle size of the active agent; if the
active agent does not disperse into the small particle sizes upon
administration, them "clumps" or agglomerated active agent
particles are formed, owing to the extremely high surface free
energy of the nanoparticulate system and the thermodynamic driving
force to achieve an overall reduction in free energy. With the
formulation of such agglomerated particles, the bioavailability of
the dosage form my fall well below that observed with the liquid
dispersion form of the nanoparticulate active agent.
[0057] In other embodiments of the invention, the redispersed
cyclosporine particles of the invention have an effective average
particle size of less than about less than about 1900 nm in
diameter, less than about 1800 nm, less than about 1700 nm, less
than about 1600 nm, less than about 1500 nm, less than about 1400
nm, less than about 1300 nm, less than about 1200 nm, less than
about 1100 nm, less than about 1000 nm, less than about 900 nm,
less than about 800 nm, less than about 700 nm, less than about 600
nm, less than about 500 nm, less than about 400 nm, less than about
300 nm, less than about 250 nm, less than about 200 nm, less than
about 150 nm, less than about 100 nm, less than about 75 nm, or
less than about 50 nm, as measured by light-scattering methods,
microscopy, or other appropriate methods.
[0058] 4. Cyclosporine Used in Conjunction with Other Active
Agents
[0059] The cyclosporine composition of the invention can
additionally comprise one or more compounds useful in the
prevention and treatment of organ transplant rejection and
autoimmune diseases such as psoriasis, rheumatoid arthritis, and
other related diseases, or the cyclosporine composition can be
administered in conjunction with such a compound. Examples of such
compounds include, but are not limited to corticosteroids,
anthralin, calcipotriene, coal tar, siaclic acid, steroids,
tazarotene, methotrexate, oral retinoids, non-steroidal
anti-inflammatory drugs, azulfidine, corticosteroids, gold, and
hydroxychoroquine.
B. Nanoparticulate Cyclosporine Composition
[0060] The invention provides a composition comprising cyclosporine
particles and at least one surface stabilizer. The surface
stabilizers preferably are adsorbed on, or associated with, the
surface of the cyclosporine particles. Surface stabilizers
especially useful herein preferably physically adhere on, or
associate with, the surface of the nanoparticulate cyclosporine
particles, but do not chemically react with the cyclosporine
particles or itself. Individually adsorbed molecules of the surface
stabilizer are essentially free of intermolecular
cross-linkages.
[0061] The present invention also includes a cyclosporine
composition together with one or more non-toxic physiologically
acceptable carriers, adjuvants, or vehicles, collectively referred
to as carriers. The composition can be formulated for parenteral
injection (e.g., intravenous, intramuscular, or subcutaneous), oral
administration in solid, liquid, or aerosol form, vaginal, nasal,
rectal, ocular, local (powders, ointments or drops), buccal,
intracisternal, intraperitoneal, or topical administration, and the
like.
[0062] 1. Surface Stabilizers
[0063] The choice of a surface stabilizer for a cyclosporine is
non-trivial and required extensive experimentation to realize a
desirable formulation. Accordingly, the present invention is
directed to the surprising discovery that nanoparticulate
cyclosporine compositions can be made.
[0064] Combinations of more than one surface stabilizer can be used
in the invention. Useful surface stabilizers which can be employed
in the invention include, but are not limited to, known organic and
inorganic pharmaceutical excipients. Such excipients include
various polymers, low molecular weight oligomers, natural products,
and surfactants. Surface stabilizers include nonionic, anionic,
cationic, ionic, and zwitterionic surfactants.
[0065] Representative examples of surface stabilizers include
hydroxypropyl methylcellulose (now known as hypromellose),
hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl
sulfate, dioctylsulfosuccinate, gelatin, casein, lecithin
(phosphatides), dextran, gum acacia, cholesterol, tragacanth,
stearic acid, benzalkonium chloride, calcium stearate, glycerol
monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax,
sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol
ethers such as cetomacrogol 1000), polyoxyethylene castor oil
derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., the
commercially available Tweens.RTM. such as e.g., Tween 20.RTM. and
Tween 80.RTM. (ICI Speciality Chemicals)); polyethylene glycols
(e.g., Carbowaxs 3550.RTM. and 934.RTM. (Union Carbide)),
polyoxyethylene stearates, colloidal silicon dioxide, phosphates,
carboxymethylcellulose calcium, carboxymethylcellulose sodium,
methylcellulose, hydroxyethylcellulose, hypromellose phthalate,
noncrystalline cellulose, magnesium aluminium silicate,
triethanolamine, polyvinyl alcohol (PVA),
4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and
formaldehyde (also known as tyloxapol, superione, and triton),
poloxamers (e.g., Pluronics F68.RTM. and F108.RTM., which are block
copolymers of ethylene oxide and propylene oxide); poloxamines
(e.g., Tetronic 908.RTM., also known as Poloxamine 908.RTM., which
is a tetrafunctional block copolymer derived from sequential
addition of propylene oxide and ethylene oxide to ethylenediamine
(BASF Wyandotte Corporation, Parsippany, N.J.)); Tetronic 1508.RTM.
(T-1508) (BASF Wyandotte Corporation), Tritons X-200.RTM., which is
an alkyl aryl polyether sulfonate (Rohm and Haas); Crodestas
F-110.RTM., which is a mixture of sucrose stearate and sucrose
distearate (Croda Inc.); p-isononylphenoxypoly-(glycidol), also
known as Olin-1OG.RTM. or Surfactant 10-G.RTM. (Olin Chemicals,
Stamford, Conn.); Crodestas SL-40.RTM. (Croda, Inc.); and SA9OHCO,
which is
C.sub.18H.sub.37CH.sub.2(CON(CH.sub.3)--CH.sub.2(CHOH).sub.4(CH.sub.20H).-
sub.2 (Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl
.beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside;
n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside;
heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucopyranoside;
n-heptyl .beta.-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside;
nonanoyl-N-methylglucamide; n-noyl .beta.-D-glucopyranoside;
octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; octyl
.beta.-D-thioglucopyranoside; PEG-phospholipid, PEG-cholesterol,
PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme,
random copolymers of vinyl pyrrolidone and vinyl acetate, and the
like.
[0066] Examples of useful cationic surface stabilizers include, but
are not limited to, polymers, biopolymers, polysaccharides,
cellulosics, alginates, phospholipids, and nonpolymeric compounds,
such as zwitterionic stabilizers, poly-n-methylpyridinium, anthryul
pyridinium chloride, cationic phospholipids, chitosan, polylysine,
polyvinylimidazole, polybrene, polymethylmethacrylate
trimethylammoniumbromide bromide (PMMTMABr),
hexyldesyltrimethylammonium bromide (HDMAB), and
polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl
sulfate.
[0067] Other useful cationic stabilizers include, but are not
limited to, cationic lipids, sulfonium, phosphonium, and
quarternary ammonium compounds, such as stearyltrimethylammonium
chloride, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut
trimethyl ammonium chloride or bromide, coconut methyl
dihydroxyethyl ammonium chloride or bromide, decyl triethyl
ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride or
bromide, C.sub.12-15dimethyl hydroxyethyl ammonium chloride or
bromide, coconut dimethyl hydroxyethyl ammonium chloride or
bromide, myristyl trimethyl ammonium methyl sulphate, lauryl
dimethyl benzyl ammonium chloride or bromide, lauryl dimethyl
(ethenoxy).sub.4 ammonium chloride or bromide, N-alkyl
(C.sub.12-18)dimethylbenzyl ammonium chloride,
N-alkyl(C.sub.14-18)dimethyl-benzyl ammonium chloride,
N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl
didecyl ammonium chloride, N-alkyl and (C.sub.12-14) dimethyl
1-napthylmethyl ammonium chloride, trimethylammonium halide,
alkyl-trimethylammonium salts and dialkyl-dimethylammonium salts,
lauryl trimethyl ammonium chloride, ethoxylated
alkyamidoalkyldialkylammonium salt and/or an ethoxylated trialkyl
ammonium salt, dialkylbenzene dialkylammonium chloride,
N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl
ammonium, chloride monohydrate, N-alkyl(C.sub.12-14) dimethyl
1-naphthylmethyl ammonium chloride and dodecyldimethylbenzyl
ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl
trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride,
alkyl benzyl dimethyl ammonium bromide, C.sub.12, C.sub.15,
C.sub.17 trimethyl ammonium bromides, dodecylbenzyl triethyl
ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC),
dimethyl ammonium chlorides, alkyldimethylammonium halogenides,
tricetyl methyl ammonium chloride, decyltrimethylammonium bromide,
dodecyltriethylammonium bromide, tetradecyltrimethylammonium
bromide, methyl trioctylammonium chloride (ALIQUAT 336.TM.),
POLYQUAT 10.TM., tetrabutylammonium bromide, benzyl
trimethylammonium bromide, choline esters (such as choline esters
of fatty acids), benzalkonium chloride, stearalkonium chloride
compounds (such as stearyltrimonium chloride and Di-stearyldimonium
chloride), cetyl pyridinium bromide or chloride, halide salts of
quaternized polyoxyethylalkylamines, MIRAPOL.TM. and ALKAQUAT.TM.
(Alkaril Chemical Company), alkyl pyridinium salts; amines, such as
alkylamines, dialkylamines, alkanolamines, polyethylenepolyamines,
N,N-dialkylaminoalkyl acrylates, and vinyl pyridine, amine salts,
such as lauryl amine acetate, stearyl amine acetate,
alkylpyridinium salt, and alkylimidazolium salt, and amine oxides;
imide azolinium salts; protonated quaternary acrylamides;
methylated quaternary polymers, such as poly[diallyl
dimethylammonium chloride] and poly-[N-methyl vinyl pyridinium
chloride]; and cationic guar.
[0068] Such exemplary cationic surface stabilizers and other useful
cationic surface stabilizers are described in J. Cross and E.
Singer, Cationic Surfactants: Analytical and Biological Evaluation
(Marcel Dekker, 1994); P. and D. Rubingh (Editor), Cationic
Surfactants: Physical Chemistry (Marcel Dekker, 1991); and J.
Richmond, Cationic Surfactants: Organic Chemistry, (Marcel Dekker,
1990).
[0069] Nonpolymeric surface stabilizers are any nonpolymeric
compound, such benzalkonium chloride, a carbonium compound, a
phosphonium compound, an oxonium compound, a halonium compound, a
cationic organometallic compound, a quarternary phosphorous
compound, a pyridinium compound, an anilinium compound, an ammonium
compound, a hydroxylammonium compound, a primary ammonium compound,
a secondary ammonium compound, a tertiary ammonium compound, and
quarternary ammonium compounds of the formula
NR.sub.1R.sub.2R.sub.3R.sub.4.sup.(+). For compounds of the formula
NR.sub.1R.sub.2R.sub.3R.sub.4.sup.(+):
(i) none of R.sub.1-R.sub.4 are CH.sub.3;
(ii) one of R.sub.1-R.sub.4 is CH.sub.3;
[0070] (iii) three of R.sub.1-R.sub.4 are CH.sub.3;
(iv) all of R.sub.1-R.sub.4 are CH.sub.3;
[0071] (v) two of R.sub.1-R.sub.4 are CH.sub.3, one of
R.sub.1-R.sub.4 is C.sub.6H.sub.5CH.sub.2, and one of
R.sub.1-R.sub.4 is an alkyl chain of seven carbon atoms or less;
(vi) two of R.sub.1-R.sub.4 are CH.sub.3, one of R.sub.1-R.sub.4 is
C.sub.6H.sub.5CH.sub.2, and one of R.sub.1-R.sub.4 is an alkyl
chain of nineteen carbon atoms or more; (vii) two of
R.sub.1-R.sub.4 are CH.sub.3 and one of R.sub.1-R.sub.4 is the
group C.sub.6H.sub.5(CH.sub.2).sub.n, where n>1; (viii) two of
R.sub.1-R.sub.4 are CH.sub.3, one of R.sub.1-R.sub.4 is
C.sub.6H.sub.5CH.sub.2, and one of R.sub.1-R.sub.4 comprises at
least one heteroatom; (ix) two of R.sub.1-R.sub.4 are CH.sub.3, one
of R.sub.1-R.sub.4 is C.sub.6H.sub.5CH.sub.2, and one of
R.sub.1-R.sub.4 comprises at least one halogen; (x) two of
R.sub.1-R.sub.4 are CH.sub.3, one of R.sub.1-R.sub.4 is
C.sub.6H.sub.5CH.sub.2, and one of R.sub.1-R.sub.4 comprises at
least one cyclic fragment; (xi) two of R.sub.1-R.sub.4 are CH.sub.3
and one of R.sub.1-R.sub.4 is a phenyl ring; or (xii) two of
R.sub.1-R.sub.4 are CH.sub.3 and two of R.sub.1-R.sub.4 are purely
aliphatic fragments.
[0072] Such compounds include, but are not limited to,
behenalkonium chloride, benzethonium chloride, cetylpyridinium
chloride, behentrimonium chloride, lauralkonium chloride,
cetalkonium chloride, cetrimonium bromide, cetrimonium chloride,
cethylamine hydrofluoride, chlorallylmethenamine chloride
(Quaternium-15), distearyldimonium chloride (Quaternium-5), dodecyl
dimethyl ethylbenzyl ammonium chloride (Quaternium-14),
Quaternium-22, Quaternium-26, Quaternium-18 hectorite,
dimethylaminoethylchloride hydrochloride, cysteine hydrochloride,
diethanolammonium POE (10) oletyl ether phosphate,
diethanolammonium POE (3) oleyl ether phosphate, tallow alkonium
chloride, dimethyl dioctadecylammoniumbentonite, stearalkonium
chloride, domiphen bromide, denatonium benzoate, myristalkonium
chloride, laurtrimonium chloride, ethylenediamine dihydrochloride,
guanidine hydrochloride, pyridoxine HCl, iofetamine hydrochloride,
meglumine hydrochloride, methylbenzethonium chloride, myrtrimonium
bromide, oleyltrimonium chloride, polyquaternium-1,
procainehydrochloride, cocobetaine, stearalkonium bentonite,
stearalkoniumhectonite, stearyl trihydroxyethyl propylenediamine
dihydrofluoride, tallowtrimonium chloride, and hexadecyltrimethyl
ammonium bromide.
[0073] The surface stabilizers are commercially available and/or
can be prepared by techniques known in the art. Most of these
surface stabilizers are known pharmaceutical excipients and are
described in detail in the Handbook of Pharmaceutical Excipients,
published jointly by the American Pharmaceutical Association and
The Pharmaceutical Society of Great Britain (The Pharmaceutical
Press, 2000), specifically incorporated by reference.
[0074] 2. Other Pharmaceutical Excipients
[0075] The pharmaceutical composition according to the invention
may also comprise one or more binding agents, filling agents,
lubricating agents, suspending agents, sweeteners, flavoring
agents, preservatives, buffers, wetting agents, disintegrants,
effervescent agents, and other excipients. Such excipients are
known in the art.
[0076] Examples of filling agents are lactose monohydrate, lactose
anhydrous, and various starches; examples of binding agents are
various celluloses and cross-linked polyvinylpyrrolidone,
microcrystalline cellulose, such as Avicel.RTM. PH101 and
Avicel.RTM. PH102, microcrystalline cellulose, and silicified
microcrystalline cellulose (ProSolv SMCC.TM.).
[0077] Suitable lubricants, including agents that act on the
flowability of the powder to be compressed, are colloidal silicon
dioxide, such as Aerosil.RTM. 200, talc, stearic acid, magnesium
stearate, calcium stearate, and silica gel.
[0078] Examples of sweeteners are any natural or artificial
sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate,
aspartame, and acsulfame. Examples of flavoring agents are
Magnasweet.RTM. (trademark of MAFCO), bubble gum flavor, and fruit
flavors, and the like.
[0079] Examples of preservatives are potassium sorbate,
methylparaben, propylparaben, benzoic acid and its salts, other
esters of parahydroxybenzoic acid such as butylparaben, alcohols
such as ethyl or benzyl alcohol, phenolic compounds such as phenol,
or quarternary compounds such as benzalkonium chloride.
[0080] Suitable diluents include pharmaceutically acceptable inert
fillers, such as microcrystalline cellulose, lactose, dibasic
calcium phosphate, saccharides, and/or mixtures of any of the
foregoing. Examples of diluents include microcrystalline cellulose,
such as Avicel.RTM. PH101 and Avicel.RTM. PH102; lactose such as
lactose monohydrate, lactose anhydrous, and Pharmatose.RTM. DCL21;
dibasic calcium phosphate such as Emcompress.RTM.; mannitol;
starch; sorbitol; sucrose; and glucose.
[0081] Suitable disintegrants include lightly crosslinked polyvinyl
pyrrolidone, corn starch, potato starch, maize starch, and modified
starches, croscarmellose sodium, cross-povidone, sodium starch
glycolate, and mixtures thereof.
[0082] Examples of effervescent agents are effervescent couples
such as an organic acid and a carbonate or bicarbonate. Suitable
organic acids include, for example, citric, tartaric, malic,
fumaric, adipic, succinic, and alginic acids and anhydrides and
acid salts. Suitable carbonates and bicarbonates include, for
example, sodium carbonate, sodium bicarbonate, potassium carbonate,
potassium bicarbonate, magnesium carbonate, sodium glycine
carbonate, L-lysine carbonate, and arginine carbonate.
Alternatively, only the sodium bicarbonate component of the
effervescent couple may be present.
[0083] 3. Nanoparticulate Cyclosporine Particle Size
[0084] The compositions of the invention contain nanoparticulate
cyclosporine particles which have an effective average particle
size of less than about 2000 nm (i.e., 2 microns) in diameter, less
than about 1900 nm, less than about 1800 nm, less than about 1700
nm, less than about 1600 nm, less than about 1500 nm, less than
about 1400 nm, less than about 1300 nm, less than about 1200 nm,
less than about 1100 nm, less than about 1000 nm, less than about
900 nm, less than about 800 nm, less than about 700 nm, less than
about 600 nm, less than about 500 nm, less than about 400 nm, less
than about 300 nm, less than about 250 nm, less than about 200 nm,
less than about 150 nm, less than about 100 nm, less than about 75
nm, or less than about 50 nm, as measured by light-scattering
methods, microscopy, or other appropriate methods.
[0085] By "an effective average particle size of less than" a
specified amount, it is meant that at least 50% of the cyclosporine
particles have a particle size of less than about 2000 nm in
diameter, 1900 nm, 1800 nm, etc., when measured by the above-noted
techniques. Preferably, at least about 70%, about 90%, or about 95%
of the cyclosporine particles have a particle size of less than the
effective average, i.e., less than about 2000 nm in diameter, 1900
nm, 1800 nm, 1700 nm, etc.
[0086] In the present invention, the value for D50 of a
nanoparticulate cyclosporine composition is the particle size below
which 50% of the cyclosporine particles fall, by weight. Similarly,
D90 is the particle size below which 90% of the cyclosporine
particles fall, by weight.
[0087] 4. Concentration of Cyclosporine and Surface Stabilizers
[0088] The relative amounts of cyclosporine and one or more surface
stabilizers can vary widely. The optimal amount of the individual
components can depend, for example, upon the particular
cyclosporine selected, the hydrophilic lipophilic balance (HLB),
melting point, and the surface tension of water solutions of the
stabilizer, etc.
[0089] The concentration of the cyclosporine can vary from about
99.5% to about 0.001%, from about 95% to about 0.1%, or from about
90% to about 0.5%, by weight, based on the total combined weight of
the cyclosporine and at least one surface stabilizer, not including
other excipients.
[0090] The concentration of the at least one surface stabilizer can
vary from about 0.5% to about 99.999%, from about 5.0% to about
99.9%, or from about 10% to about 99.5%, by weight, based on the
total combined dry weight of the cyclosporine and at least one
surface stabilizer, not including other excipients.
[0091] 5. Exemplary Nanoparticulate Cyclosporine Tablet
Formulations
[0092] Several exemplary cyclosporine tablet formulations are given
below. These examples are not intended to limit the claims in any
respect, but rather to provide exemplary tablet formulations of
cyclosporine which can be utilized in the methods of the invention.
Such exemplary tablets can also comprise a coating agent.
TABLE-US-00001 Exemplary Nanoparticulate Cyclosporine Tablet
Formulation #1 Component g/Kg Cyclosporine about 50 to about 500
Hypromellose, USP about 10 to about 70 Docusate Sodium, USP about 1
to about 10 Sucrose, NF about 100 to about 500 Sodium Lauryl
Sulfate, NF about 1 to about 40 Lactose Monohydrate, NF about 50 to
about 400 Silicified Microcrystalline Cellulose about 50 to about
300 Crospovidone, NF about 20 to about 300 Magnesium Stearate, NF
about 0.5 to about 5
TABLE-US-00002 Exemplary Nanoparticulate Cyclosporine Tablet
Formulation #2 Component g/Kg Cyclosporine about 100 to about 300
Hypromellose, USP about 30 to about 50 Docusate Sodium, USP about
0.5 to about 10 Sucrose, NF about 100 to about 300 Sodium Lauryl
Sulfate, NF about 1 to about 30 Lactose Monohydrate, NF about 100
to about 300 Silicified Microcrystalline Cellulose about 50 to
about 200 Crospovidone, NF about 50 to about 200 Magnesium
Stearate, NF about 0.5 to about 5
TABLE-US-00003 Exemplary Nanoparticulate Cyclosporine Tablet
Formulation #3 Component g/Kg Cyclosporine about 200 to about 225
Hypromellose, USP about 42 to about 46 Docusate Sodium, USP about 2
to about 6 Sucrose, NF about 200 to about 225 Sodium Lauryl
Sulfate, NF about 12 to about 18 Lactose Monohydrate, NF about 200
to about 205 Silicified Microcrystalline Cellulose about 130 to
about 135 Crospovidone, NF about 112 to about 118 Magnesium
Stearate, NF about 0.5 to about 3
TABLE-US-00004 Exemplary Nanoparticulate Cyclosporine Tablet
Formulation #4 Component g/Kg Cyclosporine about 119 to about 224
Hypromellose, USP about 42 to about 46 Docusate Sodium, USP about 2
to about 6 Sucrose, NF about 119 to about 224 Sodium Lauryl
Sulfate, NF about 12 to about 18 Lactose Monohydrate, NF about 119
to about 224 Silicified Microcrystalline Cellulose about 129 to
about 134 Crospovidone, NF about 112 to about 118 Magnesium
Stearate, NF about 0.5 to about 3
C. Methods of Making Nanoparticulate Cyclosporine Compositions
[0093] The nanoparticulate cyclosporine composition can be made
using, for example, milling, homogenization, precipitation,
freezing, or template emulsion techniques. Exemplary methods of
making nanoparticulate compositions are described in the '684
patent. Methods of making Methods of making nanoparticulate
compositions are also described in U.S. Pat. No. 5,518,187 for
"Method of Grinding Pharmaceutical Substances;" U.S. Pat. No.
5,718,388 for "Continuous Method of Grinding Pharmaceutical
Substances;" U.S. Pat. No. 5,862,999 for "Method of Grinding
Pharmaceutical Substances;" U.S. Pat. No. 5,665,331 for
"Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents
with Crystal Growth Modifiers;" U.S. Pat. No. 5,662,883 for
"Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents
with Crystal Growth Modifiers;" U.S. Pat. No. 5,560,932 for
"Microprecipitation of Nanoparticulate Pharmaceutical Agents;" U.S.
Pat. No. 5,543,133 for "Process of Preparing X-Ray Contrast
Compositions Containing Nanoparticles;" U.S. Pat. No. 5,534,270 for
"Method of Preparing Stable Drug Nanoparticles;" U.S. Pat. No.
5,510,118 for "Process of Preparing Therapeutic Compositions
Containing Nanoparticles;" and U.S. Pat. No. 5,470,583 for "Method
of Preparing Nanoparticle Compositions Containing Charged
Phospholipids to Reduce Aggregation," all of which are specifically
incorporated by reference.
[0094] The resultant nanoparticulate cyclosporine composition or
dispersion can be utilized in solid or liquid dosage formulations,
such as liquid dispersions, gels, aerosols, ointments, creams,
controlled release formulations, fast melt formulations,
lyophilized formulations, tablets, capsules, delayed release
formulations, extended release formulations, pulsatile release
formulations, mixed immediate release and controlled release
formulations, etc.
1. Milling to Obtain a Nanoparticulate Cyclosporine Dispersions
[0095] Milling a cyclosporine to obtain a nanoparticulate
dispersion comprises dispersing the cyclosporine particles in a
liquid dispersion medium in which the cyclosporine is poorly
soluble, followed by applying mechanical means in the presence of
grinding media to reduce the particle size of the cyclosporine to
the desired effective average particle size. The dispersion medium
can be, for example, water, safflower oil, ethanol, t-butanol,
glycerin, polyethylene glycol (PEG), hexane, or glycol. A preferred
dispersion medium is water.
[0096] The cyclosporine particles can be reduced in size in the
presence of at least one surface stabilizer. Alternatively,
cyclosporine particles can be contacted with one or more surface
stabilizers after attrition. Other compounds, such as a diluent,
can be added to the cyclosporine/surface stabilizer composition
during the size reduction process. A dispersion can be manufactured
continuously or in a batch mode.
2. Precipitation to Obtain a Nanoparticulate Cyclosporine
Composition
[0097] Another method of forming the desired nanoparticulate
cyclosporine composition is by microprecipitation. This is a method
of preparing stable dispersions of poorly soluble active agents in
the presence of one or more surface stabilizers and one or more
colloid stability enhancing surface active agents free of any trace
toxic solvents or solubilized heavy metal impurities. Such a method
comprises, for example: (1) dissolving the cyclosporine in a
suitable solvent; (2) adding the formulation from step (1) to a
solution comprising at least one surface stabilizer; and (3)
precipitating the formulation from step (2) using an appropriate
non-solvent. The method can be followed by removal of any formed
salt, if present, by dialysis or diafiltration and concentration of
the dispersion by conventional means.
3. Homogenization to Obtain Nanoparticulate Cyclosporine
Compositions
[0098] Exemplary homogenization methods of preparing active agent
nanoparticulate compositions are described in U.S. Pat. No.
5,510,118, for "Process of Preparing Therapeutic Compositions
Containing Nanoparticles." Such a method comprises dispersing
particles of a cyclosporine in a liquid dispersion medium, followed
by subjecting the dispersion to homogenization to reduce the
particle size of a cyclosporine to the desired effective average
particle size. The cyclosporine particles can be reduced in size in
the presence of at least one surface stabilizer. Alternatively, the
cyclosporine particles can be contacted with one or more surface
stabilizers either before or after attrition. Other compounds, such
as a diluent, can be added to the cyclosporine/surface stabilizer
composition either before, during, or after the size reduction
process. Dispersions can be manufactured continuously or in a batch
mode.
4. Cryogenic Methodologies to Obtain Nanoparticulate Cyclosporine
Compositions
[0099] Another method of forming the desired nanoparticulate
cyclosporine composition is by spray freezing into liquid (SFL).
This technology comprises an organic or organoaqueous solution of
cyclosporine with stabilizers, which is injected into a cryogenic
liquid, such as liquid nitrogen. The droplets of the cyclosporine
solution freeze at a rate sufficient to minimize crystallization
and particle growth, thus formulating nanostructured cyclosporine
particles. Depending on the choice of solvent system and processing
conditions, the nanoparticulate cyclosporine particles can have
varying particle morphology. In the isolation step, the nitrogen
and solvent are removed under conditions that avoid agglomeration
or ripening of the cyclosporine particles.
[0100] As a complementary technology to SFL, ultra rapid freezing
(URF) may also be used to created equivalent nanostructured
cyclosporine particles with greatly enhanced surface area. URF
comprises taking a water-miscible, anhydrous, organic, or
organoaqueous solution of PG derivative with stabilizers and
applying it onto a cryogenic substrate. The solvent is then
removed, by means such as lyophilization or atmospheric
freeze-drying with the resulting nanostructured PG derivative
remaining.
5. Emulsion Methodologies to Obtain Nanoparticulate Cyclosporine
Compositions
[0101] Another method of forming the desired nanoparticulate
cyclosporine composition is by template emulsion. Template emulsion
creates nanostructured cyclosporine particles with controlled
particle size distribution and rapid dissolution performance. The
method comprises an oil-in-water emulsion that is prepared, then
swelled with a non-aqueous solution comprising the cyclosporine and
stabilizers. The particle size distribution of the cyclosporine
particles is a direct result of the size of the emulsion droplets
prior to loading with the cyclosporine a property which can be
controlled and optimized in this process. Furthermore, through
selected use of solvents and stabilizers, emulsion stability is
achieved with no or suppressed Ostwald ripening. Subsequently, the
solvent and water are removed, and the stabilized nanostructured
cyclosporine particles are recovered. Various cyclosporine
particles morphologies can be achieved by appropriate control of
processing conditions.
D. Methods of Using the Nanoparticulate Cyclosporine Compositions
of the Invention
[0102] The invention provides a method of increasing
bioavailability of a cyclosporine in a subject. Such a method
comprises orally administering to a subject an effective amount of
a composition comprising a cyclosporine. The cyclosporine
composition, in accordance with standard pharmacokinetic practice,
has a bioavailability that is about 50% greater than a conventional
dosage form, about 40% greater, about 30% greater, about 20% or
about 10% greater.
[0103] The composition of the invention are useful in the
prevention and treatment of organ transplant rejection and
autoimmune diseases such as psoriasis, rheumatoid arthritis, and
other related diseases.
[0104] The cyclosporine compounds of the invention can be
administered to a subject via any conventional means including, but
not limited to, orally, rectally, ocularly, parenterally (e.g.,
intravenous, intramuscular, or subcutaneous), intracisternally,
pulmonary, intravaginally, intraperitoneally, locally (e.g.,
powders, ointments or drops), or as a buccal or nasal spray. As
used herein, the term "subject" is used to mean an animal,
preferably a mammal, including a human or non-human. The terms
patient and subject may be used interchangeably.
[0105] Compositions suitable for parenteral injection may comprise
physiologically acceptable sterile aqueous or nonaqueous solutions,
dispersions, suspensions or emulsions, and sterile powders for
reconstitution into sterile injectable solutions or dispersions.
Examples of suitable aqueous and nonaqueous carriers, diluents,
solvents, or vehicles including water, ethanol, polyols
(propyleneglycol, polyethylene-glycol, glycerol, and the like),
suitable mixtures thereof, vegetable oils (such as olive oil) and
injectable organic esters such as ethyl oleate. Proper fluidity can
be maintained, for example, by the use of a coating such as
lecithin, by the maintenance of the required particle size in the
case of dispersions, and by the use of surfactants.
[0106] The nanoparticulate cyclosporine compositions may also
contain adjuvants such as preserving, wetting, emulsifying, and
dispensing agents. Prevention of the growth of microorganisms can
be ensured by various antibacterial and antifungal agents, such as
parabens, chlorobutanol, phenol, sorbic acid, and the like. It may
also be desirable to include isotonic agents, such as sugars,
sodium chloride, and the like. Prolonged absorption of the
injectable pharmaceutical form can be brought about by the use of
agents delaying absorption, such as aluminum monostearate and
gelatin.
[0107] Solid dosage forms for oral administration include, but are
not limited to, capsules, tablets, pills, powders, and granules. In
such solid dosage forms, the active agent is admixed with at least
one of the following: (a) one or more inert excipients (or
carriers), such as sodium citrate or dicalcium phosphate; (b)
fillers or extenders, such as starches, lactose, sucrose, glucose,
mannitol, and silicic acid; (c) binders, such as
carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone,
sucrose, and acacia; (d) humectants, such as glycerol; (e)
disintegrating agents, such as agar-agar, calcium carbonate, potato
or tapioca starch, alginic acid, certain complex silicates, and
sodium carbonate; (f) solution retarders, such as paraffin; (g)
absorption accelerators, such as quaternary ammonium compounds; (h)
wetting agents, such as cetyl alcohol and glycerol monostearate;
(i) adsorbents, such as kaolin and bentonite; and (j) lubricants,
such as talc, calcium stearate, magnesium stearate, solid
polyethylene glycols, sodium lauryl sulfate, or mixtures thereof.
For capsules, tablets, and pills, the dosage forms may also
comprise buffering agents.
[0108] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs. In addition to a cyclosporine, the liquid
dosage forms may comprise inert diluents commonly used in the art,
such as water or other solvents, solubilizing agents, and
emulsifiers. Exemplary emulsifiers are ethyl alcohol, isopropyl
alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl
benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide,
oils, such as cottonseed oil, groundnut oil, corn germ oil, olive
oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl
alcohol, polyethyleneglycols, fatty acid esters of sorbitan, or
mixtures of these substances, and the like.
[0109] Besides such inert diluents, the composition can also
include adjuvants, such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
[0110] `Therapeutically effective amount` as used herein with
respect to a cyclosporine, dosage shall mean that dosage that
provides the specific pharmacological response for which a
cyclosporine is administered in a significant number of subjects in
need of such treatment. It is emphasized that `therapeutically
effective amount,` administered to a particular subject in a
particular instance will not always be effective in treating the
diseases described herein, even though such dosage is deemed a
`therapeutically effective amount` by those skilled in the art. It
is to be further understood that cyclosporine dosages are, in
particular instances, measured as oral dosages, or with reference
to drug levels as measured in blood.
[0111] One of ordinary skill will appreciate that effective amounts
of a cyclosporine can be determined empirically and can be employed
in pure form or, where such forms exist, in pharmaceutically
acceptable salt, ester, or prodrug form. Actual dosage levels of a
cyclosporine in the nanoparticulate compositions of the invention
may be varied to obtain an amount of a cyclosporine that is
effective to obtain a desired therapeutic response for a particular
composition and method of administration. The selected dosage level
therefore depends upon the desired therapeutic effect, the route of
administration, the potency of the administered cyclosporine, the
desired duration of treatment, and other factors.
[0112] Dosage unit compositions may contain such amounts of such
submultiples thereof as may be used to make up the daily dose. It
will be understood, however, that the specific dose level for any
particular patient will depend upon a variety of factors: the type
and degree of the cellular or physiological response to be
achieved; activity of the specific agent or composition employed;
the specific agents or composition employed; the age, body weight,
general health, sex, and diet of the patient; the time of
administration, route of administration, and rate of excretion of
the agent; the duration of the treatment; drugs used in combination
or coincidental with the specific agent; and like factors well
known in the medical arts.
II. Controlled Release Cyclosporine Compositions
[0113] Controlled release compositions comprising cyclosporine are
described. Controlled release compositions comprising
nanoparticulate cyclosporine are also described.
A. Multiparticulate Controlled Release Cyclosporine
Compositions
[0114] The above objects are realized by a controlled release
composition having a first component comprising a first population
of a cyclosporine or a nanoparticulate cyclosporine, and a
subsequent component comprising a subsequent population of
cyclosporine or nanoparticulate cyclosporine. The
ingredient-containing particles of the subsequent component are
coated with a modified release coating. Alternatively or
additionally, the subsequent population of cyclosporine or
nanoparticulate cyclosporine containing particles further comprises
a modified release matrix material. Following oral delivery, the
composition in operation delivers the cyclosporine in a pulsatile
or zero order manner.
[0115] In a preferred embodiment, the controlled release
composition of the present invention comprises a first component
which is an immediate release component.
[0116] The modified release coating applied to the subsequent
population of a cyclosporine or a nanoparticulate cyclosporine
causes a lag time between the release of active from the first
population of active cyclosporine-containing particles and the
release of active from the subsequent population of active
cyclosporine-containing particles. Similarly, the presence of a
modified release matrix material in the subsequent population of
active cyclosporine-containing particles causes a lag time between
the release of cyclosporine from the first population of
cyclosporine-containing particles and the release of active
ingredient from the subsequent population of active ingredient
containing particles. The duration of the lag time may be varied by
altering the composition and/or the amount of the modified release
coating and/or altering the composition and/or amount of modified
release matrix material utilized. Thus, the duration of the lag
time can be designed to mimic a desired plasma profile.
[0117] Because the plasma profile produced by the controlled
release composition upon administration is substantially similar to
the plasma profile produced by the administration of two or more IR
dosage forms given sequentially, the controlled release composition
of the present invention is particularly useful for administering a
cyclosporine or a nanoparticulate cyclosporine for which patient
tolerance may be problematical. This controlled release composition
is therefore advantageous for reducing or minimizing the
development of patient tolerance to the active ingredient in the
composition.
[0118] In a preferred embodiment of the present invention,
cyclosporine or a nanoparticulate cyclosporine and the composition
in operation delivers the cyclosporine in a bimodal or pulsatile or
zero order manner. Such a composition in operation produces a
plasma profile which substantially mimics that obtained by the
sequential administration of two IR doses as, for instance, in a
typical treatment regimen.
[0119] The present invention further relates to a controlled
release composition comprising a cyclosporine or a nanoparticulate
cyclosporine which in operation produced a plasma profile that
eliminates the "peaks" and "troughs" produced by the administration
of two or more IR dosage forms given sequentially if such a profile
is beneficial. This type of profile can be obtained using a
controlled release mechanism that allows for "zero-order"
delivery.
[0120] The present invention also provides solid oral dosage forms
comprising a composition according to the invention.
[0121] The term "particulate" as used herein refers to a state of
matter which is characterized by the presence of discrete
particles, pellets, beads or granules irrespective of their size,
shape or morphology. The term "multiparticulate" as used herein
means a plurality of discrete or aggregated particles, pellets,
beads, granules or mixture thereof, irrespective of their size,
shape or morphology.
[0122] The term "modified release" as used herein with respect to
the coating or coating material or used in any other context, means
release which is not immediate release and is taken to encompass
controlled release, sustained release and delayed release.
[0123] The term "time delay" as used herein refers to the duration
of time between administration of the composition and the release
of the cyclosporine from a particular component.
[0124] The term "lag time" as used herein refers to the time
between delivery of the cyclosporine from one component and the
subsequent delivery cyclosporine from another component.
[0125] The term "erodable" as used herein refers to formulations
which may be worn away, diminished, or deteriorated by the action
of substances within the body.
[0126] The term "diffusion controlled" as used herein refers to
formulations which may spread as the result of their spontaneous
movement, for example, from a region of higher to one of lower
concentration.
[0127] The term "osmotic controlled" as used herein refers to
formulations which may spread as the result of their movement
through a semipermeable membrane into a solution of higher
concentration that tends to equalize the concentrations of the
formulation on the two sides of the membrane.
[0128] The active ingredient in each component may be the same or
different. For example, a composition may comprise a first
component containing cyclosporine, and the subsequent component may
comprise a second active ingredient which would be desirable for
combination therapies. Indeed, two or more active ingredients may
be incorporated into the same component when the active ingredients
are compatible with each other. A drug compound present in one
component of the composition may be accompanied by, for example, an
enhancer compound or a sensitizer compound in another component of
the composition, in order to modify the bioavailability or
therapeutic effect of the drug compound.
[0129] As used herein, the term "enhancer" refers to a compound
which is capable of enhancing the absorption and/or bioavailability
of an active ingredient by promoting net transport across the GIT
in an animal, such as a human. Enhancers include but are not
limited to medium chain fatty acids; salts, esters, ethers and
derivatives thereof, including glycerides and triglycerides;
non-ionic surfactants such as those that can be prepared by
reacting ethylene oxide with a fatty acid, a fatty alcohol, an
alkylphenol or a sorbitan or glycerol fatty acid ester; cytochrome
P450 inhibitors, P-glycoprotein inhibitors and the like; and
mixtures of two or more of these agents.
[0130] The amount of the active ingredient contained in the
composition and in dosage forms made therefrom may be allocated
evenly or unevenly across the different particle populations
comprising the components of the composition and contained in the
dosage forms made therefrom. In one embodiment, the active
ingredient contained in the particles of the first component
comprises a minor portion of the total amount of active ingredient
in the composition or dosage form, and the amount of the active
ingredient in the other components comprises a major portion of the
total amount of active ingredient in the composition or dosage
form. In one such embodiment comprising two components, about 20%
of the total amount of the active ingredient is contained in the
particles of the first component, and about 80% of the total amount
of the active ingredient is contained in the particles of the
second component.
[0131] The proportion of the cyclosporine or the nanoparticulate
cyclosporine contained in each component may be the same or
different depending on the desired dosing regime. The cyclosporine
is present in the first component and in the second component in
any amount sufficient to elicit a therapeutic response. The
cyclosporine, when applicable, may be present either in the form of
one substantially optically pure enantiomer or as a mixture,
racemic or otherwise, of enantiomers. The cyclosporine is
preferably present in a composition in an amount of from 0.1-500
mg, preferably in the amount of from 1-100 mg. The cyclosporine is
preferably present in the first component in an amount of from
0.5-60 mg; more preferably the cyclosporine, is present in the
first component in an amount of from 2.5-30 mg. The cyclosporine is
present in the subsequent components in an amount within a similar
range to that described for the first component.
[0132] The time release characteristics for the delivery of the
cyclosporine or the nanoparticulate cyclosporine from each of the
components may be varied by modifying the composition of each
component, including modifying any of the excipients or coatings
which may be present. In particular, the release of the
cyclosporine may be controlled by changing the composition and/or
the amount of the modified release coating on the particles, if
such a coating is present. If more than one modified release
component is present, the modified release coating for each of
these components may be the same or different. Similarly, when
modified release is facilitated by the inclusion of a modified
release matrix material, release of the active ingredient may be
controlled by the choice and amount of modified release matrix
material utilized. The modified release coating may be present, in
each component, in any amount that is sufficient to yield the
desired delay time for each particular component. The modified
release coating may be preset, in each component, in any amount
that is sufficient to yield the desired time lag between
components.
[0133] The lag time or delay time for the release of the
cyclosporine or the nanoparticulate cyclosporine from each
component may also be varied by modifying the composition of each
of the components, including modifying any excipients and coatings
which may be present. For example, the first component may be an
immediate release component wherein the cyclosporine is released
immediately upon administration. Alternatively, the first component
may be, for example, a time-delayed immediate release component in
which the cyclosporine is released substantially in its entirety
immediately after a time delay. The subsequent component may be,
for example, a time-delayed immediate release component as just
described or, alternatively, a time-delayed sustained release or
extended release component in which the cyclosporine is released in
a controlled fashion over an extended period of time.
[0134] As will be appreciated by those skilled in the art, the
exact nature of the plasma concentration curve will be influenced
by the combination of all of these factors just described. In
particular, the lag time between the delivery (and thus also the
on-set of action) of the cyclosporine in each component may be
controlled by varying the composition and coating (if present) of
each of the components. Thus by variation of the composition of
each component (including the amount and nature of the active
ingredient(s)) and by variation of the lag time, numerous release
and plasma profiles may be obtained. Depending on the duration of
the lag time between the release of the cyclosporine from each
component and the nature of the release of the cyclosporine from
each component (i.e. immediate release, sustained release etc.),
the pulses in the plasma profile may be well separated and clearly
defined peaks (e.g. when the lag time is long) or the pulses may be
superimposed to a degree (e.g. in when the lag time is short).
[0135] In a preferred embodiment, the controlled release
composition according to the present invention has an immediate
release component and at least one modified release component, the
immediate release component comprising a first population of active
ingredient containing particles and the modified release components
comprising subsequent populations of active ingredient containing
particles. The subsequent modified release components may comprise
a controlled release coating. Additionally or alternatively, the
subsequent modified release components may comprise a modified
release matrix material. In operation, administration of such a
multi-particulate modified release composition having, for example,
a single modified release component results in characteristic
pulsatile plasma concentration levels of the cyclosporine or the
nanoparticulate cyclosporine in which the immediate release
component of the composition gives rise to a first peak in the
plasma profile and the modified release component gives rise to a
second peak in the plasma profile. Embodiments of the invention
comprising more than one modified release component give rise to
further peaks in the plasma profile.
[0136] Such a plasma profile produced from the administration of a
single dosage unit is advantageous when it is desirable to deliver
two (or more) pulses of active ingredient without the need for
administration of two (or more) dosage units. Additionally, in the
case of treating organ transplant rejection and autoimmune
diseases, it is particularly useful to have such a bimodal plasma
profile. For example, a typical cyclosporine treatment regime
consists of administration of two doses of an immediate release
dosage formulation given four hours apart. This type of regime has
been found to be therapeutically effective and is widely used. As
previously mentioned, the development of patient tolerance is an
adverse effect sometimes associated with cyclosporine treatments.
It is believed that the trough in the plasma profile between the
two peak plasma concentrations is advantageous in reducing the
development of patient tolerance by providing a period of wash out
of the cyclosporine.
[0137] In addition, a delivery system having a zero order or pseudo
zero order delivery that eliminates or minimizes the "peak" to
"trough" ratio is also described.
[0138] Any coating material which modifies the release of the
cyclosporine or the nanoparticulate cyclosporine in the desired
manner may be used. In particular, coating materials suitable for
use in the practice of the invention include but are not limited to
polymer coating materials, such as cellulose acetate phthalate,
cellulose acetate trimaletate, hydroxy propyl methylcellulose
phthalate, polyvinyl acetate phthalate, ammonio methacrylate
copolymers such as those sold under the Trade Mark Eudragit.RTM. RS
and RL, poly acrylic acid and poly acrylate and methacrylate
copolymers such as those sold under the Trade Mark Eudragit S and
L, polyvinyl acetaldiethylamino acetate, hydroxypropyl
methylcellulose acetate succinate, shellac; hydrogels and
gel-forming materials, such as carboxyvinyl polymers, sodium
alginate, sodium carmellose, calcium carmellose, sodium
carboxymethyl starch, poly vinyl alcohol, hydroxyethyl cellulose,
methyl cellulose, gelatin, starch, and cellulose based cross-linked
polymers--in which the degree of crosslinking is low so as to
facilitate adsorption of water and expansion of the polymer matrix,
hydroxypropyl cellulose, hydroxypropyl methylcellulose,
polyvinylpyrrolidone, crosslinked starch, microcrystalline
cellulose, chitin, aminoacryl-methacrylate copolymer (Eudragit.RTM.
RS-PM, Rohm & Haas), pullulan, collagen, casein, agar, gum
arabic, sodium carboxymethyl cellulose, (swellable hydrophilic
polymers) poly(hydroxyalkyl methacrylate) (m. wt. .about.5 k-5,000
k), polyvinylpyrrolidone (m. wt. .about.10 k-360 k), anionic and
cationic hydrogels, polyvinyl alcohol having a low acetate
residual, a swellable mixture of agar and carboxymethyl cellulose,
copolymers of maleic anhydride and styrene, ethylene, propylene or
isobutylene, pectin (m. wt. .about.30 k-300 k), polysaccharides
such as agar, acacia, karaya, tragacanth, algins and guar,
polyacrylamides, Polyox.RTM. polyethylene oxides (m. wt. .about.100
k-5,000 k), AquaKeep.RTM. acrylate polymers, diesters of
polyglucan, crosslinked polyvinyl alcohol and poly
N-vinyl-2-pyrrolidone, sodium starch glucolate (e.g. Explotab.RTM.;
Edward Mandell C. Ltd.); hydrophilic polymers such as
polysaccharides, methyl cellulose, sodium or calcium carboxymethyl
cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose,
hydroxyethyl cellulose, nitro cellulose, carboxymethyl cellulose,
cellulose ethers, polyethylene oxides (e.g. Polyox.RTM., Union
Carbide), methyl ethyl cellulose, ethylhydroxy ethylcellulose,
cellulose acetate, cellulose butyrate, cellulose propionate,
gelatin, collagen, starch, maltodextrin, pullulan, polyvinyl
pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty
acid esters, polyacrylamide, polyacrylic acid, copolymers of
methacrylic acid or methacrylic acid (e.g. Eudragit.RTM., Rohm and
Haas), other acrylic acid derivatives, sorbitan esters, natural
gums, lecithins, pectin, alginates, ammonia alginate, sodium,
calcium, potassium alginates, propylene glycol alginate, agar, and
gums such as arabic, karaya, locust bean, tragacanth, carrageens,
guar, xanthan, scleroglucan and mixtures and blends thereof. As
will be appreciated by the person skilled in the art, excipients
such as plasticisers, lubricants, solvents and the like may be
added to the coating. Suitable plasticisers include for example
acetylated monoglycerides; butyl phthalyl butyl glycolate; dibutyl
tartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalyl
ethyl glycolate; glycerin; propylene glycol; triacetin; citrate;
tripropioin; diacetin; dibutyl phthalate; acetyl monoglyceride;
polyethylene glycols; castor oil; triethyl citrate; polyhydric
alcohols, glycerol, acetate esters, gylcerol triacetate, acetyl
triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl
octyl phthalate, diisononyl phthalate, butyl octyl phthalate,
dioctyl azelate, epoxidised tallate, triisoctyl trimellitate,
diethylhexyl phthalate, di-n-octyl phthalate, di-i-octyl phthalate,
di-i-decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl
phthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate,
di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl
sebacate.
[0139] When the modified release component comprises a modified
release matrix material, any suitable modified release matrix
material or suitable combination of modified release matrix
materials may be used. Such materials are known to those skilled in
the art. The term "modified release matrix material" as used herein
includes hydrophilic polymers, hydrophobic polymers and mixtures
thereof which are capable of modifying the release of a
cyclosporine or a nanoparticulate cyclosporine dispersed therein in
vitro or in vivo. Modified release matrix materials suitable for
the practice of the present invention include but are not limited
to microcrystalline cellulose, sodium carboxymethylcellulose,
hydroxyalkylcelluloses such as hydroxypropylmethylcellulose and
hydroxypropylcellulose, polyethylene oxide, alkylcelluloses such as
methylcellulose and ethylcellulose, polyethylene glycol,
polyvinylpyrrolidone, cellulose acetate, cellulose acetate
butyrate, cellulose acetate phthalate, cellulose acetate
trimellitate, polyvinylacetate phthalate, polyalkylmethacrylates,
polyvinyl acetate and mixture thereof.
[0140] A controlled release composition according to the present
invention may be incorporated into any suitable dosage form which
facilitates release of the active ingredient in a pulsatile or zero
order manner. Typically, the dosage form may be a blend of the
different populations of cyclosporine-containing particles which
make up the immediate release and the modified release components,
the blend being filled into suitable capsules, such as hard or soft
gelatin capsules. Alternatively, the different individual
populations of active ingredient containing particles may be
compressed (optionally with additional excipients) into
mini-tablets which may be subsequently filled into capsules in the
appropriate proportions. Another suitable dosage form is that of a
multilayer tablet. In this instance the first component of the
controlled release composition may be compressed into one layer,
with the second component being subsequently added as a second
layer of the multilayer tablet. The populations of
cyclosporine-containing particles making up the composition of the
invention may further be included in rapidly dissolving dosage
forms such as an effervescent dosage form or a fast-melt dosage
form.
[0141] The composition according to the invention comprises at
least two populations of cyclosporine-containing particles which
have different in vitro dissolution profiles.
[0142] Preferably, in operation the composition of the invention
and the solid oral dosage forms containing the composition release
the cyclosporine or the nanoparticulate cyclosporine such that
substantially all of the cyclosporine contained in the first
component is released prior to release of the cyclosporine from the
second component. When the first component comprises an IR
component, for example, it is preferable that release of the
cyclosporine from the second component is delayed until
substantially all the cyclosporine in the IR component has been
released. Release of the cyclosporine from the second component may
be delayed as detailed above by the use of a modified release
coating and/or a modified release matrix material.
[0143] More preferably, when it is desirable to minimize patient
tolerance by providing a dosage regime which facilitates wash-out
of a first dose of the cyclosporine or the nanoparticulate
cyclosporine from a patient's system, release of the cyclosporine
from the second component is delayed until substantially all of the
cyclosporine contained in the first component has been released,
and further delayed until at least a portion the cyclosporine
released from the first component has been cleared from the
patient's system. In a preferred embodiment, release of the
cyclosporine from the second component of the composition in
operation is substantially, if not completely, delayed for a period
of at least about two hours after administration of the
composition.
[0144] The cyclosporine release of the drug from the second
component of the composition in operation is substantially, if not
completely, delayed for a period of at least about four hours,
preferably about four hours, after administration of the
composition.
B. Other Delivery Mechanisms for Controlled Release Cyclosporine
Compositions
[0145] As described herein, the invention includes various types of
controlled release systems by which the active drug may be
delivered in a pulsatile or zero order manner. These systems
include, but are not limited to: films with the drug in a polymer
matrix (monolithic devices); the drug contained by the polymer
(reservoir devices); polymeric colloidal particles or
microencapsulates (microparticles, microspheres or nanoparticles)
in the form of reservoir and matrix devices; drug contained by a
polymer containing a hydrophilic and/or leachable additive eg, a
second polymer, surfactant or plasticiser, etc. to give a porous
device, or a device in which the drug release may be osmotically
`controlled` (both reservoir and matrix devices); enteric coatings
(ionise and dissolve at a suitable pH); (soluble) polymers with
(covalently) attached `pendant` drug molecules; devices where
release rate is controlled dynamically: eg, the osmotic pump.
[0146] The delivery mechanism of the invention will control the
rate of release of the drug. While some mechanisms will release the
drug at a constant rate (zero order), others will vary as a
function of time depending on factors such as changing
concentration gradients or additive leaching leading to porosity,
etc.
[0147] Polymers used in sustained release coatings are necessarily
biocompatible, and ideally biodegradable. Examples of both
naturally occurring polymers such as Aquacoat.RTM. (FMC
Corporation, Food & Pharmaceutical Products Division,
Philadelphia, USA) (ethylcellulose mechanically spheronised to
sub-micron sized, aqueous based, pseudo-latex dispersions), and
also synthetic polymers such as the Eudragit.RTM. (Rohm Pharma,
Weiterstadt.) range of poly(acrylate, methacrylate) copolymers are
known in the art.
1. Reservoir Devices
[0148] A typical approach to controlled release is to encapsulate
or contain the drug entirely (eg, as a core), within a polymer film
or coat (ie, microcapsules or spray/pan coated cores).
[0149] The various factors that can affect the diffusion process
may readily be applied to reservoir devices (eg, the effects of
additives, polymer functionality {and, hence, sink-solution pH}
porosity, film casting conditions, etc.) and, hence, the choice of
polymer must be an important consideration in the development of
reservoir devices. Modeling the release characteristics of
reservoir devices (and monolithic devices) in which the transport
of the drug is by a solution-diffusion mechanism therefore
typically involves a solution to Fick's second law (unsteady-state
conditions; concentration dependent flux) for the relevant boundary
conditions. When the device contains dissolved active agent, the
rate of release decreases exponentially with time as the
concentration (activity) of the agent (ie, the driving force for
release) within the device decreases (ie, first order release). If,
however, the active agent is in a saturated suspension, then the
driving force for release is kept constant (zero order) until the
device is no longer saturated. Alternatively the release-rate
kinetics may be desorption controlled, and a function of the square
root of time.
[0150] Transport properties of coated tablets, may be enhanced
compared to free-polymer films, due to the enclosed nature of the
tablet core (permeant) which may enable the internal build-up of an
osmotic pressure which will then act to force the permeant out of
the tablet.
[0151] The effect of deionised water on salt containing tablets
coated in poly(ethylene glycol) (PEG)-containing silicone
elastomer, and also the effects of water on free films has been
investigated. The release of salt from the tablets was found to be
a mixture of diffusion through water filled pores, formed by
hydration of the coating, and osmotic pumping. KCl transport
through films containing just 10% PEG was negligible, despite
extensive swelling observed in similar free films, indicating that
porosity was necessary for the release of the KCl which then
occurred by `trans-pore diffusion.` Coated salt tablets, shaped as
disks, were found to swell in deionised water and change shape to
an oblate spheroid as a result of the build-up of internal
hydrostatic pressure: the change in shape providing a means to
measure the `force` generated. As might be expected, the osmotic
force decreased with increasing levels of PEG content. The lower
PEG levels allowed water to be imbibed through the hydrated
polymer; whilst the porosity resulting from the coating dissolving
at higher levels of PEG content (20 to 40%) allowed the pressure to
be relieved by the flow of KCl.
[0152] Methods and equations have been developed, which by
monitoring (independently) the release of two different salts (eg,
KCl and NaCl) allowed the calculation of the relative magnitudes
that both osmotic pumping and trans-pore diffusion contributed to
the release of salt from the tablet. At low PEG levels, osmotic
flow was increased to a greater extent than was trans-pore
diffusion due to the generation of only a low pore number density:
at a loading of 20%, both mechanisms contributed approximately
equally to the release. The build-up of hydrostatic pressure,
however, decreased the osmotic inflow, and osmotic pumping. At
higher loadings of PEG, the hydrated film was more porous and less
resistant to outflow of salt. Hence, although the osmotic pumping
increased (compared to the lower loading), trans-pore diffusion was
the dominant release mechanism. An osmotic release mechanism has
also been reported for microcapsules containing a water soluble
core.
2. Monolithic Devices (Matrix Devices)
[0153] Monolithic (matrix) devices are possibly the most common of
the devices for controlling the release of drugs. This is possibly
because they are relatively easy to fabricate, compared to
reservoir devices, and there is not the danger of an accidental
high dosage that could result from the rupture of the membrane of a
reservoir device. In such a device the active agent is present as a
dispersion within the polymer matrix, and they are typically formed
by the compression of a polymer/drug mixture or by dissolution or
melting. The dosage release properties of monolithic devices may be
dependent upon the solubility of the drug in the polymer matrix or,
in the case of porous matrixes, the solubility in the sink solution
within the particle's pore network, and also the tortuosity of the
network (to a greater extent than the permeability of the film),
dependent on whether the drug is dispersed in the polymer or
dissolved in the polymer. For low loadings of drug, (0 to 5% W/V)
the drug will be released by a solution-diffusion mechanism (in the
absence of pores). At higher loadings (5 to 10% W/V), the release
mechanism will be complicated by the presence of cavities formed
near the surface of the device as the drug is lost: such cavities
fill with fluid from the environment increasing the rate of release
of the drug.
[0154] It is common to add a plasticiser (eg, a poly(ethylene
glycol)), or surfactant, or adjuvant (ie, an ingredient which
increases effectiveness), to matrix devices (and reservoir devices)
as a means to enhance the permeability (although, in contrast,
plasticiser may be fugitive, and simply serve to aid film formation
and, hence, decrease permeability--a property normally more
desirable in polymer paint coatings). It was noted that the
leaching of PEG acted to increase the permeability of (ethyl
cellulose) films linearly as a function of PEG loading by
increasing the porosity, however, the films retained their barrier
properties, not permitting the transport of electrolyte. It was
deduced that the enhancement of their permeability was as a result
of the effective decrease in thickness caused by the PEG leaching.
This was evinced from plots of the cumulative permeant flux per
unit area as a function of time and film reciprocal thickness at a
PEG loading of 50% W/W: plots showing a linear relationship between
the rate of permeation and reciprocal film thickness, as expected
for a (Fickian) solution-diffusion type transport mechanism in a
homogeneous membrane. Extrapolation of the linear regions of the
graphs to the time axis gave positive intercepts on the time axis:
the magnitude of which decreased towards zero with decreasing film
thickness. These changing lag times were attributed to the
occurrence of two diffusional flows during the early stages of the
experiment (the flow of the `drug` and also the flow of the PEG),
and also to the more usual lag time during which the concentration
of permeant in the film is building-up. Caffeine, when used as a
permeant, showed negative lag times. No explanation of this was
forthcoming, but it was noted that caffeine exhibited a low
partition coefficient in the system, and that this was also a
feature of aniline permeation through polyethylene films which
showed a similar negative time lag.
[0155] The effects of added surfactants on (hydrophobic) matrix
devices has been investigated. It was thought that surfactant may
increase the drug release rate by three possible mechanisms: (i)
increased solubilisation, (ii) improved `wettability` to the
dissolution media, and (iii) pore formation as a result of
surfactant leaching. For the system studied (Eudragit.RTM. RL 100
and RS 100 plasticised by sorbitol, Flurbiprofen as the drug, and a
range of surfactants) it was concluded that improved wetting of the
tablet led to only a partial improvement in drug release (implying
that the release was diffusion, rather than dissolution,
controlled), although the effect was greater for Eudragit.RTM. RS
than Eudragit.RTM. RL, whilst the greatest influence on release was
by those surfactants that were more soluble due to the formation of
`disruptions` in the matrix allowing the dissolution medium access
to within the matrix. This is of obvious relevance to a study of
latex films which might be suitable for pharmaceutical coatings,
due to the ease with which a polymer latex may be prepared with
surfactant as opposed to surfactant-free. Differences were found
between the two polymers--with only the Eudragit.RTM. RS showing
interactions between the anionic/cationic surfactant and drug. This
was ascribed to the differing levels of quaternary ammonium ions on
the polymer.
[0156] Composite devices consisting of a polymer/drug matrix coated
in a polymer containing no drug also exist. Such a device was
constructed from aqueous Eudragit.RTM. latices, and was found to
give zero order release by diffusion of the drug from the core
through the shell. Similarly, a polymer core containing the drug
has been produced, but coated this with a shell that was eroded by
the gastric fluid. The rate of release of the drug was found to be
relatively linear (a function of the rate limiting diffusion
process through the shell) and inversely proportional to the shell
thickness, whereas the release from the core alone was found to
decrease with time.
3. Microspheres
[0157] Methods for the preparation of hollow microspheres
('microballoons') with the drug dispersed in the sphere's shell,
and also highly porous matrix-type microspheres ('microsponges')
have been described. The microsponges were prepared by dissolving
the drug and polymer in ethanol. On addition to water, the ethanol
diffused from the emulsion droplets to leave a highly porous
particle.
[0158] The hollow microspheres were formed by preparing a solution
of ethanol/dichloro-methane containing the drug and polymer. On
pouring into water, this formed an emulsion containing the
dispersed polymer/drug/solvent particles, by a coacervation-type
process, from which the ethanol (a good solvent for the polymer)
rapidly diffused precipitating polymer at the surface of the
droplet to give a hard-shelled particle enclosing the drug,
dissolved in the dichloromethane. At this point, a gas phase of
dichloromethane was generated within the particle which, after
diffusing through the shell, was observed to bubble to the surface
of the aqueous phase. The hollow sphere, at reduced pressure, then
filled with water, which could be removed by a period of drying.
(No drug was found in the water.) A suggested use of the
microspheres was as floating drug delivery devices for use in the
stomach.
4. Pendent Devices
[0159] A means of attaching a range of drugs such as analgesics and
antidepressants, etc., by means of an ester linkage to
poly(acrylate) ester latex particles prepared by aqueous emulsion
polymerization has been developed. These latices when passed
through an ion exchange resin such that the polymer end groups were
converted to their strong acid form could `self-catalyse` the
release of the drug by hydrolysis of the ester link.
[0160] Drugs have been attached to polymers, and also monomers have
been synthesized with a pendent drug attached. The research group
have also prepared their own dosage forms in which the drug is
bound to a biocompatible polymer by a labile chemical bond eg,
polyanhydrides prepared from a substituted anhydride (itself
prepared by reacting an acid chloride with the drug: methacryloyl
chloride and the sodium salt of methoxy benzoic acid) were used to
form a matrix with a second polymer (Eudragit.RTM. RL) which
released the drug on hydrolysis in gastric fluid. The use of
polymeric Schiff bases suitable for use as carriers of
pharmaceutical amines has also been described.
5. Enteric Films
[0161] Enteric coatings consist of pH sensitive polymers. Typically
the polymers are carboxylated and interact (swell) very little with
water at low pH, whilst at high pH the polymers ionise causing
swelling, or dissolving of the polymer. Coatings can therefore be
designed to remain intact in the acidic environment of the stomach
(protecting either the drug from this environment or the stomach
from the drug), but to dissolve in the more alkaline environment of
the intestine.
6. Osmotically Controlled Devices
[0162] The osmotic pump is similar to a reservoir device but
contains an osmotic agent (eg, the active agent in salt form) which
acts to imbibe water from the surrounding medium via a
semi-permeable membrane. Such a device, called the `elementary
osmotic pump`, has been described. Pressure is generated within the
device which forces the active agent out of the device via an
orifice (of a size designed to minimise solute diffusion, whilst
preventing the build-up of a hydrostatic pressure head which has
the effect of decreasing the osmotic pressure and changing the
dimensions {volume} of the device). Whilst the internal volume of
the device remains constant, and there is an excess of solid
(saturated solution) in the device, then the release rate remains
constant delivering a volume equal to the volume of solvent
uptake.
7. Electrically Stimulated Release Devices
[0163] Monolithic devices have been prepared using polyelectrolyte
gels which swelled when, for example, an external electrical
stimulus was applied, causing a change in pH. The release could be
modulated, by the current, giving a pulsatile release profile.
8. Hydrogels
[0164] Hydrogels find a use in a number of biomedical applications,
in addition to their use in drug matrices (eg, soft contact lenses,
and various `soft` implants, etc.).
C. Methods of Using Controlled Release Cyclosporine
Compositions
[0165] The present invention further provides a method of treating
a patient suffering from organ transplant rejection or autoimmune
diseases such as psoriasis, rheumatoid arthritis, and other related
diseases utilizing a cyclosporine or a nanoparticulate cyclosporine
comprising the administration of a therapeutically effective amount
of a solid oral dosage form of a cyclosporine to provide a pulsed
or bimodal or zero order delivery of the cyclosporine. Advantages
of the present invention include reducing the dosing frequency
required by conventional multiple IR dosage regimes while still
maintaining the benefits derived from a pulsatile plasma profile or
eliminating or minimizing the "peak" to "trough" ratio. This
reduced dosing frequency is advantageous in terms of patient
compliance to have a formulation which may be administered at
reduced frequency. The reduction in dosage frequency made possible
by utilizing the present invention would contribute to reducing
health care costs by reducing the amount of time spent by health
care workers on the administration of drugs.
[0166] In the following examples all percentages are weight by
weight unless otherwise stated. The term "purified water" as used
throughout the Examples refers to water that has been purified by
passing it through a water filtration system. It is to be
understood that the examples are for illustrative purposes only,
and should not be interpreted as restricting the spirit and scope
of the invention, as defined by the scope of the claims that
follow.
Example 1
Multiparticulate Modified Release Composition Containing
Cyclosporine
[0167] A multiparticulate modified release composition according to
the present invention comprising an immediate release component and
a modified release component containing cyclosporine is prepared as
follows.
(a) Immediate Release Component.
[0168] A solution of cyclosporine (50:50 racemic mixture) is
prepared according to any of the formulations given in Table 1. The
methylphenidate solution is then coated onto nonpareil seeds to a
level of approximately 16.9% solids weight gain using, for example,
a Glatt GPCG3 (Glatt, Protech Ltd., Leicester, UK) fluid bed
coating apparatus to form the IR particles of the immediate release
component.
TABLE-US-00005 TABLE 1 Immediate release component solutions
Amount, % (w/w) Ingredient (i) (ii) Cyclosporine 13.0 13.0
Polyethylene Glycol 6000 0.5 0.5 Polyvinylpyrrolidone 3.5 Purified
Water 83.5 86.5
(b) Modified Release Component
[0169] Cyclosporine-containing delayed release particles are
prepared by coating immediate release particles prepared according
to Example 1(a) above with a modified release coating solution as
detailed in Table 2. The immediate release particles are coated to
varying levels up to approximately to 30% weight gain using, for
example, a fluid bed apparatus.
TABLE-US-00006 TABLE 2 Modified release component coating solutions
Amount, % (w/w) Ingredient (i) (ii) (iii) (iv) (v) (vi) (vii)
(viii) Eudragit 49.7 42.0 47.1 53.2 40.6 -- -- 25.0 .RTM. RS 12.5
Eudragit -- -- -- -- -- 54.35 46.5 -- .RTM. S 12.5 Eudragit -- --
-- -- -- -- 25.0 .RTM. L 12.5 Polyvinyl- -- -- -- 0.35 0.3 -- --
pyrrolidone Diethyl- 0.5 0.5 0.6 1.35 0.6 1.3 1.1 -- phthalate
Triethyl- -- -- -- -- -- -- -- 1.25 citrate Isopropyl 39.8 33.1
37.2 45.1 33.8 44.35 49.6 46.5 alcohol Acetone 10.0 8.3 9.3 -- 8.4
-- -- -- Talc.sup.1 -- 16.0 5.9 -- 16.3 -- 2.8 2.25 .sup.1 Talc is
simultaneously applied during coating for formulations in column
(i), (iv) and (vi).
(c) Encapsulation of Immediate and Delayed Release Particles.
[0170] The immediate and delayed release particles prepared
according to Example 1(a) and (b) above are encapsulated in size 2
hard gelatin capsules to an overall 20 mg dosage strength using,
for example, a Bosch GKF 4000S encapsulation apparatus. The overall
dosage strength of 20 mg cyclosporine was made up of 10 mg from the
immediate release component and 10 mg from the modified release
component.
Example 2
Multiparticulate Modified Release Composition Containing
Cyclosporine
[0171] Multiparticulate modified release cyclosporine compositions
according to the present invention having an immediate release
component and a modified release component having a modified
release matrix material are prepared according to the formulations
shown in Table 3(a) and (b).
TABLE-US-00007 TABLE 3 (a) 100 mg of IR component is encapsulated
with 100 mg of modified release (MR) component to give a 20 mg
dosage strength product % (w/w) IR component Cyclosporine 10
Microcrystalline cellulose 40 Lactose 45 Povidone 5 MR component
Cyclosporine 10 Microcrytalline cellulose 40 Eudragit .RTM. RS 45
Povidone 5
TABLE-US-00008 TABLE 3 (b) 50 mg of IR component is encapsulated
with 50 mg of modified release (MR) component to give a 20 mg
dosage strength product. % (w/w) IR component Cyclosporine 20
Microcrystalline cellulose 50 Lactose 28 Povidone 2 MR component
Cyclosporine 20 Microcrytalline cellulose 50 Eudragit .RTM. S 28
Povidone 2
[0172] It will be apparent to those skilled in the art that various
modifications and variations can be made in the methods and
compositions of the present inventions without departing from the
spirit or scope of the invention. Thus, it is intended that the
present invention cover the modification and variations of the
invention provided they come within the scope of the appended
claims and their equivalents.
[0173] In addition, it will be apparent to those skilled in the art
that cyclosporine in nanoparticulate form may be used in
substitution of cyclosporine in the above examples. Further, the
modified release particles may further include an additional layer
of cyclosporine or nanoparticulate cyclosporine coated on top of
the modified release portion, the additional layer allowing for
immediate release of the cyclosporine or nanoparticulate
cyclosporine.
* * * * *