U.S. patent application number 16/528007 was filed with the patent office on 2020-01-09 for pharmaceutical cyclosporin compositions.
This patent application is currently assigned to Sublimity Therapeutics Limited. The applicant listed for this patent is Sublimity Therapeutics Limited. Invention is credited to Ivan Coulter.
Application Number | 20200009219 16/528007 |
Document ID | / |
Family ID | 39745242 |
Filed Date | 2020-01-09 |
United States Patent
Application |
20200009219 |
Kind Code |
A1 |
Coulter; Ivan |
January 9, 2020 |
PHARMACEUTICAL CYCLOSPORIN COMPOSITIONS
Abstract
An oral cyclosporin composition comprises minicapsules having a
core containing a cyclosporin, especially cyclosporin A in a
solubilised liquid form. The minicapsules have a release profile to
release the pre-solubilised cyclosporin, at least in the colon. The
composition may be used for treating a range of intestinal
diseases.
Inventors: |
Coulter; Ivan; (Dublin,
IE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sublimity Therapeutics Limited |
Dublin |
|
IE |
|
|
Assignee: |
Sublimity Therapeutics
Limited
Dublin
IE
|
Family ID: |
39745242 |
Appl. No.: |
16/528007 |
Filed: |
July 31, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15596759 |
May 16, 2017 |
10434140 |
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16528007 |
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15051356 |
Feb 23, 2016 |
9675558 |
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15596759 |
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|
13942492 |
Jul 15, 2013 |
9387179 |
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15051356 |
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12594534 |
Feb 22, 2010 |
8535713 |
|
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PCT/IE2008/000038 |
Apr 4, 2008 |
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13942492 |
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61006498 |
Jan 16, 2008 |
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60907490 |
Apr 4, 2007 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/5015 20130101;
A61P 37/00 20180101; A61P 3/00 20180101; A61P 1/04 20180101; A61K
9/0053 20130101; A61P 37/06 20180101; A61K 9/5073 20130101; A61K
31/635 20130101; A61P 25/28 20180101; A61K 9/5089 20130101; A61P
19/02 20180101; A61K 31/436 20130101; A61K 9/50 20130101; A61K
31/439 20130101; A61K 45/06 20130101; A61P 37/04 20180101; A61P
1/10 20180101; A61K 9/5057 20130101; A61P 3/10 20180101; A61K
9/5026 20130101; A61K 38/28 20130101; A61P 1/00 20180101; A61K
9/5047 20130101; A61K 2039/55583 20130101; A61K 9/5042 20130101;
A61K 35/741 20130101; A61K 38/13 20130101; A61P 31/00 20180101;
A61P 43/00 20180101; A61P 1/12 20180101; A61K 39/0005 20130101 |
International
Class: |
A61K 38/13 20060101
A61K038/13; A61K 9/00 20060101 A61K009/00; A61K 45/06 20060101
A61K045/06; A61K 39/00 20060101 A61K039/00; A61K 38/28 20060101
A61K038/28; A61K 35/741 20060101 A61K035/741; A61K 31/635 20060101
A61K031/635; A61K 31/439 20060101 A61K031/439; A61K 31/436 20060101
A61K031/436; A61K 9/50 20060101 A61K009/50 |
Claims
1. (canceled)
2. A method of treating ulcerative colitis by administering to a
subject a composition, the method comprising orally administering
the composition, wherein the composition comprises cyclosporin in a
solubilised liquid form in combination with a pharmaceutically
acceptable carrier(s) or excipient(s), wherein the cyclosporin and
the pharmaceutically acceptable carrier(s) or excipient(s) are
contained within a gelling agent and the composition comprises a
modified release coating suitable to provide the release of the
cyclosporin in the colon.
3. The method of claim 2, wherein the method further comprises
administering to the subject any one or a combination of
tacrolimus, sirolimus, EPA or DHA.
4. The method of claim 3, wherein the composition has a dissolution
profile, when tested in a U.S.P. Type II apparatus (paddles) at
37.degree. C. and 50 rpm, in pH 6.8 buffer as follows: 1 hour: less
than or equal to about 20% drug released.
5. The method of claim 4, wherein at 4 hours: about 20% to about
35% drug released.
6. The method of claim 5, wherein at 6 hours: about 35% to about
50% drug released.
7. The method of claim 6, wherein at 12 hours: about 50% to about
60% drug released.
8. The method of claim 7, wherein at 16 hours: about 60% to about
75% drug released.
9. The method of claim 8, wherein at 24 hours from about 75% to
about 100% drug released.
10. The method of claim 2, wherein the composition has a
dissolution profile, when tested in a U.S.P. Type II apparatus
(paddles) at 37.degree. C. and 50 rpm, in pH 6.8 buffer as follows:
4 hours: about 30% to about 50% drug released.
11. The method of claim 10, wherein at 6 hours: about 40% to about
70% drug is released.
12. The method of claim 10, wherein at 12 hours: about 70% to about
80% drug is released.
13. The method of claim 2, wherein the composition has a
dissolution profile, when tested in a U.S.P. Type II apparatus
(paddles) at 37.degree. C. and 50 rpm, in pH 6.8 buffer as follows:
4 hours: about 15% to about 60% drug released.
14. The method of claim 13, wherein at 6 hours: about 25% to about
70% drug is released.
15. The method of claim 14, wherein at 12 hours: about 45% to about
80% drug is released.
16. The method of claim 2, wherein the composition has a
dissolution profile, when tested in a U.S.P. Type II apparatus
(paddles) at 37.degree. C. and 50 rpm, in pH 6.8 buffer as follows:
4 hours: about 45% to about 60% drug released.
17. The method of claim 16, wherein at 6 hours: about 60% to about
70% drug is released.
18. The method of claim 17, wherein at 12 hours: about 70% to about
80% drug is released.
19. The method of claim 2, wherein the minicapsules have a
dissolution profile, when tested in a U.S.P. Type II apparatus
(paddles) at 37.degree. C. and 50 rpm, in pH 6.8 buffer as follows:
up to 4 hours: less than or equal to about 20% cyclosporin
released; 24 hours: from about 75% to about 100% cyclosporin
released.
20. The method of claim 19 wherein, in the dissolution profile,
less than or equal to about 20% cyclosporin is released in 1
hour.
21. The method of claim 2, wherein the composition comprises
minicapsules.
22. The method of claim 21, wherein the minicapsules have the
characteristics of minicapsules obtained by utilisation of surface
tensions of a hydrophobic core solution comprising the cyclosporin
in a solubilised form and a shell solution comprising the gelling
agent, which solutions are ejected through a nozzle having one
orifice and subject to specific frequencies and which form into a
spherical form and fall into a cooling air flow or a cooling or
hardening solution where the shell solution is gelled or
solidified.
23. The method of claim 21, wherein the minicapsules are seamless
minicapsules.
24. The method of claim 21, wherein the minicapsule are coated with
the modified release coating.
25. The method of claim 24, wherein the modified release coating
comprises two types of polymers that are applied as separate coats
to the minicapsule.
26. The method of claim 2, wherein the modified release coating
comprises a controlled release polymer.
27. The method of claim 26, wherein the controlled release polymer
is ethylcellulose.
28. The method of claim 2, wherein the modified release coating is
without the inclusion of a dissolution enhancing agent.
29. The method of claim 2, wherein the gelling agent is
gelatin.
30. The method of claim 2, wherein the cyclosporin is solubilized
in a hydrophobic solution.
31. The method of claim 21, wherein the minicapsules have applied
thereto: the modified release coating comprising a first polymer
selected from a methacrylate; ethylcellulose; and a composite of
methacrylate and ethylcellulose; and an optional separate coating
comprising a second polymer.
32. The method of claim 21, wherein the minicapsules are seamless,
and wherein the release profile comprises sustained and delayed
release of the solubilised cyclosporin.
33. The method of claim 2, wherein the minicapsules are further
adapted to allow abrupt and/or sustained release of the solubilised
cyclosporin into the proximal colon.
34. The method of claim 2, wherein the cyclosporin is protected
from absorption in the upper gastrointestinal tract.
35. The method of claim 2, wherein the release profile comprises
sustained release of the cyclosporin.
36. The method of claim 21, wherein said minicapsules comprise
minicapsules that have a coating comprising a sustained release
polymer.
37. The method of claim 2, wherein the composition further
comprises immediate release minicapsules comprising cyclosporin in
a solubilised liquid form.
38. The method of claim 2, wherein the minicapsules have a release
profile to also release solubilised cyclosporin in the ileum.
39. The method of claim 2, wherein the composition further
comprises minicapsules that have a release profile to release
solubilised cyclosporin in the small intestine.
40. The method of claim 2, wherein the method further comprises
administering to the subject hydralazine, DMOG, or another prolyl-
and/or asparaginyl hydroxylase inhibitor.
41. The method of claim 2, wherein the treating is exerting a
protective effect against ulcerative colitis.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 15/596,759, filed May 16, 2017, which is a continuation of U.S.
application Ser. No. 15/051,356, filed on Feb. 23, 2016, now U.S.
Pat. No. 9,675,558 issued Jun. 13, 2017, which is a divisional of
U.S. application Ser. No. 13/942,492, filed Jul. 15, 2013, now U.S.
Pat. No. 9,387,179 issued Jul. 12, 2016, which is a divisional of
U.S. application Ser. No. 12/594,534, which was filed on Feb. 22,
2010, now U.S. Pat. No. 8,535,713 issued Sep. 17, 2013, which is
the U.S. National Stage of International Application No.
PCT/IE2008/000038, filed Apr. 4, 2008, which was published in
English under PCT Article 21(2), which in turn claims the benefit
of U.S. Provisional Application No. 60/907,490, filed Apr. 4, 2007,
and U.S. Provisional Application No. 61/006,498, filed Jan. 16,
2008. The applications are incorporated herein in their
entirety.
[0002] The present invention relates to pharmaceutical cyclosporin
compositions.
INTRODUCTION
[0003] Cyclosporins form a class of polypeptides commonly
possessing immunosuppressive and anti-inflammatory activity. The
most commonly known cyclosporin is cyclosporin-A. Other forms of
cyclosporins include cyclosporin-B, -C, -D, and -G and their
derivatives. It should be understood that herein the terms
"cyclosporin" or "cyclosporins" refers as used herein to any of the
several cyclosporins derivatives or prodrugs thereof, or to any
mixture of any of the above.
[0004] Cyclosporin A is a hydrophobic material exhibiting poor
bioavailability. To improve the aqueous solubility of the
hydrophobic cyclosporin A, the current marketed liquid oral
formulations are emulsified using a mixture of oils, ethanol, a
triglyceride and a surfactant (U.S. Pat. No. 4,388,307). While
overcoming the solubility problem, these formulations have a
variety of difficulties, such as unpleasant taste, which is
unacceptable for long-term therapy. Therefore, the use of soft
gelatin capsule dosage forms masks the taste of the solution as
well as unitising the dose.
[0005] The bioavailability of these liquid formulations or the soft
gelatin capsule formulation containing ethanol, oils and Labrafil
surfactant, is low and variable, and reported to be about 30%. U.S.
Pat. No. 5,342,625 claim an improved formulation of cyclosporin in
the form of a microemulsion pre-concentrate. In addition to the
cyclosporin, this formulation requires a hydrophilic phase, a
lipophilic phase, and a surfactant. The microemulsion
pre-concentrate is claimed to provide enhanced bioavailability. As
cyclosporin has a narrow therapeutic index and a short half-life,
to provide adequate 24 hour protection it must be administered
twice daily.
[0006] Cyclosporin A, available in soft gelatin capsule or oral
suspension form, is indicated for the prevention of organ rejection
in kidney, liver and heart transplants, for the treatment of severe
active rheumatoid arthritis (RA) and severe recalcitrant plaque
psoriasis. Other potential indications include Bechet's disease,
anemia, nephrotic syndrome and Graft Versus Host Disease (GVHD),
including Gastro-Intestinal Graft Versus Host Disease (GI-GVHD).
Furthermore, a range or other diseases may benefit from treatment
with cyclosporin A (Landford et al. (1998) Ann Intern Med; 128:
1021-1028).
[0007] Based on the poor and intra-subject bioavailability
variability and the need for twice-daily administration,
significant dose-related nephrotoxicity and hepatotoxicity are side
effect associated with long term use of cyclosporin A. When
administered intravenously closporine A is known to be effective in
the treatment of refractory ulcerative colitis (D'Haens et al.,
Gastroenterology 2001; 120:1323-1329). In a study by Sandborn et
al. (J Clin Pharmacol, 1991; 31:76-80) the relative systemic
absorption of cyclosporin following oral and intravenous as well as
oil- and a water-based enemas was determined. Based on negligible
plasma cyclosporin concentrations following enema administration,
it was suggested that cyclosporin, even when solubilised, is poorly
absorbed from the colon. The enemas however demonstrated
considerable efficacy in the treatment of inflammatory bowel
disease (Ranzi T, et al, Lancet 1989; 2:97). Orally administered
cyclosporin demonstrated very limited efficacy in the treatment of
inflammatory bowel disease.
STATEMENTS OF INVENTION
[0008] According to the invention there is provided an oral
cyclosporin composition comprising minicapsules having a core
containing a cyclosporin in a solubilised liquid form, the
minicapsules have a release profile to release the pre-solubilised
cyclosporin at least in the colon.
[0009] In one embodiment the minicapsules have a release profile to
also release pre-solubilised cyclosporine in the Ileum.
[0010] The minicapsules may have a release profile to also release
pre-solubilised cyclosporin in the small intestine.
[0011] In one embodiment the cyclosporin is cyclosporin A. The
cyclosporin A may be present in the core in an amount of from 2.5
to 25% w/w, preferably in an amount of from 2.5 to 10% w/w.
[0012] In one embodiment when exposed to a use environment less
than 20% of the cyclosporin A is released within 4 hours,
preferably when exposed to a use environment less than 10% of the
cyclosporin A is released within 4 hours.
[0013] In one embodiment when exposed to a use environment less
than 50% of the cyclosporin A is released within 12 hours,
preferably when exposed to a use environment less than 35% of the
cyclosporin A is released within 12 hours.
[0014] When exposed to a use environment preferably less than or
equal to 100% of the cyclosporin A is released within 24 hours.
[0015] In one embodiment when exposed to a use environment less
than 10% of the cyclosporin A is released within 4 hours, less than
35% of the cyclosporin A is released within 12 hours, and
substantially all of the remaining cyclosporin A is released
between 12 and 24 hours.
[0016] In another embodiment when exposed to a use environment less
than 20% of the cyclosporin A is released within 4 hours, less than
50% of the cyclosporin A is released within 12 hours, and
substantially all of the remaining cyclosporin A is released
between 12 and 24 hours.
[0017] In a further embodiment when exposed to a use environment
less than 10% of the Cyclosporin A is released within 6 hours, less
than 30% of the cyclosporin A is released within 12 hours, less
than 70% of the cyclosporin A is released within 18 hours and up to
100% of the cyclosporin A is released at 24 hours.
[0018] The minicapsules preferably comprise a solid shell
containing the solubilised cyclosporin A. Usually the minicapsules
are modified to provide the release profile.
[0019] In one case a modified release coating is applied to the
outer shell of the minicapsules. Preferably a polymeric material is
used to achieve modified release.
[0020] The polymeric material may be methacrylate and/or
ethylcellulose.
[0021] In one embodiment the coating includes a dissolution
enhancing agent. Preferably the dissolution enhancing agent is
degraded by bacteria normally present in the lower gastrointestinal
tract. The dissolution enhancing agent may be selected from one or
more of pectin, amylose and alginate or derivatives thereof. In one
case the dissolution enhancing agent is present in an amount of
from 0.5 to 2% w/w of ethylcellulose.
[0022] In one embodiment the core comprises cyclosporin A, a
solubilisation agent, a co-emulsifier, a surfactant, a permeability
enhancer and a carrier. In one case the solubilisation agent
comprises ethanol. The solubilisation agent may comprise
triglycerides. The co-emulsifying agent may comprise fatty acid
ester complexes. The surfactant agent may comprise fatty acid ester
complexes. The permeability enhancing agent may comprise fatty acid
ester complexes. In one case the carrier comprises a hydrophobic
liquid, such as an oil, for example olive oil.
[0023] In one embodiment an outer shell layer of the minicapsules
is modified to achieve modified release. In one case the liquid
core of the minicapsules is modified to achieve modified release.
Polymeric materials may be used to achieve modified release.
[0024] The cyclosporin is preferably released along the
gastrointestinal tract in a form that maximises pre-systemic
mucosal absorption. The cyclosporin may be released along the
gastrointestinal tract in a form that maximises local
gastrointestinal activity. The cyclosporin may be released along
the gastrointestinal tract in a form that maximises
gastrointestinal lumen activity. The cyclosporin may be released
along the gastrointestinal tract in a form that maximises
chronotherapy.
[0025] In one embodiment wherein the formulation contains an
adhesive entity such as a muco or bio-adhesive.
[0026] In one embodiment the composition comprises a hard gelatine
capsule, a sprinkle, or a tablet containing the minicapsules.
[0027] In one case the minicapsules further comprise excipients to
maximise solubility of the cyclosporin. The composition may further
comprise excipients to maximise permeability of the cyclosporin at
least along the gastrointestinal lining or mucosal lining. The
composition may also comprise excipients to enhance the therapeutic
potential of the cyclosporin in the ileum and colon. The excipients
may be selected from one or more of absorption limiters, absorption
enhancers, surfactants, co-surfactants, co-solvents, essential oils
such as omega 3 oils, natural plant extracts such as neem,
ion-exchange resins, anti-oxidants, polyethers, stabilizers,
preservatives, bacteria degradable conjugation linkers such as azo
bonds, polysaccharides such as amylose, guar gum, pectin, chitosan,
inulin and cyclodextrins.
[0028] Preferably the composition facilitates mucosal absorption
over 24 hours.
[0029] The composition may be used in treating or preventing
inflammatory bowel disease; in treating ulcerative colitis; in
treating Crohn's disease; for the treatment or prevention of
graft-versus-host disease such as gastro-intestinal
graft-versus-host disease; and/or in treating or preventing
irritable bowel syndrome.
[0030] The composition may be presented for administration in
paediatric formats.
[0031] The invention also provides a composition of the invention
combined with another active pharmaceutical in a single oral dosage
form.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] The invention will be more clearly understood from the
following description of some embodiments thereof, given by way of
example only, with reference to the accompanying drawings, in
which:--
[0033] FIG. 1 is a graph showing the dissolution rate of
Cyclosporin A from minicapsules coated with 12.8% and 22.5% weight
gain Surlease.TM.;
[0034] FIG. 2 is a bar chart showing the colon length of
DSS-induced colitis mice treated with Capsule A (0.25 mg CyA/day;
immediate release), Capsule B (0.25 mg CyA/day; ileum release) and
Capsule C (0.25 mg CyA/day; colon release) for 7 days, with 6 mice
in each group;
[0035] FIG. 3 is a graph showing the average weight of DSS-induced
colitis mice treated with Capsule A (0.25 mg CyA/day; immediate
release), Capsule B (0.25 mg CyA/day; ileum release) and Capsule C
(0.25 mg CyA/day; colon release);
[0036] FIG. 4 is a graph showing the Disease Activity Index (DAI)
of DSS-induced colitis mice treated with Capsule A (0.25 mg
CyA/day; immediate release), Capsule B (0.25 mg CyA/day; ileum
release) and Capsule C (0.25 mg CyA/day; colon release) for 7 days,
with 6 mice in each group;
[0037] FIG. 5 is a graph showing the dissolution rate of
Cyclosporin A from uncoated minicapsules (uncoated), minicapsules
coated with 22% weight gain Eudragit.TM. RS (076/2007) and
minicapsules coated with 22% weight gain Eudragit.TM. RS plus 14%
weight gain Eudragit.TM. FS30D (077/2007) in 0.75% SDS (99);
[0038] FIG. 6 is a graph showing the dissolution rate of
Cyclosporin A from uncoated minicapsules (uncoated) and with
minicapsules coated with 22% (069/2007) and 37% (072/2007) weight
gain Surlease.RTM. as well as 22% weight gain Surelease.RTM. plus
14% weight gain Eudragit.TM. FS30D (075/2007) in 0.75% SDS
(99);
[0039] FIG. 7 is a graph showing the dissolution rate of
Cyclosporin A from minicapsules coated with 20% weight gain
Surlease.RTM./1% Pectin (020/2008) and 20% weight gain
Surlease.RTM./1% Pectin plus 9% weight gain Eudragit FS30D
(021/2008) in 0.75% SDS (99);
[0040] FIG. 8 is a graph showing the dissolution rate of
Cyclosporin A from minicapsules coated with 20% weight gain
Surlease.RTM./1% Pectin plus 11% weight gain Eudragit FS30D
following 2 hours in pH 7.4% phosphate buffer solution followed by
22 hours in 0.75% SDS dissolution media;
[0041] FIG. 9 is a graph showing the dissolution rate of
Cyclosporin A from minicapsules coated with 13% weight gain
Surlease.RTM. (013/2008) 13 weight gain Surelase.RTM./1% Sodium
Alginate (005/2008) and 13% weight gain Surlease.RTM./0.5% Sodium
Alginate (011/2008) in 0.75% SDS;
[0042] FIG. 10 is a graph showing the dissolution rate of
cyclosporin A from minicapsules coated with 22% Eudragit.TM. RS30D;
and
[0043] FIG. 11 is a schematic illustration of the minicapsule form
used in the formalities of the invention.
DETAILED DESCRIPTION
[0044] There is therefore a need for an improved pharmaceutical
composition of cyclosporins. The invention enables the exploitation
of the efficiency of cyclosporin in the treatment of ulcerative
colitis. In the invention the cyclosporin remains in a soluble form
in the colon and the systemic side effects associated with
long-term high oral or intravenous doses of cyclosporin. A colon
specific form that releases cyclosporin in a soluble form is
provided.
[0045] The invention provides a method of preventing or treating an
inflammatory or immune disorder, particularly relating to
inflammatory or immune diseases that effect the gastrointestinal
tract, in a subject while eliminating or reducing the toxicity
associated with the administration of cyclosporin, through the
orally delivered, colon-specific release of a therapeutically
effective amount of cyclosporin in combination with a
pharmaceutically acceptable carrier(s) or excipient(s).
[0046] The controlled release of active pharmaceutical agents is
only truly useful if the agent is available to interact with its
receptor or site of action in an active form. Unless the agent is
in a fully soluble form it is unlikely to interact with its
intended receptor or exert its desired action. The invention is a
drug delivery format that enables the release cyclosporin from the
format in soluble or readily-soluble form.
[0047] The invention provides an oral drug delivery technology that
permits the colon-specific release of pre- or readily-solubilised
cyclosporin in tandem with a controlled release formulation that
permits release and absorption in the lining of the small
intestine, the ileum and/or the colon to ensure a true once-daily
formulation.
[0048] This once-daily technology which enables colon delivery of
soluble cyclosporine is advantageous as an effective drug delivery
mechanism for enhanced treatment of diseases of colon, especially
inflammatory- or ischemic-induced diseases, (ulcerative colitis,
Crohn's disease, Gastro-Intestinal Graft Versus Host Disease
(GI-GVHD) and other infections) whereby high local concentrations
of soluble drug can be achieved while minimizing side effects that
occur because of release of drugs in the upper GIT or unnecessary
systemic absorption.
[0049] Cyclosporins are well known to have limited colonic
absorption.
[0050] Additionally, for conditions that may affect the entire
gastro-intestinal tract, including the small intestine, such as
Crohn's Disease and GI-GVHD, a sustained release format of
pre-solubilised cyclosporin, exhibiting limited systemic absorption
is provided.
[0051] The invention enables the availability of cyclosporin in a
soluble liquid. In addition to the active cyclosporin, the liquid
dosage forms may contain inert diluents commonly used in the art
such as, for example, water or other solvents, solubilizing agents
and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, fish,
neem and sesame oils), polyethers (in particular substances like
dimethyl isosorbide, dimethyl isoodide and dimethly isomannide and
mixtures of glyceryl monoesters of C8-C22 fatty acids and
hexaglyceryl to pentadecaglyceryl monoesters of C8-C22 fatty acids
in variable ratios from 1:3 to 1:8) glycerol, tetrahydrofurfuryl
alcohol, polyethylene glycols and fatty acid esters of sorbitan,
and mixtures thereof. Besides inert diluents, the oral compositions
can also include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and/or perfuming
agents.
[0052] The invention enables successful colonic delivery. In the
invention cyclosporin is protected from absorption in the
environment of the upper gastrointestinal tract (GIT) but allows
abrupt and/or sustained release into the proximal colon, which is
the optimum site for colon-targeted delivery of cyclosporin. Such
colon targeting is particularly of value for the treatment of
diseases of colon such as Crohn's diseases, ulcerative colitis, and
GVHD, including GI-GVHD.
[0053] The invention allows for a broad range of controlled release
polymer coatings to be applied. Coating materials may include any
combination of the commercially available acrylic-, methacrylic-,
ethylcellulose-based polymers (such as, but not limited to the
Eudragit.TM. and Surelease.RTM. range), as well as other polymers
with natural polysaccharides, including, but not limited to
amylose, pectin, alginate, amylopectin, chitosan, galactomannan,
guar gum and any derivatives thereof, has the potential to
customise how, where and when drugs are released from the
underlying or embedded solid, semi-solid or liquid forms. In all
examples cited in this specification, any specific polymer may be
interchanged or combined with any other polymer to enable the
required release profile according to the preferred optimal
therapeutic outcome envisaged.
[0054] The invention provides a solid oral dosage form comprising
the multiple minicapsule modified release composition of the
present invention, the said minicapsules being one layer or
multiple layer. Where a two layer minicapsule has a shell comprised
of a gelling agent with a controlled release polymer or other
coating or comprised of controlled release polymer or other
materials.
[0055] In various embodiments comprising a membrane-controlled
dosage form, the polymeric material comprises methacrylic acid
co-polymers, ammonio methacrylate co-polymers, or mixtures thereof.
Methacrylic acid co-polymers such as EUDRAGIT.TM. S and
EUDRAGIT.TM. L (Evonik) are suitable for use in the controlled
release formulations of the present invention. These polymers are
gastroresistant and enterosoluble polymers. Their polymer films are
insoluble in pure water and diluted acids. They dissolve at higher
pHs, depending on their content of carboxylic acid. EUDRAGIT.TM. S
and EUDRAGIT.TM. L can be used as single components in the polymer
coating or in combination in any ratio. By using a combination of
the polymers, the polymeric material can exhibit solubility at a pH
between the pHs at which EUDRAGIT.TM. L and EUDRAGIT.TM. S are
separately soluble.
[0056] The membrane coating can comprise a polymeric material
comprising a major proportion (i.e., greater than 50% of the total
polymeric content) of at least one pharmaceutically acceptable
water-soluble polymers, and optionally a minor proportion (i.e.,
less than 50% of the total polymeric content) of at least one
pharmaceutically acceptable water insoluble polymers.
Alternatively, the membrane coating can comprise a polymeric
material comprising a major proportion (i.e., greater than 50% of
the total polymeric content) of at least one pharmaceutically
acceptable water insoluble polymers, and optionally a minor
proportion (i.e., less than 50% of the total polymeric content) of
at least one pharmaceutically acceptable water-soluble polymer.
[0057] Ammonio methacrylate co-polymers such as EUDRAGIT.TM. RS and
EUDRAGIT.TM. RL (Evonik) are suitable for use in the modified
release formulations of the present invention. These polymers are
insoluble in pure water, dilute acids, buffer solutions, or
digestive fluids over the entire physiological pH range. The
polymers swell in water and digestive fluids independently of pH.
In the swollen state, they are then permeable to water and
dissolved active agents. The permeability of the polymers depends
on the ratio of ethylacrylate (EA), methyl methacrylate (MMA), and
trimethylammonioethyl methacrylate chloride (TAMCl) groups in the
polymer. Those polymers having EA:MMA:TAMCl ratios of 1:2:0.2
(EUDRAGIT.TM. RL) are more permeable than those with ratios of
1:2:0.1 (EUDRAGIT.TM. RS). Polymers of EUDRAGIT.TM. RL are
insoluble polymers of high permeability. Polymers of EUDRAGIT.TM.
RS are insoluble films of low permeability.
[0058] The amino methacrylate co-polymers can be combined in any
desired ratio, and the ratio can be modified to modify the rate of
drug release. For example, a ratio of EUDRAGIT.TM. RS: EUDRAGIT.TM.
RL of 90:10 can be used. Alternatively, the ratio of EUDRAGIT.TM.
RS: EUDRAGIT.TM. RL can be about 100:0 to about 80:20, or about
100:0 to about 90:10, or any ratio in between. In such
formulations, the less permeable polymer EUDRAGIT.TM. RS would
generally comprise the majority of the polymeric material with the
more soluble RL, when it dissolves, permitting creating gaps
through which solutes can enter the core and dissolved
pharmaceutical actives escape in a controlled manner.
[0059] The amino methacrylate co-polymers can be combined with the
methacrylic acid co-polymers within the polymeric material in order
to achieve the desired delay in the release of the drug. Ratios of
ammonio methacrylate co-polymer (e.g., EUDRAGIT.TM. RS) to
methacrylic acid co-polymer in the range of about 99:1 to about
20:80 can be used. The two types of polymers can also be combined
into the same polymeric material, or provided as separate coats
that are applied to the core.
[0060] Eudragit.TM. FS 30 D is an anionic aqueous-based acrylic
polymeric dispersion consisting of methacrylic acid, methyl
acrylate, and methyl methacrylate and is pH sensitive. This polymer
contains fewer carboxyl groups and thus dissolves at a higher pH
(>6.5). The advantage of such a system is that it can be easily
manufactured on a large scale in a reasonable processing time using
conventional powder layering and fluidized bed coating techniques.
In a study by Gupta et al (Int J Pharm, 213: 83-91, 2001) Eudragit
FS 30 D demonstrated its potential for colonic delivery by
resisting drug release up to pH 6.5 and the combination of
Eudragit.TM. RL and RS proved successful for the sustained delivery
of 5-ASA at the pH of the colon. Thus, Eudragit.TM. FS 30 D alone
or with other controlled release polymers holds great potential to
enable delivery of minicapsule formulations specifically to the
colon.
[0061] In addition to the EUDRAGIT.TM. polymers described above, a
number of other such copolymers can be used to control drug
release. These include methacrylate ester co-polymers such as the
EUDRAGIT.TM. NE and EUDRAGIT.TM. NM ranges. Further information on
the EUDRAGIT.TM. polymers can be found in "Chemistry and
Application Properties of Polymethacrylate Coating Systems," in
Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, ed.
James McGinity, Marcel Dekker Inc., New York, pg 109-114.
[0062] Several derivatives of hydroxypropyl methylcellulose (HPMC)
also exhibit pH dependent solubility. Shin-Etsu Chemical Co., Ltd.
esterified HPMC with phthalic anhydride to produce hydroxypropyl
methylcellulose phthalate (HPMCP), which rapidly dissolves in the
upper intestinal tract. Due to the limited compatibility of HPMCP
with several types of plasticizers, hydroxypropyl methylcellulose
acetate succinate (HPMCAS) was developed. The presence of ionizable
carboxyl groups in the HPMCAS structure cause the polymer to
solubilize at high pH (>5.5 for the LF grade and >6.8 for the
HF grade). This polymer exhibits good compatibility with a variety
of plasticizing agents and is commercially available from Shin-Etsu
Chemical Co. Ltd. under the proprietary name AQOAT.RTM. in a
powdered form to be redispersed in water.
[0063] Surelease.RTM. dispersion is a unique combination of
film-forming polymer; plasticizer and stabilizers. Designed for
sustained release and taste masking applications, Surelease is an
easy-to-use, totally aqueous coating system using ethylcellulose as
the release rate controlling polymer. The dispersion provides the
flexibility to adjust drug release rates with reproducible profiles
that are relatively insensitive to pH. The principal means of drug
release is by diffusion through the Surelease dispersion membrane
and is directly controlled by film thickness. Increasing or
decreasing the quantity of Surelease.RTM. applied can easily modify
the rate of release. With Surelease dispersion, reproducible drug
release profiles are consistent right through from development to
scale-up and production processes.
[0064] In addition to the EUDRAGIT.TM. and Surelease.RTM. polymers
discussed above, other enteric, or pH-dependent, polymers can be
used. Such polymers can include phthalate, butyrate, succinate,
and/or mellitate groups. Such polymers include, but are not limited
to, cellulose acetate phthalate, cellulose acetate succinate,
cellulose hydrogen phthalate, cellulose acetate trimellitate,
hydroxypropyl-methylcellulose phthalate,
hydroxypropylmethylcellulose acetate succinate, starch acetate
phthalate, amylose acetate phthalate, polyvinyl acetate phthalate,
and polyvinyl butyrate phthalate. Additionally, where compatible,
any combination of polymer may be blended to provide additional
controlled- or targeted-release profiles.
[0065] The coating membrane can further comprise at least one
soluble excipient to increase the permeability of the polymeric
material. Suitably, the at least one soluble excipient is selected
from among a soluble polymer, a surfactant, an alkali metal salt,
an organic acid, a sugar, and a sugar alcohol. Such soluble
excipients include, but are not limited to, polyvinyl pyrrolidone,
polyethylene glycol, sodium chloride, surfactants such as sodium
lauryl sulfate and polysorbates, organic acids such as acetic acid,
adipic acid, citric acid, fumaric acid, glutaric acid, malic acid,
succinic acid, and tartaric acid, sugars such as dextrose,
fructose, glucose, lactose, and sucrose, sugar alcohols such as
lactitol, maltitol, mannitol, sorbitol, and xylitol, xanthan gum,
dextrins, and maltodextrins. In some embodiments, polyvinyl
pyrrolidone, mannitol, and/or polyethylene glycol can be used as
soluble excipients. The at least one soluble excipient can be used
in an amount ranging from about 1% to about 10% by weight, based on
the total dry weight of the polymer. The coating process can be
carried out by any suitable means, for example, by using a
perforated pan system such as the GLATT, ACCELACOTA, Vector,
Diosna, O'Hara, HICOATER or other such coating process
equipment
[0066] The modifications in the rates of release, such as to create
a delay or extension in release, can be achieved in any number of
ways. Mechanisms can be dependent or independent of local pH in the
intestine, and can also rely on local enzymatic activity to achieve
the desired effect. Examples of modified-release formulations are
known in the art and are described, for example, in U.S. Pat. Nos.
3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533;
5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556;
and 5,733,566.
[0067] With membrane-modified extended-release dosage forms, a
semi-permeable membrane can surround the formulation containing the
active substance of interest. Semi-permeable membranes include
those that are permeable to a greater or lesser extent to both
water and solute. This membrane can include water-insoluble and/or
water-soluble polymers, and can exhibit pH-dependent and/or
pH-independent solubility characteristics. Polymers of these types
are described in detail below. Generally, the characteristics of
the polymeric membrane, which may be determined by, e.g., the
composition of the membrane, will determine the nature of release
from the dosage form.
[0068] In particular, the present invention provides for
formulations of minicapsules or minispheres wherein the modified
release is dependent upon, where appropriate, any one of the core
formulation constituents, the shell composition or the shell
coating. The minicapsules or minispheres may be produced through
the utilisation of surface tension of one or more different
solutions which when ejected through an orifice or nozzle with a
certain diameter and subject to specific frequencies and
gravitational flow, forms into a spherical form and falls into a
cooling air flow or into a cooling or hardening solution and the
outer shell solution where it is gelled or solidified. This briefly
describes the formation of seamless minispheres. According to prior
art the core solution is mainly a hydrophobic solution or
suspension. The outer shell solution can be any gel forming agent
but is normally gelatine- or alginate-based based but may also
include polymers or other materials that enable controlled release.
With the nozzle having two orifices (centre and outer), a
hydrophobic solution can be encapsulated. Where appropriate, it may
be possible that both the core and/or shell may be comprised of a
material or material composites that have been processed by a wet-
or dry-extrusion mechanism, melt or otherwise fluidized prior to
mixing or extrusion. Ideally, to enable drug content and release
consistency, it is preferred that all processes will result in
fairly uniform morphologies with a relatively smooth surface to
facilitate quite even coating layers to be added in a uniform
manner. With the nozzle having one or more orifices seamless
minicapsules for various applications can be processed using
minicapsule processing equipment enabled by, but not limited to,
Freund Spherex, ITAS/Lambo Globex or Inotech processing equipment.
As outlined above the coating process can be carried out by any
suitable means, for example, by using a perforated pan or
fluidized-based system such as the GLATT, Vector, ACCELACOTA,
Diosna, O'Hara and/or HICOATER processing equipment. Seamless
minicapsules may be manufactured using the method described in U.S.
Pat. No. 5,882,680 (Freund), the entire contents of which we
incorporated herein by reference.
[0069] The invention relates to drug delivery in the colon which
has been largely overlooked from a drug delivery perspective.
Mainly having evolved to regulate electrolyte balance and to
further breakdown complex carbohydrate structures there is a
significant flow of water from the colonic lumen into the body. In
addition, the colon is home to a natural bacterial flora to degrade
complex carbohydrates to ensure effective excretion, provide much
needed fibre and some nutrient absorption. With a much lower
concentration of proteolytic and other enzymes populated in the
colon, it is a much more benign environment for proteins and
peptides as well as other biological entities such as carbohydrates
and nucleic acids. From a drug delivery perspective, the colon
presents a number of interesting possibilities: the bacteria can be
harnessed to break down controlled release coatings that are
resistant to acidic breakdown as well as pH differentials; the
benign environment ensure than active pharmaceuticals, including
biopharmaceuticals, are less likely to be degraded if released
locally into the colon; the almost continuous flow of fluids from
the colonic lumen to the bloodstream may be harnessed to carry
hydrophilic entities from the intestine to the lumen. Finally, the
long transit time in the colon, ranging form 10-20 hours provides
greater residence and potential for interaction with the colonic
mucus and epithelial cells leading to enhanced absorption into the
cells lining the colonic lumen and beyond.
[0070] A barrier to effective colonic delivery of hydrophobic and
lipophilic drugs is that the colon did not evolve to solubilize
foodstuffs and other entities but rather to ensure electrolyte
balance and maximise fibre breakdown and fermentation. The colon
remains very porous to hydrophilic entities. By delivering
hydrophobic or lipophilic drugs to the colon in a pre-solubilised
or readily soluble format and releasing such in the colon, the
potential for absorption, local or systemic, is enhanced
significantly. The present invention permits the encapsulation of
pre-solubilized or readily soluble drugs in liquid or hydrolysable
semi-solids or solids into the minicapsule core and then modulation
of the shell to include intestinal- or colon-controlled release
polymers or coating the shell with same. The result is release of
optimized formulations at specific sites along the intestinal tract
for maximal therapeutic efficacy or systemic absorption.
[0071] Likewise, delivery of formulations that are readily broken
down in an aqueous environment or a bacteria rich environment has
the potential, when coated with colon-specific controlled release
polymers or include entities that are degraded by bacteria have the
potential to protect susceptible entities from the gastric or
intestinal environment yet ensure that they are released intact in
the colon where, once liberated, will be readily absorbed.
Redox-sensitive, pectin, alginate, chitosan or other bacterially
susceptible polymer-based matrices, coatings or other sustained
release formulations, liquid, semi-solid or solid, can be
encapsulated into or coated onto one- or multi-layered
minicapsules.
[0072] The formulations of the present invention can exist as a
multi-unit or as multi-unit minicapsules in a single-unit format.
The term "multi-unit" as used herein means a plurality of discrete
or aggregated minicapsules. Single-unit formulations include, for
example, tablets, hard gelatin capsules, caplets, and pills.
[0073] The methods and formulations of the present invention are
intended to encompass all possible combinations of components that
exhibit modified-release and immediate-release properties. For
example, a formulation and/or method of the invention can contain
components that exhibit extended-release and immediate-release
properties, or both delayed-release and immediate-release
properties, or both extended-release and delayed-release
properties, or a combination of all three properties. For example,
a multi-minicapsule or multi-minisphere formulation including both
immediate-release and extended-release components can be combined
in a capsule, which is then coated with an enteric coat to provide
a delayed-release effect. Or, for example, a delayed- and
extended-release caplet may comprise a plurality of discrete
extended-release particles held together with a binder in the
caplet, which is coated with an enteric coating to create a delay
in dissolution.
[0074] As used herein, the term "modified-release" formulation or
dosage form includes pharmaceutical preparations that achieve a
desired release of the drug from the formulation. A
modified-release formulation can be designed to modify the manner
in which the active ingredient is exposed to the desired target.
For example, a modified-release formulation can be designed to
focus the delivery of the active agent entirely in the distal large
intestine, beginning at the cecum, and continuing through the
ascending, transverse, and descending colon, and ending in the
sigmoid colon. Alternatively, for example, a modified-release
composition can be designed to focus the delivery of the drug in
the proximal small intestine, beginning at the duodenum and ending
at the ileum. In still other examples, the modified-release
formulations can be designed to begin releasing active agent in the
jejunum and end their release in the transverse colon. The
possibilities and combinations are numerous, and are clearly not
limited to these examples.
[0075] The term "modified-release" encompasses "extended-release"
and "delayed-release" formulations, as well as formulations having
both extended-release and delayed-release characteristics. An
"extended-release" formulation can extend the period over which
drug is released or targeted to the desired site. A
"delayed-release" formulation can be designed to delay the release
of the pharmaceutically active compound for a specified period.
Such formulations are referred to herein as "delayed-release" or
"delayed-onset" formulations or dosage forms. Modified-release
formulations of the present invention include those that exhibit
both a delayed- and extended-release, for example, formulations
that only begin releasing after a fixed period of time or after a
physicochemical change has occurred, for example, then continue
releasing over an extended period.
[0076] As used herein, the term "immediate-release formulation," is
meant to describe those formulations in which more than about 50%
of active ingredient is released from the dosage form in less than
about 2 hours. Such formulations are also referred to herein as
"conventional formulations."
[0077] As used herein, the phrase "drug-release profile that is
independent of surrounding pH" means effectively a drug composition
comprising a polymeric system that is non-enteric or whose
permeability and solubility properties do not change with
environmental, i.e., external, pH. Meaning, a drug composition
having release characteristics such as dissolution is substantially
unaffected by pH or regardless of pH-changes in the environment.
This is in comparison to a release profile that is pH-dependent
where the release characteristics vary according to the pH of the
environment.
[0078] Intestinal Diseases
[0079] Gastrointestinal conditions pose a significant worldwide
health problem Inflammatory bowel diseases, which genus encompass a
range of diseases including Crohn's disease and ulcerative colitis,
affect nearly 1 million people in the United States each year. The
two most common inflammatory conditions of the intestine,
ulcerative colitis (UC) and Crohn's disease (CD) are collectively
known as inflammatory bowel disease (IBD). These conditions are
diseases of the distal gut (lower small intestine, large intestine,
and rectum) rather than the proximal gut (stomach and upper small
intestine). Between the two, ulcerative colitis primarily affects
the colon, whereas Crohn's disease affects the distal small
intestine as well.
[0080] Inflammatory Bowel Disease (IBD)
[0081] Although they are distinct IBD conditions, the same drugs
are commonly used to treat both UC and CD. Drugs commonly used in
their treatment include steroids (e.g., budesonide and other
corticosteroids, and adrenal steroids such as prednisone and
hydrocortisone); cytokines such as interleukin-10; antibiotics;
immunomodulating agents such as azathioprine, 6-mercaptopurine,
methotrexate, cyclosporin, and anti-tumor necrosis factor (TNF)
agents such as soluble TNF receptor and antibodies raised to TNF;
and also antinflammatory agents such as zinc. The most commonly
prescribed agents for IBD include sulfasalazine
(salicyl-azo-sulfapyridine, or "SASP") and related 5-aminosalicylic
acid ("5-ASA") products, including mesalazine. In refractory cases
of the disease, high doses of cyclosporin, administered
intravenously, has demonstrated considerable and rapid
efficacy.
[0082] Inflammation of the ileum (the farthest segment of the small
intestine) due to Crohn's disease is known as iletis. When both the
small intestine and the large intestine are involved, the condition
is called Crohn's enterocolitis (or ileocolitis). Other descriptive
terms may be used as well. Diagnosis is commonly made by x-ray or
colonoscopy. Treatment includes medications that are
anti-inflammatories, immune suppressors, or antibiotics. Surgery
can be necessary in severe cases. Crohn's disease is an area of
active research around the world and new treatment approaches are
being investigated which have promise to improve the lives of
affected patients.
[0083] Gastrointestinal Graft-Versus-Host-Disease (GI-GVHD)
[0084] GI GVHD is a life-threatening condition and one of the most
common causes for bone marrow and stem cell transplant failure.
These procedures are being increasingly used to treat patients with
leukemia and other cancers to eliminate residual disease and reduce
the likelihood of relapse. Unlike solid organ transplants where the
patient's body may reject the organ, in GVHD it is the donor cells
that begin to attack the patient's body--most frequently the gut,
liver and skin. Patients with mild-to-moderate GI GVHD typically
develop symptoms of anorexia, nausea, vomiting and diarrhea. If
left untreated, GI GVHD can progress to ulcerations in the lining
of the GI tract, and in its most severe form, can be fatal.
Systemic immunosuppressive agents such as prednisone, which are the
current standard treatments for GI GVHD, are associated with high
mortality rates due to infection and debility. Further, these drugs
have not been approved for treating GI GVHD in the U.S. or European
Union, but rather are used off-label as investigational therapies
for this indication.
[0085] The current invention permits the release of cyclosporin A
to the colon in a novel oral, locally acting active therapy which
will reduce the need for systemic immunosuppressive drugs such as
prednisone, which is currently used to prevent and control GI GVHD.
Drugs such as prednisone have the unwanted and potentially
dangerous side effects of weakening the patient's immune system
leaving them susceptible to opportunistic infections as well as
substantially inhibiting the intended anti-cancer effect of bone
marrow and stem cell transplants. The current colon-targeted
immunosuppressant invention is designed to reduce the need for
systemic immunosuppressive drugs and thereby improve the outcome of
bone marrow and stem cell transplantation.
[0086] Cyclosporin is recognized, on- and off-label, as common
treatments for IBD and is widely used for this purpose. However,
high dose cyclosporin exhibits significant problems, including side
effects to be detailed hereinafter. Additionally, both exhibit a
half-life and efficacy profile that is less than maximal, reflected
in high and multiple daily doses, lower response and remission
rates, and higher relapse rates, related to its site and mechanism
of action and efficiency of delivery to the cells of the distal
gut. Extensive Cyclosporin absorption from the small intestine
reduces its availability at distal sites in the gut, which are the
sites of the therapeutic effect and the preferred sites of
delivery, thereby necessitating high doses to be administered.
Ideally, the cyclosporin should reach the distal gut (ileum and/or
colon) in unchanged form, but not be absorbed into the systemic
circulation as the parent compound from there. The absorption into
the systemic circulation from proximal and/or distal sites as the
parent compound results in side effects associated with the
absorbed drug and its systemic effects. Existing oral dosage forms
of cyclosporin, namely soft gelatine capsule or oral suspension,
are unsuited to controlled or ileum/colon targeted release.
Additionally, rectally administered suppositories or enemas are
inconvenient and painful.
[0087] To overcome systemic side effects and the need to administer
high doses frequently, the current invention proposes first
formulating either cyclosporin as a solubilised formulation,
encapsulating with a gelling agent to produce minicapsules. The
encapsulating agent may contain controlled release polymers that
release only in the ileum or colon or may be coated with a polymer
or other coating that results in same. The advantages are
several-fold, including: reduced systemic absorption of the active
cyclosporin or tacrolimus which is known to result in dose related
toxicities, including nephrotoxicity, release of sufficient dose of
cyclosporin in soluble form as well as a broad distribution of
cyclosporin throughout the colon. Furthermore, incorporating a
mucoadhesive into the encapsulating shell or coating the
encapsulating shell with a mucoadhesive may ensure that the
minicapsules are in contact with the colonic mucus layer prior to
releasing the active proximal to the diseased tissue. For certain
Crohn's Disease sub-groups it may be required to enable release
throughout the gastrointestinal tract, including the small
intestine. Likewise for GI-GVHD, it may be beneficial to have
sustained release throughout the entire gastrointestinal tract from
small intestine to colon.
[0088] Certain natural extracts, including Neem oil, aloe vera,
tripala, tumeric and other essential oils, including the omega
polyunsaturated oils such as EPA, DHA, conjugated linoeic acid
(CLA) and other derivatives thereof, have potential as treatments
to alleviate or prevent inflammatory bowel disease as well as other
intestinal disorders, including gastric, duodenal and intestinal
ulcers. Additionally, certain plant extracts, including berry
extracts such as blueberry, achi, resorcinolic/phenolic lipids,
resveratrol, flavanoids and derivatives thereof, alone or in
combination, have potential application in IBD and IBS and other
intestinal or systems conditions. The mode of action of berry
extracts, such as blueberry extract, remains uncertain but has
effect on intestinal motility, stool formation and colonic flora.
Yet other potential therapeutics include, but are not limited to,
proteins, therapeutic peptides, vaccines, antibodies or fragments
thereof. Local delivery to the mucosa will overcome degradation and
ensure that a high local concentration is available to enhance
therapeutic efficacy. Encapsulating any of the above, alone or in
any combination, into minicapsules or minispheres and targeting the
release to areas of the intestine that are diseased provide for
enhanced disease management as well as perhaps a reduction in any
potential for systemic side effects. Furthermore, certain oils,
including the essential oils, DHA and EPA are known to increase the
absorption of certain entities throughout the gastrointestinal
tract, including the colon.
[0089] This invention is advantageous in providing methods and
formulations for treating or preventing inflammatory bowel disease.
The invention proposes delivering effective concentrations of
pre-solubised Cyclosporin, Tacrolimus, Sirolimus, Hydralazine,
DMOG, others or derivatives thereof, to affected areas of the
gastrointestinal tract, with minimized systemic absorption of
parent drug. The invention is directed to, among other things, a
pharmaceutical composition for administration to a subject in need
thereof comprising a dose of an active pharmaceutical compound, and
pharmaceutically acceptable salts, esters and pro-drugs thereof,
and at least one pharmaceutically acceptable excipient, wherein the
composition exhibits localized release and exhibits:
[0090] For Ulcerative Colitis and Crohn's Disease--a dissolution
profile, when tested in a U.S.P. Type II apparatus (paddles) at 37.
degree. C. and 50 rpm, in pH 6.8 buffer for the test: Up to 4
hours: less than or equal to about 20% drug released; 6 hours: less
than or equal to about 35% drug released; 8 hours: less than or
equal to about 50% drug released; 12 hours: less than or equal to
about 60% drug released; 18 hours: less than or equal to about 75%
drug released; and 24 hours: from about 25% to about 100% drug
released.
[0091] For GI-GVHD--a dissolution profile, when tested in a U.S.P.
Type II apparatus (paddles) at 37. degree. C. and 50 rpm, in pH 6.8
buffer for the test: 1 hour: less than or equal to about 20% drug
released; 4 hours: less than or equal to about 35% drug released; 6
hours: less than or equal to about 50% drug released; 12 hours:
less than or equal to about 60% drug released; 16 hours: less than
or equal to about 75% drug released; and 24 hours: from about 25%
to about 100% drug released.
[0092] This invention relates to formulations and methods for
treating or preventing inflammatory bowel disease. The term
"inflammatory bowel disease" includes, but is not limited to,
ulcerative colitis, Crohn's disease and GI-GVHD. Other treatable
conditions would include but are not limited to ischemic bowel
diseases; necrotizing enterocolitis, intestinal lesions associated
with thermal burns and leukotriene B 4-mediated diseases;
intestinal inflammations/allergies such as Coeliac diseases,
proctitis, eosinophilic gastroenteritis, mastocytosis; food-related
allergic diseases which have symptomatic manifestation remote from
the gastro-intestinal tract (e.g., migraine, rhinitis and
eczema).
[0093] This invention relates to formulations and methods for
treating or preventing inflammatory bowel disease. The term
"inflammatory bowel disease" includes, but is not limited to,
ulcerative colitis, Crohn's disease and GI-GVHD. Other treatable
conditions would include but are not limited to ischemic bowel
diseases; inflammatory bowel diseases, necrotizing enterocolitis,
intestinal lesions associated with thermal burns and leukotriene
B.sub.4-mediated diseases; intestinal inflammations/allergies such
as Coeliac diseases, proctitis, eosinophilic gastroenteritis,
mastocytosis, Crohn's disease and ulcerative colitis; food-related
allergic diseases which have symptomatic manifestation remote from
the gastro-intestinal tract (e.g., migraine, rhinitis and
eczema).
[0094] As cyclosporin blocks T-cell activation, a prerequisite for
HIV proliferation, it may be useful as a prophylactic for the
prevention of HIV replication. In the particular cases of HIV-1,
HIV-2 and related retroviral strains, inhibition of T-cell mitosis
would suppress the replication of the virus, since the virus relies
upon the host T-cell's proliferative functions to replicate. The
formulations in the invention would be useful when used alone, or
in combination therapy with other immunosuppressants, for example,
but not limited to, FK506, rapamycin, picibanil, mycophenolic acid,
azathioprine, prednisolone, cyclophosphamide, brequinar, sequinivir
and leflunomide as a prophylactic for the prevention of HIV
replication which is rapid in the gastrointestinal tract following
infection. In the particular cases of HIV-1, HIV-2 and related
retroviral strains, inhibition of T-cell mitosis would suppress the
replication of the virus, since the virus relies upon the host
T-cell's proliferative functions to replicate.
[0095] The present invention provides a multiple minicapsule
modified release composition comprising at least one population of
cyclosporin-containing minicapsules which, upon administration to a
patient, exhibits a single, bimodal or multimodal release profile
throughout the entire gastrointestinal tract or at pre-specified
regions along the gastrointestinal tract.
[0096] The multiple minicapsule modified release composition may
comprise at least two populations of cyclosporin-containing
minicapsules which, upon administration to a patient, exhibits a
bimodal or multimodal release profile that results in a plasma
profile within therapeutically effective pharmacokinetic
parameters, as appropriate.
[0097] In one case the invention provides a multiple minicapsule
modified release composition comprising at least two populations of
active ingredient-containing minicapsules which, upon
administration to a patient, exhibits a pulsatile release
profile.
[0098] The invention provides a multiple minicapsule modified
release composition to protect or degradative-enzyme sensitive
active ingredients and to release such proximal to the intestinal
epithelial cell wall or in the colon, in the lumen or proximal to
the epithelial wall in the small intestine or colon.
[0099] In one case the invention provides a multiple minicapsule
modified release composition whereby the active or actives are
released in the ileum or colon, where the active is not absorbed
but may yet be locally active.
[0100] The pharmaceutically acceptable excipient may be chosen from
carriers, fillers, extenders, binders, humectants, disintegrating
agents, solution-retarding agents, absorption accelerators, wetting
agents, absorbents, lubricants, stabilizers, surfactants,
solubilising agents, permeability enhancers, oils, plant extracts,
fish extracts, marine extracts, colouring agents, buffering agents,
dispersing agents, preservatives, organic acids, and organic
bases.
[0101] The invention also provides a sachet format comprising
multiple minicapsule modified release composition of the present
invention for ease of administration to paediatrics, geriatrics or
other patient populations with swallowing difficulties, including
patients who are fed by tube.
[0102] The invention will be more clearly understood from the
following examples.
EXAMPLES
[0103] FIG. 11 schematically illustrates--liquid-filled
minicapsules with controlled release polymer coatings. This format
comprises solubilised cyclosporin encapsulated in a core C
encapsulated using a suitable gelling agent that is further coated
to permit controlled or targeted release along the gastrointestinal
tract. The cyclosporin is in an enhanced solubilised form, as a
liquid L. The open arrow represents the release of the drug
molecule M into the gastrointestinal, where it is fully soluble
when released.
Example 1 Ileum- and Colon-Specific Cyclosporin A
[0104] The core formulation was prepared as follows. Cylosporine A
was dissolved in a suitable volume of ethanol. Once dissolved, the
solution was blended with a suitable mix of Labrafil and Olive oil.
The shell solution was prepared as follows: Appropriate quantities
of gelatin and sorbitol were added to water and heated to 70
degrees C. until in solution. The minicapsules were prepared using
a Spherex Labo to produce 2-layer minicapsules, the core of which
comprises Cylosporine A in an enhanced solubilised and
permeabilised formulation. In addition, the core formulation does
enable a degree of sustained release.
TABLE-US-00001 TABLE 1 Ileum- and Colon-specific Cyclosporin A
Ingredients % w/w Core Composition Cyclosporin A 16.70 Labrafil M
1944 CS 18.2 Olive Oil 65 Ethanol 0.1 Shell Composition Gelatin
90.0 Sorbitol 10.0
[0105] To enable an ileum- and colon-specific product, the
minicapsules can be coated either with a sustained release polymer
or a combination of colonic-specific polymer and sustained release
polymers. The following options have been developed and tested:
Example 2
[0106] FIG. 1 Illustrates Cyclosporin a Release from the
Minicapsules of Example 1 Coated with 12.% and 22.5% Weight Gain
Surelease.RTM..
Example 3
[0107] Eudragit.TM. RS--Cyclosporin A containing minicapsules of
example 1 were coated with Eudragit.TM. RS with or without further
coating with Eudragit.TM. FS30D. The resulting dissolution profiles
demonstrate the possibility to delay the release of the active for
a number of hours and thereafter to release it in a sustained
manner. The results are displayed in FIG. 5.
Example 4
[0108] Surelease.RTM.--Cyclosporin A containing minicapsules of
Example 1 were coated with Surelease.RTM. with or without further
coating with Eudragit.TM. FS30D. The resulting dissolution profiles
demonstrate the possibility to delay the release of the active for
a number of hours and thereafter to release it in a sustained
manner. The results are displayed in FIG. 6.
Example 5
[0109] Surelease.RTM. and Pectin--Cyclosporin A containing
minicapsules of example 1 were coated with Surelease.RTM., with or
without the inclusion of high or low molecular weight pectin in the
coating solution and with or without further coating the
mincapsules with the pH sensitive Eudragit.TM. FS30D. The resulting
dissolution profile demonstrates the possibility to delay the
release of the active for a number of hours and thereafter to
release it in a sustained manner. The results are displayed in FIG.
7 and FIG. 8.
Example 6
[0110] Surelease.RTM. and Alginate--Cyclosporin A containing
minicapsules of example 1 were coated with Surelease.RTM., with or
without the inclusion of alginate in the coating solution and with
or without further coating the mincapsules with the pH sensitive
Eudragit.TM. FS30D. The resulting dissolution profile demonstrates
the possibility to delay the release of the active for a number of
hours and thereafter to release it in a sustained manner. The
results are displayed in FIG. 9.
Example 7
[0111] A once-daily formulation comprises minicapsules of example 1
containing cyclosporine A coated with 22% weight gain Eudragit.TM.
RS30D to provide less than 10% release up to 6 hours, less than 30%
up to 12 hours, less than 70% up to 18 hours and up to 100% at 24
hours. The results are displayed in FIG. 11.
Example 8 Ileum- and Colon-Specific Cyclosporin A
[0112] The core formulation was prepared as follows. Cylosporine A
was dissolved in a suitable volume of ethanol. Once dissolved, the
solution was blended with a suitable mix of Labrafil and Olive oil.
The shell solution was prepared as follows: Appropriate quantities
of gelatin and sorbitol were added to water and heated to 70
degrees C. until in solution. The minicapsules were prepared using
a Spherex Labo to produce 2-layer minicapsules, the core of which
comprises Cylosporine A in an enhanced solubilised and
permeabilised formulation. In addition, the core formulation does
enable a degree of sustained release.
TABLE-US-00002 TABLE 2 Ileum- and Colon-specific Cyclosporin A
Ingredients % w/w Core Composition Cyclosporin A 2.5-25 Labrafil M
1944 CS 15-35 Essential Oil 0-80 Olive Oil 0-80 Ethanol 0-20 Shell
Composition Gelatin 90.0 Sorbitol 10.0
[0113] To enable an ileum- and colon-specific product, the
minicapsules can be coated either with a sustained release polymer
or a combination of colonic-specific polymer and sustained release
polymers.
Example 9 Ileum- and Colon-Specific Cyclosporin and Neem
[0114] The core formulation was prepared as follows. Cylosporine A
was dissolved in a suitable volume of ethanol. Once dissolved, the
solution was blended with a suitable mix comprising one or more of
Labrafil, Olive oil, Neem oil or other essential oils, including
omega-3-rich fish oils. The shell solution was prepared as follows:
Appropriate quantities of gelatin and sorbitol were added to water
and heated to 70 degrees C. until in solution. The minicapsules
were prepared using a Spherex Labo to produce 2-layer minicapsules,
the core of which comprises Cylosporine A in an enhanced
solubilised and permeabilised formulation. In addition, the core
formulation does enable a degree of sustained release.
TABLE-US-00003 TABLE 3 Ileum- and Colon-specific Cyclosporin and
Neem Ingredients % w/w Core Composition Cyclosporine 0-20 Labrafil
0-35 Neem 0-75 Olive Oil 0-75 Essential Oil 0-75 Ethanol 0-20 Shell
Composition Gelatin 90.0 Sorbitol 10.0
[0115] To enable an ileum- and colon-specific product, the
minicapsules are coated either with a sustained release polymer or
a combination of colonic-specific polymer and sustained release
polymers. The sustained release coating comprises a 95:5 ratio of
Eudragit.TM. RS: Eudragit.TM. RL. The combination comprises 95:5
Eudragit.TM. RS:RL, further coated with Eudragit FS30D.
Example 10--Colon-Specific, Pre-Solubilized Cyclosporin for
Treatment of IBD
[0116] Colitis was induced in mice using DSS 2.5% in drinking
water. To determine the effectiveness of pre-solubilized
cyclosporin on the prevention or treatment of DSS-induced colitis
various formulations of pre-solubilized cyclosporin minicapsules
with differing release profiles were administered to mice daily.
The minicapsules were prepared using the method described in
Example 1 above. Referring to FIG. 2, in total, three Cyclosporin
(0.25 mg/mouse/day) mini-formulations were used in the study,
namely A (Immediate Release--small intestine: Uncoated minicapsules
containing cyclosporin A as per Example 1), B (Ileum
Release--sustained release: Minicapsules containing cyclosporin A
as per Example 1, coated with a 12.5% weight gain Eudragit.TM.
RS30D polymer coating) and C (Colon-specific Release--sustained
release: Minicapsules containing cyclosporin A as per Example 1,
coated with a 22% weight gain Eudragit.TM. RS30D polymer
coating).
[0117] Following removal of the colon from mice on Day 7, it is
observed that while the DSS still exerted a shortening affect on
the colon length, the administration of all CyA formats,
particularly the colon-specific CyA resulted in significantly
reduced colon shortening, thereby suggesting that CyA is exerting a
protective effect against DSS-induced colitis.
[0118] A major symptom of DSS-induced colitis is weight loss. From
FIG. 3 it is evident that when administered directly to the colon,
0.25 mg CyA (Capsule C) administered daily has a significant
protective effect compared mice administered with immediate
(Capsule A) or ileum-release (Capsule B) CyA. This data set
suggests that when administered specifically to the colon daily at
low concentration; CyA has a pronounced protective effect on
DSS-induced colitis.
[0119] Referring to FIG. 4, the disease activity index (DAI) is
calculated as the sum of scores of weight loss, stool consistency
and blood in feces. Normal stool=formed pellets; loose stool=pasty
and semi-formed stool which do not stick to the anus;
diarrhoea=liquid stools that stick to the anus. This composite
scoring system clearly demonstrates that daily administration of
0.25 mg CyA specifically to the colon (DSS-COAT beads) produces a
pronounced protective effect against the induction of colitis in
DSS treated mice.
[0120] Formulations and uses based on cyclosporin A are described
above. However, it will be appreciated that the invention can also
be applied to other cyclosporins including cyclosporins-B, -C, -D,
-G, derivatives, prodrugs, esters and/or salts thereof as well as
mixtures containing more than one of the above.
[0121] In addition, the invention envisages the use of a
cyclosporin in combination with another therapeutically or
propylactically active entity.
[0122] The composition may, for example by combined with another
active pharmaceutical in a single oral dosage form.
[0123] Other immunosuppressants could be considered, either alone
or in combination with cyclosporin or derivatives thereof. These
include, but are not limited to, various other calcineurin
inhibitors such as but not limited to Abetimus, Deforolimus,
Everolimus, Gusperimus, Pimecrolimus, Sirolimus, Tacrolimus,
Temsirolimus, glucocorticosteriods; cytostatics such as Anakinra,
Azathioprine, Leflunomide, Methotrexate, Mycophenolic acid,
Thalidomide; antibodies such as the T-cell receptor directed
anti-CD3 OKT3; the immunophilin receptor binder sirolimus;
interferons; opioids; TNF.alpha.-binding proteins, including, but
not limited to, infliximab, etanercept, adalimumab, cucumin and
catechins; and Mycophenolate Mofetil acid which acts as a
non-competitive, selective and reversible inhibitor of inosine
monophosphate dehydrogenase. The above list include derivatives
thereof, including those modified to include a conjugated NO
donor.
[0124] Certain natural extracts, including Neem oil, aloe vera,
tripala, tumeric and other essential oils, including the omega
polyunsaturated oils such as EPA, DHA, conjugated linoeic acid
(CLA) and other derivatives thereof, have potential as treatments
to alleviate or prevent inflammatory bowel disease as well as other
intestinal disorders, including gastric, duodenal and intestinal
ulcers. Additionally, certain plant extracts, including berry
extracts such as blueberry, achi, resorcinolic/phenolic lipids,
resveratrol, flavanoids and derivatives thereof, alone or in
combination, have potential application in IBD and IBS and other
intestinal or systems conditions. The mode of action of berry
extracts, such as blueberry extract, remains uncertain but has
effect on intestinal motility, stool formation and colonic flora.
Yet other potential therapeutics include, but are not limited to,
proteins, therapeutic peptides, vaccines, antibodies or fragments
thereof. Local delivery to the mucosa will overcome degradation and
ensure that a high local concentration is available to enhance
therapeutic efficacy. Encapsulating any of the above, alone or in
any combination, into minicapsules or minispheres and targeting the
release to areas of the intestine that are diseased provide for
enhanced disease management as well as perhaps a reduction in any
potential for systemic side effects.
[0125] The invention also includes methods of treating inflammatory
bowel disease comprising administering to a subject in need thereof
a pharmaceutical composition comprising a dose of a cyclosporin or
pharmaceutically acceptable salts, esters and pro-drugs thereof,
including various salts and enantiomers thereof or covalent or
non-covalent modified active or inactive entities, including nitric
oxide donors (NO-donors) and at least one pharmaceutically
acceptable excipient. Such formulations are preferentially
developed to ensure release in the ileum and/or colon.
[0126] The invention also provides methods of treating inflammatory
bowel disease comprising administering to a subject in need thereof
a pharmaceutical composition comprising cyclosporin and a
curcuminoid, such as, but not limited to, curcumin, with release of
same targeted to the ileum or colon.
[0127] The invention also includes non-covalent complexion of a
cyclosporin with a carrier such as cyclodextrins, maltodextrins,
dextrins or modifications thereof and targeting the release of such
to the specific sites along the gastrointestinal tract.
[0128] One more embodiment of the present invention is the
inclusion of targeted gastrointestinal release of formulations
containing live or live attenuated organisms, including bacteria or
genetically modified bacteria and/or live or live-attenuated
viruses.
[0129] In the invention, in the development of cyclosporin-based
combination treatments for inflammatory bowel disease, the
non-cyclospoine-based active pharmaceutical ingredient is
interchangeable, including any one or combination of tacrolimus,
sirolimus, hydralazine, DMOG, proply- and/or asparaginyl hydroylase
inhibitors, EPA, DHA, natural plant extracts, natural marine
extracts or other biological and active entities, which may include
siRNA constructs.
[0130] In the invention, in the development of cyclosporin-based
combination treatments for Graft-Versus-Host Disease, the
non-cyclosporine-based active pharmaceutical ingredient is
interchangeable, including any one or combination of tacrolimus,
sirolimus, EPA, DHA, natural plant extracts, natural marine
extracts or other biological and active entities, which may include
siRNA constructs.
[0131] In the invention, the immunological modulating entities,
including antigens, adjuvants, emulsions, oils, and small molecules
are interchangeable and may be utilised for the development of
vaccines, oral tolerance modulators and allergen modulators, which
may include siRNA constructs.
[0132] The invention allows for the development of solid-,
semi-solid or liquid-filled minicapsules comprising one or more
layer and produced using conventional seamless minicapsule
processes, modified melt extrusion, non-pareil coating, non-pareil
drug layering or other processes that enable the production of the
desired dosage form.
[0133] The result is modified release compositions that in
operation deliver one or more active ingredients in a unique,
bimodal or multimodal manner. The present invention further relates
to solid oral dosage forms, sachets or suppositories containing
such multiple minicapsule or minisphere controlled release
compositions as well as methods for delivering one or more active
ingredients to a patient in a bimodal or multimodal manner.
Furthermore, the invention permits targeted release of orally
delivered formulations to specific regions of the gastrointestinal
tract to maximize absorption, confer protection on the payload, to
optimize treatment of diseased intestinal tissue or enhance oral
bioavailability. Additionally, the invention enables one or more
pharmaceutical active to be administered sequentially or
concomitantly to improve disease treatment and management and to
benefit from the body's natural circadian rhythms. The invention
also permits the release of pharmaceutical actives into the ileum
and colon for the enhanced treatment of local intestinal diseases
or to facilitate the absorption of active pharmaceutical agents,
including biopharmaceuticals such as peptide and proteins.
[0134] The formulations may include the following therapeutics:
steroids (e.g., budesonide and other corticosteroids, and adrenal
steroids such as prednisone and hydrocortisone, administered alone
or in combination with a xanthine or methylxanthine compound such
as theophylline); cytokines such as interleukin-10; antibiotics;
immunomodulating agents such as azathioprine, 6-mercaptopurine,
methotrexate, and anti-tumor necrosis factor (TNF) agents such as
soluble TNF receptor and antibodies raised to TNF; and also
antinflammatory agents such as zinc are widely prescribed. The most
commonly prescribed agents for IBD include sulfasalazine
(salicyl-azo-sulfapyridine, or "SASP") and related 5-aminosalicylic
acid ("5-ASA") products are commonly prescribed and due to
significant side-effects of some of these as well as the above
mentioned therapies would benefit from targeted colonic delivery
and in some cases, pre-formulated to enhance solubility or
permeability.
[0135] The invention may also be used to deliver live organisms,
including various bacteria such as probiotics, to specific regions
of the intestine or colon where they exert protective or
therapeutic effects. Steidler et al (Science 2000; 289:1352-5) have
shown that it is possible to first develop genetically modified
bacteria to produce proteins and then to target the release of such
proteins, including anti-inflammatory cytokines to regions of the
gastrointestinal tract where they will optimally exert protective
or therapeutic effects. The bacteria may be formulated for storage
stability and target the release of such agents to the site of
optimal action.
[0136] The invention further provides a multiple minicapsule
modified release composition comprising at least two populations of
different active ingredient-containing minicapsules in which the
two or more actives are released concomitantly.
[0137] Alternatively, the invention provides a multiple minicapsule
modified release composition comprising at least two populations of
different active ingredient-containing minicapsules in which the
two or more actives are released sequentially.
[0138] The invention is not limited to the embodiments herein
before described which may be varied in detail.
* * * * *