U.S. patent application number 17/246086 was filed with the patent office on 2022-03-17 for formulations.
This patent application is currently assigned to Sublimity Therapeutics Limited. The applicant listed for this patent is Sublimity Therapeutics Limited. Invention is credited to Vincenzo Aversa, Ivan Coulter, Bernard Francis McDonald, Monica Rosa.
Application Number | 20220080026 17/246086 |
Document ID | / |
Family ID | 1000005990390 |
Filed Date | 2022-03-17 |
United States Patent
Application |
20220080026 |
Kind Code |
A1 |
Coulter; Ivan ; et
al. |
March 17, 2022 |
FORMULATIONS
Abstract
The present invention relates to a formulation comprising a
pharmaceutically active ingredient and a coating. The invention
also relates to the use of the formulation in the treatment and
prevention of disorders of the gastrointestinal tract. Also
disclosed are methods for preparing the formulations.
Inventors: |
Coulter; Ivan; (Co. Bublin,
IE) ; Aversa; Vincenzo; (Co. Dublin, IE) ;
McDonald; Bernard Francis; (Co. Monaghan, IE) ; Rosa;
Monica; (Dublin, IE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sublimity Therapeutics Limited |
Dublin |
|
IE |
|
|
Assignee: |
Sublimity Therapeutics
Limited
Dublin
IE
|
Family ID: |
1000005990390 |
Appl. No.: |
17/246086 |
Filed: |
April 30, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15034847 |
May 5, 2016 |
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PCT/EP2014/074057 |
Nov 7, 2014 |
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17246086 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/10 20130101;
A61K 31/502 20130101; A61K 9/5089 20130101; A61K 31/196 20130101;
A61K 9/4858 20130101; A61K 47/14 20130101; A61K 47/36 20130101;
A61K 9/5036 20130101; A61K 9/5073 20130101; A61K 31/635 20130101;
A61K 9/4866 20130101; A61K 47/20 20130101; A61K 9/5026 20130101;
A61K 9/1658 20130101; A61K 9/5047 20130101; A61K 9/0053 20130101;
A61K 47/42 20130101; A61K 38/13 20130101 |
International
Class: |
A61K 38/13 20060101
A61K038/13; A61K 9/50 20060101 A61K009/50; A61K 9/16 20060101
A61K009/16; A61K 31/196 20060101 A61K031/196; A61K 31/502 20060101
A61K031/502; A61K 47/10 20060101 A61K047/10; A61K 47/14 20060101
A61K047/14; A61K 47/20 20060101 A61K047/20; A61K 47/36 20060101
A61K047/36; A61K 47/42 20060101 A61K047/42; A61K 9/00 20060101
A61K009/00; A61K 9/48 20060101 A61K009/48; A61K 31/635 20060101
A61K031/635 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 8, 2013 |
GB |
1319791.8 |
Claims
1-2. (canceled)
3. A pharmaceutical formulation comprising a core, a first coating
and a second coating outside the first coating, wherein the core
comprises a hydrogel forming polymer matrix and a pharmaceutically
active ingredient comprising cyclosporin A, wherein the first
coating comprises a water-soluble cellulose ether and the first
coating has a thickness of from 10 .mu.m to 100 .mu.m, wherein the
second coating comprises a single polymer, wherein the polymer is a
delayed release pH independent polymer and the first coating is
present in an amount to provide a higher % release of the
pharmaceutically active ingredient from the pharmaceutical
formulation than a corresponding pharmaceutical formulation without
the first coating at 12 hours from the start of a dissolution
test.
4-113. (canceled)
114. The pharmaceutical formulation of claim 3, wherein the first
coating has a thickness of from 10 .mu.m to 50 .mu.m.
115. The pharmaceutical formulation of claim 3, wherein the first
coating is present in an amount corresponding to a weight gain due
to the coating of from 1% to 9% by weight of the core.
116. The pharmaceutical formulation of claim 3, wherein the first
coating is present in an amount corresponding to a weight gain due
to the coating of from 8% to 20%.
117. The pharmaceutical formulation of claim 3, wherein the first
coating comprising a water-soluble cellulose ether is in contact
with the core.
118. The pharmaceutical formulation of claim 3, wherein the second
coating is in contact with the first coating comprising a
water-soluble cellulose ether.
119. The pharmaceutical formulation of claim 3, wherein the second
coating is present in an amount corresponding to a weight gain due
to the additional coating of from 2% to 40%.
120. The pharmaceutical formulation of claim 3, wherein the delayed
release polymer is water-soluble or water-permeable in an aqueous
medium with a pH greater than 6.5.
121. The pharmaceutical formulation of claim 3, wherein the delayed
release polymer comprises ethyl cellulose.
122. The pharmaceutical formulation of claim 3, wherein the
water-soluble cellulose ether is selected from any one or a
combination of: methyl cellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxyethyl methylcellulose and
hydroxypropylmethyl cellulose.
123. The pharmaceutical formulation of claim 122, wherein the
water-soluble cellulose ether is hydroxypropylmethyl cellulose.
124. The pharmaceutical formulation of claim 3, wherein the first
coating is present in an amount corresponding to a weight gain due
to the coating of from 0.5% to 20% by weight of the core.
125. The pharmaceutical formulation of claim 3, wherein the first
coating is present in an amount corresponding to a weight gain due
to the coating in a range selected from: 0.5% to 15%; 1% to 15%; 1%
to 12%; 1% to 10%; 1% to 8%; 1% to 6%; 1% to 4%, 2% to 10%; 2% to
8%; 2% to 6%; 2% to 4%; 4% to 8%; 4% to 7%, 5% to 7%; 7% to 20%; 7%
to 16%; 9% to 20%; 9% to 16%; 10% to 15%; or 12% to 16%.
126. The pharmaceutical formulation of claim 3, wherein the
hydrogel forming polymer matrix comprises a hydrocolloid, a
non-hydrocolloid gum or chitosan.
127. The pharmaceutical formulation of claim 3, wherein the
hydrogel forming polymer matrix comprises gelatin, agar, a
polyethylene glycol, starch, casein, chitosan, soya bean protein,
safflower protein, alginates, gellan gum, carrageenan, xanthan gum,
phthalated gelatin, succinated gelatin, cellulosephthalate-acetate,
oleoresin, polyvinylacetate, polymerisates of acrylic or
methacrylic esters and polyvinylacetate-phthalate and any
derivative of any of the foregoing; or a mixture of one or more
such a hydrogel forming polymer.
128. The pharmaceutical formulation of claim 3, wherein the
hydrogel forming polymer matrix comprises a hydrocolloid selected
from carrageenan, gelatin, agar and pectin, or a combination
thereof.
129. The pharmaceutical formulation of claim 3, wherein the
hydrogel forming polymer matrix further comprises a
plasticiser.
130. The pharmaceutical formulation of claim 3, wherein the
hydrogel forming polymer matrix encapsulates the active
ingredient.
131. The pharmaceutical formulation of claim 3, wherein the core is
in the form of a solid colloid, the colloid comprising a continuous
phase and a disperse phase, wherein the continuous phase comprises
the hydrogel forming polymer matrix.
132. The pharmaceutical formulation of claim 131, wherein the
disperse phase comprises a hydrophobic phase.
133. The pharmaceutical formulation of claim 131, wherein the
disperse phase comprises a liquid lipid.
134. The pharmaceutical formulation of claim 131, wherein the
disperse phase comprises a glyceride composition.
135. The pharmaceutical formulation of claim 131, wherein the
disperse phase comprises an oil phase selected from caprylic/capric
triglyceride; caprylic/capric/linoleic triglyceride;
caprylic/capric/succinic triglyceride; and propylene glycol
dicaprylate/dicaprate.
136. The pharmaceutical formulation of claim 131, wherein the
disperse phase comprises an oil phase selected from linoleoyl
macrogolglycerides (polyoxylglycerides) and caprylocaproyl
macrogolglycerides.
137. The pharmaceutical formulation of claim 131, wherein the
disperse phase further comprises a solvent, wherein the solvent is
miscible with the disperse phase and water.
138. The pharmaceutical formulation of claim 131, wherein the
disperse phase comprises an oil phase which represents 10-85% by
dry weight of the core.
139. The pharmaceutical formulation of claim 131, wherein the
active ingredient is in solution or suspended in the continuous
phase or the disperse phase.
140. The pharmaceutical formulation of claim 139, wherein the
active ingredient is: a. in solution in the disperse phase; b. in
solution in the continuous phase; c. suspended in the disperse
phase; or d. suspended in the continuous phase.
141. The pharmaceutical formulation of claim 131, wherein the core
further comprises an anionic surfactant present in at least the
continuous phase, the anionic surfactant having an HLB value of at
least 10.
142. The pharmaceutical formulation of claim 131, wherein the
continuous phase comprises a hydrogel forming polymer matrix and
the disperse phase comprises an oil phase comprising an oil wherein
the oil has an HLB in the range 0-10.
143. The pharmaceutical formulation of claim 142, wherein the oil
has an HLB of 1-5.
144. The pharmaceutical formulation of claim 142, wherein the oil
phase comprises a triglyceride.
145. The pharmaceutical formulation of claim 131, wherein the
disperse phase comprises an oil phase selected from caprylic/capric
triglyceride; caprylic/capric/linoleic triglyceride;
caprylic/capric/succinic triglyceride; and propylene glycol
dicaprylate/dicaprate; and a polyethoxylated castor oil.
146. The pharmaceutical formulation of claim 137, wherein the
solvent is 2-(2-ethoxyethoxy)ethanol.
147. The pharmaceutical formulation of claim 131, wherein the
disperse phase comprises: a pharmaceutically active ingredient
comprising cyclosporin A; a medium chain mono- di- or
tri-glyceride; and a solvent, and wherein the continuous phase
comprises: an anionic surfactant, a hydrogel forming polymer matrix
which comprises a hydrocolloid selected from carrageenan, gelatin,
agar and pectin, or a combination thereof; and optionally a
plasticiser.
148. The pharmaceutical formulation of claim 3, wherein the core
comprises a hydrogel forming polymer comprising gelatin in an
amount of 300 to 700 mg/g, the core further comprising medium chain
mono, di or tri-glycerides in an amount of 20 to 200 mg/g, and the
pharmaceutical formulation further comprises the following
components: co-solvent in an amount of 150 to 250 mg/g; and anionic
surfactant in an amount of 15 to 50 mg/g.
149. The pharmaceutical formulation of claim 3, wherein the
formulation is in the form of a minibead.
150. The pharmaceutical formulation of claim 3, wherein the largest
cross sectional dimension of a core is from about 0.01 mm to about
5 mm.
151. A pharmaceutical formulation comprising a multiplicity of
minibeads of claim 149.
152. The pharmaceutical formulation of claim 3, wherein the
formulation is for oral administration.
153. The pharmaceutical formulation of claim 3, the core having the
characteristics of a core formed by mixing a disperse phase with a
continuous phase to form a colloid, wherein the continuous phase is
an aqueous phase comprising hydrogel forming polymer and the
disperse phase is a hydrophobic phase, wherein the pharmaceutically
active ingredient is in the continuous phase or the disperse phase,
wherein the colloid is gelled to form the core.
154. The pharmaceutical formulation of claim 153, wherein the
continuous phase further comprises an anionic surfactant.
155. The pharmaceutical formulation of claim 153, wherein the core
comprises a hydrogel forming polymer matrix and a hydrophobic phase
dispersed in the a hydrogel forming polymer matrix, wherein the
core comprises gelatin, SDS, sorbitol, polyethoxylated castor oil,
caprylic/capric triglyceride, and 2-(ethoxyethoxy)ethanol; wherein
the aqueous phase comprises gelatin, sorbitol and SDS; and the
disperse phase comprises polyethoxylated castor oil,
caprylic/capric triglyceride, 2-(ethoxyethoxy)ethanol and
cyclosporin A.
156. The pharmaceutical formulation of claim 3, formulated into a
unit dosage form for oral administration comprising from 0.1 mg to
1000 mg of the active ingredient.
157. The pharmaceutical composition of claim 3, wherein the second
coating further comprises at least one excipient.
158. The pharmaceutical composition of claim 157, wherein the at
least one excipient is selected from a plasticizer and/or a
glidant.
Description
[0001] This is a continuation of U.S. application Ser. No.
15/034,847, filed May 5, 2016, which is a U.S. National Stage of
International Application No. PCT/EP2014/074057 filed Nov. 7, 2014,
which was published in English under PCT Article 21(2), which in
turn claims the benefit of Great Britain Application No. 1319791.8,
filed Nov. 8, 2013. These applications are incorporated herein in
their entireties.
[0002] This invention relates to a formulation comprising a
pharmaceutically active ingredient and a coating. The invention
also relates to the use of the formulation in the treatment and
prevention of disorders of the gastrointestinal tract. Also
disclosed are methods for preparing the formulations.
BACKGROUND
[0003] Formulating pharmaceutically active ingredients into a form
suitable for administration to a patient is a developed area of
science. It is also a key consideration for the efficacy of a drug.
There are many examples of methods for formulating drugs and other
active ingredients. The aim of these formulations are varied and
can range from increasing systemic absorption, allowing for a new
route of administration, improving bioavailability, reducing
metabolism of the active, or avoiding undesirable routes of
administration.
[0004] WO 2008/122965 discloses oral cyclosporin minicapsule
compositions with modified release properties which release
cyclosporin in at least the colon. WO2010/133609 discloses
compositions comprising a water-soluble polymer matrix in which are
dispersed droplets of oil, the compositions comprising a modified
release coating. The disclosed compositions also contain an active
principle.
BRIEF SUMMARY OF THE DISCLOSURE
[0005] It has surprisingly been found that pharmaceutical
formulations which have a coating which is or comprises a
water-soluble cellulose ether have a higher total release of active
from the formulation and/or a greater rate of release of the active
compared to a formulation which does not have the coating. This
coat constitutes the first coating. The first coating may also be
referred to as a subcoat. The greater extent and/or rate of release
of the active provides a formulation which has a novel in-vitro
release profile (and consequently a novel in-vivo pharmacokinetic
profile) compared to the same formulations without the coating. In
vitro dissolution testing has also shown that formulations
according to the invention reduce batch to batch variability in the
in-vitro release profile. Accordingly, the formulations are
expected to demonstrate a reduced inter and/or intra-patient
variability compared to formulations lacking the coating.
[0006] The formulation may comprise a second coating to control or
modulate release of the active ingredient, for example cyclosporin
A, mesalazine and hydralazine, from the formulation. Advantageously
the coating is a polymeric coating to provide delayed and/or
sustained release of the active ingredient, for example cyclosporin
A, mesalazine or hydralazine, from the formulation. Suitable such
coatings are described in more detail below and include a coating
which is or comprises a coating selected from a controlled release
polymer, a sustained release polymer, an enteric polymer, a pH
independent polymer, a pH dependent polymer and a polymer
specifically susceptible to degradation by bacterial enzymes in the
gastrointestinal tract, or a combination of two or more such
polymers. In a particular embodiment the second coating is or
comprises a pH-independent polymer, for example a coating which is
or comprises ethyl cellulose. In a further specific embodiment the
second coating is or comprises a pH-independent polymer, for
example ethyl cellulose, and a water-soluble polysaccharide, for
example pectin or chitosan, or a combination thereof, particularly
pectin. The respective polymers of the first coating and the second
coating are different. Often the second coating does not have any
polymer found in the first coating; for example, if the first
coating comprises (e.g. is) a hydroxypropylmethyl cellulose, then
the second coating will not also comprise a hydroxypropylmethyl
cellulose. In addition the situation is contemplated where the
first coating is or comprises a water-soluble ether or ester of a
cellulose ether, the major component(s) (e.g. more than 50%) of the
second coating is or comprises a different polymer to that of the
first coating. Accordingly, the first and second coatings suitably
provide two layers of material as part of the composition. It is to
be understood that when the second coating comprises a mixture of
components, minor components of the outer second coating may be the
same as the material of the sub-coating. By way of example, when
the first coating is or comprises HPMC and the second coating
comprises ethyl cellulose, the ethyl cellulose may optionally
further comprise a minor amount (e.g. less than 50%, 40%, 30% or
20%) of the first coating material, HPMC in this example. In such
embodiments the first coating and the second coating are considered
to be different.
[0007] According to an embodiment of the invention, the active
ingredient optionally is or comprises cyclosporin A, hydralazine or
mesalazine, said coating which is or comprises a water-soluble
cellulose ether is a first coating and the formulation further
comprises a second coating outside the first coating; and wherein
the second coating is or comprises a coating, suitably a polymeric
coating, to control or modulate release of the active ingredient
from the formulation. The polymeric coating may be as further
described elsewhere in this specification.
[0008] In the invention the first coating suitably is or comprises
a water-soluble cellulose ether. The water-soluble cellulose ether
may be any cellulose ether or derivative of a cellulose ether, for
example an ester of a cellulose ether, that is soluble in water.
Therefore, the water-soluble cellulose ether may be selected from:
an alkyl cellulose; a hydroxyalkyl cellulose; a hydroxyalkyl alkyl
cellulose; and a carboxyalkyl cellulose. Suitably the first coating
is or comprises one or more water-soluble cellulose ethers selected
from: methyl cellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose and hydroxypropylmethyl cellulose, and combinations
thereof. In particular embodiments the first coating is or
comprises a water-soluble hydroxypropyl methylcellulose. The
water-soluble cellulose ethers and water-soluble derivatives
thereof (e.g. water-soluble esters of a cellulose ether) present in
the first coating (sub-coat) suitably form at least 20%, 40%, 50%,
60%, 70%, 80%, 85% or 90% by weight of the dry weight of the first
coating.
[0009] The formulation of the invention may comprise a core, a
first coating outside the core, wherein the first coating is a
water-soluble cellulose ether as described above and elsewhere
herein; and a second coating outside the first coating; wherein the
core comprises a hydrogel-forming polymer matrix and a
pharmaceutically active ingredient, optionally a hydrophobic or
hydrophilic active ingredient, for example cyclosporin A,
hydralazine or mesalazine.
[0010] In accordance with the present invention there is provided a
pharmaceutical formulation comprising a core and a coating, wherein
the core comprises a hydrogel forming polymer matrix and a
pharmaceutically active ingredient and the coating comprises or is
a water soluble cellulose ether and the coating is present in an
amount corresponding to a weight gain due to the coating of from
0.5% to 20% by weight of the core.
[0011] The coating of the present invention modifies the release of
the active ingredient from the formulation. There would be an
expectation that a coating on a formulation would slow the rate of
release of the active ingredient within a formulation. One might
reasonably expect this as coating the formulation with additional
material would provide an additional barrier to a dissolution
medium coming into contact with the active ingredient in the
formulation. In contrast to this expected outcome, the present
invention surprisingly provides a formulation with a coating
comprising or being a water soluble cellulose ether that increases
the rate of release of the active ingredient compared to a
formulation without the coating. In addition the coating of the
present invention has the beneficial effect of maintaining the
active ingredient in solution, whereas a comparable formulation
lacking the coating of the invention provides less of the active
ingredient in solution as time progresses. Without wishing to be
bound by theory, it is believed that the coating prevents
precipitation of the active ingredient from solution, thereby
maintaining a higher amount of the active in solution.
[0012] Throughout the present application active ingredient,
active, and pharmaceutically active ingredient are used
interchangeably and all refer to the same subject matter.
[0013] The formulation of the present invention may take any form
known to the person skilled in the art. Preferably, the formulation
is an oral formulation. The formulation may be in the form of a
single minibead or a multiplicity of minibeads.
[0014] The formulation may comprise a coating present in an amount
corresponding to a weight gain due to the coating selected from
ranges of from: 0.5% to 15%; 1% to 15%; 1% to 12%; 1% to 10%; 1% to
8%; 1% to 6%; 1% to 4%, 2% to 10%; 2% to 8%; 2% to 6%; 2% to 7%; 2%
to 4%; 4% to 8%; 4% to 7%, 4% to 6%, 5% to 7%; 7% to 20%; 7% to
16%; 9% to 20%; 9% to 16%; 10% to 15%; and 12% to 16%.
[0015] The formulation of the invention may comprise a coating with
a thickness of 1 .mu.m to 1 mm. Thus, the % weight gain due to the
coating specified above may correspond to a thickness of 1 .mu.m to
1 mm.
[0016] The invention also provides for a pharmaceutical formulation
comprising a core and a coating, wherein the core comprises a
hydrogel forming polymer matrix and a pharmaceutically active
ingredient, wherein the coating comprises or is a water-soluble
cellulose ether and the coating has a thickness of from 1 .mu.m to
1 mm.
[0017] The coating may have a thickness selected from ranges of
from: 1 .mu.m to 500 .mu.m; 10 .mu.m to 250 .mu.m; 10 .mu.m to 100
.mu.m; 10 .mu.m to 50 .mu.m; 10 .mu.m to 20 .mu.m; 50 .mu.m to 100
.mu.m; 100 .mu.m to 250 .mu.m; 100 .mu.m to 500 .mu.m; 50 .mu.m to
500 .mu.m; 50 .mu.m to 250 .mu.m; 100 .mu.m to 1 mm; 500 .mu.m to 1
mm. The coating having the thicknesses disclosed in this paragraph
may be any of the coatings in the application. In particular the
coating referred to in this paragraph may be the water-soluble
cellulose ether coating.
[0018] Any of the pharmaceutical formulations of the invention may
comprise a further, or second, coating. The second coating may be
outside the first coating. The second coating may be or comprise a
delayed release polymer. Where the formulations of the invention
comprise a second coating the coating referred to above may be
referred to as the first coating. Any disclosure given below in
relation to a second coating is also applicable to the second
coating referred to in this paragraph. In any embodiment and any
aspect of the invention the first and second coating may be
different.
[0019] The invention therefore, contemplates a pharmaceutical
formulation comprising a core, a first coating and a second coating
outside of the first coating, wherein the core comprises a
pharmaceutically active ingredient, the first coating comprises or
is a water soluble cellulose ether, and the second coating
comprises or is a delayed release polymer, wherein the first
coating is present in an amount corresponding to a weight gain due
to the coating of from 0.5% to 20% by weight of the core. The core
may optionally further comprise a hydrogel forming polymer.
[0020] In addition, the invention provides for a pharmaceutical
formulation comprising a core, a first coating and a second coating
outside of the first coating, wherein the core comprises a
pharmaceutically active ingredient, the first coating comprises or
is a water soluble cellulose ether, and the second coating
comprises or is a delayed release polymer, and the first coating
has a thickness of from 1 .mu.m to 1 mm. The core may optionally
further comprise a hydrogel forming polymer.
[0021] Included in the invention is a pharmaceutical formulation
comprising a core and a coating, wherein the core comprises a
pharmaceutically active ingredient and the coating comprises or is
a water-soluble cellulose ether. The coating is present in an
amount to provide a higher % in solution of the pharmaceutically
active ingredient from the formulation than a formulation without
the coating at 0.5 hours from the start of a dissolution test to
measure the % in solution of the pharmaceutically active ingredient
in a dissolution medium consisting of water, the dissolution test
being carried out in accordance with USP <711> Dissolution
using Apparatus II (paddle apparatus) operated with a paddle speed
of 75 rpm and with the dissolution medium at a temperature of
37.degree. C..+-.0.5.degree. C. Alternatively, the higher % in
solution of the active ingredient from the formulation may be at 20
mins, 40 mins 1 hour or 1.5 hours from the start of a dissolution
test instead of at 0.5 hours. Additionally, the higher % in
solution of the active ingredient from the formulation may be at
time points selected from: 20 mins and 40 mins; 0.5 hours and 1
hour; 1 hour and 1.5 hours; or 0.5 hours, 1 hour and 1.5 hours. The
% in solution of the active ingredient from the formulation may be
higher for a period selected from one of those spanning from: 0
hours to 0.5 hours; 0 hours to 1 hour; 0 hours to 1.5 hours; or 0.5
hours to 1.5 hours. Preferably, the % in solution of the
pharmaceutically active ingredient from the formulation of the
invention is higher than a formulation without the coating for the
period up to 1.5 hours from the start of the dissolution test.
[0022] In embodiments the higher % in solution of the
pharmaceutically active ingredient is at 0.5 hours and a time point
selected from: 20 mins, 40 mins, 1 hour 1.5 hours, and any
combination thereof. In embodiments the higher % in solution of the
pharmaceutically active ingredient may be for the period up to 1.5
hours from the start of the dissolution test.
[0023] The % in solution of the active of a formulation of the
invention with the coating may be higher than a formulation without
the coating at a specific time point by: 10 or more, 15 or more, 20
or more, 30 or more, 40 or more, or 45 or more at 0.5 hours; 10 or
more, 15 or more, or 20 or more at 1 hour; and/or 3 or more, 5 or
more, 8 or more, or 10 or more at 1.5 hours. The higher % in
solution values described herein may be attained when a single time
point is specified, more than one time point is specified or where
a period has been specified.
[0024] For example, a formulation of the invention with the coating
may give a % in solution that is 10 or more higher at 0.5 hours and
10 or more higher at 1 hour and 5 or more higher at 1.5 hours.
[0025] It is contemplated within this aspect of the invention that
the coating may further be present in an amount corresponding to a
% weight gain by weight of the core of: from 1% to 15%, from 1% to
12%, from 2% to 15%, from 2% to 12%, from 1% to 9%, from 2% to 8%,
from 2% to 3%, from 2% to 5%, from 5% to 7%, from 4% to 6.5%, from
6% to 7%, or from 2% to 7%. Preferably, the coating may be present
in an amount corresponding to a weight gain of from 1% to 9%, from
2% to 8%, from 4% to 6.5%, from 2% to 5% or from 2% to 7%,
optionally from 4% to 6.5%, from 2% to 5% or from 2% to 7%. The %
weight gain of the coating relative to the core may be combined
with any of the specified higher % in solution values and any time
point.
[0026] For example, the coating may be present in an amount to
provide a higher % in solution of the pharmaceutically active
ingredient at 0.5 hours, wherein the % in solution of the active
may be higher by 30, optionally 35 and the coating may be present
in an amount corresponding to a % weight gain by weight of the core
of from 2% to 7%, optionally from 2% to 4%. Alternatively, the
coating may be present in an amount to provide a higher % in
solution of the pharmaceutically active ingredient at 0.5 hours,
wherein the % in solution of the active may be higher by 40,
optionally 45 and the coating may be present in an amount
corresponding to a % weight gain by weight of the core of from 4%
to 7%, optionally from 5% to 7%.
[0027] The invention also contemplates a formulation comprising a
core and a coating, wherein the core comprises a pharmaceutically
active ingredient and the coating comprises or is a water-soluble
cellulose ether. The coating is present in an amount to provide a %
in solution of more than 60% of the pharmaceutically active
ingredient at 1 hour from the start of a dissolution test to
measure the % in solution of the pharmaceutically active ingredient
in a dissolution medium consisting of water, the dissolution test
being carried out in accordance with USP <711> Dissolution
using Apparatus II (paddle apparatus) operated with a paddle speed
of 75 rpm and with the dissolution medium at a temperature of
37.degree. C..+-.0.5.degree. C. Alternatively, the % in solution of
the active ingredient may be more than 65%, 70%, 75%. The % in
solution may also be selected from a range from: 60% to 90%, 65% to
85%, 68% to 83%, 68% to 73%, 72% to 78%, 75% to 85%, or 77% to 83%,
68% to 78% preferably 68% to 83%.
[0028] In combination with or as an alternative to any of the
amounts of % in solution disclosed in the preceding paragraph the
coating may be present in an amount to additionally or
alternatively provide a % in solution of: more than 35%, 38%, 48%,
50%, 60%, 65%, 70% or 75% at 0.5 hours from the start of the
dissolution test; and/or more than 75% at 1.5 hours.
[0029] It is contemplated within this aspect of the invention that
the coating may further be present in an amount corresponding to a
% weight gain by weight of the core of: from 1% to 15%, from 1% to
12%, from 2% to 15%, from 2% to 12%, from 1% to 9%, from 2% to 8%,
from 2% to 3%, from 2% to 5%, from 5% to 7%, from 4% to 6.5%, from
6% to 7%, or from 2% to 7%. Preferably, the coating may be present
in an amount corresponding to a weight gain of from 1% to 9%, from
2% to 8%, from 4% to 6.5%, from 2% to 5% or from 2% to 7%,
optionally from 4% to 6.5%, from 2% to 5% or from 2% to 7%. The %
weight gain of the coating relative to the core may be combined
with any of the specified % in solution values and any time
point.
[0030] For example, the coating may be present in an amount to
provide a % in solution of more than 70%, optionally more than 75%
or from 70% to 90% or from 75% to 85%, of the pharmaceutically
active ingredient at 1 hour, and the coating may be present in an
amount corresponding to a % weight gain by weight of the core of
from 2% to 7%, optionally from 2% to 4% or 5% to 6%. Alternatively,
the coating may be present in an amount to provide a % in solution
of more than 65%, optionally more than 68% or from 65% to 90% or
from 68% to 78%, of the pharmaceutically active ingredient at 1
hour, and the coating may be present in an amount corresponding to
a % weight gain by weight of the core of from 9% to 20%, optionally
from 9% to 16% or 10% to 15%.
[0031] Also contemplated by the invention is a pharmaceutical
formulation comprising a core and a coating, wherein the core
comprises a pharmaceutically active ingredient, optionally a
hydrophobic active ingredient, and the coating comprises or is a
water-soluble cellulose ether. The coating is present in an amount
to provide a % in solution of the pharmaceutically active
ingredient of more than 75%, optionally 80%, at 12 hours from the
start of a dissolution test in a dissolution medium consisting of
water, the dissolution test being carried out in accordance with
USP <711> Dissolution using Apparatus II (paddle apparatus)
operated with a paddle speed of 75 rpm and with the dissolution
medium at a temperature of 37.degree. C..+-.0.5.degree. C. In an
alternative or in addition to the coating being present in an
amount to provide a % in solution of the pharmaceutically active
ingredient of more than 75% at 12 hours, the coating may be present
in an amount to provide a % in solution of the pharmaceutically
active ingredient of: more than 70%, (for example more than 75% or
80%) at 14 hours; more than 60% (for example more than 65%, 70% or
75%) at 16 hours; more than 50% (for example more than 55%, 60%,
65%, or 70%) at 18 hours; more than 40% (for example more than 45%,
50%, 55%, 60%, 65% or 70%) at 20 hours; more than 40% (for example
more than 45%, 50%, 55%, 60%, 65% or 70%) at 22 hours; or 35% (for
example more than 40%, 45%, 50%, 55%, 60%, or 65%) at 24 hours. In
an embodiment the coating is present in an amount to provide a % in
solution specified in this paragraph at one or more of the time
points specified in this paragraph.
[0032] For example, in an embodiment the % in solution is more than
75% at 12 hours and more than 35%, optionally more than 50%, at 24
hours. Alternatively, the % in solution is more than 80% at 12
hours and more than 50% at 24 hours. The % in solution may be more
than 75% at 12 hours and more than 70% at 14 hours. The % in
solution may be more than 75% at 12 hours and more than 60% at 16
hours. The % in solution may be more than 75% at 12 hours and more
than 50% at 18 hours. The % in solution may be more than 75% at 12
hours and more than 40% at 20 hours. The % in solution may be more
than 75% at 12 hours and more than 40% at 22 hours. The % in
solution may be more than 75% at 12 hours, more than 60% at 16
hours and more than 35% at 24 hours. The % in solution may be more
than 75% at 12 hours, more than 70% at 14 hours, more than 60% at
16 hours, more than 50% at 18 hours, more than 40% at 20 hours,
more than 40% at 22 hours, and more than 35% at 24 hours.
[0033] It is contemplated within this aspect of the invention that
the coating may further be present in an amount corresponding to a
% weight gain by weight of the core of: from 7% to 20%, from 8% to
20%, from 9% to 20%, from 8% to 17%, from 8% to 16%, from 9% to
16%, from 10% to 15%, from 12% to 17%, from 8% to 12%, or from 9%
to 12%. Preferably, the coating may be present in an amount
corresponding to a weight gain of from 9% to 16%, from 10% to 15%,
from 12% to 17%, from 8% to 12%, or from 9% to 12%, optionally from
9% to 16%, or from 10% to 15%. The % weight gain of the coating
relative to the core may be combined with any of the specified % in
solution values and any time point.
[0034] For example, the coating may be present in an amount to
provide a % in solution of more than 70%, optionally more than 75%
or 80%, of the pharmaceutically active ingredient at 12 hours, and
the coating may be present in an amount corresponding to a % weight
gain by weight of the core of from 9% to 16%, from 10% to 15%, from
12% to 17%, from 8% to 12%, or from 9% to 12%, optionally from 9%
to 16%, or from 10% to 15%. Alternatively, the coating may be
present in an amount to provide a % in solution of more than 70%,
optionally more than 75% or 80%, of the pharmaceutically active
ingredient at 12 hours and more than 50%, optionally more than 50%,
55%, 65%, 70% or 75%, at 16 hours, and the coating may be present
in an amount corresponding to a % weight gain by weight of the core
of from 9% to 16%, from 10% to 15%, from 12% to 17%, from 8% to
12%, or from 9% to 12%, optionally from 9% to 16%, or from 10% to
15%. Further similar combinations of features are contemplated by
the invention.
[0035] Also contemplated by the invention is a pharmaceutical
formulation comprising a core and a coating, wherein the core
comprises a pharmaceutically active ingredient, optionally a
hydrophobic active ingredient, and the coating comprises or is a
water-soluble cellulose ether. The coating is present in an amount
to provide a higher % in solution of the pharmaceutically active
ingredient from the formulation than a corresponding formulation
without the coating at 12 hours from the start of a dissolution
test in a dissolution medium consisting of water, the dissolution
test being carried out in accordance with USP <711>
Dissolution using Apparatus II (paddle apparatus) operated with a
paddle speed of 75 rpm and with the dissolution medium at a
temperature of 37.degree. C..+-.0.5.degree. C. In an alternative or
in addition to the coating being present in an amount to provide a
higher % in solution of the pharmaceutically active ingredient at
12 hours, the higher % in solution of the active ingredient from
the formulation may be at 10, 11, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, 24 hours or any combination of one or more thereof,
from the start of a dissolution test.
[0036] A hydrophobic active ingredient is any active that is
substantially insoluble in water. The active may have some
solubility in water. Therefore, a hydrophobic active ingredient is
one which is more readily soluble in a non-aqueous phase as opposed
to water. In addition a hydrophobic active ingredient may be an
active that falls within Class II or Class IV of the
Biopharmaceutics Classification System, these classes containing
highly permeable, low solubility drugs and low permeability, low
solubility drugs respectively. Solubilities of components of the
invention, e.g. active entities, functional components, etc., in a
solvent (for example water) may be defined as follows, the
solubility being measured at 25.degree. C. and parts being by
weight:
TABLE-US-00001 Descriptive Team Parts of Solvent for 1 part of
solute Very Soluble Less than 1 Freely Soluble From 1 to 10 Soluble
From 10 to 30 Sparingly Soluble From 30 to 100 Slightly Soluble
From 100 to 1000 Very Slightly Soluble From 1000 to 10,000
Practically Insoluble More than 10,000
[0037] In embodiments the coating is present in an amount to
provide a higher % in solution of the pharmaceutically active
ingredient from the formulation than for a corresponding
formulation without the coating at time points selected from the
following combinations: 12 hours and 10 hours; 12 hours and 14
hours; 12 hours and 14 hours and 16 hours; 12 hours, 14 hours, 16
hours and 18 hours; and 12 hours, 14 hours, 16 hours, 18 hours and
20 hours.
[0038] In embodiments the coating is present in an amount to
provide a higher % in solution of the pharmaceutically active
ingredient from the formulation than for a corresponding
formulation without the coating for a period selected from one of
those spanning from: 8 hours to 16 hours, 10 to 16 hours; 10 to 18
hours; 10 to 24 hours; 12 to 18 hours; 12 to 22 hours; 12 to 24
hours; 4 to 24 hours; and 0 to 24 hours, preferably 12 to 24
hours.
[0039] In addition, the % in solution for a formulation with the
coating may be higher than for a corresponding formulation without
the coating at a specific time point by more than: 5 or 10 at 12
hours; 5, 10, or 15 at 14 hours; 5, 10, 15, 20, or 25 at 16 hours;
5, 10, 15, 20, 25, or 30 at 18 hours; 5, 10, 15, 20, 25, 30, or 35
at 20 hours; 5, 10, 15, 20, 25, 30, or 35 at 22 hours; and/or 5,
10, 15, 20, 25, 30, 35, or 40 at 24 hours. The higher values of %
in solution described herein may be attained when a single time
point is specified, more than one time point is specified or where
a period is specified.
[0040] For example, the % in solution for a formulation with the
coating may be higher than for a corresponding formulation without
the coating by more than: 5 (optionally 10) at 12 hours; or 5
(optionally 10) at 12 hours and 10 (optionally 15) at 14 hours; or
5 (optionally 10) at 12 hours, 10 (optionally 15) at 14 hours, and
15 (optionally 20) at 16 hours; or 5 (optionally 10) at 12 hours,
10 (optionally 15) at 14 hours, 15 (optionally 20) at 16 hours, and
20 (optionally 25) at 18 hours; or 5 (optionally 10) at 12 hours,
10 (optionally 15) at 14 hours, 15 (optionally 20) at 16 hours, 20
(optionally 25) at 18 hours, and 25 (optionally 30) at 20 hours; or
5 (optionally 10) at 12 hours, 10 (optionally 15) at 14 hours, 15
(optionally 20) at 16 hours, 20 (optionally 25) at 18 hours, 25
(optionally 30) at 20 hours, and 20 (optionally 25) at 22 hours; or
5 (optionally 10) at 12 hours, 10 (optionally 15) at 14 hours, 15
(optionally 20) at 16 hours, 20 (optionally 25) at 18 hours, 25
(optionally 30) at 20 hours, 20 (optionally 25) at 22 hours, and 20
(optionally 30) at 24 hours. By way of illustration, the % in
solution achieved by a formulation of the invention may be 50% at
12 hours and the % in solution achieved by a corresponding
formulation without the coating may be 40% at 12 hours: in this
case the % in solution for the formulation with the coating is
higher than that for the formulation without the coating by 10.
[0041] It is contemplated within this aspect of the invention that
the coating may further be present in an amount corresponding to a
% weight gain by weight of the core of: from 5% to 20%, from 7% to
20%, from 8% to 20%, from 9% to 20%, from 8% to 17%, from 8% to
16%, from 5% to 16%, from 9% to 16%, from 10% to 15%, from 12% to
17%, from 8% to 12%, or from 9% to 12%. Preferably, the coating may
be present in an amount corresponding to a weight gain of from 9%
to 16%, from 10% to 15%, from 12% to 17%, from 8% to 12%, or from
9% to 12%, optionally from 9% to 16%, or from 10% to 15%. The %
weight gain of the coating relative to the core may be combined
with any of the specified % in solution values and any time
point.
[0042] For example, the coating may be present in an amount to
provide a higher % in solution of the pharmaceutically active
ingredient at 12 hours (i.e. a higher % in solution than that
achieved by a corresponding formulation without the coating),
wherein the % in solution of the active may be higher by 5,
optionally 10, and the coating may be present in an amount
corresponding to a % weight gain by weight of the core of from 9%
to 16%, from 10% to 15%, from 12% to 17%, from 8% to 12%, or from
9% to 12%, optionally from 9% to 16%, or from 10% to 15%.
Alternatively, the coating may be present in an amount to provide a
higher % in solution of the pharmaceutically active ingredient at
12 hours, wherein the % in solution of the active may be higher by
5, optionally 10, and by 5, optionally 10, 15, 20, or 25, at 16
hours and the coating may be present in an amount corresponding to
a % weight gain by weight of the core of from 9% to 16%, from 10%
to 15%, from 12% to 17%, from 8% to 12%, or from 9% to 12%,
optionally from 9% to 16%, or from 10% to 15%.
[0043] The invention contemplates a pharmaceutical formulation
comprising a core and a coating, wherein the core comprises a
pharmaceutically active ingredient and the coating comprises or is
a water-soluble cellulose ether. The coating is present in an
amount to provide a decrease (compared to a corresponding
formulation without the coating) in % in solution of the
pharmaceutically active ingredient of 15 or less in a period from
10 hours to 16 hours from the start of a dissolution test in a
dissolution medium consisting of water, the dissolution test being
carried out in accordance with USP <711> Dissolution using
Apparatus II (paddle apparatus) operated with a paddle speed of 75
rpm and with the dissolution medium at a temperature of 37.degree.
C..+-.0.5.degree. C.
[0044] Alternatively, the period may be selected from a period
from: 8 hours to 16 hours; 6 hours to 16 hours; 4 hours to 16
hours; 8 hours to 14 hours; 6 hours to 14 hours; 4 hours to 14
hours; 8 hours to 18 hours, 6 hours to 18 hours, or 4 hours to 16
hours. The decrease in % in solution may be 10 or less, 8 or less,
5 or less, or 3 or less. The decrease in % in solution may be any
amount selected from 15 or less, 10 or less, or 5 or less at any
time point specified.
[0045] For example, the decrease in % in solution may be 10 or less
for the period of 8 to 16 hours. The decrease in % in solution may
be 15 or less for the period of 4 to 18 hours. The decrease in % in
solution may be 10 or less for the period of 4 to 18 hours. The
decrease in % in solution may be 8 or less for the period of 4 to
18 hours. The decrease in % in solution may be 10 or less for the
period of 4 to 16 hours. The decrease in % in solution may be 8 or
less for the period of 4 to 16 hours. The decrease in % in solution
may be 3 or less for the period of 6 to 12 hours. The decrease in %
in solution may be 15 or less for the period of 6 to 16 hours. The
decrease in % in solution may be 10 or less for the period of 6 to
16 hours. The decrease in % in solution may be 5 or less for the
period of 6 to 16 hours.
[0046] It is contemplated within this aspect of the invention that
the coating may further be present in an amount corresponding to a
% weight gain by weight of the core of: from 5% to 20%, from 7% to
20%, from 8% to 20%, from 9% to 20%, from 8% to 17%, from 8% to
16%, from 9% to 16%, from 5% to 16%, from 10% to 15%, from 12% to
17%, from 8% to 12%, or from 9% to 12%. Preferably, the coating may
be present in an amount corresponding to a weight gain of from 9%
to 16%, from 10% to 15%, from 12% to 17%, from 8% to 12%, or from
9% to 12%, optionally from 9% to 16%, or from 10% to 15%. The %
weight gain of the coating relative to the core may be combined
with any of the specified % in solution values and any time
point.
[0047] Throughout the disclosure of this application any change in
the % in solution, for example where the % in solution is said to
be higher by a certain value or the % in solution has decreased by
a certain value, the value of the change has been given as a digit.
This digit signifies the absolute amount that the % in solution has
changed by; for example where the % in solution of the active of a
formulation of the invention with the coating is said to be higher
than a formulation without the coating by more than 10 means that
where the % in solution of the formulation without the coating is
50% the % in solution of the formulation of the invention will be
more than 60%.
[0048] Also contemplated by the invention is a pharmaceutical
formulation comprising a core, a first coating and a second coating
outside the first coating, wherein the core comprises a
pharmaceutically active ingredient, the first coating comprises or
is a water-soluble cellulose ether, further wherein the second
coating comprises or is a delayed release polymer, wherein the
first coating is present in an amount to provide a higher % release
of the pharmaceutically active ingredient from the pharmaceutical
formulation than a corresponding pharmaceutical formulation without
the first coating at 12 hours from the start of a dissolution
test.
[0049] Unless specified otherwise the dissolution medium used in
the dissolution test of any aspect of the invention may be a
dissolution medium representative of the in-vivo medium in which
the formulation is to be used. Specifically, aspects of the
invention where there is a first coating and a second coating. In
such embodiments the dissolution test may be any dissolution test
known to the person skilled in the art to represent the
gastrointestinal tract. Preferably the dissolution test is carried
out in accordance with USP <711> Dissolution using Apparatus
II (paddle apparatus) operated with a paddle speed of 75 rpm and
with the relevant dissolution medium at a temperature of 37.degree.
C.
[0050] In embodiments of the invention the dissolution test may be
a two stage dissolution test and the two stage dissolution test may
consist of a first stage having a dissolution medium of 750 ml 0.1N
HCl into which the formulation is placed and a second stage
commencing at 2 hours, wherein 250 ml 0.2M tribasic sodium
phosphate containing 2% sodium dodecyl sulphate (SDS) is added to
the dissolution medium and the pH adjusted to 6.8. This dissolution
test may be particularly suitable for measuring release of
hydrophobic actives, for example cyclosporin, from the
formulation.
[0051] In other embodiments the dissolution test may consist of a
dissolution medium consisting of 1000 ml of a 0.05M pH 7.5
phosphate buffer prepared by dissolving monobasic potassium
phosphate and sodium hydroxide in water. This dissolution test may
be particularly suitable for measuring release of hydrophilic
actives, for example hydralazine and mesalamine, from the
formulation. In particular the dissolution test may be the
dissolution test described below: 0.05M pH 7.5 phosphate buffer
prepared by dissolving 6.8 g of monobasic potassium phosphate and 1
g of sodium hydroxide in water to make 1000 mL of solution, and
adjusting with 10N sodium hydroxide to a pH of 7.5.+-.0.05; 900 mL
are used in a USP Apparatus 2 with a paddle speed of 75 RPM and
with the dissolution medium temperature at 37.degree.
C..+-.0.5.degree. C.
[0052] In particular the two stage dissolution test was carried out
in accordance with USP <711> Dissolution using Apparatus II
(paddle apparatus) operated with a paddle speed of 75 rpm and with
the dissolution medium at a temperature of 3.sup.7.degree.
C..+-.0.5.degree. C. In the first stage of the test the dissolution
medium is 750 ml of 0.1N HCl simulating the gastric environment. At
the start of the test (t=0) the sample is placed in the dissolution
medium. At 2 hours the second stage of the dissolution test is
initiated. In the second stage 250 ml of 0.2M tribasic sodium
phosphate containing 2% sodium dodecyl sulphate (SDS) is added to
the dissolution medium and the pH adjusted to 6.8.+-.0.05 using 2N
NaOH or 2N HCl as required.
[0053] In any of the formulations comprising a first coating and
second coating, the first coating may be present in an amount to
provide a higher % release of the pharmaceutically active
ingredient at any point in time after 3 hours from the start of the
dissolution test. For example, the higher % release may be at 3
hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10
hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours,
17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23
hours or 24 hours. The higher % release may be at one or more of
the time points, preferably one or more consecutive time
points.
[0054] For example, the higher % release may be at: 3 hours and 4
hours; 3 hours, 4 hours and 5 hours; 3 hours, 4 hours, 5 hours, 11
hours, 12 hours, and 13 hours; 11 hours 12 hours, and 13 hours; or
11 hours, 12 hours, 13 hours, 14 hours, 20 hours, 21 hours, 22
hours and 24 hours.
[0055] The higher % release may be for a period selected from one
or a combination of periods of from: 11 to 12 hours, 11 to 13
hours, 12 to 13 hours, 11 to 14 hours, 10 to 14 hours, 18 to 22
hours, 20 to 24 hours, 4 to 8 hours, 3 to 8 hours, 3 to 12 hours, 3
to 6 hours, 8 to 14 hours, 8 to 18 hours, 8 to 22 hours, 6 to 22
hours, 8 to 24 hours, 4 to 14 hours, 4 to 18 hours 4 to 22 hours, 4
to 24 hours, 3 to 20 hours, 3 to 22 hours or 3 to 24 hours.
[0056] The higher % release may be at 16 hours, 17 hours, and 18
hours; or at 14 hours, 15 hours, 16 hours, 17 hours and 18 hours.
The higher % release may be for the period of 18 to 22 hours or 20
to 24 hours. Optionally, the dissolution medium is deionised
water.
[0057] In addition, the % in solution for a formulation with the
coating may be higher than for a corresponding formulation without
the coating at a specific time point by more than: 5, 10, 15, 20 or
25 at 12 hours; 5, 10, 15, or 20 at 14 hours; 5, 10, 15, or 20 at
16 hours; 5, 10, 15, or 20 at 18 hours; 5, 10 or 15 at 20 hours; 5
or 10 at 22 hours; 5 or 10 at 24 hours; 5, 10, 15, 20 or 25 at 10
hours; 5, 10, 15, or 20 at 8 hours; 5, 10, 15, or 20 at 6 hours; 5
or 10 at 4 hours. The higher values of % in solution described
herein may be attained when a single time point is specified, more
than one time point is specified or where a period is
specified.
[0058] For example, the % in solution for a formulation with the
coating may be higher than for a corresponding formulation without
the coating by more than: 5 (optionally 10, 15, 20 or 25) at 12
hours; or 5 (optionally 10, 15, 20 or 25) at 12 hours and 5
(optionally 10, 15 or 20) at 14 hours; or 5 (optionally 10, 15, 20
or 25) at 10 hours and 5 (optionally 10, 15, 20 or 25) at 12 hours;
or 5 (optionally 10, 15, or 20) at 8 hours 5 (optionally 10, 15, 20
or 25) at 10 hours and 5 (optionally 10, 15, 20 or 25) at 12 hours;
or 5 (optionally 10, 15, or 20) at 6 hours, 5 (optionally 10, 15,
or 20) at 8 hours or 5 (optionally 10, 15, 20 or 25) at 10 hours
and 5 (optionally 10, 15, 20 or 25) at 12 hours; or 5 (optionally
10, 15, 20 or 25) at 12 hours, 5 (optionally 10, 15, or 20) at 14
hours, and 5 (optionally 10, 15, or 20) at 16 hours; or 5
(optionally 10, 15, 20 or 25) at 10 hours, 5 (optionally 10, 15, 20
or 25) at 12 hours, and 5 (optionally 10, 15, or 20) at 14 hours;
or 5 (optionally 10, 15, 20 or 25) at 10 hours, 5 (optionally 10,
15, 20 or 25) at 12 hours, 5 (optionally 10, 15, or 20) at 14 hours
and 5 (optionally 10, 15, or 20) at 16 hours; or 5 (optionally 10,
15, 20 or 25) at 12 hours, 5 (optionally 10, 15, or 20) at 14
hours, 5 (optionally 10, 15, or 20) at 16 hours, and 5 (optionally
10, 15, or 20) at 18 hours; or 5 (optionally 10, 15, 20 or 25) at
10 hours, 5 (optionally 10, 15, 20 or 25) at 12 hours, 5
(optionally 10, 15, or 20) at 14 hours, 5 (optionally 10, 15, or
20) at 16 hours, and 5 (optionally 10, 15, or 20) at 18 hours; or 5
(optionally 10, 15, or 20) at 8 hours or 5 (optionally 10, 15, 20
or 25) at 10 hours, 5 (optionally 10, 15, 20 or 25) at 12 hours, 5
(optionally 10, 15, or 20) at 14 hours, 5 (optionally 10, 15, or
20) at 16 hours, and 5 (optionally 10, 15, or 20) at 18 hours; or 5
(optionally 10, 15, or 20) at 6 hours, 5 (optionally 10, 15, or 20)
at 8 hours, 5 (optionally 10, 15, 20 or 25) at 10 hours, 5
(optionally 10, 15, 20 or 25) at 12 hours, 5 (optionally 10, 15, or
20) at 14 hours, 5 (optionally 10, 15, or 20) at 16 hours, and 5
(optionally 10, 15, or 20) at 18 hours; or 5 (optionally 10, 15, 20
or 25) at 12 hours, 5 (optionally 10, 15, or 20) at 14 hours, 5
(optionally 10, 15, or 20) at 16 hours, and 5 (optionally 10, 15,
or 20) at 18 hours, and 5 (optionally 10 or 15) at 20 hours; or 5
(optionally 10, 15, 20 or 25) at 10 hours, 5 (optionally 10, 15, 20
or 25) at 12 hours, 5 (optionally 10, 15, or 20) at 14 hours, 5
(optionally 10, 15, or 20) at 16 hours, and 5 (optionally 10, 15,
or 20) at 18 hours, and 5 (optionally 10 or 15) at 20 hours; or 5
(optionally 10, 15, or 20) at 8 hours, 5 (optionally 10, 15, 20 or
25) at 10 hours, 5 (optionally 10, 15, 20 or 25) at 12 hours, 5
(optionally 10, 15, or 20) at 14 hours, 5 (optionally 10, 15, or
20) at 16 hours, and 5 (optionally 10, 15, or 20) at 18 hours, and
5 (optionally 10 or 15) at 20 hours; or 5 (optionally 10, 15, or
20) at 6 hours, 5 (optionally 10, 15, or 20) at 8 hours, 5
(optionally 10, 15, 20 or 25) at 10 hours, 5 (optionally 10, 15, 20
or 25) at 12 hours, 5 (optionally 10, 15, or 20) at 14 hours, 5
(optionally 10, 15, or 20) at 16 hours, and 5 (optionally 10, 15,
or 20) at 18 hours, and 5 (optionally 10 or 15) at 20 hours; or 5
(optionally 10, 15, 20 or 25) at 12 hours, 5 (optionally 10, 15, or
20) at 14 hours, 5 (optionally 10, 15, or 20) at 16 hours, and 5
(optionally 10, 15, or 20) at 18 hours, 5 (optionally 10 or 15) at
20 hours, and 5 (optionally 10) at 22 hours; or 5 (optionally 10,
15, 20 or 25) at 12 hours, 5 (optionally 10, 15, or 20) at 14
hours, 5 (optionally 10, 15, or 20) at 16 hours, and 5 (optionally
10, 15, or 20) at 18 hours, 5 (optionally 10 or 15) at 20 hours, 5
(optionally 10) at 22 hours, and 5 (optionally 10) at 24 hours; or
5 (optionally 10) at 12 hours, 10 (optionally 15) at 14 hours, 15
(optionally 20) at 16 hours, 20 (optionally 25) at 18 hours, 25
(optionally 30) at 20 hours, and 20 (optionally 25) at 22 hours; or
5 (optionally 10) at 12 hours, 10 (optionally 15) at 14 hours, 15
(optionally 20) at 16 hours, 20 (optionally 25) at 18 hours, 25
(optionally 30) at 20 hours, 20 (optionally 25) at 22 hours, and 20
(optionally 30) at 24 hours.
[0059] The invention also contemplates a pharmaceutical formulation
comprising a core, a first coating and a second coating outside of
the first coating, wherein the core comprises a pharmaceutically
active ingredient, the first coating comprises or is a
water-soluble cellulose ether, further wherein the second coating
comprises or is a delayed release polymer, wherein the first
coating is present in an amount to provide a % release of the
pharmaceutically active ingredient of more than 50%, optionally
more than 55% and 60% (for example more than 65%, 70%, 75%, 80%,
85% or 90%) at 12 hours from the start of a dissolution test,
wherein the dissolution test is described above.
[0060] The first coating may be present in an amount to provide a %
release of the pharmaceutically active ingredient at 12 hours of
from: 70% to 95%, 75% to 95%, 70% to 90%, 75% to 90%, 70% to 85%,
70% to 80%, or 75% to 85%, preferably 75% to 95%, 80% to 95% or
from 85% to 95%.
[0061] The first coating may be present in an amount to provide a %
release of the pharmaceutically active ingredient at 12 hours of
from 55% to 80%.
[0062] The first coating may further be present in an amount to
provide a % release of the pharmaceutically active ingredient in an
amount of more than 40%, (optionally more than 45% or more than
50%) at 6 hours or 4 hours from the start of the dissolution test.
The % release of the pharmaceutically active ingredient may be in
an amount of from 40% to 65% (optionally 45% to 65%) at 6 hours or
4 hours from the start of the dissolution test. Optionally, the
first coating may be present in a weight gain of from 1% to 20% and
the second coating may be present in a weight gain of from 4% to
25%, optionally from 4% to 15%, from 4% to 12%, from 15% to 25%
from 4% to 6% or 8% to 13%. Where the % release is 20% or more
(optionally 45% or more) at 4 hours the second coating is
preferably present in a weight gain of at least 4%, preferably no
more than 25% and optionally 4% to 6%. Where the % release is 40%
or more (optionally 45% or more) at 6 hours the second coating is
preferably present in a weight gain of at least 4%, preferably no
more than 25% and optionally 8% to 13%.
[0063] The first coating may further or alternatively be present in
an amount to provide a % release of the pharmaceutically active
ingredient in an amount of more than 15% (for example more than
20%, 25%, 28% or 30%), optionally from 25% to 40% or from 25% to
35%, at 4 hours from the start of the dissolution test. Optionally,
the first coating may be present in a weight gain of from 1% to 20%
and the second coating may be present in a weight gain of from 4%
to 15%, optionally from 4% to 6% or 8% to 13%.
[0064] The first coating may be present in an amount to provide a %
release of the pharmaceutically active ingredient in an amount of
more than 25%, optionally from 25% to 40% or 25% to 35%, at 6
hours. Optionally, the first coating may be present in a weight
gain of from 1% to 20% and the second coating may be present in a
weight gain of from 4% to 15%, optionally from 4% to 6% or 8% to
13%. Where the % release of the active ingredient is more than 25%,
optionally from 25% to 40% or 25% to 35%, at 6 hours the active
ingredient may be a hydrophilic active ingredient, for example
mesalamine, optionally suspended in the disperse phase. The
disperse phase is described in more detail below.
[0065] In embodiments the % release at 12 hours may be more than
80%, wherein the first coating may be present in a weight gain of
from 1% to 20% and the second coating may be present in a weight
gain of from 4% to 15%, optionally from 4% to 6% or 8% to 13%.
[0066] In embodiments the active ingredient is a hydrophobic
active, for example cyclosporin A. In embodiments the active
ingredient is a hydrophobic active, for example cyclosporin A and
the % release is more than 70% (optionally 75% or 80%) at 12 hours.
Optionally, the first coating may be present in an amount
corresponding to a weight gain due to the coating of from 0.5% to
20% by weight of the core (optionally from 1% to 16%, from 4% to
16%, from 4% to 12%, or from 3% to 6%) and/or the second coating is
present in an amount corresponding to a weight gain due to the
second coating of from 2% to 20% by weight. (optionally 4% to 20%,
4% to 15%, 8% to 18%, or 8% to 12%).
[0067] The first coating may be present in an amount to provide a %
release of the pharmaceutically active ingredient at 12 hours of
from 55% to 80%, a % release of the pharmaceutically active
ingredient at 6 hours of from 25% to 40%, and a % release of the
pharmaceutically active ingredient at 4 hours of more than 15%.
[0068] In any aspect of the invention and any embodiment the core
may comprise a hydrogel forming polymer matrix. The hydrogel
forming polymer matrix may be as described below.
[0069] The core of a pharmaceutical formulation of any aspect or
embodiment of the invention may be in the form of a solid colloid.
The colloid comprises a continuous phase and a disperse phase.
Suitable continuous phases and disperse phases which may be used to
form the core are defined in more detail below and in the detailed
description of the invention. The continuous phase may comprise or
be the hydrogel forming polymer matrix. Hence, where the continuous
phase is the hydrogel forming polymer matrix, the formulation of
the invention may take the form of a solid unit of the hydrogel
forming polymer comprising a disperse phase. The disperse phase may
be droplets dispersed in the continuous phase, or the hydrogel
forming polymer matrix. The disperse phase may comprise or be a
hydrophobic phase.
[0070] The continuous phase of a solid colloid core is or comprises
a hydrogel-forming polymer matrix. In embodiments the
hydrogel-forming polymer matrix is or comprises a hydrocolloid, a
non-hydrocolloid gum or chitosan. In a particular embodiment the
hydrogel-forming polymer matrix is or comprises gelatin, agar, a
polyethylene glycol, starch, casein, chitosan, soya bean protein,
safflower protein, alginates, gellan gum, carrageenan, xanthan gum,
phthalated gelatin, succinated gelatin, cellulosephthalate-acetate,
oleoresin, polyvinylacetate, polymerisates of acrylic or
methacrylic esters and polyvinylacetate-phthalate and any
derivative of any of the foregoing; or a mixture of two or more
such polymers. In a further embodiment the hydrogel-forming polymer
matrix is or comprises a hydrocolloid selected from carrageenan,
gelatin, agar and pectin, or a combination thereof optionally
selected from gelatin and agar or a combination thereof.
Particularly, the polymer of the hydrogel-forming polymer matrix is
or comprises gelatin. In an embodiment, the hydrogel-forming
polymer does not comprise a cellulose or a cellulose derivative,
e.g. does not comprise a cellulose ether.
[0071] In this aspect of the invention the core may be in the form
of a solid colloid the colloid comprising a continuous phase and a
disperse phase and the pharmaceutically active ingredient may be in
solution or suspended in the disperse phase. For example, the
active ingredient may be a hydrophobic active ingredient in
solution in the disperse phase or a hydrophilic active ingredient
suspended in the disperse phase.
[0072] In embodiments of this aspect of the invention the active
ingredient may be a hydrophobic active ingredient, for example
cyclosporin, and the active ingredient may be in solution in the
disperse phase. The first coating may be present in a weight gain
of from 0.5% to 20% and the second coating may be present in a
weight gain of from 8% to 12% and the first coating is present in
an amount to provide a % release of 80% or more. Optionally, the
water-soluble cellulose ether may be hydroxyl propyl methyl
cellulose.
[0073] In a further aspect the invention contemplates a
pharmaceutical formulation comprising a core, a first coating and a
second coating outside of the first coating, wherein the core
comprises a pharmaceutically active ingredient, the first coating
comprises or is a water-soluble cellulose ether, further wherein
the second coating comprises or is a delayed release polymer,
wherein the first coating is present in an amount to provide a %
release of the pharmaceutically active ingredient of more than 70%,
(for example more than 75% or 80%) at 6 hours from the start of a
dissolution test, wherein the dissolution test is as described
above.
[0074] In embodiments the first coating is present in an amount to
provide a % release of from 75% to 95% or from 80% to 90% of the
pharmaceutically active ingredient at 6 hours.
[0075] The second coating may be present in an amount to provide a
weight gain of 2% to 20%, 5% to 15%, 8% to 12%, 2% to 8%, 3% to 7%,
or 4% to 6%.
[0076] The active ingredient may be a hydrophobic active
ingredient, for example cyclosporin A. The active ingredient may be
in solution in the disperse phase.
[0077] The invention also contemplates a pharmaceutical formulation
comprising a core, a first coating and a second coating outside of
the first coating, wherein the core comprises a pharmaceutically
active ingredient, optionally a hydrophilic active ingredient, the
first coating comprises or is a water-soluble cellulose ether,
further wherein the second coating comprises or is a delayed
release polymer, wherein the first coating is present in an amount
to provide a % release of the pharmaceutically active ingredient of
more than 30% (for example more than 35%, 40%, 45%, 50%, 55% or
60%) at 12 hours from the start of a dissolution test, wherein the
dissolution test is as described above.
[0078] The first coating may be present in an amount to allow
release of from 30% to 80%, optionally 30% to 70%, 35% to 70%, 40%
to 70%, 40% to 50% or 60% to 70% of the active ingredient at 12
hours.
[0079] The first coating may be present in a weight gain selected
from a range of from: 1% to 20%, 4% to 7%, 5% to 7%, 4% to 15%, 4%
to 12% and 8% to 12%. The second coating may be present in a weight
gain selected from a range of from: 8% to 12%.
[0080] The active ingredient may be in solution in the continuous
phase of the formulation, where the formulation is in the form of a
solid colloid comprising a continuous phase and a disperse phase.
The active ingredient may be a hydrophilic active ingredient, for
example mesalazine or hydralazine, which is in solution in the
continuous phase. In embodiments the active ingredient is a
hydrophilic active in solution in the continuous phase, the first
coating is present in an amount to provide a % release of 35% to
50% and a weight gain of 4% to 7%, and the second coating is
present in a weight gain of 8% to 12%. In alternative embodiments
the active ingredient is a hydrophilic active in solution in the
continuous phase, the first coating is present in an amount to
provide a % release of 55% to 75% and a weight gain of 8% to 12%,
and the second coating is present in a weight gain of 8% to
12%.
[0081] It is to be understood that the individual embodiments
described above may be combined with one or more of the other
embodiments described to provide further embodiments of the
invention defined by for example a combination of one or more of
the embodiments to the time points, time periods, % in solution, %
released, values of the increase of higher % in solution, values of
the increase of higher % released.
[0082] The first coating may be in contact with the core. The
second coating may be on the first coating. In embodiments the
first coating is in contact with the core and the second coating is
on the first coating.
[0083] The second coating may be or may comprise a delayed release
polymer and the delayed release polymer may be selected from an
enteric polymer, a pH independent polymer, a pH dependent polymer
and a polymer specifically susceptible to degradation by bacterial
enzymes in the gastrointestinal tract, or a combination of two or
more such polymers. Hence, the second coating may be any of the
aforementioned delayed release polymers or any may be or possess
the characteristics mentioned in relation to the delayed release
polymer mentioned below.
[0084] In embodiments the delayed release polymer may be
water-soluble or water-permeable in an aqueous medium with a pH
greater than 6.5. The delayed release polymer may be or comprise a
pH-independent polymer, for example ethyl cellulose.
[0085] In any aspect and any embodiment of the invention the
water-soluble cellulose ether may be selected from any one or a
combination of: methyl cellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose and hydroxypropyl methylcellulose. The
water-soluble cellulose ether may preferably be hydroxylpropyl
methylcellulose.
[0086] In embodiments the first coating may be or comprise
hydroxypropyl methyl cellulose and the second coating may be or
comprise ethyl cellulose.
[0087] It is contemplated within any aspect or embodiment where
there is a first coating and a second coating that the first
coating may be present in a % weight gain relative to the core of
from 0.5% to 20%. In addition the first coating may be present in
an amount corresponding to a weight gain due to the coating
selected from ranges of from: 0.5% to 15%; 1% to 15%; 1% to 12%; 1%
to 10%; 1% to 8%; 1% to 6%; 1% to 4%, 2% to 10%; 2% to 8%; 2% to
6%; 2% to 7%; 2% to 4%; 4% to 8%; 4% to 7%, 4% to 6%, 5% to 7%; 7%
to 20%; 7% to 16%; 9% to 20%; 9% to 16%; 10% to 15%; and 12% to
16%.
[0088] It is contemplated within any aspect or embodiment where
there is a first coating and a second coating that the second
coating may be present in a % weight gain of from 2% to 40%. In
addition the second coating may be present in an amount
corresponding to a weight gain due to the coating selected from
ranges of from: 4% to 30%, 4% to 7%, 7% to 40%, 7% to 30%, 8% to
25%, 8% to 20%, 2% to 25%, 2% to 20%, 4% to 25%, 4% to 20%, 4% to
15%, 4% to 13%, 7% to 15%, 7% to 13%, 8% to 12%, 9% to 12% and 20%
to 25%.
[0089] Throughout the disclosure of this application the weight
gain of the first coating is given as a % by weight of the core and
the weight gain of the second coating is given as a % by weight of
the formulation that is coated by the second coating, for example
the core and the first coating.
[0090] In any aspect and embodiment of the invention the first
coating may be present in a % weight gain relative to the core of
from 0.5% to 20%, preferably 1% to 16% or 4% to 16%, and the second
coating may be present in a % weight gain of 4% to 24%, 7% to 24%,
22% to 24%, 7% to 15%, or 8% to 12%, preferably 22% to 24%, 7% to
15%, or 8% to 12%.
[0091] The hydrogel forming polymer may be or comprise a
hydrocolloid, a non-hydrocolloid gum or chitosan. The hydrogel
forming polymer may be a reversible hydrocolloid, for example a
thermoreversible hydrocolloid or a thermoreversible hydrogel
forming polymer. Alternatively, the hydrogel forming polymer may be
or comprise an irreversible hydrocolloid. The hydrogel forming
polymer matrix may be or comprise gelatin, agar, a polyethylene
glycol, starch, casein, chitosan, soya bean protein, safflower
protein, alginates, gellan gum, carrageenan, xanthan gum,
phthalated gelatin, succinated gelatin, cellulosephthalate-acetate,
oleoresin, polyvinylacetate, polymerisates of acrylic or
methacrylic esters and polyvinylacetate-phthalate and any
derivative of any of the foregoing; or a mixture of one or more
such a hydrogel forming polymers. The hydrogel forming polymer
matrix may be or comprise a hydrocolloid selected from carrageenan,
gelatin, agar and pectin, or a combination thereof optionally
selected from gelatin and agar or a combination thereof, more
optionally the polymer of the a hydrogel forming polymer matrix is
or comprises gelatin. The hydrogel forming polymer matrix is or
comprises a non-hydrocolloid gum optionally selected from a
cross-linked salt of alginic acid. In preferred embodiments the
hydrogel forming polymer is or comprises gelatin.
[0092] In embodiments the hydrogel forming polymer further
comprising a plasticiser, optionally a plasticiser selected from
glycerin, a polyol for example sorbitol, polyethylene glycol and
triethyl citrate or a mixture thereof, particularly sorbitol.
[0093] The hydrogel forming polymer matrix may encapsulate the
active ingredient. The active ingredient may be encapsulated as a
suspension in the hydrogel forming polymer matrix or in solution.
The active ingredient may be in solution or suspended in another
component, for example a hydrophobic phase or the disperse phase
discussed elsewhere, of the formulation that is also encapsulated
by the hydrogel forming polymer matrix.
[0094] The core of the pharmaceutical formulation of the invention
may be in the form of a solid colloid the colloid comprising a
continuous phase and a disperse phase, wherein the continuous phase
optionally comprises the hydrogel forming polymer matrix. Hence the
pharmaceutical formulation of all aspects of the invention may
comprise at least the following features a core and a first
coating, wherein the core comprises an active ingredient and is in
the form of a solid colloid comprising a continuous phase and a
disperse phase, and the coating comprises or is a water soluble
cellulose ether. The continuous phase may be formed of the hydrogel
forming polymer matrix.
[0095] In embodiments the active ingredient is or is comprised in
the disperse phase of the core. In embodiments, the active
ingredient is comprised in the continuous phase of the core. In
embodiments, a first active ingredient is or is comprised in the
disperse phase of the core and a second active ingredient is
comprised in the continuous phase of the core.
[0096] The disperse phase may be solid, semi-solid or liquid. In
particular, the disperse phase may be liquid. In other particular
instances the disperse phase may be semi-solid, for example it may
be waxy.
[0097] The disperse phase may be a hydrophobic phase, for example a
hydrophobic phase which is a solid, a semi-solid or a liquid.
Suitably the disperse phase is or comprises a liquid lipid and
optionally a solvent miscible therewith.
[0098] The active ingredient may be dissolved in the disperse
phase. The active ingredient may be suspended in the disperse
phase. The disperse phase may be as described elsewhere herein, for
example it may be as described in the immediately preceding two
paragraphs.
[0099] In a particular embodiment the disperse phase is or
comprises a liquid lipid and a solvent, wherein the solvent is
miscible with the liquid lipid and water, optionally wherein the
solvent is selected from 2-(2-ethoxyethoxy)ethanol and a
poly(ethylene glycol), particularly wherein the solvent is
2-(2-ethoxyethoxy)ethanol. In a further embodiment the disperse
phase is or comprises an oil phase comprising a medium chain mono-
di- or triglyceride (particularly a medium chain triglyceride), a
polyethoxylated castor oil and 2-(ethoxyethoxy)ethanol. The
disperse phase as described in this paragraph may contain a
hydrophobic active ingredient, for example, cyclosporin A, or a
hydrophobic active ingredient, for example mesalazine.
[0100] In embodiments the formulation further comprises one or more
surfactants, suitable surfactants are described in more detail in
the detailed description of the invention. In those embodiments
where the formulation comprises a core in the form of a solid
colloid, the colloid comprising a continuous phase and a disperse
phase, wherein the continuous phase comprises the hydrogel-forming
polymer matrix, surfactant may be present in the continuous phase,
the disperse phase or both the continuous phase and the disperse
phase. Accordingly in one embodiment the core further comprises a
surfactant present in at least the continuous phase, the surfactant
having an HLB value of greater than 10, for example greater than
20. In a further embodiment the disperse phase further comprises a
surfactant with an HLB value in the range of from 1 to 10, for
example from 1 to 5.
[0101] The core may have the characteristics of a core formed by
mixing a disperse phase with a continuous phase to form a colloid,
wherein the continuous phase is an aqueous phase comprising
hydrogel forming polymer and the disperse phase is a hydrophobic
phase, wherein the pharmaceutically active ingredient is in the
continuous phase or the disperse phase, wherein the colloid is
gelled to form the core.
[0102] The active ingredient may be a hydrophobic active ingredient
or a hydrophilic active ingredient. The active ingredient may be
present in the core in solution or in suspension and this is true
for when the disperse phase or the continuous phase comprises the
active ingredient. In embodiments where the active ingredient is a
hydrophobic active ingredient it may be in solution in the disperse
phase, for example where the disperse phase is or comprises a
hydrophobic phase, a liquid lipid, an oil, a polyunsaturated fatty
acid or a solvent, or suspended in the continuous phase. In
embodiments where the active ingredient is a hydrophilic active
ingredient it may be suspended in the disperse phase, for example
where the disperse phase is or comprises a hydrophobic phase, a
liquid lipid, an oil, a polyunsaturated fatty acid or a solvent, or
in solution in the continuous phase.
[0103] The core of the formulation may comprise a hydrogel-forming
polymer matrix and a pharmaceutically active ingredient and have
the characteristics of a core obtained by a process comprising:
(i) dissolving a hydrogel-forming polymer in an aqueous liquid to
form an aqueous solution; (ii) dissolving or dispersing the active
ingredient in a liquid to form a solution or dispersion
(particularly a solution) of the active ingredient in the liquid
(an oil phase); (iii) mixing the aqueous solution (i) and the
solution or dispersion (ii) to form a colloid; (iv) ejecting the
colloid through a nozzle to form droplets; (v) causing or allowing
the a hydrogel-forming polymer to gel or solidify to form a
hydrogel-forming polymer matrix; and (vi) drying the solid.
[0104] The solution or dispersion (ii) (oil phase) may be prepared
by dissolving or dispersing the cyclosporin A in a suitable
hydrophobic liquid. The hydrophobic liquid may be for example, any
of the oils or liquid lipids described herein. By way of example
the hydrophobic liquid may be, or comprise, saturated or
unsaturated fatty acids or a triglyceride, or an ester or ether
thereof with polyethylene glycols. A particular oil for the oil
phase is or comprises a triglyceride, for example an oil comprising
a medium chain triglyceride, optionally wherein the oil comprises a
triglyceride of at least one fatty acid selected from fatty acids
having 6, 7, 8, 9, 10, 11 or 12 carbon atoms, e.g. C.sub.8-C.sub.10
fatty acids.
[0105] In a variant, the core of the formulation may comprise a
hydrogel-forming polymer matrix and a pharmaceutically active
ingredient and have the characteristics of a core obtained by a
process comprising:
(i) dissolving in an aqueous liquid a hydrogel-forming polymer and
the active ingredient to form an aqueous solution; (ii) mixing the
aqueous solution (i) and a second liquid (an oil phase) to form a
colloid; (iii) ejecting the colloid through a nozzle to form
droplets; (iv) causing or allowing the a hydrogel-forming polymer
to gel or solidify to form a hydrogel-forming polymer matrix; and
(v) drying the solid.
[0106] The active ingredient used in all methods described in this
specification may be one described herein, for example it may be
hydrophilic or it may be hydrophobic. It may be selected from the
hydrophilic active ingredients described herein. It may be selected
from the hydrophobic active ingredients described herein.
[0107] Suitably the aqueous phase pre-mix (i) further comprises an
anionic surfactant, e.g. as described elsewhere herein, for example
sodium dodecyl sulphate (SDS).
[0108] In one embodiment the core having the characteristics of a
core obtained by the process above is a core comprising a
hydrogel-forming polymer matrix and a non-aqueous phase dispersed
in the hydrogel-forming polymer matrix, wherein the core is or
comprises gelatin, SDS, sorbitol, polyethoxylated castor oil,
caprylic/capric triglyceride, 2-(ethoxyethoxy)ethanol; wherein the
aqueous solution (i) is or comprises gelatin, sorbitol and SDS; and
the solution or dispersion (ii) is or comprises polyethoxylated
castor oil, caprylic/capric triglyceride, 2-(ethoxyethoxy)ethanol
and the active ingredient.
[0109] The core of the formulation may alternatively comprise a
hydrogel-forming polymer matrix and a pharmaceutically active
ingredient and have the characteristics of a core obtained by a
process comprising:
(a) dissolving a hydrogel-forming polymer in an aqueous liquid to
form an aqueous solution; (b) before, during or after dissolving
the hydrogel-forming polymer in the aqueous liquid, mixing the
active ingredient in the aqueous liquid; (c) then ejecting the
aqueous liquid comprising the hydrogel-forming polymer and the
active ingredient through a nozzle to form droplets; (d) causing or
allowing the a hydrogel-forming polymer to gel or solidify to form
a hydrogel-forming polymer matrix; and (e) drying the solid.
[0110] In the method of the immediately preceding paragraph, the
active ingredient may be dissolved in the aqueous liquid or, for
example, it may be dispersed in the aqueous liquid in particulate
form.
[0111] Cores having the characteristics of cores obtained by the
above-described processes, for example cores obtained by the
processes, are coated to provide a coating that comprises or is a
water-soluble cellulose ether, optionally with a second coating to
control or modify release, preferably a polymeric coating as
described above and herein. The coated formulation may be obtained
by applying to the core the coating, e.g. applying to the core
first and second coatings as described. Before the coating is
applied, the core may be made by a process having steps (i) to
(vi), (i) to (v) or (a) to (e) described above. Suitable methods
for applying the coating(s) are described below and include
applying the coatings by spray coating a coating formulation onto
the core. The processes having steps (i) to (vi), (i) to (v) or (a)
to (e) themselves form aspects of the invention.
[0112] It has been found that the use of certain surfactants during
the manufacture of the compositions are particularly effective in
stabilising the colloid (for example emulsion), resulting from the
mixing of the aqueous solution (i) and oil phase (ii) comprising
the hydrophobic active ingredient, e.g. cyclosporin A. When the
colloid comprises an oil-in-water emulsion, it has been found that
the presence of a surfactant having an HLB of up to 10
(particularly up to 8) in the oil phase is particularly effective
in stabilising the emulsion during the preparation of the
composition. The presence of such surfactants has been found to
inhibit the formation of crystals of the hydrophobic active
ingredient, e.g. cyclosporin A, after the formation of the colloid
(oil-in-water emulsion). The presence of a surfactant with an HLB
of up to 10 maintains the hydrophobic active ingredient, e.g.
cyclosporin A, in solution in the oil phase during manufacture and
may also provide favourable release of the hydrophobic active
ingredient, e.g. cyclosporin A, in a solubilised form from the
composition following oral administration of the composition to a
subject. Compositions comprising a surfactant with an HLB of up to
10 in at least the oil phase may exhibit high rates of release
and/or extent of release of the hydrophobic active ingredient, e.g.
cyclosporin A, from the composition compared to the use of
surfactants with a higher HLB value in the oil phase. The presence
of a surfactant with an HLB of up to 10 in at least the oil phase
in the composition may inhibit the precipitation of the hydrophobic
active ingredient, e.g. cyclosporin A, after release of the
hydrophobic active ingredient, e.g. cyclosporin A, from the
composition thereby retaining higher levels of the hydrophobic
active ingredient in a solubilised form within the GI tract, for
example in the colon. The compositions described herein wherein the
composition comprises an oil phase and a surfactant having an HLB
of up to 10 form a further independent aspect of the invention.
[0113] Accordingly provided is a pharmaceutical formulation
comprising a core and a coating, wherein the core comprises a
pharmaceutically active ingredient and is in the form of a solid
colloid comprising a continuous phase and a disperse phase, wherein
the continuous phases comprises a hydrogel forming polymer matrix
and the disperse phase comprises a surfactant with an HLB value in
the range of from 1 to 10, for example from 1 to 5, and the coating
comprises or is a water soluble cellulose ether and the coating is
present in an amount corresponding to a weight gain due to the
coating of from 0.5% to 20% by weight of the core.
[0114] Similarly there is provided a pharmaceutical formulation
comprising a core and a coating, wherein the core comprises a
pharmaceutically active ingredient and is in the form of a solid
colloid comprising a continuous phase and a disperse phase, wherein
the continuous phases comprises a hydrogel forming polymer matrix
and the disperse phase comprises a surfactant with an HLB value in
the range of from 1 to 10, for example from 1 to 5, and the coating
comprises or is a water-soluble cellulose ether and the coating has
a thickness of from 1 .mu.m to 1 mm.
[0115] The disperse phase may comprise an oil phase. In an
embodiment the oil phase comprises an oil and a surfactant
(suitably a non-ionic surfactant) wherein the oil and the
surfactant both have an HLB in the range 0-10. Accordingly, a core
of the present invention may comprise a pharmaceutically active
ingredient and may be in the form of a solid colloid comprising a
continuous phase and a disperse phase, wherein the continuous
phases comprises a hydrogel forming polymer matrix and the disperse
phase comprises an oil phase comprising an oil and a surfactant
(suitably a non-ionic surfactant) wherein the oil and the
surfactant both have an HLB in the range 0-10. For example the oil
has an HLB of 1-5, for example 1 to 4 or 1-2 and the surfactant has
an HLB 2-8, for example 3-7, 2-6, or 3-4).
[0116] The surfactant present in the oil phase may be any of the
surfactants described herein with an HLB value up to 10 The
surfactant present in the oil phase may a HLB value selected from:
up to 8, up to 7, 1-8, 1-7, 1-5, 2-5, 1-4, 1-3, 1-2, 2-4, 3-4, 5-8,
6-8 and 6-7. Suitably the surfactant present in the oil phase is a
non-ionic surfactant having an HLB value above.
[0117] The oil may be any of the oils described herein. Suitably
the oil is not itself a surfactant. However, certain oils,
particularly those derived from natural sources will comprise
components which may have surface active properties. For example
many triglyceride oils also comprise mono and diglyceride
components and may therefore exhibit some surfactant like
properties. Accordingly the oil suitably has an HLB value of 0-10,
however suitably the oil has an HLB which is close to 0 for example
an HLB of 0 to 3, optionally about 0, about 1 or about 2.
[0118] The oil and the surfactant present in the oil phase may both
independently have an HLB value of 0 to 10. The oil may have an HLB
of 1-5 and the surfactant may have an HLB of 2-8, optionally 3-7,
2-6, or 3-4. Suitably the oil and the surfactant are different.
[0119] The active ingredient may be a hydrophobic active
ingredient, e.g. cyclosporin A, and may be soluble in the oil. The
hydrophobic active ingredient, e.g. cyclosporin A, may be soluble
in the surfactant used in the oil phase. Suitably the hydrophobic
active ingredient, e.g. cyclosporin A, is soluble in both the oil
and the surfactant. Suitably, substantially all of the cyclosporin
A may be dissolved in the oil phase.
[0120] The oil phase may further comprises a solvent, wherein the
solvent is miscible with the disperse phase and water, optionally
wherein the solvent is selected from 2-(2-ethoxyethoxy)ethanol and
a poly(ethylene glycol), particularly wherein the solvent is
2-(2-ethoxyethoxy)ethanol.
[0121] The hydrogel forming polymer of the core may be any of the
hydrogel forming polymers described herein.
[0122] The composition may further comprise additional surfactants
in addition to the surfactant discussed above, i.e. the surfactant
present in the disperse phase or oil phase. In particular the
continuous phase comprising the hydrogel forming polymer may
further comprise one or more surfactants. Surfactants which may be
present in the continuous phase are any of the surfactants
described herein as being suitable for inclusion in the aqueous
(continuous) phase of the composition. Suitably the continuous
phase comprises one or more anionic surfactant, for example at
least one surfactant selected from fatty acid salts, alkyl sulfates
and bile salts, particularly the surfactant in the continuous phase
is or comprises an alkyl sulfate, for example sodium dodecyl
sulfate.
[0123] The active ingredient may be an immunosuppressant, a
hydroxylase inhibitor, or an anti-inflammatory; optionally the
active ingredient is cyclosporin A, hydralazine or mesalazine.
Cyclosporin or mesalamine may conveniently be used for example in a
process having steps (i) to (vi) described above. Hydralazine may
conveniently be used for example in a process having steps (i) to
(vi), (i) to (v) or (a) to (e) described above, in particular a
process having steps (i) to (v) above.
[0124] The core may further comprise a surfactant, optionally
wherein the surfactant is an anionic surfactant, optionally
selected from alkyl sulphates, carboxylates or phospholipids, or a
non-ionic surfactant, optionally selected from sorbitan-based
surfactants, PEG-fatty acids, or glyceryl fatty acids, or
poloxamers, or a combination thereof. Hence the pharmaceutical
formulation of all aspects of the invention may comprise at least
the following features, a core and a first coating, wherein the
core comprises an active ingredient and a surfactant, and the
coating comprises or is a water soluble cellulose ether.
[0125] In embodiments where the core is in the form of a solid
colloid, the surfactant may be in the disperse phase or the
continuous phase. The surfactant in the continuous phase may be an
anionic surfactant, for example at least one surfactant selected
from fatty acid salts and bile salts, particularly an alkyl
sulphate, for example sodium dodecyl sulphate. The surfactant in
the disperse phase may be a non-ionic surfactant.
[0126] In embodiments the core comprises both a non-ionic
surfactant and an anionic surfactant. The anionic surfactant, for
example sodium dodecyl sulphate, may be in the disperse phase and
the non-ionic surfactant, for example polyethoxylated castor oil
may be in the disperse phase. Alternatively, the anionic
surfactant, for example sodium dodecyl sulphate, may be in the
continuous phase and the non-ionic surfactant, for example
polyethoxylated castor oil may be in the disperse phase.
[0127] In embodiments the core further comprises a combination of
excipients selected from: a non-ionic surfactant and a solvent; an
anionic surfactant and a solvent; an anionic surfactant, a
non-ionic surfactant and a solvent; a non-ionic surfactant and an
oil; an anionic surfactant and an oil; a non-ionic surfactant, an
anionic surfactant and an oil; and a non-ionic surfactant, an
anionic surfactant, a solvent and an oil. Preferably, the anionic
surfactant is an alkyl sulphate, for example sodium dodecyl
sulphate, the non-ionic surfactant polyethoxylated castor oil, the
oil is a medium chain mono-, di- and/or tri-glyceride, for example
caprylic/capric triglyceride, and the solvent is
2-(ethoxyethoxy)ethanol.
[0128] The pharmaceutical formulation may further comprise an
excipient selected from: a surfactant, a solubiliser, a
permeability enhancer, a disintegrant, a crystalisation inhibitor,
a pH modifier, a stabiliser, or a combination thereof.
[0129] The core of a pharmaceutical formulation of the invention
may comprise a disperse phase being or comprising:
[0130] a pharmaceutically active ingredient, for example
cyclosporin, hydralazine or mesalamine;
[0131] a medium chain mono- di- or tri-glyceride, for example
caprylic/capric triglyceride;
[0132] a non-ionic surfactant, for example a polyethoxylated castor
oil; and
[0133] a solvent, for example 2-(ethoxyethoxy)ethanol and may
further comprise a continuous phase being or comprising:
[0134] an anionic surfactant, for example at least one surfactant
selected from fatty acid salts and bile salts, particularly an
alkyl sulphate, for example sodium dodecyl sulphate
[0135] a hydrogel forming polymer matrix which is or comprises a
hydrocolloid selected from carrageenan, gelatin, agar and pectin,
or a combination thereof optionally selected from gelatin and agar
or a combination thereof, more optionally the polymer of the a
hydrogel forming polymer matrix is or comprises gelatin; and
[0136] optionally a plasticiser, for example a plasticiser selected
from glycerin, a polyol for example sorbitol, polyethylene glycol
and triethyl citrate or a mixture thereof, particularly
sorbitol.
[0137] In a variant of the formulation described in the immediately
preceding paragraph, the disperse phase is free, or substantially
free of active ingredient, the active ingredient being dissolved in
the continuous phase.
[0138] In one embodiment the formulation comprises a core and a
coating outside the core, wherein the core is in the form of a
solid colloid, the colloid comprising a continuous phase and a
disperse phase, wherein the disperse phase is or comprises:
[0139] a hydrophobic active, for example cyclosporin A;
[0140] a medium chain mono- di- and/or tri-glyceride, for example
caprylic/capric triglyceride;
[0141] a polyethoxylated castor oil; and
[0142] a co-solvent, for example 2-(ethoxyethoxy)ethanol;
and wherein the continuous phase is or comprises:
[0143] a hydrogel-forming polymer matrix which is or comprises a
hydrocolloid selected from carrageenan, gelatin, agar and pectin,
or a combination thereof optionally selected from gelatin and agar
or a combination thereof, more optionally the polymer of the
water-soluble polymer matrix is or comprises gelatin;
[0144] optionally a plasticiser, optionally a plasticiser selected
from glycerin, a polyol for example sorbitol, polyethylene glycol
and triethyl citrate or a mixture thereof, particularly sorbitol;
and
[0145] an anionic surfactant, for example at least one surfactant
selected from fatty acid salts and bile salts, particularly an
alkyl sulphate, for example sodium dodecyl sulphate;
and wherein the coating on the core is any of the coatings
described herein. Suitably the coating comprises a first coating
and a second coating outside the first coating; and wherein
[0146] the first coating is the coating which is or comprises a
water-soluble cellulose ether as described above; and
[0147] the second coating is or comprises a coating, suitably a
polymeric coating, as defined above to control or modulate release
of cyclosporin A from the formulation.
[0148] In embodiments comprising a first coating and a second
coating, for example as mentioned in the immediately preceding
paragraph, a particular first coating is or comprises
hydroxypropylmethyl cellulose and a particular second coating
outside the first coating is or comprises a pH independent polymer,
for example ethyl cellulose; more particularly the second coating
is or comprises ethyl cellulose and optionally a polysaccharide
selected from water soluble and naturally occurring
polysaccacharides, for example pectin or another water-soluble
naturally occurring polysaccharide. The second coating may
therefore contain pectin or another said polysaccharide or it may
be substantially free of pectin and other said polysaccharides.
There are therefore disclosed second coatings which comprise
ethylcellulose as a controlled release polymer and which further
comprise pectin or another said polysaccharide as well as second
coatings which comprise ethylcellulose as a controlled release
polymer and which do not further comprise pectin or another said
polysaccharide.
[0149] The core may comprise a hydrogel forming polymer comprising
gelatin, optionally in an amount of 300 to 700 mg/g, the core
further comprising medium chain mono, di and/or tri-glycerides,
optionally in an amount of 20 to 200 mg/g, wherein the
pharmaceutical formulation further comprises the following
components:
[0150] solvent, for example 2-(ethoxyethoxy)ethanol, optionally in
an amount of 150 to 250 mg/g;
[0151] non-ionic surfactant, for example a polyethoxylated castor
oil, optionally in an amount of 80 to 200 mg/g; and
[0152] anionic surfactant, for example sodium dodecyl suplphate, in
an amount of 15 to 50 mg/g.
[0153] Where the core is a colloid, the active ingredient may be
dissolved in the continuous phase of the colloid.
[0154] It is not a requirement of the invention that the core
contain a disperse phase: the core may have a single phase which is
for example a hydrogel-forming polymer matrix, the matrix having an
active ingredient dissolved therein. For example, the active
ingredient may be hydralazine.
[0155] The invention includes within its scope formulations wherein
the core is a colloid having a disperse phase and the continuous
phase (matrix phase) of the colloid further includes dispersed
particles of a pharmaceutically active ingredient, for example
microparticles or nanoparticles. The disperse phase and continuous
phase may otherwise be as described elsewhere in this
specification,
[0156] The pharmaceutical formulation of the invention and/or the
core may be in the form of a minibead. It may be that the core is a
minibead and the first coating and, where applicable, the second
coating in conjunction with the core are in the form of a minibead.
However, it may be possible for the core to be a minibead and the
formulation not to be a minibead. The formulation may additionally
comprise a multiplicity of minibeads. Hence the invention
contemplates a minibead with the features of the pharmaceutical
formulations disclosed herein.
[0157] The formulation or the minibead may have a largest cross
sectional dimension of a core of from about 0.01 mm to about 5 mm,
for example from 1 mm to 5 mm, as in the case of from 1 mm to 3 mm
or 1 mm to 2 mm. The minibead may be spheroidal. The spheroidal
minibeads may have an aspect ratio of no more than 1.5, for example
from 1.1 to 1.5.
[0158] In embodiments the pharmaceutical formulation does not
comprise an antigen selected from inactivated and attenuated
microorganisms.
[0159] The pharmaceutical formulation of the invention may be for
oral administration. The formulation may be formulated into a unit
dosage form for oral administration comprising from 0.1 mg to 1000
mg, optionally from 1 mg to 500 mg, for example 10 mg to 300 mg, or
25 to 250 mg suitably about 25 mg, 35 mg, about 75 mg, about 180
mg, about 210 mg or about 250 mg of pharmaceutically active
ingredient. Suitably the formulation is in a multiple minibead unit
dosage form selected from soft or hard gel capsules, gelatin
capsules, HPMC capsules, compressed tablets or sachets. The
minibeads may be as described elsewhere herein.
[0160] A further aspect of the invention provides a formulation
described herein for use as a medicament. The active ingredient may
be an immunosuppressant, for example cyclosporin A; the formulation
may comprise at least one further active ingredient, for example at
least one further immunosuppressant. In particular there is
provided a formulation in which the active ingredient is an
immunosuppressant for use in the treatment, e.g. prevention, of a
condition of the GIT. The formulation may be for use in the
treatment of an inflammatory bowel disease, irritable bowel
syndrome, Crohn's disease, ulcerative colitis, celiac disease,
graft-versus-host disease, gastrointestinal graft-versus-host
disease, gastroenteritis, duodenitis, jejunitis, ileitis, peptic
ulcer, Curling's ulcer, appendicitis, colitis, pseudomembraneous
colitis, diverticulosis, diverticulitis, pouchitis, endometriosis,
colorectal carcinoma and adenocarcinoma.
[0161] In embodiments where the pharmaceutical formulation does not
comprise a second coating, the formulation may be for use in the
treatment of conditions that affect the small intestine. Such
formulations may be able to treat conditions selected from celiac
disease, GVHD or Crohn's disease.
[0162] The invention additionally provides a method for
administering an pharmaceutically active ingredient to a subject,
comprising orally administering to the subject a formulation
described herein. The method may be performed in the treatment,
e.g. prevention, of disease. The subject may be a mammal, in
particular a human. Also provided is a method for treating a
condition of the GI tract in a subject, preferably a human, in need
thereof comprising orally administering to the mammal a
therapeutically effective amount of a formulation described herein
and wherein the pharmaceutically active ingredient is one that is
potentially effective in the method. For example, the condition may
be inflammatory and the active ingredient an immunosuppressant, for
example cyclosporin A. Conditions of the GI tract which may be
treated or prevented include the conditions disclosed herein.
[0163] A further aspect of the invention provides the use of a
formulation described herein for use in the manufacture of a
medicament for the treatment, e.g. prevention, of a condition of
the GIT. Conditions of the GI tract include those disclosed
herein.
[0164] The invention also contemplates a method of treating a
condition selected from inflammatory bowel disease, irritable bowel
disease, Crohn's disease, ulcerative colitis, celiac disease, graft
vs host disease, gastrointestinal graft-versus-host disease,
gastroenteritis, duodenitis, jejunitis, ileitis, peptic ulcer,
Curling's ulcer, appendicitis, colitis, pseudomembraneous colitis,
diverticulosis, diverticulitis, endometriosis, colorectal carcinoma
and adenocarcinoma, wherein the method comprises administering a
pharmaceutical formulation of the invention.
[0165] In another aspect the invention provides a method of
treating conditions that affect the small intestine, wherein the
method comprises administering a pharmaceutical formulation of the
invention which does not comprise a second coating. The conditions
of the small intestine may be selected from celiac disease, GVHD or
Crohn's disease.
[0166] In an aspect of the invention there is provided a process
for making a pharmaceutical formulation, the process comprising the
step of:
[0167] coating a core with a coating comprising HPMC wherein the
weight gain due to the coating is from 0.5% to 20% of the weight of
the pharmaceutical formulation. The core may comprise a
pharmaceutically active ingredient and may be a core as described
in this specification.
[0168] The process of the immediately preceding paragraph may
further comprise producing the core, wherein producing the core
comprises the steps of:
[0169] mixing a non-aqueous phase with an aqueous phase to form a
solid colloid, wherein at least one of the aqueous phase or the
non-aqueous phase comprise a pharmaceutically active ingredient,
wherein
(a) the non-aqueous phase comprises a surfactant; and (b) the
aqueous phase comprises a hydrogel forming polymer; and
[0170] then causing or allowing the emulsion to solidify.
[0171] Included in the invention is a method of producing more than
one batch of a multiplicity of solid unit dosage forms comprising a
core, a first coating and a second coating outside the first
coating, wherein the core comprises an active ingredient and a
hydrogel forming polymer matrix, the first coating comprises or is
a water-soluble cellulose ether, and the second coating comprises
or is a delayed release polymer, further wherein the first coating
is present in an amount to provide each of the more than one
batches with a plot of % release of the active ingredient against
time with a difference of less than 5 units of % release at any
time point in the plot, wherein the method comprises, forming a
batch of cores, coating the cores with the first coating in an
amount to provide a weight gain due to the coating of from 0.5% and
20% and coating the core with the second coating to provide the one
or more batches.
[0172] In embodiments the coating is present in an amount to
provide a weight gain of from 8% to 12% or any other weight gain
mentioned herein.
[0173] A method of minimising inter-batch variability in a
dissolution profile of a multiplicity of solid unit dosage forms
from two or more batches, the method comprising:
[0174] forming two or more batches of a multiplicity of solid unit
dosage forms; and
[0175] coating the solid unit dosage forms of each batch with a
coating comprising hydroxylpropyl methyl cellulose, wherein the
weight gain due to the coating is from 0.5% to 20%.
[0176] Where this specification mentions a plurality of batches,
e.g. two or more batches, the number of batches may be at least
100, optionally at least 1000.
[0177] Another aspect of the invention is a method of avoiding
systemic side effects of cyclosporin, the method comprising
providing a composition comprising cyclosporin and a coating
present in an amount corresponding to a weight gain of 0.5% to 20%
of hydroxylpropyl methylcellulose. The method may be used in the
treatment of a condition selected from inflammatory bowel disease,
irritable bowel disease, Crohn's disease, ulcerative colitis,
celiac disease, graft vs host disease, gastrointestinal
graft-versus-host disease, gastroenteritis, duodenitis, jejunitis,
ileitis, peptic ulcer, Curling's ulcer, appendicitis, colitis,
pseudomembraneous colitis, diverticulosis, diverticulitis,
endometriosis, colorectal carcinoma and adenocarcinoma.
[0178] The coating of the invention increases the rate and/or
extent of release of the active ingredient from the formulation
compared to a corresponding formulation without the coating. The
formulations of the invention are therefore expected to provide
high concentrations of the active ingredient in-vivo following oral
administration, which may improve the oral bioavailability of the
active, thereby enhancing the therapeutic benefit of the active
ingredient. Enhanced bioavailability may also enable a lower dose
of the active to be administered and thereby reduce the size of a
unit dosage form or reduce the number of unit dosage form
administered to a patient (for example by reducing the number
and/or size of capsules required). Accordingly the invention
provides the use of formulation of the invention to increase the
bioavailability of an active ingredient. The invention further
provides a method for increasing the oral bioavailability of an
active agent the method comprising administering to a patient a
formulation of the invention.
[0179] Formulations of the invention which release the active in
the stomach and/or upper GI tract (e.g. the small intestine) may be
particularly beneficial for improving bioavailability. Accordingly,
formulations of the invention which release high amounts of the
active in the first 2 to 4 hours of the dissolution test described
herein are preferred. Suitably such formulations may be the
formulations described herein comprising a first coat (e.g. a
water-soluble cellulose ether) and no second coating.
[0180] For certain active ingredients it may be desirable to limit
or delay release of the active from the formulation until the
formulation has passed through the stomach and upper GI tract. The
formulations of the invention comprising a second coat may be
particularly suitable for such applications. The second coat acts
to delay release from the formulation, whilst the presence of the
coating of the invention (e.g. HPMC) increases the amount of active
released when the formulation releases the active in the lower GI
tract. The period of delay to the release of the active as a result
of the presence of the second coating can be tailored by
appropriate selection of the nature or amount of second coating
used. For a given second coating material a higher weight gain of
coating will generally increase the time period between
administration of the formulation and release of the active. The
formulations of the invention can therefore be used to provide high
levels of release of active agent at very specific parts of the GI
tract to provide, for example, topical treatment to diseased tissue
within the GI tract. Such delayed release formulations may be
particularly beneficial when the active has undesirable side
effects which may arise from systemic absorption higher in the GI
tract.
[0181] Included in this description by reference are the subject
matters of the appended claims. The description is therefore to be
read together with the claims and features mentioned in the claims
are applicable to the subject matters of the description. For
example, a feature described in a process claim is applicable also
to products mentioned in the description, where the feature is
manifested in the product. For example, a feature mentioned in a
product claim is applicable also to relevant process subject
matters contained in this description. Similarly, a feature
mentioned in the description in the context of a process is
applicable also to products mentioned in the description, where the
feature is manifested in the product. Also, a feature mentioned in
the description in the context of a product is applicable also to
relevant process subject matters contained in this description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0182] Embodiments of the invention are further described
hereinafter with reference to the accompanying drawings, in
which:
[0183] FIG. 1 is a graph plotting % of cyclosporin in solution
against time over 4 hours and showing the release profiles of
minibeads of Example 1 and Examples 2a-c with differing levels of a
coating comprising hydroxypropyl methylcellulose compared to the
release profile of a core of Example 1 which does not have a
hydroxypropyl methylcellulose coating.
[0184] FIG. 2 is a graph plotting % of cyclosporin in solution
against time over 24 hours and showing the release profiles of
minibeads of Example 1 and Examples 2a-c with differing levels of a
coating comprising hydroxypropyl methylcellulose compared to the
release profile of a core of Example 1 which does not have a
hydroxypropyl methylcellulose coating.
[0185] FIG. 3 is a graph plotting % of cyclosporin released against
time over 24 hours and showing the release profiles of minibeads of
Examples 5b-d with differing levels of a coating comprising
hydroxypropyl methylcellulose compared to the release profile of a
minibead of Example 5a which does not have a hydroxypropyl
methylcellulose coating.
[0186] FIG. 4 is a graph plotting % of cyclosporin released against
time over 24 hours and showing the release profiles of minibeads of
Example 1 and Examples 5f and 5g with differing levels of a coating
comprising hydroxypropyl methylcellulose compared to the release
profile of a minibead of Example 5e which does not have a
hydroxypropyl methylcellulose coating.
[0187] FIG. 5 is a graph plotting % of cyclosporin released against
time over 24 hours and showing the release profiles of minibeads of
Examples 5i and 5j with differing levels of a coating comprising
hydroxypropyl methylcellulose compared to the release profile of a
minibead of Example 5h which does not have a hydroxypropyl
methylcellulose coating.
[0188] FIG. 6 is a graph plotting % of cyclosporin released against
time over 24 hours and showing the release profiles of minibeads of
Examples 9b and 9c with differing levels of a hydroxypropyl
methylcellulose coating compared to the release profile of a
minibead of Example 9a which does not have a hydroxypropyl
methylcellulose coating.
[0189] FIG. 7 is a graph containing the release profiles of FIG. 3
and FIG. 6 in a single graph.
[0190] FIG. 8 is a graph plotting % of mesalazine released against
time over 24 hours and showing the release profiles of minibeads of
Examples 12b and 12c with differing levels of a coating comprising
hydroxypropyl methylcellulose compared to the release profile of a
minibead of Example 12a which does not have a hydroxypropyl
methylcellulose coating.
[0191] FIG. 9 is a graph plotting % of hydralazine released against
time over 24 hours and showing the release profiles of minibeads of
Examples 14b-c and 14e-f with differing levels of a coating
comprising hydroxypropyl methylcellulose and differing levels of a
Sureleas/Pectin coating compared to the release profiles of a
minibeads of Example 14a and 14d which do not have a hydroxypropyl
methylcellulose coating.
[0192] FIG. 10 is a graph plotting % of celecoxib released against
time over 18 hours and showing the release profiles of minibeads of
Examples 16 with a coating comprising hydroxypropyl methylcellulose
and a Surelease coating compared to the release profile of
minibeads which do not have a hydroxypropyl methylcellulose
coating.
[0193] FIG. 11 is a graph plotting % of cyclosporin released
against time over 24 hours and showing the reduction in the
variability of the release profiles of different batches of
minibeads with a coating comprising hydroxypropyl methylcellulose
and a Surelease/Pectin second coating.
[0194] FIG. 12 is a scanning electron microscope image of a cross
section of a minibead of the invention.
[0195] FIG. 13 is a enlarged image of a portion of the image in
FIG. 12 showing two distinct layers of coatings.
DETAILED DESCRIPTION
[0196] The term "treatment", and the therapies encompassed by this
invention, include the following and combinations thereof: (1)
reducing the risk of or inhibiting, e.g. delaying, initiation
and/or progression of, a state, disorder or condition; (2)
preventing, e.g. reducing the risk of, or delaying the appearance
of clinical symptoms of a state, disorder or condition developing
in a patient (e.g. human or animal) that may be afflicted with or
predisposed to the state, disorder or condition but does not yet
experience or display clinical or subclinical symptoms of the
state, disorder or condition; (3) inhibiting the state, disorder or
condition (e.g., arresting, reducing or delaying the development of
the disease, or a relapse thereof in case of maintenance treatment,
of at least one clinical or subclinical symptom thereof); and/or
(4) relieving the condition (e.g. causing regression of the state,
disorder or condition or at least one of its clinical or
subclinical symptoms). Where the formulation of the invention is
used in the treatment of a patient, treatment contemplates any one
or more of: maintaining the health of the patient; restoring or
improving the health of the patient; and delaying the progression
of the disorder. The benefit to a patient to be treated may be
either statistically significant or at least perceptible to the
patient or to the physician. It will be understood that a
medicament will not necessarily produce a clinical effect in every
patient to whom it is administered, and this paragraph is to be
understood accordingly. The formulations and methods described
herein are of use for therapy and/or prophylaxis of disease.
[0197] The treatments may include maintenance therapy of patients
who have suffered a disorder and whose condition has subsequently
improved, e.g. because of treatment. Such patients may or may not
suffer a symptomatic disorder. Maintenance therapy aims to arrest,
reduce or delay (re-)occurrence or progression of a disorder.
[0198] "Effective amount" means an amount sufficient to achieve the
desired treatment, e.g. result in the desired therapeutic or
prophylactic response. The therapeutic or prophylactic response can
be any response that a user (e.g., a clinician) will recognise as
an effective response to the therapy. It is further within the
skill of one of ordinary skill in the art to determine appropriate
treatment duration, appropriate doses, and any potential
combination treatments, based upon an evaluation of therapeutic or
prophylactic response.
[0199] The terms "dry" and "dried" as applied to formulations of
the disclosure may each include reference to formulations
containing less than 5% free water by weight, e.g. less than 1%
free water by weight. Primarily, however, "dry" and "dried" as
applied to formulations of the disclosure mean that the hydrogel
present in the initial solidified formulation has dried
sufficiently to form a rigid formulation. Where a solid colloid is
referred to this also refers to a dried colloid according to the
definition herein.
[0200] Ingredients and excipients of the described formulations are
suitable for the intended purpose. For example, pharmaceutical
formulations comprise pharmaceutically acceptable ingredients.
[0201] If not otherwise stated, ingredients, components, excipients
etc. of the formulation of the invention are suitable for one or
more of the intended purposes discussed elsewhere herein.
[0202] For the avoidance of doubt, it is hereby stated that the
information disclosed earlier in this specification under the
heading "Background" is relevant to the invention and is to be read
as part of the disclosure of the invention.
[0203] Throughout the description and claims of this specification,
the words "comprise" and "contain" and variations of them mean
"including but not limited to", and they are not intended to (and
do not) exclude other moieties, additives, components, integers or
steps. Throughout the description and claims of this specification,
the singular encompasses the plural unless the context otherwise
requires. In particular, where the indefinite article is used, the
specification is to be understood as contemplating plurality as
well as singularity, unless the context requires otherwise.
[0204] Features, integers, characteristics, compounds, chemical
moieties or groups described in conjunction with a particular
aspect, embodiment or example of the invention are to be understood
to be applicable to any other aspect, embodiment or example
described herein unless incompatible therewith. All of the features
disclosed in this specification (including any accompanying claims,
abstract and drawings), and/or all of the steps of any method or
process so disclosed, may be combined in any combination, except
combinations where at least some of such features and/or steps are
mutually exclusive. The invention is not restricted to the details
of any foregoing embodiments. The invention extends to any novel
one, or any novel combination, of the features disclosed in this
specification (including any accompanying claims, abstract and
drawings), or to any novel one, or any novel combination, of the
steps of any method or process so disclosed.
[0205] The reader's attention is directed to all papers and
documents which are filed concurrently with or previous to this
specification in connection with this application and which are
open to public inspection with this specification, and the contents
of all such papers and documents are incorporated herein by
reference.
Dissolution Profile
[0206] Reference to "a two stage dissolution test using a USP
Apparatus II with a paddle speed of 75 rpm and a dissolution medium
temperature of 37.degree. C.; wherein for the first 2 hours of the
dissolution test the dissolution medium is 750 ml of 0.1 N HCl, and
for the remainder of the dissolution test 250 ml of 0.2M tribasic
sodium phosphate containing 2% SDS is added to the dissolution
medium which is then adjusted to pH 6.8" is an in-vitro test
carried out in accordance with the USP <711> Dissolution test
using Apparatus II (paddle apparatus) operated with a paddle speed
of 75 rpm and with the dissolution medium at a temperature of
37.degree. C..+-.5.degree. C. At the start of the test (t=0) the
sample is placed in the dissolution acidic medium. After 2 hours an
aliquot of the medium is taken for subsequent analysis and
immediately (suitably within 5 minutes) the second stage of the
dissolution test is initiated. In the second stage 250 ml of 0.2M
tribasic sodium phosphate containing 2% sodium dodecyl sulphate
(SDS) is added to the dissolution medium and the pH adjusted to
6.8.+-.0.05 using 2N NaOH or 2N HCl as required. Samples of the
dissolution medium are taken at time points during the second stage
of the test, for example at 4, 6, 12 and 24 hours from the start of
the test (i.e. from t=0 at the start of the first stage). The
samples are analysed for the active dissolved in the medium. The "%
released" is the amount of active (e.g. cyclosporin) in solution in
the respective dissolution medium at a particular time point
relative to the amount of active in the composition at the start of
the test. The concentration of active in a sample may be measured
using standard techniques, such as Reverse Phase HPLC as
illustrated in the Examples. References to "a two stage dissolution
test" refer to this test method.
Formulation
[0207] The formulation comprises a matrix and a pharmaceutically
active ingredient. The matrix may be formed with a hydrogel-forming
polymer, and may contain additional excipient(s) to the polymer.
The active ingredient is contained within the matrix. The active
ingredient may be in solution or in suspension, or in a combination
thereof; however the invention is not limited to formulations
comprising a solution or suspension of the active and it includes,
for example, active ingredients encapsulated in liposomes or
cyclodextrin. The matrix may contain inclusions in which the active
ingredient is comprised; for example, the inclusions may comprise a
hydrophobic medium in which the active ingredient is dissolved or
suspended. An active ingredient may therefore be directly dissolved
or suspended in the matrix, or it may be dissolved or suspended
indirectly in the matrix by way of inclusions in which the active
ingredient is dissolved or suspended.
[0208] The formulation, therefore, comprises a matrix-forming
polymer, in particular a hydrogel-forming polymer. The matrix of
the formulation may be or comprise a polymer matrix comprising a
polymer selected from a water-permeable polymer, a water-swellable
polymer and a biodegradable polymer. In particular, the matrix is
or comprises a hydrogel-forming polymer described in more detail
below.
[0209] Modified release of the active ingredient from the
formulation may be achieved by virtue of the properties of the
matrix material. For example the matrix may be a permeable or
erodible polymer within which the active ingredient is contained,
e.g. dissolved or suspended; following oral administration the
matrix is gradually dissolved or eroded thereby releasing the
active ingredient from the matrix. Erosion may be achieved by
biodegradation of a biodegradable polymer matrix. Where the matrix
is permeable, water permeates the matrix enabling the drug to
diffuse from the matrix. A matrix formed with a hydrogel-forming
polymer may therefore include a modified release polymer. As such
modified release polymers may be mentioned cellulose derivatives,
for example hydroxypropylmethyl cellulose, poly(lactic acid),
poly(glycoloic)acid, poly(lactic-co glycolic acid copolymers),
polyethylene glycol block co-polymers, polyorthoesters,
polyanhydrides, polyanhydride esters, polyanhydride imides,
polyamides and polyphosphazines.
Water Soluble Cellulose Ether Coating
[0210] The invention provides pharmaceutical formulations that have
a coating which is or comprises a water-soluble cellulose ether.
The invention provides pharmaceutical formulations that have a
polymer coating, wherein the polymer is or comprises a
water-soluble cellulose ether. The water-soluble cellulose ether
may be, for example selected from methyl cellulose, hydroxyethyl
cellulose, hydroxylpropyl cellulose and hydroxypropylmethyl
cellulose.
[0211] Suitably the material of the first coating (i.e. the
sub-coating) is different to the second coating on the composition.
For example, where the first coating is or comprises a
water-soluble ester of a cellulose ether, the major component(s)
(e.g. more than 50%) of the second coating is or comprises a
different polymer to that of the first coating. Accordingly, the
first and second coatings suitably provide two layers of material
as part of the composition. It is to be understood that when the
second coating comprises a mixture of components, minor components
of the outer second coating may the same as the material of the
first coating. By way of example, when the first coating is or
comprises HPMC and the second coating comprises ethyl cellulose,
the ethyl cellulose may optionally further comprise a minor amount
(e.g. less than 50%, 40%, 30% or 20%) of the first coating
material, HPMC in this example. In such embodiments the sub-coat
and the second coating are considered to be different.
[0212] The water-soluble cellulose ether may be a water-soluble
cellulose ether selected from an alkyl cellulose, for example
methyl cellulose, ethyl methyl cellulose; a hydroxyalkyl cellulose,
for example hydroxyethyl cellulose (available as Cellosize.TM. and
Natrosol.TM.) hydroxypropyl cellulose (available as Klucel.TM.) or
hydroxymethyl cellulose; a hydroxyalkyl alkyl cellulose, for
example hydroxyethyl methyl cellulose (NEMC), hydroxypropyl methyl
cellulose (available as Methocel.TM., Pharmacoat.TM., Benecel.TM.)
or ethyl hydroxyethyl cellulose (EHEC); and a carboxyalkyl
cellulose, for example carboxymethyl cellulose (CMC). Suitably the
water-soluble cellulose ether may, for example be selected from
methyl cellulose, hydroxyethyl cellulose, hydroxylpropyl cellulose
and hydroxypropylmethyl cellulose.
[0213] The water-soluble cellulose ether may be a low viscosity
polymer which is suitable for application as a film or coating to
the formulation. The viscosity of the polymer may be from about 2
to about 60 mPas, for example a viscosity of: about 2 to about 20
mPas; about to 2 to about 8 mPas; more suitably a viscosity of
about 4 to about 10 mPas, for example about 4 to about 6 mPas.
Alternatively, the viscosity of the polymer may fall outside any or
all of the just-mentioned ranges, for example be above 20 mPas.
Alternatively, the viscosity of the polymer may fall outside any or
all of the just-mentioned ranges, for example be above 20 mPas. The
viscosity of the polymer may be determined by measuring the
viscosity of a 2% solution of the polymer in water at 20''C using a
Ubbelode viscometer using ASTM standard methods (D1347 and
D2363).
[0214] The water soluble cellulose ether may be a water-soluble
hydroxypropylmethyl cellulose (HPMC or hypromellose). HPMC is
prepared by modifying cellulose to substitute hydroxy groups with
methoxy and hydroxypropyl groups. Each anhydroglucose unit in the
cellulose chain has three hydroxyl groups. The amount of
substituent groups on the anhydroglucose units may be expressed as
the degree of substitution. If all three hydroxyl groups on each
unit are substituted, the degree of substitution is 3. The number
of substituent groups on the ring determines the properties of the
HPMC. The degree of substitution may also be expressed as the
weight % of the methoxy and hydroxypropyl groups present. Suitably
the HPMC has from about 19 to about 30% methoxy substitution and
from about 7 to about 12% hydroxypropyl substitution. Particularly
the HPMC has 25 to 30% methoxy substitution and 7 to 12%
hydroxypropyl substitution. Suitably the HPMC Is a low viscosity
HPMC which is suitable for application as a film or coating to the
formulation. The viscosity of the HPMC is suitably from about 2 to
60 mPas, for example about 2 to about 20 mPas, more suitably a
viscosity of about 4 to about 10 mPas. The viscosity of the HPMC is
determined by measuring the viscosity of a 2% solution of the HPMC
hi water at 20.degree. C. using a Ubbelode viscometer using ASTM
standard methods (D1347 and D2363). Such HPMC is available as for
example Methocel.TM., for example Methocel.TM. E, including
Methocel.TM. E5.
[0215] When the first coating is or comprises a water-soluble
derivative of a cellulose ether, the derivative may, for example be
a water-soluble ester of a cellulose ether. Water-soluble esters of
cellulose ethers are well known and may comprise esters of a
cellulose ether, formed with one or more suitable acylating
agent(s). Acylation agents may be, for example suitable acids or
acid anhydrides or acyl halides. Accordingly the ester of a
cellulose ether may contain a single ester moiety or two or more
ester moieties to give a mixed ester. Examples of water-soluble
esters of cellulose ethers may be water-soluble phthalate, acetate,
succinate, propionate or butyrate esters of a cellulose ether (for
example HPMC). Suitably the water-soluble ester of a cellulose
ether is a water-soluble phthalate, acetate-succinate, propionate,
acetate-propionate or acetate-butyrate ester of a cellulose ether
(for example HPMC).
[0216] In one embodiment the water-soluble ester of a cellulose
ether may be or comprise a water-soluble ester of any of the
water-soluble cellulose ethers described above in relation to the
sub-coating.
[0217] Particular water-soluble esters of cellulose ethers are
water-soluble esters of HPMC. Esters of HPMC which are soluble in
water at a pH greater than 5.5 may be or comprise hydroxypropyl
methylcellulose phthalate (HPMCP), or hydroxypropyl methylcellulose
acetate succinate (HPMCAS) in which the presence of ionisable
carboxyl groups causes the polymer to solubilize at high pH
(>5.5 for the LF grade and >6.8 for the HF grade). These
polymers are commercially available from Shin-Etsu Chemical Co.
Ltd.
[0218] The cellulose ether-containing coating may comprise or be
hypromellose, e.g. it may be made of a mixture of hypromellose,
titanium dioxide and polyethylene glycol; the coating may comprise
at least 20 wt % hypromellose and optionally at least 50% or at
least 75 wt % hypromellose, e.g. at least 80 wt % or at least 85 wt
% or 90 wt % hypromellose. The coating material used to form the
coating may therefore comprise a dry weight percentage of
hypromellose mentioned in the preceding sentence.
[0219] If it is desired for the coating to use a mixture of
hypromellose, titanium dioxide and polyethylene glycol, commercial
products corresponding to such mixtures are available including
Opadry White, a product commercialised by Colorcon. More generally,
there may be mentioned various products commercialised under the
trade name Opadry and Opadry II. Further non limiting examples
include Opadry YS-1-7706-G white, Opadry Yellow 03692357, Opadry
Blue 03690842). These formulations are available as dry film
coating formulations that can be diluted in water shortly before
use. Opadry and Opadry II formulations comprise a cellulosic film
forming polymer (e.g., HPMC and/or HPC), and may contain
polydextrose, maltodextrin, a plasticizer (e.g., triacetin,
polyethylene glycol), polysorbate 80, a colorant (e.g., titanium
dioxide, one or more dyes or lakes), and/or other suitable
film-forming polymers (e.g., acrylate-methacrylate copolymers).
Suitable OPADRY or OPADRY II formulations may comprise a
plasticizer and one or more of maltodextrin, and polydextrose
(including but not limited to a) triacetin and polydextrose or
maltodextrin or lactose, or b) polyethylene glycol and polydextrose
or maltodextrin). Particularly preferred commercial products are
Opadry White (HPMC/HPC-based) and Opadry II White
(PVA/PEG-based).
[0220] The cellulose ether-containing coating may also be applied
as a simple solution comprising water and the polymer of the first
coating. For example when the polymer is an HPMC, for example such
as Methocel, the first coating may be applied to the core as an
aqueous solution or dispersion of the HPMC. Optionally the coating
solution may include other solvents such as an alcohol.
Alternatively the coating may be applied as a solution or
dispersion in a volatile organic solvent.
[0221] Suitably the coating that contains a water soluble cellulose
ether is present in an amount corresponding to a weight gain of the
formulation due to the coating of from 0.5% to 40% (for example
from 0.5% to 30%; from 0.5% to 20%; from 1% to 25%; from 1% to 15%;
from 1% to 6%; from 1% to 4%; from 4% to 6%; from 6% to 10%; from
9% to 15%; or from 12% to 15%) by weight based upon the weight of
the formulation prior to applying the coating.
[0222] In another embodiment the first coating that contains a
water-soluble cellulose ether is present in an amount corresponding
to a weight gain due to the first coating in a range selected from
9 to 30%, suitably 9% to 20%, or particularly 10% to 15% by weight
based upon the weight of the formulation prior to applying the
coating.
[0223] Suitably the coating that contains a water soluble cellulose
ether provides a coating thickness on the formulation of from about
10 .mu.m to about 1 mm, for example, from about 10 .mu.m to about
500 .mu.m, from about 50 .mu.m to about 1 mm, or about from about
50 .mu.m to about 500 .mu.m. The thickness may therefore be from
about 100 .mu.m to about 1 mm, e.g. 100 .mu.m to about 750 .mu.m or
about 100 .mu.m to about 500 .mu.m. The thickness may be from about
250 .mu.m to about 1 mm, e.g. about 250 .mu.m to about 750 .mu.m or
250 .mu.m to about 500 .mu.m. The thickness may be from about 500
.mu.m to about 1 mm, e.g. about 750 .mu.m to about 1 mm or about
500 .mu.m to about 750 .mu.m. The thickness may therefore be from
about 10 .mu.m to about 100 .mu.m, e.g. from about 10 .mu.m to
about 50 .mu.m or about 50 .mu.m to about 100 .mu.m.
[0224] When the first coating comprises a water-soluble cellulose
ether the cellulose ether(s) suitably forms at least 40%, 50%, 60%,
70%, 80%, 85% or 90% by weight of the dry weight of the first
coating. Alternatively the water-soluble cellulose ether is the
first coating.
[0225] It is preferred to dry the formulation of the invention
before the first coating that contains a water-soluble cellulose
ether is applied, as is described in more detail below in relation
to the coating process.
[0226] It has been found that applying to a core comprising a
pharmaceutically active ingredient a sub-coating, referred to
elsewhere in the application as the subcoat (hence the subcoat and
the first coating are equivalent), that contains a water soluble
cellulose ether prior to applying a delayed release coating
provides unexpected advantages. The presence of such a sub-coating
has been found to enhance the dissolution properties of the delayed
release formulations according to the invention. In particular the
presence of such a sub-coating has been found to increase the rate
of release of the active ingredient from the formulation and also
to increase the amount of the active ingredient released in a set
time period compared to formulations prepared without using such a
sub-coating. These findings are unexpected, because it would have
been expected that the presence of a sub-coating in addition to a
delayed release outer coating would act to delay or inhibit release
of drug from the formulation and, at a given time, for there to be
less drug released, because there is a thicker coating present.
However, as illustrated in the Examples, contrary to these
expectations both the extent and rate of release of active
ingredient are increased compared to formulations without such a
sub-coating. Accordingly, delayed release formulation formulations
according to the invention which comprise a sub-coat that comprises
or is a water-soluble cellulose ether and a delayed release coating
outside the sub-coat, provide a unique dissolution profile. The
presence of such a sub-coating has also been found to reduce
batch-to-batch variability, particularly when the core is in the
form of a minibead. A sub-coating that comprises or is a
water-soluble cellulose ether may therefore also reduce intra- and
inter-patient variability as a result of a more consistent
dissolution profile. The unique properties of sub-coated
formulations according to the invention (particularly the
dissolution profile) are expected to contribute to favourable
pharmacokinetic properties of the formulations according to the
invention.
[0227] Accordingly in an embodiment there is provided a formulation
comprising a pharmaceutically active ingredient, wherein the
formulation further comprises a first coating; and wherein the
first coating is or comprises a water-soluble cellulose ether.
[0228] The formulation may have a second coating comprising or
being a delayed release polymer.
[0229] Accordingly in an embodiment there is provided a formulation
comprising a pharmaceutically active ingredient, wherein the
formulation further comprises a first coating and a second coating
outside the first coating; and wherein
[0230] the first coating is or comprises a water-soluble cellulose
ether; and
[0231] the second coating is or comprises a delayed release
coating, e.g. is or comprises a delayed release polymer.
[0232] An aspect of the invention resides in a multiple minibead
composition comprising at least two populations of active
ingredient-containing minibeads, wherein members of at least one
minibead population are minibeads as described herein (i.e.
formulations of the invention in minibead format). It will be
understood that the two populations are different.
Such a plural minibead population composition may comprise or
consist of the following two populations: a first population having
a coating that is or comprises a water-soluble cellulose ether but
having no outer coating, e.g. as described herein; and a second
population having a first coating that is or comprises a
water-soluble cellulose ether and a second coating that is or
comprises a delayed release coating, for example as described
herein e.g. a coating that is or comprises a delayed release
polymer.
[0233] The respective minibeads of each population of a plural
minibead composition may contain the same active ingredient(s) as
the minibeads of some or all of the other populations, or they may
contain different active ingredient(s) thereto, e.g. a different
combination. Thus, all the minibeads of a multiple minibead
population may contain the same active ingredient(s), for example
they may all contain an active ingredient selected from
immunosuppressants (e.g. cyclosporin), hydroxylase inhibitors (e.g.
hydralazine) and anti-inflammatories (e.g. mesalazine). More
generally, all the minibeads of a multiple minibead population may
contain any identical active ingredient, for example selected from
those described herein.
[0234] A multiple population composition may be for use in treating
a disorder of the GI tract, for example as described herein. Such a
formulation may be for use in treating a disorder affecting
multiple regions of the GIT, e.g. the upper intestine and the lower
intestine, and may comprise an active ingredient selected from
immunosuppressants (e.g. cyclosporin), hydroxylase inhibitors (e.g.
hydralazine) and anti-inflammatories (e.g. mesalazine).
[0235] The minibeads of a multiple population composition may by
way of example be contained in a gel capsule or a sachet.
[0236] An example of an active ingredient of a formulation of the
disclosure is cyclosporin A. Suitably in the embodiment of the
preceding paragraph the first coating (sub-coating) is applied to a
core comprising cyclosporin A. In a particular embodiment the core
is or comprises a pharmaceutically active ingredient, for example
cyclosporin A, in a polymeric matrix, particularly a water-soluble
polymer matrix. Still more particularly the core comprises a
hydrogel-forming polymer matrix and cyclosporin A. Such cores are
described in more detail below. Cyclosporin A may be replaced in
this example by hydaralazine or mesalazine.
[0237] The second coating is outside the first coating and may be
any of the delayed release coatings described herein. In
particular, the second coating is or comprises a pH independent
polymer modified release coating described above. For example the
second coating may be or comprise an enteric coating or a pH
independent coating. The second coating may comprise a mixture of
polymers including a polymer degradable by bacterial or other
enzymes. In a particular embodiment the second coating comprises
ethyl cellulose and optionally a water-soluble polysaccharide, in
particular one susceptible to degradation by colonic bacteria,
suitably pectin. Accordingly the second coating may comprise the
Surelease-pectin mixture described above. The second coating may be
or comprise ethyl cellulose (e.g. Surelease.TM.) and a pore former,
wherein the pore-former is a water-soluble excipient which acts to
enhance the permeability of the coating when placed in an aqueous
environment such as that found in the lower GI tract. Suitable pore
formers include those described above. In embodiments the second
coating does not comprise a pore former, thus the second coating
may not comprise pectin.
[0238] Accordingly in one embodiment of the invention there is
provided a formulation comprising a core, a first coating and a
second coating outside the first coating; and wherein:
[0239] the core comprises a polymer matrix, in particular a
hydrogel-forming polymer matrix, and a pharmaceutically active
ingredient;
[0240] the first coating is or comprises a water-soluble cellulose
ether, particularly hydroxypropylmethyl cellulose;
[0241] the second coating is or comprises a modified release
coating or delayed release coating, particularly a pH independent
modified release coating;
[0242] the first coating is present in an amount corresponding to a
weight gain due to the first coating in a range selected from: (i)
from 8% to 12%, for example about 10%; (ii) from 4% to 6%, for
example about 5%; or (iii) about 6% to about 10%, for example about
7%, about 7.5%, about 8%, about 8.5%, about 9% or about 9.5% by
weight based upon the weight of the formulation prior to applying
the first coating; and wherein
[0243] the second coating is present in an amount corresponding to
a weight gain of the formulation due to the second coating selected
from (a) from 10% to 12%, for example about 11% or about 11.5%; (b)
from 16% to 18%, for example about 17%; or (c) from about 8% to
about 12%, for example about 8.5%, about 9%, about 9.5%, about 10%,
about 10.5% or about 11% by weight based upon the weight of the
formulation prior to applying the second coating.
[0244] The first and second coatings in the embodiment of the
immediately preceding paragraph are suitably any of the first and
second coatings described above or below. Accordingly it is
intended that the coatings described in this section may be applied
to any of the formulations described herein to provide a delayed
release coating if required. The coatings are particularly useful
to provide a modified release coating to the cores comprising a
polymer matrix and pharmaceutically active ingredient described in
this application.
[0245] The presence of a sub-coating as described in this
specification, amongst other things, increases the amount of active
ingredient released from the formulation during dissolution
compared to formulations without such a sub-coating. Accordingly
there is provided a delayed release formulation comprising a
pharmaceutically active ingredient, wherein the formulation
comprises a first coating (sub coating) and second coating as
described herein; wherein the first coating is present in an amount
to provide a % release of the active ingredient that is higher than
a % release of the active ingredient from a corresponding
formulation without the first coating throughout a time period from
8 hours to 18 hours, when measured in the dissolution test
described herein. For example the sub-coated formulation provides a
higher % release in the period between 10 hours and 16 hours,
suitably between 10 hours and 14 hours and more particularly at
about 10 hours, about 12, hours about 14 hours or about 16 hours in
the dissolution test. A sub-coated formulation of the invention
may, for example, provide 2% or higher, 5% or higher or 10% or
higher more active ingredient release at a given time point during
the dissolution test compared to the same formulation without the
subcoating, for example 2 to 15% more active ingredient; the
teaching of this paragraph applies in particular to cyclosporin
A.
Polymer Matrix Core
[0246] The formulation of the invention comprises a core wherein
the core comprises a pharmaceutically active ingredient and a
continuous phase or matrix phase to provide mechanical strength. In
embodiments the active ingredient phase is or comprises a disperse
phase within the continuous phase or matrix. The continuous phase
or matrix phase suitably comprises a water-soluble polymer matrix
and in particular comprises a hydrogel-forming polymer matrix. The
core may comprise a polymer matrix wherein the matrix-forming
polymer is a hydrogel-forming polymer or a combination thereof.
[0247] The active ingredient may be present as a disperse phase
within the hydrogel-forming polymer matrix (continuous phase or
aqueous phase) of the core. The disperse phase may be hydrophobic,
in which instance the active ingredient may be hydrophobic, but may
alternatively be hydrophilic. For example the disperse phase may
comprise a lipid and cyclosporin A or another hydrophobic active.
The cores may be prepared by dispersing the active ingredient phase
within the aqueous phase to form a colloid and then causing the
formulation to solidify (gel), thereby immobilising the active
ingredient within the hydrogel-forming polymer matrix.
[0248] The core may have the form of a solid colloid, the colloid
comprising a continuous phase and a disperse phase, wherein the
continuous phase is or comprises the hydrogel-forming polymer and
the disperse phase is or comprises a pharmaceutically active
ingredient, for example a plurality of pharmaceutically active
ingredients. The disperse phase may comprise a vehicle containing
the active ingredient, for example containing it as a solution or a
suspension. The vehicle may be hydrophobic, and may comprise or be
a solution of a hydrophobic active ingredient or a suspension of a
hydrophilic active ingredient. The disperse phase may by way of
example be liquid, semi-solid or solid.
[0249] The core may have the characteristics of a dried colloid in
which the active ingredient is dispersed within the
hydrogel-forming polymer matrix. Thus, the core may have the form
of a dried colloid, the colloid comprising a continuous phase and a
disperse phase, wherein the continuous phase is or comprises the
hydrogel-forming polymer and the disperse phase is or comprises a
pharmaceutically active ingredient, for example a plurality of
pharmaceutically active ingredients. The disperse phase may
comprise a vehicle containing the active ingredient, for example
containing it as a solution or a suspension. The vehicle may be
hydrophobic, and may comprise or be a solution of a hydrophobic
active ingredient or a suspension of a hydrophilic active
ingredient. The disperse phase may by way of example be liquid,
semi-solid or solid. The dried colloid may be a dried emulsion,
i.e. the core may have the characteristics of a dried colloid.
[0250] Such cores comprising a water-soluble polymer, particularly
a hydrogel-forming polymer and a disperse phase comprising
cyclosporin A are described in more detail below.
Delayed Release Coatings
[0251] The invention provides formulations having a coating that
comprises, or is, a coating-forming polymer, wherein the
coating-forming polymer is a hydrogel-forming polymer; the coating
may be a first coating outside which is a second coating. The
second coating may be a delayed release coating, although the
invention does not require that the second coating be a delayed
release coating. The second coating may comprise or be a delayed
release polymer.
[0252] Thus according to one embodiment of the present invention,
there is provided a pharmaceutical formulation comprising a core, a
first coating and a second coating outside the first coating,
wherein the core comprises a pharmaceutically active ingredient and
the first coating comprises or is a water-soluble cellulose
ether.
[0253] The first coating may be present in an amount described
elsewhere in this specification.
[0254] The second coating may be present in an amount described
elsewhere herein. Suitably the second coating provides a coating
thickness on the formulation of from about 10 .mu.m to about 1 mm,
for example, from about 10 .mu.m to about 500 .mu.m, from about 50
.mu.m to about 1 mm, or about from about 50 .mu.m to about 500
.mu.m. The thickness may therefore be from about 100 .mu.m to about
1 mm, e.g. 100 .mu.m to about 750 .mu.m or about 100 .mu.m to about
500 .mu.m. The thickness may be from about 250 .mu.m to about 1 mm,
e.g. about 250 .mu.m to about 750 .mu.m or 250 .mu.m to about 500
.mu.m. The thickness may be from about 500 .mu.m to about 1 mm,
e.g. about 750 .mu.m to about 1 mm or about 500 .mu.m to about 750
.mu.m. The thickness may therefore be from about 10 .mu.m to about
100 .mu.m, e.g. from about 10 .mu.m to about 50 .mu.m or about 50
.mu.m to about 100 .mu.m.
[0255] The core is preferably in the form of a minibead, for
example as described hereafter in more detail, for example in the
form of a solid colloid. The second coat may be a film or it may be
a membrane. The second coat, e.g. film or membrane, may serve to
delay release until after the stomach; the coat may therefore be an
enteric coat. The delayed release coat may comprise one or more
delayed release substances, preferably of a polymeric nature (e.g.
methacrylates etc; polysaccharides etc as described in more detail
below), or combination of more than one such substance, optionally
including other excipients, for example, plasticizers. Preferred
plasticizers, if they are used, include hydrophilic plasticizers
for example triethyl citrate (TEC) which is particularly preferred
when using the Eudragit.RTM. family of polymers as coatings as
described below. Another preferred plasticiser, described in more
detail below in relation to coating with ethyl cellulose, is
dibutyl sebacate (DBS). Alternative or additional optionally
included excipients are glidants. A glidant is a substance that is
added to a powder or other medium to improve its flowability. A
typical glidant is talc which is preferred when using the
Eudragit.RTM. family of polymers as coatings.
[0256] The delayed release coating may be applied as described
below and may vary as to thickness and density. The amount of coat
is defined by the additional weight added to (gained by) the dry
formulation (e.g. bead) to which it is applied. Weight gain is
preferably in the range 0.1% to 50%, preferably from 1% to 15% of
the dry weight of the bead, more preferably in the range 3% to 10%
or in the range 5-12% or in the range 8-12%.
[0257] Polymeric coating material of a delayed release coating may
comprise methacrylic acid co-polymers, ammonio methacrylate
co-polymers, or mixtures thereof. Methacrylic acid co-polymers such
as, for example, EUDRAGIT.TM. S and EUDRAGIT.TM. L (Evonik) are
particularly suitable. These polymers are gastroresistant and
enterosoluble polymers. Their polymer films are insoluble in pure
water and diluted acids. They may 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
variety of pH levels, e.g. between the pHs at which EUDRAGIT.TM. L
and EUDRAGIT.TM. S are separately soluble. In particular, the
coating may be an enteric coating comprising one or more
co-polymers described in this paragraph. A particular coating
material to be mentioned is Eudragit L 30 D-55.
[0258] The trade mark "EUDRAGIT" is used hereinafter to refer to
methacrylic acid copolymers, in particular those sold under the
trade mark EUDRAGIT by Evonik.
[0259] The delayed release coating, where present, can comprise a
polymeric material comprising a major proportion (e.g., greater
than 50% of the total polymeric coating content) of at least one
pharmaceutically acceptable water-soluble polymer, and optionally a
minor proportion (e.g., less than 50% of the total polymeric
content) of at least one pharmaceutically acceptable water
insoluble polymer. Alternatively, the membrane coating can comprise
a polymeric material comprising a major proportion (e.g., greater
than 50% of the total polymeric content) of at least one
pharmaceutically acceptable water insoluble polymer, and optionally
a minor proportion (e.g., less than 50% of the total polymeric
content) of at least one pharmaceutically acceptable water-soluble
polymer.
[0260] Ammonio methacrylate co-polymers such as, for example,
EUDRAGIT.TM. RS and EUDRAGIT.TM. RL (Evonik) are suitable for use
in the present invention. These polymers are insoluble in pure
water, dilute acids, buffer solutions, and/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 (TAMCI) groups in the polymer. For example,
those polymers having EA:MMA:TAMCI 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. A diffusion-controlled
pH-independent polymer in this family is RS 30 D which is a
copolymer of ethyl acrylate, methyl methacrylate and a low content
of methacrylic acid ester with quaternary ammonium groups present
as salts to make the polymer permeable. RS 30 D is available as an
aqueous dispersion.
[0261] 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 generally
comprises the majority of the polymeric material with the more
soluble RL, when it dissolves, permitting gaps to be formed through
which solutes can come into contact with the core allowing for the
active to escape in a controlled manner.
[0262] 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 and/or
portion of the coating and/or exposure of the formulation within
the coating to allow egress of drug and/or dissolution of the
immobilization or water-soluble polymer matrix. 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 beads.
[0263] 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.
A further example is EUDRAGIT.RTM. L 30D-55 which is an aqueous
dispersion of anionic polymers with methacrylic acid as a
functional group. It is available as a 30% aqueous dispersion.
[0264] 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, for
example, 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 the
entirety of which is incorporated herein by reference.
[0265] Several derivatives of hydroxypropyl methylcellulose (HPMC)
also exhibit pH dependent solubility and may be used in the
invention for the delayed release coating. As examples of such
derivatives may be mentioned HPMC esters, for example hydroxypropyl
methylcellulose phthalate (HPMCP), which rapidly dissolves in the
upper intestinal tract and hydroxypropyl methylcellulose acetate
succinate (HPMCAS) in which the presence of ionisable carboxyl
groups causes the polymer to solubilize at high pH (>5.5 for the
LF grade and >6.8 for the HF grade). These polymers are
commercially available from Shin-Etsu Chemical Co. Ltd. As with
other polymers described herein as useful for delayed release
coatings, HPMC and derivatives (e.g. esters) may be combined with
other polymers e.g. EUDRAGIT RL-30 D.
[0266] Other polymers may be used to provide a coating in
particular enteric, or pH-dependent, polymers. 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.
pH Independent Polymer Delayed Release Coatings
[0267] In a particular embodiment the second coating, where
present, is or comprises a polymeric coating which is
pH-independent in its dissolution profile and/or in its ability to
release the active ingredient incorporated in the formulations of
the invention. A pH-independent polymer delayed release coating
comprises a delayed release polymer, optionally a plurality of
delayed release polymers, and one or more other optional
components. The other components may serve to modulate the
properties of the formulation. Examples have already been given
(e.g., Eudragit RS and RL).
[0268] Another example of a pH-independent polymeric coating is a
coating that comprises or is ethylcellulose; a pH-independent
polymeric coating may have a delayed release polymer that is
ethylcellulose, therefore. It will be understood that an
ethylcellulose formulation for use in coating a dosage form may
comprise, in addition to ethylcellulose and--in the case of a
liquid formulation--a liquid vehicle, one or more other components.
The other components may serve to modulate the properties of the
formulation, e.g. stability or the physical properties of the
coating such as the flexibility of the film coating. The
ethylcellulose may be the sole delayed release polymer in such a
formulation. The ethylcellulose may be in an amount of at least
50%, at least 60%, at least 70%, at least 80%, at least 90% or at
least 95% by weight of the dry weight of a coating formulation for
use in coating a dosage form. Accordingly, an ethylcellulose
coating may include other components in addition to the
ethylcellulose. The ethylcellulose may be in an amount of at least
50%, at least 60%, at least 70%, at least 80%, at least 90% or at
least 95% by weight of the ethylcellulose coating. Consequently,
ethylcellulose may be in an amount of at least 50%, at least 60%,
at least 70%, at least 80%, at least 90% or at least 95% by weight
of the dry weight of the second coating. Suitably the ethyl
cellulose coating further comprises a plasticizer as described
below to improve the flexibility of the film and to improve the
film-forming properties of the coating formulation during
application of the coating.
[0269] A particular ethylcellulose coating formulation which may be
applied to the first coating is a dispersion of ethylcellulose in a
sub-micron to micron particle size range, e.g. from about 0.1 to 10
.mu.m in size, homogeneously suspended in water with the aid of an
emulsification agent, e.g. ammonium oleate. The ethylcellulose
dispersion may optionally and preferably contain a plasticizer.
Suitably plasticisers include for example dibutyl sebacate (DBS),
diethylphthalate, triethyl citrate, tributyl citrate, triacetin, or
medium chain triglycerides. The amount of plasticizer present in
the coating formulation will vary depending upon the desired
properties coating. Typically the plasticizer comprises from 1 to
50%, for example about 8 to about 50% of the combined weight of the
plasticizer and ethyl cellulose. Such ethylcellulose dispersions
may, for example, be manufactured according to U.S. Pat. No.
4,502,888, which is incorporated herein by reference. One such
ethylcellulose dispersion suitable for use in the present invention
and available commercially is marketed under the trademark
Surelease.RTM., by Colorcon of West Point, Pa. USA. In this
marketed product, the ethylcellulose particles are, e.g., blended
with oleic acid and a plasticizer, then optionally extruded and
melted. The molten plasticized ethylcellulose is then directly
emulsified, for example in ammoniated water optionally in a high
shear mixing device, e.g. under pressure. Ammonium oleate can be
formed in situ, for instance to stabilize and form the dispersion
of plasticized ethylcellulose particles. Additional purified water
can then be added to achieve the final solids content. See also
U.S. Pat. No. 4,123,403, which is incorporated herein by
reference.
[0270] The trademark "Surelease.RTM." is used hereinafter to refer
to ethylcellulose coating materials, for example a dispersion of
ethylcellulose in a sub-micron to micron particle size range, e.g.
from about 0.1 to 10 .mu.m in size, homogeneously suspended in
water with the aid of an emulsification agent, e.g. ammonium
oleate. In particular, the trademark "Surelease.RTM." is used
herein to refer to the product marketed by Colorcon under the
Surelease.RTM. trademark.
[0271] Surelease.RTM. dispersion is an example of a combination of
film-forming polymer, plasticizer and stabilizers which may be used
as a second coating to adjust rates of active principle release
with reproducible profiles that are relatively insensitive to pH.
The principal means of drug release is by diffusion through the
Surelease.RTM. dispersion membrane and is directly controlled by
film thickness. Use of Surelease.RTM. is particularly preferred and
it is possible to increase or decrease the quantity of
Surelease.RTM. applied as coating in order to modify the
dissolution of the coated formulation. Unless otherwise stipulated,
use of the term "Surelease" may apply to Surelease E-7-19020,
E-7-19030, E-7-19040 or E-7-19050. An ethylcellulose coating
formulation, for example Surelease E-7-19020, may comprise
ethylcellulose blended with oleic acid and dibutyl sebacate, then
extruded and melted. The molten plasticized ethylcellulose is then
directly emulsified in ammoniated water in a high shear mixing
device under pressure. Ammonium oleate is formed in situ to
stabilize and form the dispersion of plasticized ethylcellulose
particles. Additional purified water is then added to achieve the
final solids content. An ethylcellulose coating formulation, for
example Surelease E-7-19030, may additionally comprise colloidal
anhydrous silica dispersed into the material. An ethylcellulose
coating formulation, for example Surelease E-7-19040, may comprise
medium chain triglycerides instead of dibutyl sebacate, in
particular in a formulation comprising colloidal anhydrous silica
and oleic acid. An ethylcellulose coating formulation, for example
Surelease E-7-19050, may derive from blending ethylcellulose with
oleic acid before melting and extrusion. The molten plasticized
ethylcellulose is then directly emulsified in ammoniated water in a
high shear mixing device under pressure. Ammonium oleate is formed
in situ to stabilize and form the dispersion of plasticized
ethylcellulose particles. However, formulations that comprise
medium chain triglycerides, colloidal anhydrous silica and oleic
acid are preferred. Surelease E-7-19040 is particularly
preferred.
[0272] The invention also contemplates using combinations of
ethylcellulose, e.g. a Surelease formulation, with other coating
components, for example sodium alginate, e.g. sodium alginate
available under the trade name Nutrateric.TM.
[0273] In addition to the EUDRAGIT.TM. and Surelease.RTM. polymers
discussed above, where compatible, any combination of coating
polymers disclosed herein may be blended to provide additional
delayed-release profiles.
[0274] The delayed release coating can further comprise at least
one soluble excipient to increase the permeability of the polymeric
material. These soluble excipients can also be referred to or are
pore formers. Suitably, the at least one soluble excipient or pore
former is selected from among a soluble polymer, a surfactant, an
alkali metal salt, an organic acid, a sugar, a polysaccharide, and
a sugar alcohol. Such soluble excipients include, but are not
limited to, polyvinyl pyrrolidone, polyvinyl alcohol (PVA),
polyethylene glycol, a water-soluble hydroxypropyl methyl
cellulose, sodium chloride, surfactants such as, for example,
sodium lauryl sulfate and polysorbates, organic acids such as, for
example, acetic acid, adipic acid, citric acid, fumaric acid,
glutaric acid, malic acid, succinic acid, and tartaric acid, sugars
such as, for example, dextrose, fructose, glucose, lactose, and
sucrose, sugar alcohols such as, for example, lactitol, maltitol,
mannitol, sorbitol, and xylitol, xanthan gum, dextrins, and
maltodextrins; and a polysaccharide susceptible of degradation by a
bacterial enzyme normally found in the colon, for example
polysaccharides include chondroitin sulphate, pectin, dextran, guar
gum and amylase, chitosan etc. and derivatives of any of the
foregoing. 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 0.1% to about 15% by weight, based on the total dry
weight of the polymer coating, for example from about 0.5% to about
10%, about 0.5% to about 5%, about 1% to about 3%, suitably about
2% based on the total dry weight of the polymer coating. The
delayed release coating may be free from HPMC.
[0275] 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 all of which are incorporated herein by reference in
their entirety.
[0276] The addition to Surelease.TM. or other pH-independent
polymer substance of a second polymer (e.g. a polysaccharide,
especially a heteropolysaccharide) which is susceptible to
degradation by colonic bacterial enzymes (and optionally or
alternatively by pancreatic or other relevant enzymes), helps
provide targeted release of the active ingredient to a site or
sites within the GI tract where the second polymer is degraded. By
varying the amount of second polymer added present in the coating
the dissolution profile may be optimized to provide the required
release of cyclosporin A from the formulation.
[0277] In a particular embodiments the delayed release coating
provides for release of the active agent in at least the colon.
Accordingly in one embodiment the coating comprises a combination
of ethylcellulose (preferably a described above, and particularly
formulated with an emulsification agent such as, for example,
ammonium oleate and/or a plasticizer such as, for example, dibutyl
sebacate or medium chain triglycerides) and a polysaccharide
susceptible of degradation by a bacterial enzyme normally found in
the colon. Such polysaccharides include chondroitin sulphate,
pectin, dextran, guar gum and amylase, chitosan etc. and
derivatives of any of the foregoing. Chitosan may be used in
connection with obtaining a colon-specific release profile;
additionally or alternatively, pectin may be so used.
[0278] The use of polysaccharides by themselves for delayed release
coating purposes has been tried with limited success. Most of the
non-starch polysaccharides suffer from the drawback of lacking good
film forming properties. Also, they tend to swell in the GI tract
and become porous, resulting in the early release of the drug. Even
amorphous amylose, which is resistant to degradation by pancreatic
alpha amylase but capable of degradation by colonic bacterial
enzymes, has the disadvantage of swelling in aqueous media although
this can be controlled by incorporating insoluble polymer, for
example ethyl cellulose and/or acrylate, into the amylose film.
Amylose however is not water-soluble and although water-insoluble
polysaccharides are not excluded, use of a water-soluble
polysaccharide (WSP) susceptible of bacterial enzymic degradation
brings particularly advantageous results when used as a coating in
accordance with this embodiment of the present invention. A
particularly preferred polysaccharide in this embodiment of the
present invention is pectin. Various kinds of pectin may be used
including pectin of different grades available i.e. with differing
degrees of methylation (DM), i.e. percentage of carbonyl groups
esterified with methanol, for example pectins with a DM of more
than 50%, known as High Methoxy (HM) Pectins or Low Methoxy (LM)
pectins, or a pectin combination comprising an HM pectin and an LM
pectin. It is also possible in this embodiment to use pectins
having various degrees of acetylation (DAc). Taken together, the DM
and DAc or the degree of substitution is known as Degree of
Esterification (DE). pectins of various DE's may be used according
to the invention. As an alternative to pectin, sodium alginate may
be used as a polysaccharide according to an embodiment of the
invention. However, other embodiments may conveniently include
amylose and/or starch which contains amylose. Various grades of
starch, containing different percentages of amylose may be used
including for example Hylon V (National Starch Food Innovation)
which has an amylose percentage of 56% or Hylon VII which has an
amylose percentage of 70%. The remaining percentage is amylopectin.
The polysaccharides pectin, amylose and sodium alginate are
particularly preferred for achieving colon delivery of the active
ingredient.
[0279] It has been found that water-soluble polysaccharide,
suitably pectin, can act as a former of pores in the coating
otherwise provided by ethylcellulose (preferably Surelease). By
"pores" is not meant shaft-like holes from the surface to the core
of the formulation, rather areas of weakness or absence of coating
occurring stochastically on and within the coating of the
invention. As mentioned above, pore formation may also be achieved
by inclusion of other soluble excipients within the polymer coating
to increase the permeability of the polymeric material.
[0280] Pore formers have been described before in connection with
Surelease (see e.g. US 2005/0220878).
[0281] According to a particular embodiment of the invention the
delayed release coating comprises ethylcellulose, e.g.
Surelease.TM., and a water-soluble polysaccharide (WSP) wherein the
proportion of ethylcellulose (in particular Surelease.TM.) to WSP
is ideally in the range 90:10 to 99:1, preferably, 95:5 to 99:1,
more preferably 97:3 to 99:1, for example about 98:2 based upon the
dry weight of the coating.
[0282] Suitably in this embodiment and other embodiments described
herein in which ethylcellulose (Surelease) is used as a coating,
the weight gain of the formulation due to application of the
coating comprising ethylcellulose (e.g. Surelease.TM. and WSP) is
in the range of from 1 to 30% (for example from: 3% to 25%; 5% to
15%; 8% to 14%; 10% to 12%; 12% to 18%; or 16% to 18%, suitably the
weight gain is about 11%, about 11.5%, or about 17%). It is
particularly preferred that when a WSP is used in this embodiment,
the WSP is pectin. Particularly favoured weight gains using
coatings comprising ethylcellulose, e.g. Surelease.TM., are those
in the range 5-12%, 8-12%, 5 to 10%, suitably about 8%, about 8.5%,
about 9%, about 9.5%, about 10%, about 10.5%, about 11%, about
11.5% or about 12%.
[0283] Accordingly in an embodiment the second coating comprises
ethyl cellulose and a water soluble polysaccharide (particularly
pectin) wherein the water-soluble polysaccharide (WSP) is present
in an amount of 0.1% to about 10% by weight, based on the dry
weight of the second coating. Suitably the WSP is present in an
amount of from about 0.5% to about 10%, for example about 0.5% to
about 5%, about 1% to about 3%, suitably about 2% based on the
total dry weight of the second coating. In this embodiment the WSP
is preferably pectin. In this embodiment the second formulation
suitably further comprises a plasticizer. Suitable plasticizers
include these described above in relation to Surelease.TM. Suitably
the weight gain of the formulation due to application of the second
coating in this embodiment is in the range of from 1 to 30% (for
example from: 3% to 25%; 5% to 15%; 8% to 14%; 10% to 12%; 12% to
18%; or 16% to 18%, suitably the weight gain is about 11%, about
11.5%, or about 17%).
[0284] In an embodiment the delayed release polymer is not a
water-soluble cellulose ether. Where the second coating comprises
or is a delayed release polymer the delayed release polymer may not
be the same as the water-soluble cellulose ether of the first
coating. Accordingly the second coating may not be the same as the
first coating.
Outer Barrier or Protective Coating
[0285] The formulations compositions described herein may comprise
a protective coating outside the second coating. The protective
coating may help to protect the second coating from damage
resulting for, for example formulating the composition into a final
dosage form, or during the handling, transport or storage of the
formulation. The protective coating is suitably applied to the
outer surface of the formulation. The protective coating may be
applied directly to the second coating such that the protective
coating is in contact with the second coating. The protective
coating is suitably a water soluble coating which does not
adversely affect the release of the active ingredient(s) from the
formulation when in use. Suitably the protective coating is or
comprises a water-soluble polymer. The protective coating may
comprise a water-soluble cellulosic or PVA film-forming polymer.
Suitably the protective coating may be or comprise Opadry
(HPMC/HPC-based), Opadry II (PVA/PEG-based) or polyvinyl
alcohol-polyethylene glycol graft copolymers (Kollicoat IR) as
described herein. The protective coating may be present as a layer
of from about 2 to about 50 .mu.m. Suitably the protective coating
is applied to give a weight-gain of from about 0.5 to about 10%,
based upon the weight of the formulation prior to applying the
protective coating.
Continuous Phase Polymer Matrix (Aqueous Phase)
[0286] This section of the specification relating to the polymer
matrix recites amounts of constituents in terms of percent by
weight of the formulation. In the context of this section of the
specification, what is meant is percent by weight of the dry weight
of the core, i.e. excluding coating(s).
[0287] It will be recalled that the core may comprise a matrix or
continuous phase and optionally, but not necessarily, also a
disperse phase or discontinuous phase. Suitably the continuous
phase of the core is or comprises a hydrogel-forming polymer. A
hydrogel-forming polymer is a polymer capable of forming a
hydrogel. A hydrogel may be described as a solid or semi-solid
material, which exhibits no flow when at rest, comprising a network
(matrix) of hydrophilic polymer chains that span the volume of an
aqueous liquid medium.
[0288] The core may comprise a hydrogel-forming polymer selected
from the group consisting of: gelatin; agar; agarose; pectin;
carrageenan; chitosan; alginate; starch; xanthan gum; gum Arabic;
guar gum; locust bean gum; polyurethane; polyether polyurethane;
cellulose; cellulose ester, cellulose acetate, cellulose
triacetate; cross-bonded polyvinyl alcohol; polymers and copolymers
of acrylic acid, hydroxyalkyl acrylates, hydroxyethyl acrylate,
diethylene glycol monoacrylate, 2-hydroxypropylacrylate,
3-hydroxypropyl acrylate; polymers and copolymers of methacrylic
acid, hydroxyethyl methacrylate, diethyleneglycol monomethacrylate,
2-hydroxypropyl methacrylate, 3-hydroxypropyl methacrylate,
dipropylene glycol monomethylacrylate; vinylpyrrolidone; acrylamide
polymers and copolymers, N-methylacrylamide, N-propylacrylamide;
methacrylamide polymers and copolymers, N-isopropylmethacrylamide,
N-2-hydroxyethylmethacrylamide; and vinyl pyrrolidone; and
combinations thereof. In specific embodiments binary or tertiary
etc combinations of any of the above substances are foreseen.
[0289] In a further embodiment the hydrogel-forming polymer is
selected from the group consisting of gelatin, agar, a polyethylene
glycol, starch, casein, chitosan, soya bean protein, safflower
protein, alginates, gellan gum, carrageenan, xanthan gum,
phthalated gelatin, succinated gelatin, cellulosephthalate-acetate,
oleoresin, polyvinylacetate, polymerisates of acrylic or
methacrylic esters and polyvinylacetate-phthalate and any
derivative of any of the foregoing; or a mixture of one or more
such a hydrogel-forming polymers
[0290] The hydrogel-forming polymer may also be referred to as a
hydrocolloid i.e. a colloid system wherein the colloid particles
are disperse in water and the quantity of water available allows
for the formation of a gel. In embodiments it is preferred to use
reversible hydrocolloids preferably thermo-reversible hydrocolloids
(e.g. agar, agarose, gelatin etc) as opposed to irreversible
(single-state) hydrocolloids. Thermo-reversible hydrocolloids can
exist in a gel and sol state, and alternate between states with the
addition or elimination of heat. Gelatin, agar and agarose are
thermo-reversible, rehydratable colloids and are particularly
preferred. Gelatin derivatives such as, for example, succinated or
phthalated gelatins are also contemplated. Thermoreversible
hydrocolloids which may be used according to the invention, whether
individually or in combination, include those derived from natural
sources such as, for example, carrageenan (extracted from seaweed),
gelatin (extracted from bovine, porcine, fish or vegetal sources),
agar (from seaweed), agarose (a polysaccharide obtained from agar)
and pectin (extracted from citrus peel, apple and other fruits). A
non-animal based hydrocolloid may be preferred for certain
applications e.g. administration to vegetarians or to individuals
not wishing to ingest animal products for religious or health
reasons. In relation to the use of carrageenan, reference is made
to US patent application 2006/0029660 A1 (Fonkwe et al), the
entirety of which is incorporated herein by reference. The
hydrogel-forming polymer may comprise or be a combination of
gelatin with one or more other thermoreversible hydrocolloids, e.g.
with one or more other of the thermoreversible hydrocolloids just
listed. The hydrogel-forming polymer may comprise or be a
combination of gelatin with agar; optionally, at least one further
thermoreversible hydrocolloid may be included in the combination,
for example one just listed.
[0291] Thermo-reversible colloids present a benefit over other
hydrogel-forming polymers. Gelation or hardening of
thermo-reversible colloids occurs by cooling the colloid, e.g. in a
liquid cooling bath or by air flow. Gelation of other
hydrogel-forming polymers, which is chemically driven, can lead to
leakage of the formulation contents into the gelation medium as the
hardening process can take time to occur. Leakage of the content of
the formulation may lead to an inaccurate quantity of the active
ingredient within the formulation. Thermo-reversible colloids are
also known as thermo-reversible gels, and it is therefore preferred
that the hydrogel former be a thermo-reversible gelling agent.
[0292] Another term which may be applied to hydrogel formers which
are advantageous is "thermotropic": a thermotropic gelling agent
(which the reader will infer is preferred as a hydrogel former used
in the invention) is one caused to gel by a change in temperature
and such gelling agents are able to gel more rapidly than those
whose gelling is chemically induced, e.g. ionotropic gelling agents
whose gelling is induced by ions, for example chitosan. In
embodiments of the invention, therefore, the hydrogel former is a
thermotropic gel-forming polymer or a combination of such
polymers.
[0293] The manufacture of the formulation to prepare a core may
require that the hydrogel-forming polymer be present as a solution,
which is preferably an aqueous solution. The hydrogel-forming
polymer represents between 5% and 50%, preferably between 10% and
30%, still more preferably between 15% and 20% by weight of the
aqueous phase during manufacture as described herein. In addition
the hydrogel-forming polymer may comprise 8 to 35%, (for example
15-25%, preferably 17-18%) hydro-gel forming polymer; 65%-85%
(preferably 77-82%) of water plus, optionally, from 1-5%
(preferably 1.5 to 3%) sorbitol. When present surfactant (e.g.
anionic surfactant) in the aqueous phase pre-mix may be present in
an amount of 0.1 to 5% (preferably 0.5 to 4%) wherein all parts are
by weight of the aqueous phase.
[0294] In embodiments the formulation comprises at least 25%,
suitably at least 40% by weight based upon the dry weight of the
formulation of the hydrogel-forming polymer. For example the
hydrogel-forming polymer is present form 25 to 70%, for example 40
to 70% suitably 45 to 60% of the formulation, wherein the % is by
weight based upon the dry weight of the formulation.
[0295] In embodiments the hydrogel-forming polymer is a
pharmaceutically acceptable polymer.
[0296] In certain embodiments the hydrogel-forming polymer is
gelatin. In certain embodiments the hydrogel-forming polymer
comprises gelatin. In certain embodiments the gelatin comprises at
least 40%, for example 40 to 70% suitably 45 to 60% of the
formulation, wherein the % is by weight based upon the dry weight
of the formulation.
[0297] The hydrogel-forming polymer may optionally comprise a
plasticiser for example sorbitol or glycerine, or a combination
thereof. In particular one or more plasticisers may be combined
with gelatin.
[0298] In embodiments in which the hydrogel-forming polymer
comprises or is gelatin, reference is hereby made to "Bloom
strength", a measure of the strength of a gel or gelatin developed
in 1925 by O. T. Bloom. The test determines the weight (in grams)
needed by a probe (normally with a diameter of 0.5 inch) to deflect
the surface of the gel 4 mm without breaking it. The result is
expressed in Bloom (grades) and usually ranges between 30 and 300
Bloom. To perform the Bloom test on gelatin, a 6.67% gelatin
solution is kept for 17-18 hours at 10.degree. C. prior to being
tested.
[0299] When the hydrogel-forming polymer comprises or is gelatin
the bloom strength of the gelatin may be in the range of 125 Bloom
to 300 Bloom, 200 Bloom to 300 Bloom and preferably 250 Bloom to
300 Bloom. It should be appreciated that higher bloom strength
gelatin can be replaced by lower bloom strength gelatin at higher
concentrations.
[0300] According to the invention, in embodiments in which the
hydrogel-forming polymer matrix comprises or is gelatin, the
gelatin may be sourced by a variety of means. For example, it can
be obtained by the partial hydrolysis of collagenous material, such
as the skin, white connective tissues, or bones of animals. Type A
gelatin is derived mainly from porcine skins by acid processing,
and exhibits an isoelectric point between pH 7 and pH 9, while Type
B gelatin is derived from alkaline processing of bones and animal
(bovine) skins and exhibits an isoelectric point between pH 4.7 and
pH 5.2. Type A gelatin is somewhat preferred. Gelatin for use in
the invention may also be derived from the skin of cold water fish.
Blends of Type A and Type B gelatins can be used in the invention
to obtain a gelatin with the requisite viscosity and bloom strength
characteristics for bead manufacture.
[0301] Lower temperature gelatin (or gelatin derivatives or
mixtures of gelatins with melting point reducers) or other polymer
matrices able to be solidified at lower temperatures (e.g. sodium
alginate) may also be used. It is therefore believed that polymer
which comprises or is low temperature gelatin is a preferred matrix
polymer.
[0302] According to the invention, in embodiments in which the
polymer comprises or is gelatin, the starting gelatin material is
preferably modified before manufacture to produce "soft gelatin" by
the addition of a plasticizer or softener to the gelatin to adjust
the hardness of the formulation of the invention. The addition of
plasticizer achieves enhanced softness and flexibility as may be
desirable to optimise dissolution and/or further processing such
as, for example, coating. Useful plasticizers of the present
invention for combination with gelatin or another hydrogel-forming
polymer include glycerine (1,2,3-propanetriol), D-sorbitol
(D-glucitol), sorbitol BP (a non-crystallizing sorbitol solution)
or an aqueous solution of D-sorbitol, sorbitans (e.g. Andidriborb
85/70), mannitol, maltitol, gum arabic, triethyl citrate,
tri-n-butyl citrate, dibutylsebacate. Other or similar low
molecular weight polyols are also contemplated for example ethylene
glycol and propylene glycol. Polyethylene glycol and polypropylene
glycol may also be used although these are less preferred.
Glycerine and D-sorbitol may be obtained from the Sigma Chemical
Company, St. Louis, Mo. USA or Roquette, France. Some active agents
and excipients included for other functions may act as
plasticisers.
[0303] Softeners or plasticisers, if utilized, can be ideally
incorporated in a proportion rising to 30%, preferably up to 20%
and more preferably up to 10% by dry weight of the formulation of
the invention, even more preferably between 3 and 8%, and most
preferably between 4% and 6%.
[0304] Although not essential, the hydrogel-forming polymer matrix
may also optionally contain a disintegrant where it is particularly
desired to enhance the rate of disintegration of the formulation of
the invention. Examples of disintegrants which may be included are
alginic acid, croscarmellose sodium, crospovidone, low-substituted
hydroxypropyl cellulose and sodium starch glycolate.
[0305] A crystallisation inhibitor (e.g. approximately 1% by dry
weight of the formulation) may also be included in the formulation
of the invention. An example is hydroxy propyl/methyl cellulose
(HPC or HPMC, hypromellose etc) which may play other roles such as,
for example, emulsifier.
[0306] In another embodiment, the hydrogel-forming polymer matrix
is chitosan which can exist in the form of biogels with or without
additives as described e.g. in U.S. Pat. No. 4,659,700 (Johnson
& Johnson); by Kumar Majeti N.V. Ravi in Reactive and
Functional Polymers, 46, 1, 2000; and by Paul et al. in ST. P.
Pharma Science, 10, 5, 2000 the entirety of all 3 of which is
incorporated herein by reference. Chitosan derivatives e.g.
thiolated entities are also contemplated.
[0307] The hydrogel-forming polymer matrix may be a
non-hydrocolloid gum. Examples are the cross-linked salts of
alginic acid. For example, aqueous solutions of sodium alginate
gums extracted from the walls of brown algae have the well known
property of gelling when exposed to di- and trivalent cations. A
typical divalent cation is calcium, often in the form of aqueous
calcium chloride solution. It is preferred in this embodiment that
the cross-linking or gelling have arisen through reaction with such
a multivalent cation, particularly calcium.
[0308] The hydrogel-forming polymer matrix may have a low water
content, therefore the formulation may have a low water content. As
described below, during manufacture of a core the disperse phase,
optionally comprising an active ingredient, is mixed with an
aqueous solution of the hydrogel-forming polymer and the
formulation is gelled, for example to provide cores which are
minibeads. Suitably the cores are dried following formation to
reduce the water content present in the core.
[0309] In certain embodiments the formulation does not comprise
compounds containing a disulphide bond. In embodiments the
hydrogel-forming polymer does not comprise compounds containing a
disulphide bond.
[0310] The hydrogel-forming polymer matrix forming the continuous
phase of the core (aqueous phase) may further comprise a
surfactant. Surfactants which may be used in the formulation are
described in the section "surfactants" below.
[0311] Surfactant which may be present in the continuous aqueous
phase of the core include, for example a surfactant selected from
the group consisting of: cationic; amphoteric (zwitterionic);
anionic surfactants, for example perfluoro-octanoate (PFOA or PFO),
perfluoro-octanesulfonate (PFOS), sodium dodecyl sulfate (SDS),
ammonium lauryl sulfate, and other alkyl sulfate salts, sodium
laureth sulfate, also known as sodium lauryl ether sulfate (SLES)
and alkyl benzene sulphonate; and non-ionic surfactants for example
perfluorocarbons, polyoxyethyleneglycol dodecyl ether (e.g. Brij
such as, for example, Brij 35), Myrj (e.g. Myrj 49, 52 or 59),
Tween 20 or 80 (also known as Polysorbate) (Brij, Myrj and Tween
products are available commercially from Croda), poloxamers which
are nonionic triblock copolymers composed of a central hydrophobic
chain of polyoxypropylene (poly(propylene oxide)) flanked by two
hydrophilic chains of polyoxyethylene (poly(ethylene oxide)), or a
combination of the foregoing. In particular, the surfactant may be
selected from, or comprise, anionic surfactants and combinations
thereof, the anionic surfactants optionally being those mentioned
in this paragraph. A particular class of surfactant comprises
sulfate salts. A preferred anionic surfactant in the aqueous phase
is SDS. Mixtures of anionic surfactants may be used. Mixtures of
further surfactants are also contemplated, e.g. mixtures comprising
perfluorocarbons.
[0312] In embodiments of the invention, the core comprises a
hydrophilic surfactant which, without being bound by theory, is
believed at least partially to partition the aqueous phase (polymer
matrix).
[0313] Such surfactants intended for such inclusion in the aqueous
phase of the core are preferably readily diffusing or diffusible
surfactants to facilitate manufacturing and processing of the
formulation of the invention.
[0314] The surfactant may have an HLB of at least 10 and optionally
of at least 15, e.g. at least 20, or at least 30 and optionally of
38-42, e.g. 40. Such surfactants can be of any particular type
(ionic, non-ionic, zwitterionic) and may comprise as a proportion
of dry weight of the formulation from 0.1% to 6%, e.g. 0.1% to 5%.
0.1% to 4% or 0.1% to 3%, more preferably in a proportion of at
least 1% and in particular between 1.0 and 4.5 or 5%, ideally
within or just outside the 2-4% range, for example from 2 to 3% or
approximately 2% or approximately 4%.
[0315] Unless otherwise stated or required, all percentages and
ratios are by weight.
[0316] In one embodiment the anionic surfactant may be an anionic
surfactant selected from alkyl sulphates, carboxylates or
phospholipids, or combinations thereof.
[0317] The physical form of the surfactant at the point of
introduction into the aqueous phase during preparation of the core
plays a role in the ease of manufacture of the core. As such,
although liquid surfactants can be employed, it is preferred to
utilize a surfactant which is in solid form (e.g. crystalline,
granules or powder) at room temperature, particularly when the
aqueous phase comprises gelatin.
[0318] In general, mixtures of surfactants can be utilised e.g. to
achieve optimum long term stability of the formulation of the
invention with shorter chain surfactants in general facilitating
shorter term stability (an aid to processing) and longer chain
surfactants facilitating longer term stability (an aid to shelf
life). In some embodiments, shorter chain surfactants have up to
C.sub.10 alkyl (e.g. C.sub.6-C.sub.10 alkyl) as the hydrophobic
portion of the surfactant whilst longer chain surfactants have
C.sub.10 or higher alkyl (e.g. C.sub.10-C.sub.22 alkyl) as the
hydrophobic portion of the surfactant. It is envisaged that
C.sub.10 alkyl surfactants may facilitate processing or facilitate
prolongation of shelf life, or both, depending on the identity of
the other excipients and of the active principle(s). Higher alkyl
may in particular implementations of the invention be
C.sub.11-C.sub.22 or C.sub.12-C.sub.22 alkyl, and in some
embodiments has a length of no greater than C.sub.18.
[0319] The matrix phase may comprise pharmaceutically active agent
in solution in the matrix phase. Such active agents in solution in
the matrix phase are therefore not present as a separate phase but
are part of the continuous matrix phase. Active agents suitable to
be in solution in the matrix phase are those which are soluble in
the aqueous premix which, during manufacture, is used to form the
matrix phase. Additionally or alternatively, a pharmaceutically
active agent may be comprised in a disperse phase.
Disperse Phase
[0320] The polymer matrix of the core described above (for example
a hydrogel-forming polymer) may comprise a disperse phase. Suitably
the disperse phase, where present, may comprise a pharmaceutically
active agent, in particular a hydrophobic active agent. The
invention also includes formulations in which the disperse phase
comprises a hydrophilic pharmaceutically active agent. In
embodiments, therefore, the disperse phase comprises cyclosporin A
or another hydrophobic active. In such embodiments the hydrophobic
active is preferably soluble in the disperse phase, i.e. the
disperse phase comprises a vehicle in which the active is
dissolved. Embodiments wherein the hydrophobic active is soluble in
the disperse phase are preferred, because such formulations release
the cyclosporin in a solubilised form, which may enhance the
therapeutic effect of the drug at the site of release, for example
by enhancing absorption into the colonic mucosa.
[0321] In embodiments a pharmaceutically active agent is or is
comprised in the disperse phase.
[0322] The disperse phase may comprise a water immiscible phase
(also referred to herein asan oil phase). The water immiscible
phase may be solid, semi-solid or liquid at ambient temperature
(e.g. 25.degree. C.), and therefore the oil phase may for example
be waxy at ambient temperature. The oil phase may be or may
comprise a liquid lipid and optionally a solvent miscible
therewith. A pharmaceutically active ingredient may be present in
the oil phase. Suitably the active ingredient is soluble in the oil
phase.
[0323] The disperse phase may comprise a combination of oils. The
liquid lipid may be a short-, medium- or long-chain triglyceride
formulation, or a combination thereof. A medium chain
triglyceride(s) (MCT) comprises one or more triglycerides of at
least one fatty acid selected from C.sub.6, C.sub.7, C.sub.8,
C.sub.9, C.sub.10, C.sub.11 and C.sub.12 fatty acids. It will be
understood that commercially available triglyceride, in particular
MCT, formulations useful in the invention are mixtures derived from
natural products and usually or always contain minor amounts of
compounds which are not MCTs; the term "medium chain triglyceride
formulation" is therefore to be interpreted to include such
formulations. A short chain triglyceride(s) comprises one or more
triglycerides of at least one short chain fatty acid selected from
C.sub.2-C.sub.5 fatty acids. A long chain triglyceride(s) comprises
one or more triglycerides of at least one long chain fatty acid
having at least 13 carbon atoms.
[0324] The liquid lipid may comprise or be triglycerides and/or
diglycerides. Such glycerides may be selected from medium chain
glycerides or short chain triglycerides or a combination
thereof.
[0325] The liquid lipid may be a caprylic/capric triglyceride, i.e.
a caprylic/capric triglyceride formulation (which it will be
understood may contain minor amounts of compounds which are not
caprylic/capric triglycerides).
[0326] Said solvent which is optionally included in an oil phase
may be miscible with both the liquid lipid and with water. Examples
of suitable solvents are 2-(2-ethoxyethoxy)ethanol available
commercially under trade names Carbitol.TM., Carbitol cellosolve,
Transcutol.TM., Dioxitol.TM., Poly-solv DE.TM., and Dowanal DE.TM.;
or the purer Transcutol.TM. HP (99.9). Transcutol P or HP, which
are available commercially from Gattefosse, are preferred. Another
possible co-solvent is poly(ethylene glycol). PEGs of molecular
weight 190-210 (e.g. PEG 200) or 380-420 (e.g. PEG 400) are
preferred in this embodiment. Suitable PEGs can be obtained
commercially under the name "Carbowax" manufactured by Union
Carbide Corporation although many alternative manufacturers or
suppliers are possible.
[0327] The disperse phase may represent from 10-85% by dry weight
of the core.
[0328] As discussed above the disperse phase may be an oil phase
comprising any pharmaceutically suitable oil, e.g. a liquid lipid.
The oil phase may be present as oil drops. In terms of dry weight
of the core, the oil phase may comprise a proportion from 10% to
85%, e.g. 15% to 50%, for example 20% to 30% or from 35% to 45%.
The term "oil" means any substance that is wholly or partially
liquid at ambient temperature or close-to-ambient temperature e.g.
between 10.degree. C. and 40.degree. C. or between 15.degree. C.
and 35.degree. C., and which is hydrophobic but soluble in at least
one organic solvent. Oils include vegetable oils (e.g. neem oil)
and petrochemical oils.
[0329] Oils which may be included in the oil phase include
poly-unsaturated fatty acids such as, for example, omega-3 oils for
example eicosapentanoic acid (EPA), docosohexaenoic acid (DHA),
alpha-linoleic acid (ALA), conjugated linoleic acid (CLA).
Preferably ultrapure EPA, DHA or ALA or CLA are used e.g. purity up
to or above 98%. Omega oils may be sourced e.g. from any
appropriate plant e.g. sacha inchi. Such oils may be used singly
e.g. EPA or DHA or ALA or CLA or in any combination. Combinations
of such components including binary, tertiary etc combinations in
any ratio are also contemplated e.g. a binary mixture of EPA and
DHA in a ratio of 1:5 available commercially under the trade name
Epax 6000. The oil part of the oil phase may comprise or be an oil
mentioned in this paragraph.
[0330] Oils which may be included in the oil phase are particularly
natural triglyceride-based oils which include olive oil, sesame
oil, coconut oil, palm kernel oil, neem oil. The oil may be or may
comprise saturated coconut and palm kernel oil-derived caprylic and
capric fatty acids and glycerin e.g. as supplied under the trade
name Miglyol.TM. a range of which are available and from which one
or more components of the oil phase of the invention may be
selected including Miglyol.TM. 810, 812 (caprylic/capric
triglyceride); Miglyol.TM. 818: (caprylic/capric/linoleic
triglyceride); Miglyol.TM. 829: (caprylic/capric/succinic
triglyceride; Miglyol.TM. 840: (propylene glycol
dicaprylate/dicaprate). Note that Miglyol.TM. 810/812 are MCT
formulations which differ only in C.sub.8/C.sub.10-ratio and
because of its low C.sub.10-content, the viscosity and cloud point
of Miglyol.TM. 810 are lower. The Miglyol.TM. range is available
commercially from Sasol Industries. As noted above, oils which may
be included in the oil phase need not necessarily be liquid or
fully liquid at room temperature. Waxy-type oils are also possible:
these are liquid at manufacturing temperatures but solid or
semi-solid at normal ambient temperatures. The oil part of the oil
phase may comprise or be an oil mentioned in this paragraph.
[0331] Alternative or additional oils which may be included in the
oil phase according to the invention are other medium chain
triglyceride formulations such as for example Labrafac.TM.
Lipophile manufactured by Gattefosse in particular product number
WL1349. Miglyol.TM. 810, 812 are also medium chain triglyceride
formulations.
[0332] Accordingly the oil phase may be or comprise medium chain
mono-di- or tri-glycerides.
[0333] The medium chain glyceride(s) (e.g. mono- di- or
tri-glyceride(s)) mentioned herein are those which comprise one or
more triglycerides of at least one fatty acid selected from fatty
acids having 6, 7, 8, 9, 10, 11 or 12 carbon atoms, e.g.
C.sub.8-C.sub.10 fatty acids.
[0334] The oil phase may further comprise one or more surfactants
as described below under the section "surfactants". For example the
oil phase may comprise one or more non-ionic or amphoteric
surfactants. Particularly the oil phase may comprise one or more
non-ionic surfactants listed under "surfactants" below. The
presence of a surfactant in the oil phase may also provide enhanced
solubilisation of an active ingredient contained in it (i.e. act as
a solubiliser) and/or may provide enhanced emulsification when the
disperse phase is mixed with the aqueous polymer phase during
preparation of the core (i.e. act as an emulsifier).
[0335] Surfactant in the oil phase may for example be or comprise
polyethoxylated castor oils (polyethylene glycol ethers) which can
be prepared by reacting ethylene oxide with castor oil. Commercial
preparations may also be used as a surfactant/solubilizer e.g.
those commercial preparations which contain minor components such
as, for example, polyethyelene glycol esters of ricinoleic acid,
polyethyelene glycols and polyethyelene glycol ethers of glycerol.
A preferred example is Kolliphor EL, previously known as Cremophor
EL. Another surfactant which may be present in the oil phase is for
example a phospholipid.
[0336] In embodiments the surfactant in the oil phase may be or
comprise a non-ionic surfactant selected from sorbitan-based
surfactants, PEG-fatty acids, glyceryl fatty acids, or
poloxamers.
[0337] Within embodiments, the HLB of the oil may be in the range
0-10 (optionally 1-8, e.g. 1-6 and sometimes 1-5).
[0338] In another embodiment the oil phase comprises an oil with an
HLB in the range range 0-10 (preferably 1-5) and a surfactant
(suitably a non-ionic surfactant) with an HLB in the range 10-20
and optionally 11-20 (preferably 11-15) range 0-10 (preferably
1-5).
[0339] In another embodiment the oil phase comprises an oil and a
surfactant (suitably a non-ionic surfactant) wherein the oil and
the surfactant both have an HLB in the range range 0-10. For
example the oil has an HLB of 1-5, for example 1 to 4 or 1-2 and
the surfactant has an HLB 2-8, for example 3-7, 2-6, or 3-4).
[0340] Suitable oils with a low HLB (HLB less than 10) include
medium chain triglycerides, linoleoyl macrogolglycerides
(polyoxylglycerides), caprylocaproyl macrogolglycerides and
caprylic/capric triglyceride. In terms of commercial products,
particularly preferred oils in the lower HLB range are Labrafac.TM.
Lipophile (e.g. 1349 WL), Captex 355 and Miglyol 810.
[0341] One example of a surfactant with high HLB which may be used
in a low HLB oil includes polyethoxylated castor oils (polyethylene
glycol ethers), for example the commercial product Kolliphor
EL.
[0342] In an embodiment the oil phase comprises of a surfactant of
high HLB and an oil of low HLB in a ratio of 1-4:1 by weight, e.g.
1.2-3.0:1 by weight, preferably 1.5-2.5:1 by weight and most
preferably 1.8-2.2:1 by weight (high HLB: low HLB) advantageously
stabilizes the emulsion before and after immobilization of the oil
droplets in the aqueous phase. In this context "stabilize" means in
particular that the embodiment improves dissolution and/or
dispersion of the formulation in vitro. In this embodiment "high"
HLB is generally intended above 10, preferably from 10-14, more
preferably between 12 and 13. By "low" HLB is generally intended
below 10, preferably in the range 1 to 4, more preferably 1 to
2.
[0343] It is to be understood that the oil phase in the embodiments
above may further comprise or more solvents, for example
2-(2-ethoxyethoxy)ethanol or low molecular weight PEG as mentioned
above.
[0344] A particular oil phase comprises an oil (low HLB), a high
HLB non-ionic surfactant and a co-solvent. For example the
following three commercial products: Transcutol P (as co-solvent),
Myglyol 810 (as oil) and Kolliphor EL (surfactant). Miglyol has a
low HLB and Kolliphor EL has a high HLB. An oil phase may therefore
comprise or consist of a combination of the following and
optionally a pharmaceutically active ingredient: 2-ethoxyethanol,
an MCT and particularly a caprylic/capric triglyceride formulation,
and a polyethoxylated castor oil.
[0345] A hydrophobic active ingredient is preferably soluble in the
oil phase. As discussed below in relation to preparation of the
core, the hydrophobic active ingredient is suitably dissolved in
the oil phase and the oil phase in mixed with an aqueous phase
comprising the hydrogel-forming polymer.
[0346] The disperse phase (oil phase) may be or comprise a
glyceride formulation, optionally wherein the disperse phase is or
comprises a fatty acid monoglyceride, diglyceride or triglyceride
or a combination thereof, or the disperse phase is or comprises a
caprylic/capric triglyceride formulation.
[0347] The disperse phase of the colloidal core may comprise
self-assembly structures, for example micelles, vesicles, liposomes
or nanoparticles, or at least the structures which result from
drying aqueous colloids of such types (have the characteristics of
structures which result from drying aqueous colloids of such
types). The invention in particular includes formulations in which
the disperse phase is micellar, i.e. formed of micelles and/or
promicelles. The term "promicelle" refers to a part of a
formulation which will form a micelle upon contact with water, e.g.
gastrointestinal contents.
[0348] The following discussion for convenience refers to micelles
but is applicable in general to other self-assembly structures. A
micelle-forming surfactant is present as micelles dispersed within
the hydrogel-forming polymer in a "wet" (not yet dried) composition
made as an intermediate in the manufacturing process described
herein. It is believed also to be present as micelles in the dried
composition but observability of micelles or micelle-like
structures in the dried composition is not a requirement of the
invention. It is mentioned at this point that the presence of a
surfactant in micelle form does not require that the entire
surfactant content of a composition is in micelle form as it is
considered more probable that a portion of the surfactant will be
outside the micelles. Thus in the "wet" composition, whether the
hydrogel-forming polymer is in the gel state or the sol (liquid)
state may comprise the micelle-forming surfactant at a
concentration above the critical micelle concentration.
[0349] The diameter of the dispersed micelles may be between 0.5 nm
and 200 nm, 1 nm and 50 nm, or 5 nm and 25 nm. The size of the
micelles may be determined by dynamic light scattering or diffusion
NMR techniques known within the art. Although the size of the
micelles is given as a diameter this does not imply that the
micelles must be purely spherical species only that they may
possess some approximately circular dimension.
[0350] The surfactant may be a non-ionic surfactant. The surfactant
may be a polyoxyethylated surfactant. The surfactant has a
hydrophilic head which may be a hydrophilic chain, for example a
polyoxyethylene chain or a polyhydroxylated chain.
[0351] The surfactant of course has a hydrophobic part and in
particular a hydrophobic chain. The hydrophobic chain may be a
hydrocarbon chain, for example having at least 6 carbon atoms and
optionally at least 10 carbon atoms, and particularly of at least
12 carbon atoms; some hydrocarbon chains have no more than 22
carbon atoms, for example C.sub.10-C.sub.20, C.sub.12-C.sub.20 or
C.sub.15-C.sub.20 hydrocarbon chains. It may be an alkyl chain,
e.g. having a number of carbon atoms just mentioned. It may be an
alkenyl chain comprising one or more carbon-carbon double bonds,
e.g. having a number of carbon atoms just mentioned. The surfactant
may comprise a hydrocarbon chain, e.g. alkyl chain or alkenyl
chain, that is substituted provided that it maintains a hydrophobic
characteristic. There may for example be one or two substituents,
for example a single substituent, e.g. selected from halogen (e.g.
F or Cl), hydroxy, thiol oxo, nitro, cyano; hydroxy or thiol
substituents may be esterified by for example a fatty acid. One
class of surfactants comprise a hydrocarbon monosubstituted by
hydroxy; optionally, at least a portion of the hydroxy groups of an
aliquot of surfactant, e.g. of the surfactant in a bead, may be
esterified by a fatty acid or mono-hydroxy fatty acid as disclosed
herein or etherified by a fatty alcohol for example having at least
6 carbon atoms and optionally at least 10 carbon atoms, and
particularly of at least 12 carbon atoms; some hydrocarbon chains
have no more than 22 carbon atoms, for example C.sub.10-C.sub.20,
C.sub.12-C.sub.20 or C.sub.15-C.sub.20 fatty alcohols.
[0352] The hydrophobic chain may be part of an esterified fatty
acid R.sup.1--COOH or of an etherified or esterified fatty ether
R.sup.1--COH where R' is the hydrophobic chain, e.g. as mentioned
in the preceding paragraph. The ester-forming or, as the case may
be, ether-forming group will typically comprise a hydrophilic
chain.
[0353] As mentioned, the surfactant may have a hydrophilic chain
and may be a non-ionic surfactant, and may satisfy both
requirements. The hydrophilic chain may be a poly(ethyleneglycol),
also known as poly(oxyethylene) or macrogol. The hydrophilic chain
may be of the formula --(O--CH.sub.2--CH.sub.2).sub.n--OR where n
is 5 or 6 to 50 and R is H or alkyl, e.g. ethyl or methyl. The
invention includes implementations in which n is from 6 to 40, e.g.
from 6 to 35. In some embodiments, n is from 6 to 25 and optionally
is from 8 to 25 or from 8 to 15. In other embodiments, n is from 8
to 50 or from 8 to 40, e.g. is from 10 to 50, 10 to 40 or 10 to 35.
In a particular embodiment, n is 15. For all hydrophilic chains of
the formula --(O--CH.sub.2--CH.sub.2).sub.n--OR, in one class of
embodiments R is H.
[0354] The hydrophilic chain may be a polyhydroxylated chain (for
example a C.sub.5-C.sub.20 e.g. C.sub.5-C.sub.10 chain), e.g.
having a hydroxy group on the carbon atoms of the chain, for
example a glucamide.
[0355] The micelle-forming surfactant may comprise a combination of
a hydrophobic chain as described above and a hydrophilic chain as
described above. It may therefore be, or comprise, a macrogol ester
of a fatty acid as described herein or a macrogol ether of a fatty
alcohol as described herein.
[0356] Micelle-forming surfactants comprising a hydrophobic chain
and a hydrophilic chain can be selected from the group consisting
of: macrogol esters; macrogol ethers; diblock copolymers; triblock
copolymers; and amphiphilic polymers. In certain embodiments of the
invention any combinations of the group are included within the
invention.
[0357] Examples of macrogol esters which are suitable for use in
the present invention are macrogol esters of fatty acids having at
least 6 carbon atoms and optionally at least 10 carbon atoms, and
particularly of at least 12 carbon atoms; some fatty acids have no
more than 22 carbon atoms, for example C.sub.10-C.sub.20,
C.sub.12-C.sub.20 or C.sub.15-C.sub.20 fatty acids. The fatty acids
may be saturated or unsaturated but are in particular saturated. To
be mentioned are macrogol 25 cetostearyl ether (Cremophor.RTM.
A25); macrogol 6 cetostearyl ether (Cremophor.RTM. A6); macrogol
glycerol ricinoleate 35 (Cremophor.RTM. EL); macrogol-glycerol
hydroxystearate 40 (Cremophor.RTM. RH 40);
macrogol-15-hydroxystearate (Solutol.RTM. HS 15). Examples of
macrogol ethers which are suitable for use in the present invention
are macrogol ethers of fatty alcohols having at least 6 carbon
atoms and optionally at least 10 carbon atoms, and particularly of
at least 12 carbon atoms; some fatty alcohols have no more than 22
carbon atoms, for example C.sub.10-C.sub.20, C.sub.12-C.sub.20 or
C.sub.15-C.sub.20 fatty alcohols. The fatty alcohols may be
saturate or unsaturated but are in one embodiment saturated.
[0358] Examples of amphiphilic polymers which are suitable for use
in the present invention are: alkyl glucamides; fatty alcohol
poly(ethoxyl)ates also known as polyethoxylated alkyl ethers;
poly(ethoxyl)ated fatty acid esters (Myrj or Solutol); fatty amide
polyethoxylate; fatty amine ethoxylate; alkylphenol ethoxylate;
polyethoxylated sorbitan esters (polysorbates); polyethoxylated
glycerides; or poly-glycerol esters.
[0359] Examples of copolymers, which are suitable for use in the
present invention are: pluronics (poloxamers);
polyvinylpyrollidone-polyvinylacetate (Plasdone S630); aminoalkyl
methacrylate copolymer (Eudragit EPO); methacrylic acid--methyl
methacrylate copolymer (Eudragit S100, L100); polycaprolactone-PEG;
polycaprolactone-methoxy--PEG; poly(aspartic acid)-PEG;
poly(benzyl-L-glutamate)-PEG; poly(D,L-lactide)methoxy-PEG;
poly(benzyl-L-aspartate-PEG; or poly(L-lysine)-PEG
[0360] In a preferred embodiment the micelle-forming surfactant cis
a macrogol ester, more preferably a macrogol ester that conforms to
the European Pharmacopoeia monograph number 2052
macrogol-15-hydroxystearate, such as Kolliphor.RTM. HS 15 marketed
by BASF.
[0361] Kolliphor.RTM. HS 15 consists of polyglycol mono- and
di-esters of 12-hydroxystearic acid and about 30% of free
polyethylene glycol. The main components of the ester part have the
following chemical structures:
##STR00001##
where x and y are integers and a small part of the 12-hydroxy group
can be etherified with polyethylene glycol.
[0362] Suitable surfactants comprise those which during manufacture
combine with the aqueous phase (including hydrogel-forming polymer)
in an amount above their CMC to form a clear liquid. Kolliphor.RTM.
HS 15 is such a surfactant.
[0363] In certain embodiments the weight ratio of the
micelle-forming surfactant to the antigen is from 10:1 to 100:1,
optionally from 50:1 to 100:1. In some embodiments, the ratio is
from 80:1 to 90:1. In particular embodiments, the ratio is from
50:1 to 60:1.
[0364] In particular embodiments, the compositions of the invention
comprise a combination of micelle-forming compounds. Such a
combination of micelle-forming compounds may consist of two or more
surfactants as mentioned in the preceding section of this
specification. Alternatively, a surfactant may be combined with one
or more other compounds at least potentially able to form micelles
with the surfactant, optionally selected from cationic lipids and
glycolipids, amongst others. As an additional option, a composition
may comprise a plurality of surfactants as mentioned in the
preceding section of this specification and one or more other
compounds at least potentially able to form micelles with the
surfactant, optionally selected from cationic lipids and
glycolipids, amongst others.
[0365] The invention therefore includes compositions as described
herein which comprise:
[0366] two or more micelle-forming surfactants, e.g. two or more
surfactants having a hydrophobic chain and a hydrophilic chain;
[0367] a compound, e.g. a single compound or two or more compounds,
selected from cationic lipids and glycolipids;
[0368] two or more micelle-forming surfactants and a compound, e.g.
a single compound or two or more compounds, selected from cationic
lipids and glycolipids.
[0369] A disperse phase which is or comprises a surfactant may
enhance the absorption of an active ingredient, for example
cyclosporin A, into the tissue of the GIT, for example by forming
self-assembly structures, such as micelles, which are associated
with the active ingredient and thus present the drug to the mucosa
tissue of the GI tract in a form which enhances uptake/absorption
in the tissue.
[0370] The oil phase may also include one or more volatile or
non-volatile solvents, which may be the same or different from the
solvent or co-solvent previously mentioned. Such solvents may for
example remain in the formulation of the invention following
processing e.g. initial dissolution of the components present in
the core, and have no particular function in the core formulation.
Alternatively, such solvents if present may function to maintain
the cyclosporin a dissolved state (in solution) within the oil
phase or to facilitate dispersion, egress etc. In other
embodiments, the solvent may have partly or fully evaporated during
processing and therefore be present in only minor quantities if at
all. In a related embodiment, the solvent, particularly when a
solvent which is both oil and water-soluble is used, may be partly
or completely present in the aqueous phase of the core. An example
of such a solvent is ethanol. Another example is transcutol which
is already mentioned as a co-solvent.
[0371] Accordingly, the core may comprise a hydrogel-forming
polymer matrix which forms a continuous phase and a disperse phase
comprising an active ingredient, particularly a hydrophobic active
ingredient, a high HLB non-ionic surfactant compound, a low HLB
oil, and optionally a co-solvent. Optionally, the active ingredient
may be a hydrophobic active ingredient.
[0372] The core may comprise a continuous phase which is or
comprises a hydrogel-forming polymer and a disperse phase which is
or comprises an active ingredient, optionally a hydrophobic active
ingredient e.g. cyclosporin, and an oil phase, the oil phase
comprising an oil and one or more surfactants, wherein the oil and
the surfactant have an HLB of up to 10. The presence of a
surfactant with an HLB of up to 10 has been found to provide
advantageous effects during the manufacture of the composition by
for example inhibiting crystallisation of cyclosporin from the oil
phase when the disperse phase is mixed with the continuous phase to
form a colloid, for example an oil in water emulsion. Such
compositions form a further aspect of the invention.
[0373] The presence of a surfactant with an HLB of up to 10 in the
oil phase may enhance the rate and or extent of release of an
active ingredient, optionally a hydrophobic active ingredient e.g.
cyclosporin from the composition following oral administration. The
presence of the surfactant may act to maintain a high proportion of
the an active ingredient, optionally a hydrophobic active
ingredient e.g. cyclosporin in a solubilised form after it has been
released from the composition into an aqueous medium such as that
found in the lower GI tract, particularly the colon.
[0374] The core may have the form of a solid colloid, the colloid
comprising a continuous phase being or comprising a hydrogel
forming polymer and a disperse phase being or comprising an active
ingredient, optionally a hydrophobic active ingredient e.g.
cyclosporin, and an oil phase, the oil phase comprising an oil and
one or more surfactants, wherein the surfactant has an HLB of up to
10, for example an HLB in the range 1-10. The pharmaceutical
formulation is suitably a modified release composition. However,
the core may be used to provide an instant release composition by,
for example using the core without a modified release coating.
[0375] The HLB value of the surfactant present in the oil phase may
be may be up to 8, up to 7, 1-8, 1-7, 1-5, 2-5, 1-4, 1-3, 1-2, 2-4,
3-4, 5-8, 6-8 or 6-7, for example the HLB value may be about 1,
about 2, about 3, about 4, about 5, about 6 or about 7. The
surfactant may be any surfactant having an HLB value with the
ranges described above, for example any of the surfactants
described herein under the section "surfactants" herein or
elsewhere in the description and examples. The surfactant is
suitably a non-ionic surfactant. The cyclosporin may be soluble in
the surfactant, for example the cyclosporin may have a solubility
of more than about 200 mg/g in the surfactant. Thus, the surfactant
may have a cyclosporin solubility of more than about 200 mg/g,
optionally more than about 250 mg/g. The surfactant may have a
cyclosporin solubility of from about 200 mg/g to about 500 mg/g,
optionally from about 250 mg/g to about 500 mg/g, about 200 mg/g to
about 400 mg/g, from about 225 mg/g to about 375 mg/g, from about
250 mg/g to about 375 mg/g, from about 200 mg/g to about 300 mg/g,
from about 300 mg/g to about 400 mg/g, from about 250 mg/g to about
350 mg/g, from about 225 mg/g to about 275 mg/g, from about 350
mg/g to about 400 mg/g. Preferably, the surfactant has a
cyclosporin solubility of from about 200 mg/g to about 400 mg/g or
from about 225 mg/g to about 375 mg/g. Solubility of cyclosporin in
a surfactant may be carried out following the protocol described in
Development of a Self Micro-Emulsifying Tablet of Cyclosporine-A by
the Liquisolid Compact Technique, Zhao et al (International Journal
of Pharmaceutical Sciences and Research, 2011, Vol. 2(9),
2299-2308) which is incorporated herein by reference.
[0376] The surfactant may have an HLB of up to 6 and a cyclosporin
solubility of from 200 mg/g to 400 mg/g. The surfactant may have an
HLB value of 2-6 (optionally 3-6) and a cyclosporin solubility of
from about 200 mg/g to about 400 mg/g. The surfactant may have an
HLB value of 2-6 (optionally 3-6) and a cyclosporin solubility of
from about 250 mg/g to about 400 mg/g. The surfactant may have an
HLB value of 2-6 (optionally 3-6) and a cyclosporin solubility of
from about 225 mg/g to about 275 mg/g. The surfactant may have an
HLB value of 2-6 (optionally 3-6) and a cyclosporin solubility of
from about 250 mg/g to about 350 mg/g.
[0377] The surfactant may be or comprise a surfactant selected
from: fatty acid glycerides, polyethylene glycol fatty acid esters,
propylene glycol fatty acid esters, fatty acid lactic acid ester,
sucrose fatty acid esters, sorbitan fatty acid esters, polyethylene
glycol fatty alcohol ethers, ethylene oxide-propylene oxide block
co-polymers and polyoxyethylene ethers; wherein the surfactant has
an HLB value of up to 10, up to 8, or particularly a HLB value
described above for example 1 to 8, or 1 to 4.
[0378] The surfactant may be or comprise a surfactant selected
from: fatty acid glycerides, polyethylene glycol fatty acid esters,
propylene glycol fatty acid esters, fatty acid lactic acid esters
or sucrose fatty acid esters, wherein the surfactant has an HLB
value of up to 10, up to 8, or particularly a HLB value described
above for example 1 to 8 or 1 to 4.
[0379] The surfactant may be or comprise a fatty acid glyceride,
wherein the surfactant has an HLB value of up to 10, up to 8, or
particularly a HLB value described above, for example 1 to 8 or 1
to 4.
[0380] The surfactant may be or comprise a sorbitan fatty acid
ester, for example a sorbitan mono, di- or tri-fatty acid ester and
wherein the surfactant has an HLB value described above, for
example 1 to 8 or 1 to 4. The fatty acid may be or comprise for
example one or more C.sub.10-C.sub.20, C.sub.12-C.sub.20 or
C.sub.15-C.sub.20 fatty acids. The fatty acids may be saturated or
unsaturated. A particular surfactant is or comprises sorbitan
trioleate (commercially available as Span 85), Another particular
surfactant is or comprises sorbitan monopalmitate (commercially
available as Span 40).
[0381] The surfactant may be or comprise polyethylene glycol fatty
acid esters, suitably esters with for example one or more
C.sub.10-C.sub.20, C.sub.12-C.sub.20 or C.sub.15-C.sub.20 fatty
acid, which acid may be saturated or unsaturated. Suitably the
surfactant is or comprises a mixture comprising polyethylene glycol
fatty acid esters and fatty acid glycerides, wherein the fatty acid
is a C.sub.15-C.sub.20 fatty acid, which may be saturated or
unsaturated.
[0382] The surfactant may be or comprise a polyglycerised fatty
acid for example polyglyceryl dioleate. Accordingly the surfactant
may act as an emulsifierand may be polyglyceryl-3 dioleate (for
example products sold under the trade mark Plurol.RTM. Oleique
[0383] The weight ratio of surfactant having a HLB value of up to
10:oil may be from about 5:1 to about 1:5, from about 3:1 to about
1:2, from about 3:1 to about 1:1 or from about 2.5:1 to 1.5:1.
Suitably the weight ratio may be about 1:1, about 2:1, about 2.5:1,
about 3:1, about 1:1.5 or about 1:2.
[0384] The surfactant having a HLB value of up to 10 may be present
in the composition in an amount of from about 5% to about 20%, from
about 8% to about 15%, or from about 10% to about 14% by weight
based upon the dry weight of the core. It is to be understood that
reference to the "dry weight of the core" means the weight of the
components present in the uncoated core other than water.
[0385] The oil may be any of the oils described herein,
particularly the oils described in the section "Disperse Phase".
The oil may be or comprise a short-, medium- or long-chain
triglyceride composition, or a combination thereof. A medium chain
triglyceride(s) (MCT) comprises one or more triglycerides of at
least one fatty acid selected from C.sub.6, C.sub.7, C.sub.8,
C.sub.9, C.sub.10, C.sub.11 and C.sub.12 fatty acids. A particular
oil phase is, or comprises a triglyceride based oil, such as those
commercially available as Miglyol.TM., for example Miglyol.TM. 810,
812 (caprylic/capric triglyceride); Miglyol.TM. 818:
(caprylic/capric/linoleic triglyceride); Miglyol.TM. 829:
(caprylic/capric/succinic triglyceride).
[0386] The oil may be present in the pharmaceutical formulation in
an amount of from about 2% to about 25%, from about 3% to about
20%, from about 3% to about 10% or from about 5% to about 10% by
weight based upon the dry weight of the core.
[0387] The oil phase may also comprise a solvent. Suitable solvents
are as described herein in relation to the disperse phase and are
suitable miscible with both the oil and water. The solvent may be
presently in the composition in an amount of form about 1% to 30%,
for about 5% to about 30%, for about 10% to about 25%, or from
about 12% to about 22% by weight based upon the dry weight of the
core. A particular solvent is 2-(2-ethoxyethoxy)ethanol (available
commercially as for example Transcutol.TM. P or HP).
[0388] The hydrogel-forming polymer may be or comprise one or more
of the hydrogel-forming polymers described herein, particularly
those described under "Continuous Phase Polymer Matrix". Suitably
the hydrogel-forming polymer is or comprises a hydrogel-forming
polymer selected from the group consisting of gelatin, agar, a
polyethylene glycol, starch, casein, chitosan, soya bean protein,
safflower protein, alginates, gellan gum, carrageenan, xanthan gum,
phthalated gelatin, succinated gelatin, cellulosephthalate-acetate,
oleoresin, polyvinylacetate, hydroxypropyl methyl cellulose,
polymerisates of acrylic or methacrylic esters and
polyvinylacetate-phthalate and any derivative of any of the
foregoing; or a mixture of one or more such a hydrogel forming
polymers. A particular hydrogel-forming polymer is selected from
carrageenan, gelatin, agar and pectin, or a combination thereof,
particularly gelatin and/or agar, more particularly gelatin. The
hydrogel forming polymer is suitably present in the core in a
gelled state such that the polymer forms a solid matrix within
which the disperse phase is dispersed to provide for example a
solid colloid. The hydrogel-forming polymer is preferably
sufficiently gelled to provide a core which is sufficiently rigid
to enable to be handled and further processed into a dosage form or
to be coated with for example a modified release coating as
described herein.
[0389] The hydrogel-forming polymer may be present in an amount of
from about 20% to about 70%, about 20% to about 55%, about 25% to
about 50%, about 30% to about 50%, or about 40% to about 45% by
weight based upon the dry weight of the core.
[0390] The continuous phase may comprise a suitably plasticiser,
particularly when the hydrogel-forming polymer is or comprises
gelatin. A particular plasticiser is Sorbitol. When present the
plasticiser may be present at for example up to about 20% or up to
about 10%, suitably from about 3% to about 8%, or from about 4% to
about 6% by weight based upon the dry weight of the core.
[0391] The continuous phase may comprise a surfactant. The
surfactant present in the continuous phase is preferably different
to the surfactant present in the oil phase. Suitable surfactants
which may be present in the continuous phase are as described
herein under the section "Continuous Phase Polymer Matrix".
Accordingly particular surfactants which may be present in the
continuous phase may be cationic, amphoteric (zwitterionic) or
anionic surfactants. Suitably the surfactant present in the
continuous phase is or comprises an anionic surfactant, more
particularly a hydrophilic anionic surfactant. The surfactant in
the continuous phase may be or comprise at least one surfactant
selected from fatty acid salts, alkyl sulfates and bile salts,
particularly an alkyl sulfate, for example a C.sub.10-C.sub.22
alkyl sulphate suitably sodium dodecyl sulphate. The surfactant
present in the continuous phase, particularly anionic surfactant is
present in the composition in an amount of from 0.1% to 6%, e.g.
0.1% to 5%. 0.1% to 4%, 0.1% to 3%, 1% to 4%, 1.5% to 4.5%, or 2.5%
to 4.5% preferably in an amount 2-4% by weight based upon the dry
weight of the core.
[0392] The cyclosporin A is suitably present in the composition in
an amount for from about 5% to about 20%, from about 8% to about
15%, or from about 9% to about 14% % by weight based upon the dry
weight of the core.
[0393] In a particular embodiment there is provided a
pharmaceutical formulation comprising a core having the form of a
solid colloid, the colloid comprising a continuous phase being or
comprising a hydrogel forming polymer and a disperse phase;
wherein the disperse phase is or comprises: cyclosporin A; an oil
being or comprising: a short-, medium- or long-chain triglyceride
composition, or a combination thereof, for example a
caprylic/capric triglyceride, a caprylic/capric/linoleic
triglyceride; and a caprylic/capric/succinic triglyceride; one or
more non-ionic surfactants with an value HLB of up to 10, up to 8,
up to 7, 1-8, 1-7, 1-5, 2-5, 1-4, 1-3, 1-2, 2-4, 3-4, 5-8, 6-8 or
6-7, for example about 1, about 2, about 3, about 4, about 5, about
6 or about 7; optionally wherein the surfactant is or comprises a
fatty acid glyceride, a sorbitan fatty acid ester, or a
polyethylene glycol fatty acid ester; and optionally a solvent,
wherein the solvent is miscible with the oil and with water, for
example 2-(2-ethoxyethoxy)ethanol; wherein the continuous phase is
or comprises: [0394] a hydrogel-forming polymer, for example a
hydrogel forming polymer being or comprising carrageenan, gelatin,
agar and pectin, or a combination thereof, optionally gelatin or
agar or a combination thereof, more optionally the polymer of the a
hydrogel forming polymer matrix is or comprises gelatin; [0395] an
anionic surfactant, optionally an anionic surfactant is selected
from fatty acid salts, alkyl sulphates and bile salts, particularly
an alkyl sulfate, for example a C.sub.10-C.sub.22 alkyl sulphate
suitably, sodium dodecyl sulphate; and [0396] optionally a
plasticiser, for example sorbitol.
[0397] In another embodiment there is provided a pharmaceutical
formulation comprising a core having the form of a solid colloid,
the colloid comprising a continuous phase being or comprising a
hydrogel forming polymer and a disperse phase;
wherein the disperse phase is or comprises: [0398] from about 8% to
about 15% cyclosporin A; [0399] from about 2% to about 20%, for
example about 3% to about 10% of oil being or comprising a
caprylic/capric triglyceride, a caprylic/capric/linoleic
triglyceride; and a caprylic/capric/succinic triglyceride,
preferably a caprylic/capric triglyceride; [0400] one or more
non-ionic surfactants with an value HLB of up to 10, up to 8, up to
7, 1-8, 1-7, 1-5, 2-5, 1-4, 1-3, 1-2, 2-4, 3-4, 5-8, 6-8 or 6-7,
for example about 1, about 2, about 3, about 4, about 5, about 6 or
about 7; optionally wherein the surfactant is or comprises a fatty
acid glyceride, a sorbitan fatty acid ester, or a polyethylene
glycol fatty acid ester, optionally wherein the non-ionic
surfactant is present in an amount of from about 8% to about 15%;
and [0401] optionally from about 12% to about 22% solvent, wherein
the solvent is miscible with the oil and with water, for example
2-(2-ethoxyethoxy)ethanol; wherein the continuous phase is or
comprises: [0402] from about 30% to about 70%, for example about
30% to about 50% hydrogel-forming polymer, optionally wherein the
hydrogel forming polymer is or comprises carrageenan, gelatin, agar
and pectin, or a combination thereof, optionally gelatin or agar or
a combination thereof, more optionally wherein the hydrogel forming
polymer matrix is or comprises gelatin; [0403] an anionic
surfactant, optionally an anionic surfactant is selected from fatty
acid salts, alkyl sulphates and bile salts, particularly an alkyl
sulfate, for example a C.sub.10-C.sub.22 alkyl sulphate suitably
sodium dodecyl sulphate, optionally wherein the anionic surfactant
is present in an amount of from about 0.1% to about 5%, suitably
from 2% to 4%; and [0404] optionally up to about 10% plasticiser,
for example sorbitol; wherein all % are % by weight based upon the
dry weight of the core.
[0405] In another embodiment there is provided an orally
administered modified release composition comprising a core having
the form of a solid colloid, the colloid comprising a continuous
phase being or comprising a hydrogel forming polymer and a disperse
phase;
wherein the disperse phase is or comprises: [0406] from about 8% to
about 15% cyclosporin A; [0407] from about 3% to about 10% of oil
being or comprising a caprylic/capric triglyceride; [0408] one or
more non-ionic surfactants with an value HLB of up to 7, for
example 1-7, or 2-4 wherein the surfactant is or comprises a fatty
acid glyceride, a sorbitan fatty acid ester, or a polyethylene
glycol fatty acid ester, optionally wherein the non-ionic
surfactant is present in an amount of from about 8% to about 15%;
and [0409] optionally from about 12% to about 22% solvent, wherein
the solvent is miscible with the oil and with water, for example
2-(2-ethoxyethoxy)ethanol; wherein the continuous phase is or
comprises: [0410] from about 30% to about 50% hydrogel-forming
polymer selected from gelatin or agar or a combination thereof,
optionally wherein the hydrogel forming polymer matrix is or
comprises gelatin; [0411] 0.1% to about 5%, suitably from 2% to 4%
anionic surfactant for example sodium dodecyl sulphate; and [0412]
optionally up to about 10% plasticiser, for example sorbitol;
wherein all % are % by weight based upon the dry weight of the
core.
[0413] In a particular embodiment the core is in the form of a
solid colloid, the colloid comprising a continuous phase and a
disperse phase, wherein the continuous phase comprises the
hydrogel-forming polymer; wherein
the disperse phase is or comprises: [0414] a pharmaceutically
active ingredient, for example cyclosporin A or another hydrophobic
active ingredient; [0415] a medium chain mono-, di- and/or
tri-glyceride, for example a medium chain triglyceride,
particularly caprylic/capric triglyceride; [0416] a polyethoxylated
castor oil; and [0417] a co-solvent (for example
2-(ethoxyethoxy)ethanol); and wherein the continuous phase is or
comprises: [0418] a hydrogel-forming polymer matrix which is or
comprises a hydrocolloid selected from carrageenan, gelatin, agar
and pectin, or a combination thereof optionally selected from
gelatin and agar or a combination thereof, more particularly the
polymer of the a hydrogel-forming polymer matrix is or comprises
gelatin; [0419] a plasticiser, optionally a plasticiser selected
from glycerin, a polyol for example sorbitol, polyethylene glycol
and triethyl citrate or a mixture thereof, particularly sorbitol;
and [0420] an anionic surfactant, for example at least one
surfactant selected from fatty acid salts, alkyl sulphates and bile
salts, particularly an alkyl sulphate, for example sodium dodecyl
sulphate.
[0421] In a further specific embodiment the core comprises a
hydrogel-forming polymer matrix comprising gelatin in an amount of
300 to 700 mg/g, the core further comprising an active ingredient,
medium chain mono-, di- and/or tri-glycerides (for example medium
chain triglyceride, particularly caprylic/capric triglyceride) in
an amount of 20 to 200 mg/g, and the core further comprises the
following components: [0422] co-solvent (for example
2-(ethoxyethoxy)ethanol) in an amount of 150 to 250 mg/g; [0423]
non-ionic surfactant in an amount of 80 to 200 mg/g; and [0424]
anionic surfactant in an amount of 15 to 50 mg/g, wherein weights
are based upon the dry weight of the core.
[0425] Suitably in the embodiment of the immediately preceding
paragraph the active ingredient is cyclosporin and the cyclosporin
A may be present in an amount of 60 to 180 mg/g, for example of 60
to 150 mg/g, 80 to 120 mg/g or particularly 80 to 100 mg/g. The
non-ionic and anionic surfactants are as defined herein, for
example an anionic surfactant selected from alkyl sulphates,
carboxylates or phospholipids (particularly SDS); or a non-ionic
surfactant selected from sorbitan-based surfactants, PEG-fatty
acids, or glyceryl fatty acids or poloxamers. A particular
non-ionic surfactant is a polyethoxylated castor oil (for example
Cremophore EL).
[0426] The cores described above comprising hydrogel-forming
polymer matrix and a pharmaceutically active ingredient,
particularly cyclosporin A, are coated as described herein to
provide a formulation according to the invention. A particular
coating for these embodiments is a coating comprising [0427] a
first coating (sub-coating) which is or comprises a water-soluble
cellulose ether, particularly hydroxypropylmethyl cellulose; [0428]
a second coating outside the first coating which is or comprises a
modified release coating, particularly a pH independent modified
release coating, more especially a coating comprising ethyl
cellulose (e.g. Surelease) still more particularly a coating
comprising ethyl cellulose and a water-soluble polysaccharide such
as pectin (e.g. a Surelease-pectin coating as described herein);
and wherein [0429] the first coating is present in an amount
corresponding to a weight gain due to the first coating in a range
selected from: (i) from 8% to 12%, for example about 10%; or (ii)
from 4% to 6%, for example about 5% by weight based upon the weight
of the formulation prior to applying the first coating; and wherein
[0430] the second coating is present in an amount corresponding to
a weight gain of the formulation due to the second coating selected
from (a) from 10% to 12%, for example about 11% or about 11.5%; or
(b) from 16% to 18%, for example about 17% by weight based upon the
weight of the formulation prior to applying the second coating.
[0431] The disperse phase may comprise particles of an active
ingredient dispersed in the matrix. The particles may be
microparticles (e.g. 1-999 .mu.m size) or nanoparticles (e.g. 1-999
nm size.) In particular, therefore, the disperse phase may comprise
a particulate hydrophobic drug dispersed within the matrix.
Surfactant
[0432] The formulation may contain one or more surfactants, for
example surfactants may be present in the core (including in the
hydrogel-forming polymer matrix, and in the disperse phase or
both). Surfactants may also be present in one or more of the
coatings applied to the core.
[0433] Suitable surfactants can be anionic, cationic, zwitterionic,
or non-ionic. In the description and claims of this specification,
the term "surfactant" is employed as a contraction for "surface
active agent". For the purposes of this description and claims, it
is assumed that there are four major classifications of
surfactants; therefore the surfactant may be: anionic, cationic,
non-ionic, and amphoteric (zwitterionic). The non-ionic surfactant
remains whole, has no charge in aqueous solutions, and does not
dissociate into positive and negative ions. Anionic surfactants are
water-soluble, have a negative charge and dissociate into positive
and negative ions when placed in water. The negative charge lowers
the surface tension of water and acts as the surface-active agent.
Cationic surfactants have a positive charge, and also dissociate
into positive and negative ions when placed in water. In this case,
the positive ions lower the surface tension of the water and act as
the surfactant. The amphoteric (zwitterionic) surfactant assumes a
positive charge in acidic solutions and performs as a cationic
surfactant, or it assumes a negative charge in an alkaline solution
and acts as an anionic surfactant.
[0434] The surfactant(s) may be selected from: anionic surfactants
and combinations thereof; from non-ionic surfactants and
combinations thereof; and from combination of an anionic surfactant
(e.g. a single such surfactant or a plurality thereof) and a
non-ionic surfactant (e.g. a single such surfactant or a plurality
thereof).
[0435] Surfactants can also be classified according to their
hydrophilic-lipophilic balance (HLB) which is a measure of the
degree to which the surfactant is hydrophilic or lipophilic,
determined by calculating values for the different regions of the
molecule, as described (originally for non-ionic surfactants) by
Griffin in 1949 and 1954 and later by Davies. The methods apply a
formula to the molecular weight of the whole molecule and of the
hydrophilic and lipophilic portions to give an arbitrary
(semi-empirical) scale up to 40 although the usual range is between
0 and 20. An HLB value of 0 corresponds to a completely hydrophobic
molecule, and a value of 20 would correspond to a molecule made up
completely of hydrophilic components. The HLB value can be used to
predict the surfactant properties of a molecule:
TABLE-US-00002 HLB Value Expected properties .sup. 0 to 3
antifoaming agent from 4 to 6 W/O emulsifier from 7 to 9 wetting
agent from 8 to 18 an O/W emulsifier from 13 to 15 typical of
detergents .sup. 10 to 18 solubiliser or hydrotrope
[0436] Although HLB numbers are assigned to surfactants other than
the non-ionic, for which the system was invented, HLB numbers for
anionic, cationic, non-ionic, and amphoteric (zwitterionic)
surfactants can have less significance and often represent a
relative or comparative number and not the result of a mathematical
calculation. This is why it is possible to have surfactants above
the "maximum" of 20. HLB numbers can however be useful to describe
the HLB requirement of a desired application for a given emulsion
system in order to achieve good performance.
Non-Ionic Surfactants
[0437] The surfactant may be or comprise at least one surfactant
selected from the following non-ionic surfactants.
[0438] PEG-fatty acid monoester surfactants, PEG-fatty acid diester
surfactants, PEG-fatty acid monoester and diester surfactant
mixtures, PEG glycerol fatty acid esters, transesterified products
of oils and alcohols, lower alcohol fatty acid esters,
polyglycerised fatty acids, propylene glycol fatty acid esters,
mono and diglyceride surfactants, sterol and sterol derivative
surfactants, PEG-sorbitan fatty acid esters, sorbitan fatty acid
esters, polyethylene glycol alkyl ethers, sugar ester surfactants,
polyethylene glycol alkyl phenol surfactants, POE-POP block
copolymers, fatty acid salts, bile salts, phospholipids, phosphoric
acid esters, carboxylates, acyl lactylates, sulphates and
sulfonates, and cationic surfactants.
[0439] A PEG-fatty acid mono ester surfactant for example PEG 4-100
monolaurate, PEG 4-100 monooleate, PEG 4-100 monostearate,
PEG-laurate, PEG-oleate, PEG stearate, and PEG ricinoleate. A
PEG-fatty acid diester surfactant for example PEG dilaurate; PEG
dioleate, PEG distearate, PEG dipalmitate. A mixture of PEG-fatty
acid mono- and diesters.
[0440] A PEG glycerol fatty acid ester for example PEG glyceryl
laurate, PEG glyceryl stearate, PEG glyceryl oleate.
[0441] PEG-sorbitan fatty acid esters for example PEG sorbitan
laurate, PEG sorbitan monolaurate, PEG sorbitan monopalmitate, PEG
sorbitan monostearate, PEG sorbitan tristearate, PEG sorbitan
tetrastearate, PEG sorbitan monooleate, PEG sorbitan oleate, PEG
sorbitan trioleate, PEG sorbitan tetraoleate, PEG sorbitan
monoisostearate, PEG sorbitol hexaoleate, PEG sorbitol
hexastearate.
[0442] Propylene glycol fatty acid esters for example propylene
glycol monocaprylate, propylene glycol monolaurate, propylene
glycol oleate, propylene glycol myristate, propylene glycol
monostearate, propylene glycol hydroxy stearate, propylene glycol
ricinoleate, propylene glycol isostearate, propylene glycol
monooleate, propylene glycol dicaprylate/dicaprate, propylene
glycol dioctanoate, propylene glycon caprylate/caprate, propylene
glycol dilaurate, propylene glycol distearate, propylene glycol
dicaprylate, propylene glycol dicaprate.
[0443] A sorbitan fatty acid ester for example sorbitan
monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan
monostearate, sorbitan trioleate, sorbitan sesquioleate, sorbitan
tristearate, sorbitan monoisostearate, sorbitan sesquistearate.
[0444] Lower alcohol fatty acid esters for example ethyl oleate,
isopropy myristate, isopropyl palmitate, ethyl linoleate, isopropyl
linoleate.
[0445] Polyoxyethylene-polyoxypropylene block copolymers for
example poloxamer 105, poloxamer 108, poloxamer 122, poloxamer 123,
poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 183,
poloxamer 184, poloxamer 185, poloxamer 188, poloxamer 212,
poloxamer 215, poloxamer 217, poloxamer 231, poloxamer 234,
poloxamer 235, poloxamer 237, poloxamer 238, poloxamer 282,
poloxamer 284, poloxamer 288, poloxamer 331, poloxamer 333,
poloxamer 334, poloxamer 335, poloxamer 338, poloxamer 401,
poloxamer 402, poloxamer 403, poloxamer 407.
[0446] Polyglycerised fatty acids for example polyglyceryl
stearate, polyglyceryl oleate, polyglyceryl isostearate,
polyglyceryl laurate, polyglyceryl ricinoleate, polyglyceryl
linoleate, polyglyceryl pentaoleate, polyglyceryl dioleate,
polyglyceryl distearate, polyglyceryl trioleate, polyglyceryl
septaoleate, polyglyceryl tetraoleate, polyglyceryl
decaisostearate, polyglyceryl decaoleate, polyglyceryl monooleate,
dioleate, polyglyceryl polyricinoleate.
[0447] PEG alkyl ethers for example PEG oleyl ether, PEG lauryl
ether, PEG cetyl ether, PEG stearyl ether.
[0448] PEG alkyl phenols for example PEG nonyl phenol, PEG octyl
phenol ether.
[0449] Transesterification products of alcohol or polyalcohol with
natural or hydrogenated oils for example PEG castor oil, PEG
hydrogenated castor oil, PEG corn oil, PEG almond oil, PEG apricot
kernel oil, PEG olive oil, PEG-6 peanut oil, PEG hydrogenated palm
kernel oil, PEG palm kernel oil, PEG triolein, PEG corn glycerides,
PEG almond glycerides, PEG trioleate, PEG caprylic/capric
triglyceride, lauroyl macrogol glyceride, stearoyl macrogol
glyceride, mono, di, tri, tetra esters of vegetable oils and
sorbitol, pentaerythrityl tetraisostearate, pentaerythrityl
distearate, pentaerythrityl tetraoleate, pentaerythrityl
tetrastearate, pentaerythrityl tetracaprylate/tetracaprate,
pentaerythrityl tetraoctanoate.
[0450] Oil-soluble vitamins for example vitamins A, D, E, K, and
isomers, analogues, and derivatives thereof. The derivatives
include, for example, organic acid esters of these oil-soluble
vitamin substances, for example the esters of vitamin E or vitamin
A with succinic acid. Derivatives of these vitamins include
tocopheryl PEG-1000 succinate (Vitamin E TPGS) and other tocopheryl
PEG succinate derivatives with various molecular weights of the PEG
moiety, for example PEG 100-8000.
[0451] Sterols or sterol derivatives (e.g. esterified or etherified
sterols as for example PEGylated sterols) for example cholesterol,
sitosterol, lanosterol, PEG cholesterol ether, PEG cholestanol,
phytosterol, PEG phytosterol.
[0452] Sugar esters for example sucrose distearate, sucrose
distearate/monostearate, sucrose dipalmitate, sucrose monostearate,
sucrose monopalmitate, sucrose monolaurate, alkyl glucoside, alkyl
maltoside, alkyl maltotrioside, alkyl glycosides, derivatives and
other sugar types: glucamides.
[0453] Carboxylates (in particular carboxylate esters) for example
ether carboxylates, succinylated monoglycerides, sodium stearyl
fumarate, stearoyl propylene glycol hydrogen succinated,
mono/diacetylated tartaric acid esters of mono- and diglycerides,
citric acid esters of mono-, diglycerides, glyceryl-lacto esters of
fatty acids; acyl lactylates: lactylic esters of fatty acids,
calcium/sodium stearoyl-2-lactylate calcium/sodium stearoyl
lactylate, alginate salts, propylene glycol alginate.
[0454] A fatty acid monoglyceride, diglyceride or triglyceride or a
combination thereof.
Anionic Surfactants
[0455] Anionic surfactants may be selected from following anionic
surfactants.
[0456] Fatty acid salts and bile salts for example sodium caproate,
sodium caprylate, sodium caprate, sodium laurate, sodium myristate,
sodium myristolate, sodium palmitate, sodium palmitoleate, sodium
oleate, sodium ricinoleate, sodium linoleate, sodium linolenate,
sodium stearate, sodium lauryl sulfate, sodium tetradecyl sulfate,
sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate; sodium
cholate, sodium taurocholate, sodium glycocholate, sodium
deoxycholate, sodium taurodeoxycholate, sodium glycodeoxycholate,
sodium ursodeoxycholate, sodium chenodeoxycholate, sodium
taurochenodeoxycholate, sodium glyco chenodeoxycholate, sodium
cholylsarcosinate, sodium N-methyl taurocholate
[0457] Phospholipids for example egg/soy lecithin, cardiolipin,
sphingomyelin, phosphatidylcholine, phosphatidyl ethanolamine,
phosphatidic acid, phosphatidyl glycerol, phosphatidyl serine.
[0458] Phosphoric acid esters having the general formula
RO--PO.sub.3.sup.-M.sup.+ where the R group is an ester forming
group, e.g. an alkyl, alkenyl or aryl group optionally substituted
by a PEG moiety through which the alkyl, alkenyl or aryl group is
coupled to the phosphate moiety. R may be a residue of a long chain
(e.g. >C9) alcohol or a phenol. Specific examples include
diethanolammonium polyoxyethylene-10 oleyl ether phosphate,
esterification products of fatty alcohols or fatty alcohol
ethoxylates with phosphoric acid or anhydride.
[0459] Sulfates and sulfonates (in particular esters thereof) for
example ethoxylated alkyl sulfates, alkyl benzene sulfones,
.alpha.-olefin sulfonates, acyl isethionates, acyl taurates, alkly
glyceryl ether sulfonates, octyl sulfosuccinate disodium, disodium
undecylenamideo-MEA-sulfosuccinate, alkyl phosphates and alkyl
ether phosphates.
Cationic Surfactants
[0460] Cationic surfactants may be selected from the following
cationic surfactants.
[0461] Hexadecyl triammonium bromide, dodecyl ammonium chloride,
alkyl benzyldimethylammonium salts, diisobutyl
phenoxyethoxydimethyl benzylammonium salts, alkylpyridinium salts;
betains (trialkylglycine): lauryl betaine
(N-lauryl,N,N-dimethylglycine); ethoxylated amines:
polyoxyethylene-15 coconut amine, alkyl-amines/diamines/quaternaty
amines and alkyl ester.
Emulsifiers
[0462] The surfactant may act as an emulsifier such surfactants
include non-ionic emulsifiers, for example selected from: a mixture
of triceteareth-4 phosphate, ethylene glycol palmitostearate and
diethylene glycol palmitostearate (for example sold under the trade
mark SEDFOS.TM. 75); sorbitan esters, e.g. sorbitan monooleate,
sorbitan monolaurate, sorbitan monpalmitate, sorbitan monostearate
(for example products sold under the trade mark Span.RTM.), PEG-8
beeswax e.g. sold under the trade mark Apifil.RTM.; a mixture of
cetyl alcohol, ceteth-20 and steareth-20 (for example Emulcire.TM.
61 WL 2659); a mixture of glyceryl monostearate EP/NF and PEG-75
palmitostearate (for example Gelto.TM. 64); a mixture of PEG-6
stearate and PEG-32 stearate (for example Tefose.RTM. 1500); a
mixture of PEG-6 palmitostearate, ethylene glycol palmitostearate,
and PEG-32 palmitostearate (e.g. Tefose.RTM. 63); triglycerol
diisostearate (for example products sold under the trade mark
Plurol)Diisostearique.RTM.; polyglyceryl-3 dioleate (for example
products sold under the trade mark Plurol.RTM. Oleique).
Other Excipients
[0463] The formulation optionally contains one or more of the
following additional substances or categories of substances. For
example, the formulation may contain a protectant such as, for
example, a proteolytic enzyme inhibitor or a protector against acid
degradation or both (e.g. an alkali for example sodium hydroxide);
an adhesive entity such as, for example, a muco- or bio-adhesive;
excipients to maximize solubility of the active ingredient;
excipients to maximize permeability of the active ingredient in the
GIT. Typical excipients for enhancing the permeability of the
epithelial barrier include but are not limited to sodium caprate,
sodium dodecanoate, sodium palmitate, SNAC, chitosan and
derivatives thereof, fatty acids, fatty acid esters, polyethers,
bile salts, phospholipids, alkyl polyglucosides, hydroxylase
inhibitors, antioxidants (e.g. ascorbic acid) and/or nitric oxide
donors. The preceding list is of particular interest to enhance
permeability in the ileum.
[0464] To enhance permeability in the colon, typical excipients
include, but not limited to sodium caprate, sodium dodecanoate,
sodium palmitate, SNAC, chitosan and derivatives thereof, fatty
acids, fatty acid esters, polyethers, bile salts, phospholipids,
alkyl polyglucosides, hydroxylase inhibitors, antioxidants and/or
nitric oxide donors, including nitric oxide donor groups covalently
attached to various pharmaceutically active ingredients.
[0465] The formulation may further comprise excipients to enhance
the therapeutic potential of an active ingredient, for example
cyclosporin A or another immunosuppressant, in the ileum and colon
including, but not limited to absorption limiters, essential oils
such as, for example, omega 3 oils, natural plant extracts such as,
for example, neem, ion-exchange resins, bacteria degradable
conjugation linkers such as, for example, azo bonds,
polysaccharides such as, for example, amylose, guar gum, pectin,
chitosan, inulin, cyclodextrins, chondroitin sulphate, dextrans,
guar gum and locust bean gum, nuclear factor kappa B inhibitors,
acids such as, for example, fumaric acid, citric acid and others,
as well as modifications thereof.
[0466] The formulation may further comprise excipients to reduce
systemic side effects associated with absorption of certain active,
for example cyclosporin or other immunosuppressants, in the GIT,
such as the small intestine, including, but not limited to,
antioxidants, such as, for example, curcuminoids, flavanoids or
more specifically including curcumin, beta-carotene,
.alpha.-tocopherol, ascorbate or lazaroid.
[0467] The formulation may further or separately comprise
antioxidants (such as, for example, ascorbic acid or BHT--butyl
hydroxy toluene) taste-masking or photosensitive components or
photoprotective components. Antioxidants may be incorporated in the
aqueous phase (e.g. hydrophilic antioxidants) or in the disperse
phase of the core (e.g. hydrophobic antioxidants such as, for
example, vitamin E) for example up to 1% by weight, preferably
between 0.01 and 0.50% by weight, more preferably between 0.10 to
0.20% by weight.
[0468] The formulation may further comprise immune-enhancing
nutrients such as vitamins A/B/C/E; carotenoids/beta-carotene and
iron, manganese, selenium, zinc, especially when the formulation
contains an immunosuppressant, as in the case of an
immunosuppressant targeted to the ileum and/or colon, e.g. the
colon. Such nutrients may be present in formulation, or if the
formulation has a coating, for example if it is the form of a bead,
the nutrients may be included in the coating.
[0469] The formulation may also include other well know excipients
used in pharmaceutical formulations including colorants, taste
masking agents, diluents, fillers, binders etc. The presence of
such optional additional components will of course depend upon the
particular dosage form adopted.
Active Ingredients
[0470] The active ingredients suitable for use in the
pharmaceutical compositions and methods of the present invention
are not particularly limited, as the compositions are surprisingly
capable of delivering active ingredients with widely differing
physico-chemical properties whilst still achieving have a higher
total release of active from the formulation and/or a greater rate
of release of the active compared to a formulation which does not
have the coating. The active ingredient may be hydrophilic,
lipophilic, amphiphilic or hydrophobic. The active ingredient may
be solubilised in the formulation. The active ingredient may be
suspended in the formulation. Active ingredients can be any
compound or mixture of compounds having therapeutic or other value
when administered to an animal, particularly to a human or other
mammal (the formulations of the invention are in particular for
administration to humans or other mammals), for example drugs,
nutrients, cosmeceuticals, diagnostic agents, nutritional agents.
In particular, the active ingredient is pharmaceutically active. It
should be appreciated that the categorisation of an active
ingredient as hydrophilic or hydrophobic may change, depending upon
the particular salts, isomers, analogues and derivatives used. The
active ingredient may be one mentioned in the examples of this
specification.
[0471] The active ingredient agent may be hydrophobic. Hydrophobic
active ingredients are compounds with little or no water
solubility. Intrinsic water solubilities (i.e., water solubility of
the non-ionised form) for hydrophobic active ingredients may be
less than about 1% by weight, and typically less than about 0.1% or
0.01% by weight. The active ingredient is in particular a
hydrophobic drug.
[0472] Suitable hydrophobic active ingredients are not limited by
therapeutic category, and can be, for example, analgesics,
anti-inflammatory agents, antihelminthics, anti-arrhythmic agents,
anti-bacterial agents, anti-viral agents, anti-coagulants,
anti-depressants, anti-diabetics, anti-epileptics, anti-fungal
agents, anti-gout agents, anti-hypertensive agents, anti-malarials,
anti-migraine agents, anti-muscarinic agents, anti-neoplastic
agents, erectile dysfunction improvement agents,
immunosuppressants, anti-protozoal agents, anti-thyroid agents,
anxiolytic agents, sedatives, hypnotics, neuroleptics,
beta-blockers, cardiac inotropic agents, corticosteroids,
diuretics, anti-parkinsonian agents, gastro-intestinal agents,
histamine receptor antagonists, hydroxylase inhibitors (e.g.
asparaginyl hydroxylase inhibitors, prolyl hydroxylase inhibitors),
keratolytics, lipid regulating agents, anti-anginal agents, COX-2
inhibitors, leukotriene inhibitors, macrolides, muscle relaxants,
nutritional agents, opioid analgesics, protease inhibitors, sex
hormones, stimulants, muscle relaxants, anti-osteoporosis agents,
anti-obesity agents, cognition enhancers, anti-urinary incontinence
agents, nutritional oils, anti-benign prostate hypertrophy agents,
essential fatty acids, non-essential fatty acids, and mixtures
thereof.
[0473] Specific, non-limiting examples of suitable hydrophobic
active ingredients are: acetretin, albendazole, albuterol,
aminoglutethimide, amiodarone, amlodipine, amphetamine,
amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen,
beclomethasone, benezepril, benzonatate, betamethasone,
bicalutanide, budesonide, bupropion, busulfan, butenafine,
calcifediol, calcipotriene, calcitriol, camptothecin, candesartan,
capsaicin, carbamezepine, carotenes, celecoxib, cerivastatin,
cetirizine, chlorpheniramine, cholecalciferol, cilostazol,
cimetidine, cinnarizine, ciprofloxacin, cisapride, clarithromycin,
clemastine, clomiphene, clomipramine, clopidogrel, codeine,
coenzyme Q10, cyclobenzaprine, cyclosporins, danazol, dantrolene,
dexchlorpheniramine, diclofenac, dicoumarol, digoxin,
dehydroepiandrosterone, dihydroergotamine, dihydrotachysterol,
dirithromycin, DMOG, donezepil, efavirenz, eposartan,
ergocalciferol, ergotamine, essential fatty acid sources, etodolac,
etoposide, famotidine, fenofibrate, fentanyl, fexofenadine,
finasteride, fluconazole, flurbiprofen, fluvastatin, fosphenytoin,
frovatriptan, furazolidone, gabapentin, gemfibrozil, glibenclamide,
glipizide, glyburide, glimepiride, griseofulvin, halofantrine,
ibuprofen, irbesartan, irinotecan, isosorbide dinitrate,
isotretinoin, itraconazole, ivermectin, ketoconazole, ketorolac,
lamotrigine, lansoprazole, leflunomide, lisinopril, loperamide,
loratadine, lovastatin, L-thryroxine, lutein, lycopene,
medroxyprogesterone, mifepristone, mefloquine, megestrol acetate,
methadone, methoxsalen, metronidazole, miconazole, midazolam,
miglitol, minoxidil, mitoxantrone, montelukast, nabumetone,
nalbuphine, naratriptan, nelfinavir, nifedipine, nilsolidipine,
nilutanide, nitrofurantoin, nizatidine, omeprazole, oprevelkin,
oestradiol, oxaprozin, paclitaxel, paracalcitol, paroxetine,
pentazocine, pioglitazone, pizofetin, pravastatin, prednisolone,
probucol, progesterone, pseudoephedrine, pyridostigmine,
rabeprazole, raloxifene, rofecoxib, repaglinide, rifabutine,
rifapentine, rimexolone, ritanovir, rizatriptan, rosiglitazone,
saquinavir, sertraline, sibutramine, sildenafil citrate,
simvastatin, sirolimus, spironolactone, steroids, sumatriptan,
tacrine, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene,
telmisartan, teniposide, terbinafine, terazosin,
tetrahydrocannabinol, tiagabine, ticlopidine, tirofibran,
tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin,
troglitazone, trovafloxacin, ubidecarenone, valsartan, venlafaxine,
verteporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin
K, zafirlukast, zileuton, zolmitriptan, zolpidem, and zopiclone. Of
course, salts, isomers and derivatives of the above-listed
hydrophobic active ingredients may also be used, as well as
mixtures.
[0474] Among the above-listed hydrophobic active ingredients, there
may in particular be mentioned: celecoxib, cyclosporins and
especially cyclosporin A, sirolimus, steroids, tacrolimus,
pharmaceutically acceptable salts, isomers and derivatives thereof,
and mixtures thereof. The active ingredient may optionally not be
celecoxib.
[0475] The active ingredient may be hydrophilic. Amphiphilic
compounds are also included within the class of hydrophilic active
ingredients. Apparent water solubilities for hydrophilic active
ingredients are greater than about 0.1% by weight, and typically
greater than about 1% by weight. The hydrophilic active ingredient
is in particular a hydrophilic drug. The hydrophilic active
ingredient may be a cosmeceutical, a diagnostic agent, or a
nutritional agent.
[0476] Suitable hydrophilic active ingredients are not limited by
therapeutic category, and can be, for example, analgesics,
anti-inflammatory agents, antihelminthics, anti-arrhythmic agents,
anti-bacterial agents, anti-viral agents, anti-coagulants,
anti-depressants, anti-diabetics, anti-epileptics, anti-fungal
agents, anti-gout agents, anti-hypertensive agents, anti-malarials,
anti-migraine agents, anti-muscarinic agents, anti-neoplastic
agents, erectile dysfunction improvement agents,
immunosuppressants, anti-protozoal agents, anti-thyroid agents,
anxiolytic agents, sedatives, hypnotics, neuroleptics,
beta-blockers, cardiac inotropic agents, corticosteroids,
diuretics, anti-parkinsonian agents, gastro-intestinal agents,
histamine receptor antagonists, hydroxylase inhibitors (e.g.
asparaginyl hydroxylase inhibitors, prolyl hydroxylase inhibitors),
keratolytics, lipid regulating agents, anti-anginal agents, COX-2
inhibitors, leukotriene inhibitors, macrolides, muscle relaxants,
nutritional agents, opioid analgesics, protease inhibitors, sex
hormones, stimulants, muscle relaxants, anti-osteoporosis agents,
anti-obesity agents, cognition enhancers, anti-urinary incontinence
agents, nutritional oils, anti-benign prostate hypertrophy agents,
essential fatty acids, non-essential fatty acids, and mixtures
thereof
[0477] Likewise, the hydrophilic active ingredient can be a
cytokine, a peptidomimetic, a peptide, a protein, a toxoid, a
serum, an antibody, a vaccine, a nucleoside, a nucleotide, a
portion of genetic material, a nucleic acid, or a mixture
thereof.
[0478] Specific, non-limiting examples of suitable hydrophilic
active ingredients include: acarbose; acyclovir; acetyl cysteine;
acetylcholine chloride; alatrofloxacin; alendronate; aglucerase;
amantadine hydrochloride; ambenomium; amifostine; amiloride
hydrochloride; aminocaproic acid; amphotericin B; antihemophilic
factor (human), antihemophilic factor (porcine); antihemophilic
factor (recombinant), aprotinin; asparaginase; atenolol; atracurium
besylate; atropine; azithromycin; aztreonam; BCG vaccine;
bacitracin; becalermin; belladona; bepridil hydrochloride;
bleomnycin sulfate; calcitonin human; calcitonin salmon;
carboplatin; capecitabine; capreomycin sulfate; cefamandole nafate;
cefazolin sodium; cefepime hydrochloride; cefixime; cefonicid
sodium; cefoperazone; cefotetan disodium; cefotaxime; cefoxitin
sodium; ceftizoxime; ceftriaxone; cefuroxime axetil; cephalexin;
cephapirin sodium; cholera vaccine; chorionic gonadotropin;
cidofovir; cisplatin; cladribine; clidinium bromide; clindamycin
and clindamycin derivatives; ciprofloxacin; clodronate;
colistimethate sodium; colistin sulfate; corticotropin;
cosyntropin; cromolyn sodium; cytarabine; dalteparin sodium;
danaparoid; desferrioxamine; denileukin diflitox; desmopressin;
diatrizoate meglumine and diatrizoate sodium; dicyclomine;
didanosine; dirithromycin; dopamine hydrochloride; dornase alpha;
doxacurium chloride; doxorubicin; etidronate disodium; enalaprilat;
enkephalin; enoxaparin; enoxaprin sodium; ephedrine; epinephrine;
epoetin alpha; erythromycin; esmolol hydrochloride; factor IX;
famciclovir; fludarabine; fluoxetine; foscarnet sodium;
ganciclovir; granulocyte colony stimulating factor,
granulocyte-macrophage stimulating factor; growth
hormones--recombinant human; growth hormone--bovine; gentamycin;
glucagon; glycopyrolate; gonadotropin releasing hormone and
synthetic analogues thereof; GnRH; gonadorelin; grepafloxacin;
haemophilus B conjugate vaccine; hepatitis A virus vaccine
inactivated; hepatitis B virus vaccine inactivated; heparin sodium;
hydralazine, indinavir sulfate; influenza virus vaccine;
interleukin-2; interleukin-3; insulin-human, insulin lispro;
insulin porcine; insulin NPH; insulin aspart; insulin glargine;
insulin detemir; interferon alpha; interferon beta; ipratropium
bromide; ifosfamide; Japanese encephalitis virus vaccine;
lamivudine; leucovorin calcium; leuprolide acetate, levofloxacin;
lincomycin and lincomycin derivatives; lobucavir; lomefloxacin;
loracarbef; mannitol; measles virus vaccine; meningococcal vaccine;
menotropins; mepenzolate bromide; mesalamine; methenamine;
methotrexate; methscopolamine; metformin hydrochloride; metoprolol;
mezocillin sodium; mivacurium chloride; mumps viral vaccine;
nedocromil sodium; neostigmine bromide; neostigmine methyl sulfate;
neurontin; norfloxacin; octreotide acetate; ofloxacin; olpadronate;
oxytocin; pamidronate disodium; pancuronium bromide; paroxetine;
perfloxacin; pentamidine isethionate; pentostatin; pentoxifylline;
periciclovir; pentagastrin; pentholamine mesylate; phenylalanine;
physostigmine salicylate; plague vaccine; piperacillin sodium;
platelet derived growth factor-human; pneumococcal vaccine
polyvalent; poliovirus vaccine inactivated; poliovirus vaccine live
(OPV); polymyxin B sulfate; pralidoxime chloride; pramlintide,
pregabalin; propafenone; propenthaline bromide; pyridostigmine
bromide; rabies vaccine; residronate; ribavarin; rimantadine
hydrochloride; rotavirus vaccine; salmeterol xinafoate; sinealide;
small pox vaccine; solatol; somatostatin; sparfloxacin;
spectinomycin; stavudine; streptokinase; streptozocin;
suxamethonium chloride; tacrine hydrochloride; terbutaline sulfate;
thiopeta; ticarcillin; tiludronate; timolol; tissue type
plasminogen activator; TNFR:Fc; TNK-tPA; trandolapril; trimetrexate
gluconate; trospectinomycin; trovafloxacin; tubocurarine chloride;
tumor necrosis factor; typhoid vaccine live; urea; urokinase;
vancomycin; valacyclovir; valsartan; varicella virus vaccine live;
vasopressin and vasopressin derivatives; vecuronium bromide;
vinblastine; vincristine; vinorelbine; vitamin B12; warfarin
sodium; yellow fever vaccine; zalcitabine; zanamivir; zolendronate;
zidovudine; pharmaceutically acceptable salts, isomers and
derivatives thereof; and mixtures thereof.
[0479] Among the above-listed hydrophilic active ingredients, there
may be mentioned in particular hydralazine and mesalamine.
[0480] Optionally, the active ingredient may be cyclosporin A,
hydralazine, mesalamine or celecoxib.
Shape, Size and Geometry
[0481] The formulation of the invention can be formed into a
limitless number of shapes and sizes. In the section below
describing the process for making the formulation, various methods
are given including pouring or introducing a fluid dispersion into
a mould where it hardens or can be caused to harden. Thus the
formulation can be created in whichever form is desired by creating
an appropriate mould (e.g. in the shape of a disc, pill or tablet).
However, it is not essential to use a mould. For example, the
formulation may be formed into a sheet e.g. resulting from pouring
a fluid dispersion onto a flat surface where it hardens or can be
caused to harden.
[0482] Preferably, the formulation may be in the form of spheres or
spherical-like shapes made as described below. Preferably, the
formulation of the invention is in the form of substantially
spherical, seamless minibeads. The absence of seams on the minibead
surface is an advantage e.g. in further processing, for example
coating, since it allows more consistent coating, flowability etc.
The absence of seams on the minbeads also enhances consistency of
dissolution of the beads.
[0483] The preferred size or diameter range of minibeads according
to the invention can be chosen to avoid retention in the stomach
upon oral administration of the minibeads. Larger dosage forms are
retained for variable periods in the stomach and pass the pyloric
sphincter only with food whereas smaller particles pass the pylorus
independently of food. Selection of the appropriate size range (see
below) thus makes the therapeutic effect post-dosing more
consistent. Compared to a single large monolithic oral format such
as, for example, a traditional compressed pill, a population of
beads released into the GI tract (as foreseen by the dosage form of
the present invention) permits greater intestinal lumen dispersion
so enhancing absorption via exposure to greater epithelial area,
and achieves greater topical coating in certain parts of the GI
tract for example the colon). Reduction of residence time in the
ileo-caecal junction is another potential advantage.
[0484] The formulation of the invention is preferably monolithic
meaning internally (i.e. cross-sectionally) homogeneous, excluding
a possible thin skin of matrix material and excluding any coating
layers.
[0485] The minibeads provided for by the formulation of the present
invention generally range in diameter from 0.5 mm to 10 mm with the
upper limit preferably 5 mm, e.g. 2.5 mm A particularly convenient
upper limit is 2 mm or 1.7 mm. The lower limit can preferably be 1
mm, e.g. 1.2 mm, more preferably from 1.3 mm, most preferably from
1.4 mm. In one embodiment the diameter is from 0.5 to 2.5 mm, for
example from 1 mm to 3 mm, 1 mm to 2 mm, 1.2 mm to 3 mm or 1.2 mm
to 2 mm. The minibeads may have a diameter of no more than 2.5 mm,
irrespective of their minimum size. The beads may have a diameter
of no more than 2 mm, irrespective of their minimum size.
[0486] A minibead as described herein may have an aspect ratio of
no more than 1.5, e.g. of no more than 1.3, for example of no more
than 1.2 and, in particular, of from 1.1 to 1.5, 1.1 to 1.3 or, 1.1
to 1.2. A population of minibeads as described herein, e.g. at
least 10 beads, may have an average aspect ratio of no more than
1.5, e.g. of no more than 1.3, for example of no more than 1.2 and,
in particular, of from 1 to 1.5, 1 to 1.3 or 1 to 1.2. The aspect
ratios mentioned in this paragraph optionally apply to coated
minibeads and optionally apply to uncoated minibeads. Average
aspect ratio is suitably determined for a population of minibeads,
e.g. at least 10 minibeads, using a particle size analyser, for
example an Eyecon.TM. particle characteriser of Innopharma Labs,
Dublin 18, Ireland.
[0487] The minibeads of the disclosure may, therefore, have a size
as disclosed above and an aspect ratio of from 1 to 1.5. The beads
of the disclosure may have a size as disclosed above and an aspect
ratio of no more than 1.3, for example of no more than 1.2 and, in
particular, of from 1.1 to 1.5, 1.1 to 1.3 or, 1.1 to 1.2.
[0488] Bead size (diameter) may be measured by any suitable
technique, for example microscopy, sieving, sedimentation, optical
sensing zone method, electrical sensing zone method or laser light
scattering. For the purposes of this specification, bead size is
measured by analytical sieving in accordance with USP General Test
<786> Method I (USP 24-NF 18, (U.S. Pharmacopeial Convention,
Rockville, Md., 2000), pp. 1965-1967).
[0489] In embodiments, minibeads of the invention are monodisperse.
In other embodiments, minibeads of the invention are not
monodisperse. By "monodisperse" is meant that for a population of
beads (e.g. at least 100, more preferably at least 1000) the
minibeads have a coefficient of variation (CV) of their diameters
of 35% or less, optionally 25% or less, for example 15% or less,
such as e.g. of 10% or less and optionally of 8% or less, e.g. 5%
or less. A particular class of polymer beads has a CV of 25% or
less. CV when referred to in this specification is defined as 100
times (standard deviation) divided by average where "average" is
mean particle diameter and standard deviation is standard deviation
in particle size. Such a determination of CV is performable using a
sieve.
[0490] The invention includes minibeads having a CV of 35% and a
mean diameter of 1 mm to 2 mm, e.g. 1.5 mm. The invention also
includes minibeads having a CV of 20% and a mean diameter of 1 mm
to 2 mm, e.g. 1.5 mm, as well as minibeads having a CV of 10% and a
mean diameter of 1 mm to 2 mm, e.g. 1.5 mm. In one class of
embodiments, 90% of minibeads have a diameter of from 0.5 mm to 2.5
mm, e.g. of from 1 mm to 2 mm.
Dosage Forms
[0491] The formulation of the invention is prepared as an orally
administrable dosage form suitable for pharmaceutical use. In those
embodiments where the formulation is in the form of a minibead, the
present invention provides for a dosage form comprising a plurality
of the minibeads for example as a capsule, a tablet, a sprinkle or
a sachet.
[0492] In embodiments the dosage form comprising a population of
beads may be presented in a single unit dosage form e.g. contained
in a single hard gel capsule which releases the beads e.g. in the
stomach. Alternatively the beads may be presented in a sachet or
other container which permits the beads to be sprinkled onto food
or into a drink or to be administered via a feeding tube for
example a naso-gastric tube or a duodenal feeding tube.
Alternatively, the beads may be administered as a tablet for
example if a population of beads is compressed into a single tablet
as described below. Alternatively, the beads may be filled e.g.
compressed into a specialist bottle cap or otherwise fill a space
in a specialised bottle cap or other element of a sealed container
(or container to be sealed) such that e.g. on twisting the bottle
cap, the beads are released into a fluid or other contents of the
bottle or vial such that the beads are disperse (or dissolve) with
or without agitation in such contents. An example is the Smart
Delivery Cap manufactured by Humana Pharma International (HPI)
S.p.A, Milan, Italy.
[0493] The dosage form may be formulated in such a way so that the
beads of the invention can be further developed to create a larger
mass of beads e.g. via compression (with appropriate oil or
powder-based binder and/or filler known to persons skilled in the
art. The larger (e.g. compressed) mass may itself take a variety of
shapes including pill shapes, tablet shapes, capsule shapes etc. A
particular problem which this version of the bead embodiment solves
is the "dead space" (above the settled particulate contents) and/or
"void space" (between the particulate content elements) typically
found in hard gel capsules filled with powders or pellets. In such
pellet- or powder-filled capsules with dead/void space, a patient
is required to swallow a larger capsule than would be necessary if
the capsules contained no such dead space. The beads of this
embodiment of the invention may readily be compressed into a
capsule to adopt the inner form of whichever capsule or shell may
be desired leaving much reduced, e.g. essentially no, dead/void
space. Alternatively the dead or void space can be used to
advantage by suspending beads in a vehicle such as, for example, an
oil which may be inert or may have functional properties such as,
for example, permeability enhancement or enhanced dissolution or
may comprise an active ingredient being the same or different from
any active ingredients in the bead. For example, hard gelatin or
HPMC capsules may be filled with a liquid medium combined with
uncoated and/or coated beads. The liquid medium may be one or more
of the surfactant phase constituents described herein or it may be
one or more surfactants. Particularly preferred but non-limiting
examples are corn oil, sorbitane trioleate (sold under the trade
mark SPAN 85), propylene glycol dicaprylocaprate (sold under the
trade mark Labrafac), 2-(2-ethoxyethoxy)ethanol (sold under the
trade mark Transcutol P) and polysorbate 80 (sold under the trade
mark Tween 80).
[0494] In a representative embodiment the bead of the dosage form
is prepared as described herein for example by mixing together at
least the following materials: a hydrogel-forming polymer; and
cyclosporin A, suitably cyclosporin A dissolved in a hydrophobic
material, such as an oil to form a dispersion of the cyclosporin A
in the hydrogel-forming polymer. The dispersion is immobilized
within the solidified bead by ejection from a single orifice nozzle
into a suitable cooling liquid. Following removal of the drying
liquid the bead is coated with a modified release coating (the
second coating) (suitably with a sub-coat under the modified
release coating), the coated bead is the filled into a gelatin or
HPMC capsule suitable for pharmaceutical use.
[0495] Suitably the dosage form is prepared as a unit dosage form
containing from for oral administration comprising from 0.1 mg to
1000 mg, optionally from 1 mg to 500 mg, for example 10 mg to 300
mg, or 25 to 250 mg suitably about 25 mg, about 35 mg, about 50 mg,
about 75 mg, about 100 mg, about 150 mg, about 180 mg, about 200
mg, about 210 mg or about 250 mg cyclosporin A
Determination of Contents and Distribution of Formulations
[0496] The identity and/or distribution of one or more of the
components of a formulation according to the invention can be
determined by any method known to those skilled in the art. The
distribution of one or more components of a formulation can, for
example, be determined by near-infrared (NIR) chemical imaging
technology. NIR chemical imaging technology can be used to generate
images of the surface or cross section of a formulation, for
example a minibead. The image produced by this technique shows the
distribution of one or more components of the formulation. In
addition to NIR chemical imaging technology, the distribution of
one or more components of a formulation such as minibead, for
example, be determined by time-of-flight secondary ion mass
spectrometry (ToFSIMS). ToFSIMS imaging can reveal the distribution
of one or more components within the formulation. The images
produced by ToFSIMS analysis or NIR analysis can show the
distribution of components across a surface of the formulation or a
cross section of the formulation. The methods described in this
paragraph are applicable, for example, to formulations comprising a
polymer matrix, e.g. a dried, colloid, solution or dispersion.
Manufacturing Processes
[0497] Various methods may be used to prepare the formulations of
the invention.
[0498] In those embodiments where the formulation comprises an
active ingredient in a water-insoluble polymer matrix, a basic
method for making the core is to mix a fluid form of the matrix
material, for example a water-insoluble polymer matrix material
(e.g. poly(amides), poly(amino-acids), hyaluronic acid;
lipoproteins; poly(esters), poly(orthoesters), poly(urethanes) or
poly(acrylamides), poly(glycolic acid), poly(lactic acid) and
corresponding co-polymers (poly(lactide-co-glycolide acid; PLGA);
siloxane, polysiloxane; dimethylsiloxane/methylvinylsiloxane
copolymer;
poly(dimethyl-siloxane/methylvinylsiloxane/methylhydrogensiloxane)
dimethylvinyl or trimethyl copolymer; silicone polymers; alkyl
silicone; silica, aluminium silicate, calcium silicate, aluminium
magnesium silicate, magnesium silicate, diatomaceous silica etc as
described more generally elsewhere herein), with an active
ingredient to form a mixture that may take the form of a
suspension, solution or a colloid. The mixture is processed to form
a core. For example the formulation may be shaped into the desired
form using a molding or hot-melt extrusion process to form
beads.
[0499] Methods for preparing cores comprising an active ingredient
and a water-soluble polymer matrix are described below. Generally
these cores are coated to give the final formulation of the
invention.
[0500] Generally, the manufacturing processes described herein
comprise mixing of liquid(s). Such mixing processes must be
performed at temperatures at which the substances to be mixed in
the liquid state are in liquid form. For example, thermoreversible
gelling agents must be mixed at a temperature where they are in the
liquid state, for example at a temperature of 50 to 75.degree. C.,
for example 50 to 70.degree. C., or 55-75.degree. C., e.g.
60-70.degree. C. and in particular embodiments about 55.degree. C.
or 65.degree. C. in the case of mixing formulations comprising
aqueous gelatin. Similarly other components of the formulation may
need to be heated to melt the component for example waxes or
surfactants which may be used in the disperse phase.
[0501] Cores comprising a hydrogel-forming polymer and an active
ingredient as disclosed herein may be made by mixing materials
comprising for example water, a hydrogel-forming polymer and a
surfactant to form an aqueous continuous phase, and mixing a
disperse phase. At least one of the aqueous phase and the disperse
phase comprises a pharmaceutically active ingredient, the active
ingredient may be dissolved in the phase which contains it, for
example both phases may be a clear liquid before they are mixed
together. For example, the disperse phase may comprise an active
ingredient, (for example a disperse phase comprising an oil, an
optional solvent, cyclosporin A or another hydrophobic active and a
surfactant) with the aqueous phase to form a colloid; the active
ingredient may in particular be a hydrophobic active ingredient
e.g. cyclosporin A or alternatively it may be a hydrophilic active
ingredient, or a combination comprising e.g. a hydrophobic active
ingredient and a hydrophilic active ingredient. The colloid may
have the form of an emulsion or microemulsion wherein the disperse
phase is dispersed in the aqueous continuous phase. The
hydrogel-forming polymer is then caused or allowed to gel.
Suitably, the process includes formulating or processing the core
formulation into a desired form, e.g. a bead (also termed a
minibead), which forming process may comprise moulding but
preferably comprises ejecting the aqueous colloid through a single
orifice nozzle to form droplets which are caused or allowed to pass
into a cooling medium, e.g. a water-immiscible cooling liquid, in
which the droplets cool to form for e.g. beads.
[0502] The mixing of the materials may comprise mixing an aqueous
premix (or aqueous phase) and a disperse phase premix (e.g. oil
phase premix), wherein the aqueous premix comprises water and
water-soluble substances whilst the disperse phase premix may
comprise a vehicle containing an active ingredient. The vehicle may
be a hydrophobic liquid, for example a liquid lipid, or it may be
or comprise a material, for example a surfactant, for forming
self-assembly structures. In particular, a disperse phase premix
may comprise an active ingredient, for example cyclosporin A, oil
and other oil soluble components for example surfactant and an
optional solvent. The premixes may contain one or more surfactants
suitable for the phase they are to form, as previously
mentioned.
[0503] The aqueous premix comprises, or usually consists of, a
solution in water of water-soluble constituents, namely the
hydrogel-forming polymer and water-soluble excipient(s), and any
water-soluble active ingredient destined for the matrix phase. The
aqueous premix may include a plasticiser for the hydrogel-forming
polymer, as described elsewhere in this specification. The aqueous
premix may include a surfactant, e.g. to increase polymer viscosity
and improve emulsification and thereby help prevent precipitation
of active agent during processing. SDS is an example of such a
surfactant. In any event, the constituents of the aqueous premix
may be agitated for a period sufficient to dissolve/melt the
components, for example, from 1 hour to 12 hours to form the
completed aqueous premix.
[0504] The disperse phase pre-mix may comprise a hydrophobic active
ingredient as a dispersion or preferably a solution in a vehicle as
described above, for example in a liquid comprising an oil or in a
liquid comprising component(s) of self-assembly structures. For
example an oil phase pre-mix may therefore be a liquid lipid, for
example a medium chain triglyceride (MCT) formulation, the medium
chain triglyceride(s) being one or more triglycerides of at least
one fatty acid selected from C.sub.6-012 fatty acids, and
cyclosporin A or another hydrophobic active ingredient. Suitably an
oil phase pre-mix is stirred at ambient temperature to form a
solution of the active ingredient in the oil. In some embodiments,
the components of the oil phase premix are mixed (or otherwise
agitated) for a period of, for example, 10 minutes to 3 hours to
form the premix. The disperse phase premix may comprise a
hydrophilic active ingredient in particulate form, for example
microparticles or nanoparticles; the particulate active ingredient
may for example be suspended in a vehicle comprising or consisting
of an oil, e.g. a liquid lipid.
[0505] The two premixes may be combined and agitated, for example
for a period of a few seconds to an hour, for example from 30
seconds to 1 hour, suitably 5 mins to an hour, to form a dispersion
of the disperse phase in an aqueous hydrogel-forming polymer, which
dispersion may then be further processed to form the final
formulation. The two premixes may be combined into the dispersion
by agitation in a mixing vessel; they may additionally or
alternatively be combined in a continuous flow mixer.
[0506] Where the disperse phase is particulate, the manufacturing
process may not involve combining two liquid premixes but may
instead comprise combining the particulate ingredient directly into
the liquid which is to form the continuous phase (water,
hydrogel-forming polymer and any other constituents), or into a
precursor of the liquid. There is thereby formed a liquid
comprising dispersed particulate active ingredient, and this
dispersion is then formed into the core by a process which
comprises causing or allowing the polymer to gel.
[0507] The basic method for making a core comprising an active
ingredient and hydrogel-forming polymer matrix, therefore, is to
mix a liquid form (preferably a solution) of the hydrogel-forming
polymer (or mixture of polymers) with the active ingredient (and
other disperse phase components) to form a dispersion in the
polymer, which later in the process forms a hydrogel. The method
normally comprises mixing together an aqueous polymer phase premix
and a disperse phase premix. Taking account of the final
formulation required (as described elsewhere herein), the disperse
phase pre-mix and the liquid hydrogel-forming polymer (i.e. the
solution or suspension of hydrogel-forming polymer) may be mixed in
a weight ratio of from 1:1 to 1:10, particularly 1:4 to 1:9, e.g.
1:5 to 1:7. In general, only gentle stirring of the components is
required using a magnetic or mechanical system, e.g. overhead
stirrer, as would be familiar to a person skilled in the art to
achieve a dispersion of the disperse phase in the aqueous phase to
form a colloid (which may be in the form of for example an emulsion
or micro emulsion in which the aqueous hydrogel is the continuous
phase). Continuous stirring is preferred. Mixing may also be
achieved using an in-line mixing system. Any appropriate laboratory
stirring apparatus or industrial scale mixer may be utilized for
this purpose for example the Magnetic Stirrer (manufactured by
Stuart) or Overhead Stirrer (by KNF or Fisher). It is preferred to
set up the equipment in such a way as to minimise evaporation of
contents such as, for example, water. In one embodiment of the
process of the invention, it is preferred to utilise a closed
system for stirring in order to achieve this aim. In-line mixing
may be particularly suitable for closed system processing. Suitably
mixing of the two components takes place at a temperature of 50 to
70.degree. C., or 55-75.degree. C., e.g. 60-70.degree. C.
[0508] The mixing of the two phases results in a colloid wherein
the aqueous hydrogel-forming polymer is an aqueous continuous phase
and the component(s) not soluble in the aqueous phase are a
disperse phase. The colloid may have the form of an emulsion or
microemulsion.
[0509] In embodiments where the disperse phase is or comprises a
surfactant, the amount of the surfactant may be selected such that,
upon combination of the disperse phase premix with the aqueous
pre-mix, the surfactant concentration in the combined mixture
exceeds the CMC for the surfactant used such that micelles are
formed in the aqueous phase comprising the hydrogel-forming
polymer. Depending on the concentration of surfactant used,
self-assembly structures other than micelles may also form. The CMC
for a particular surfactant may be determined using well known
methods, for example as described in Surfactants and Polymers in
Aqueous Solutions Second Edition, Chapter 2, Holmberg et al. In
embodiments mixing of the aqueous phase and a disperse phase which
is or comprises a surfactant may result in the formation of a clear
liquid, for example a microemulsion, in which the aqueous phase
comprising the hydrogel-forming polymer is the continuous phase.
Microemulsions are a thermodynamically stable dispersion of
self-assembly structures in the aqueous phase, the size of the
self-assembly structures being sufficiently small to give a
transparent appearance. The size of the self-assembly structures
present as the disperse phase resulting from the mixing of the
aqueous and surfactant phases may be from about 0.5 nm to 200 nm,
for example about 1 nm to 50 nm, or about 5 nm to 25 nm. The size
of the self-assembly structures formed and other characteristics
such as the optical isotropicity of the formulation (for example a
microemulsion) may be determined using well known techniques such
as dynamic light scattering.
[0510] Where the polymer matrix substantially consists of gelatin
with the addition of sorbitol, the aqueous phase of polymer matrix
is prepared by adding the appropriate quantities of sorbitol (and
surfactant if desired) to water, heating to approximately 50 to
75.degree. C., for example 60-75.degree. C. until in solution and
then adding gelatin, although the precise order and timing of
addition is not critical. A typical "gelatin solution" comprises 8
to 35%, (for example 15-25%, preferably 17-18%) gelatin; 65%-85%
(preferably 77-82%) of water plus from 1-5% (preferably 1.5 to 3%)
sorbitol. When present, surfactant (e.g. anionic surfactant) in the
aqueous phase premix may be present in an amount of 0.1 to 5%
(preferably 0.5 to 4%) wherein all parts are by weight of the
aqueous phase.
[0511] Optionally the processing temperature required for a
standard gelatin can be reduced to a desirable target temperature
e.g. 37.degree. C. by use of lower melting-point gelatin (or
gelatin derivatives or mixtures of gelatins with melting point
reducers) or other polymer matrix material such as, for example,
sodium alginate. If gelatin droplets are being formed by machine
extrusion and immediately cooled, e.g. in a cooling bath,
additional appropriate inlet tubing can be used to introduce an oil
phase containing cyclosporin A at ambient temperature into the
hotter fluid gelatin solution (and the mixture can be immediately
homogenized) very shortly before ejection from a beading nozzle or
other dropletting process such that the duration of exposure of the
cyclosporin A to the higher temperature gelatin is limited so
reducing the degree of any heat-dependent degradation of the active
ingredient. This process may use any appropriate device such as,
for example, a homogenizer, e.g. a screw homogenizer, in
conjunction with an extrusion-type apparatus as described for
example in WO 2008/132707 (Sigmoid Pharma) the entirety of which is
incorporated herein by reference.
[0512] The colloid is formed by combining of the disperse phase
premix or particulate active ingredient with the liquid aqueous
phase with stirring as described above. The resultant colloidal
dispersion then has the formulation of a solidified core described
above but with liquid water still present in the core
formulation.
[0513] Optionally the active ingredient may be added after mixing
the aqueous phase and other components of a disperse phase of the
type comprising a vehicle in addition to the active ingredient,
however, it is preferred that the active ingredient is added
together with the other components of the disperse phase as a
premix.
[0514] The resulting colloid is then poured or introduced into a
mould or other vessel or poured onto sheets or between sheets or
delivered dropwise (or extruded) into another fluid such that the
polymer matrix-containing aqueous phase, on solidification, takes
the form of the mould, vessel, sheet or droplet/bead intended. It
is preferred to progress to mould-forming e.g. beading without
delay.
[0515] Solidification (gelling) can occur in a variety of ways
depending on the polymer of the matrix, for example by changing the
temperature around the mould, vessel, sheet, droplet/bead etc or by
applying a solidification fluid or hardening solution so that the
moulded shape is gelled or solidified. In certain embodiments both
temperature change and application of a solidifying fluid or
hardening solution are employed together or simultaneously.
[0516] In the preferred embodiment in which the core comprising the
active ingredient takes the form of beads, the beads may be formed
for example by dropping the colloid dropwise into a fluid which
effects solidification. Where the viscosity of the formulation to
be beaded reaches a certain point, drop formation becomes more
difficult and specialised apparatus is then preferred.
[0517] By use of the term "dry", it is not sought to imply that a
drying step is necessary to produce the dry core (although this is
not excluded) rather that the solid or solidified aqueous external
phase is substantially free of water or free of available water.
Solidification of the aqueous phase (external phase) may have
arisen through various means including chemically (e.g. by
cross-linking) or physically (e.g. by cooling or heating). In this
respect, the term "aqueous phase" is nevertheless employed in this
document to denote the external (continuous) phase of the core even
though water, in certain embodiments, is largely absent from (or
trapped within the cross-linked matrix of) the core. The external
phase of the core is however water-soluble and dissolves in aqueous
media.
[0518] In the case where solidification can be achieved by raising
or reducing temperature, the temperature of the solidification
fluid can be adapted to achieve solidification of the core at a
desired rate. For example, when gelatin is used as the
hydrogel-forming polymer, the solidification fluid is at a lower
temperature than the temperature of the emulsion thus causing
solidification, i.e. gelling, of the polymer matrix. In this case,
the solidification fluid is termed a cooling fluid.
[0519] In the case where solidification can be achieved chemically,
e.g. by induction of cross-linking on exposure to a component of
the solidification fluid, the concentration of such component in
the solidification fluid and/or its temperature (or other
characteristic or content) can be adjusted to achieve the desired
rate and degree of solidification. For example, if alginate is
chosen as the polymer matrix, one component of the solidification
fluid may be a calcium-containing entity (such as, for example,
calcium chloride) able to induce cross-linking of the alginate and
consequent solidification. Alternatively, the same or similar
calcium-containing entity may be included (e.g. disperse) in the
aqueous phase of the fluid emulsion prior to beading and triggered
to induce cross-linking e.g. by applying a higher or lower pH to a
solidification fluid into which droplets of emulsion fall dropwise
or are introduced. Such electrostatic cross-linking can be varied
as to the resulting characteristics of the bead by control of
calcium ion availability (concentration) and other physical
conditions (notably temperature). The solidification fluid may be a
gas (for example air) or a liquid or both. For example, when
gelatin is used as the hydrogel-forming polymer matrix, the
solidification fluid can be initially gaseous (e.g. droplets
passing through cooling air) and then subsequently liquid (e.g.
droplets passing into a cooling liquid). The reverse sequence may
also be applied while gaseous or liquid cooling fluids alone may
also be used. Alternatively, the fluid may be spray-cooled in which
the emulsion is sprayed into a cooling gas to effect
solidification.
[0520] In the case of gelatin or other water-soluble polymer (or
polymer mixture) destined to form an immobilization matrix, it is
preferred that the solidification fluid be a non-aqueous liquid
(such as, for example, medium chain triglycerides, mineral oil or
similar preferably with low HLB to ensure minimal wetting) which
can conveniently be placed in a bath (cooling bath) to receive the
droplets of the colloid as they solidify to form the beads of the
core. Use of a non-aqueous liquid allows greater flexibility in
choice of the temperature at which cooling is conducted.
[0521] Where a liquid cooling bath is employed, it is generally
maintained at less than 20.degree. C., preferably maintained in the
range 5-15.degree. C., more preferably 8-12.degree. C. when
standard gelatin is used as the hydrogel-forming polymer. If a
triglyceride is chosen as the cooling fluid in the cooling bath, a
preferred example is Miglyol 810 from Sasol.
[0522] If alginate is selected as the polymer matrix, a typical
method of making beads involves dropwise addition of a 3% sodium
alginate solution in which oil droplets are disperse as described
above into a 4.degree. C. crosslinking bath containing 0.1 M
calcium chloride to produce calcium alginate (this method can be
referred to as "diffusion setting" because the calcium is believed
to diffuse into the beads to effect cross-linking or setting).
Using a syringe pump, or Inotech machine, droplets can be generated
or extruded (egg at 5 mL/h if a pump is used) through a sterile
needle or other nozzle (described elsewhere herein) which can be
vibrating as discussed elsewhere herein. Airflow of between 15 and
20 L/min through 4.5 mm tubing can be applied downwards over the
needle to reduce droplet size if desired. Newly formed beads can
then be stirred in the calcium chloride bath for up to an hour. If
carrageenan is used as the polymer matrix both salt and reduction
in temperature e.g. by dropping into cooling oil may be used to
obtain solidification.
[0523] An alternative approach when using alginate is internal
gelation in which the calcium ions are disperse in the aqueous
phase prior to their activation in order to cause gelation of
hydrocolloid particles. For example, this can be achieved by the
addition of an inactive form of the ion that will cause
crosslinking of the alginate, which is then activated by a change
in e.g. pH after sufficient dispersion of the ion is complete (see
Glicksman, 1983a; Hoefler, 2004 which are both incorporated herein
by reference). This approach is particularly useful where rapid
gelation is desired and/or where the diffusion approach may lead to
loss of API by diffusion thereof into the crosslinking bath.
[0524] Where another ionotropic polymer is used than alginate,
suitable analogous processes may be used to those described herein
in relation to alginate.
[0525] Following shape-forming, moulding or beading, the resultant
shapes or forms may be washed then dried if appropriate. In the
case of beads solidified in a solidification fluid, an optional
final step in the method of production described above therefore
comprises removal of the solidified beads from the solidification
fluid. This may be achieved e.g. by collection in a mesh basket
through which the solidification fluid (e.g. medium chain
triglycerides) is drained and the beads retained and is preferably
conducted without delay e.g. as soon as the beads have formed or
within 5, 10, 15, 20, 25 or 30 minutes of their formation. Excess
solidification fluid may then be removed using a centrifuge (or
other apparatus or machine adapted to remove excess fluid) followed
by drying of the beads to remove water or free water and/or removal
of some or all of any additional solvent e.g. ethanol or isopropyl
alcohol used to dissolve or facilitate dissolution of the active
principle in preceding steps optionally followed by washing (e.g.
using ethyl acetate) and a subsequent "drying" step to remove
excess solvent (e.g. ethyl acetate). Isopropyl alcohol is an
example of a solvent which is preferably removed later in
processing to reduce residues in the oil or aqueous phase. Drying
can be achieved by any suitable process known in the art such as
use of a drum drier (e.g. Freund Drum dryer which may be part of
the Spherex equipment train if used) with warm air at between
15.degree. C. and 25.degree. C., preferably around 20.degree. C.
leading to evaporation or entrainment of the water by the air.
Alternatively, drying may be carried out using of a fluid bed drier
(e.g. Glatt GPCG 1.1) with warm air between 40.degree. C. and
60.degree. C. Use of gelatin as the polymer matrix (e.g. as
principal constituent of the aqueous immobilisation phase) in most
cases requires a drying step and for beads this is preferably
achieved by drying in air as above described. The resultant
formulation (the formulation of the invention) is essentially dry
as described in more detail above.
[0526] In general, the beads may be generated by the application of
surface tension between the liquid dispersion (the mixture of the
aqueous and surfactant phases) and an appropriate solidification
fluid such as, for example, gas or liquid in order to create the
spherical or substantially spherical shape of the ultimate
beads.
[0527] Alternatively, the beads may be produced through ejection or
extrusion of the liquid dispersion through an orifice or nozzle
with a certain diameter and optionally subject to vibration (using
selected vibrational frequencies) and/or gravitational flow.
Examples of machines which may be used are encapsulation prilling,
drop pelletising, spray cooling or spray congealing machines for
example the Freund Spherex, ITAS/Lambo, Globex, Inotech, GEA Niro,
Droppo, Buchi, Gelpell processing equipment processing equipment.
Operation of the Spherex machine manufactured by Freund as may be
desired to manufacture beads according to the present invention is
described in U.S. Pat. No. 5,882,680 (Freund), the entire contents
of which are incorporated herein by reference. It is preferred to
select a vibrational frequency in the region of 2-200 Hz, suitably
10-15 Hz, although the ultimate choice (and separately the
amplitude of vibration selected) depends on the viscosity of the
dispersion to be beaded. If the polymer matrix is chosen to
solidify at lower temperature, it may be appropriate to maintain
the lines to the orifice/nozzle at a certain temperature to
maintain the fluidity of the solution. Suitably the colloid is
ejected through a single-orifice nozzle, e.g. having a diameter of
from 0.1 mm to 5 mm (for example 0.5-5 mm), to form drops which are
then caused or allowed to fall into a cooling oil or other
hardening medium and allowed to harden to form seeds, after which
the seeds are recovered from the cooling oil and dried.
[0528] It will be appreciated, therefore, that the invention
includes a process for manufacturing a core comprising a
pharmaceutically active ingredient in a polymer matrix, which
process comprises: forming an aqueous premix which comprises water
and water soluble/dispersible materials (including therefore a
hydrogel-forming polymer) and a disperse phase premix (e.g. an oil
phase premix) which comprises the active ingredient and optionally
a vehicle and other excipients (e.g. oil(s) and oil
soluble/dispersible materials), and combining the two premixes to
form a colloid (disperse phase) within an aqueous phase comprising
the hydrogel-forming polymer. The colloid may then be formed into a
shaped unit, for example a bead to provide the core comprising the
active ingredient. More particularly the manufacture of a core
comprising pharmaceutically active ingredient and a polymer matrix
(suitably a hydrogel-forming polymer matrix may comprise:
(i) forming an aqueous phase pre-mix comprising a solution in water
of water-soluble constituents (e.g. of a hydrogel-forming polymer,
any water-soluble excipient(s), as described elsewhere herein);
(ii) forming a disperse phase pre-mix typically comprising a
dispersion or preferably a solution of an active ingredient, e.g.
cyclosporin A, in a liquid, optionally where the liquid is an oil
(and optionally together with other disperse phase constituents
(e.g. surfactant, solvents etc as described elsewhere herein));
(iii) mixing the aqueous phase pre-mix (i) and the disperse phase
pre-mix (ii) to form a colloid; (iv) ejecting the colloid through a
nozzle to form droplets; (v) causing or allowing the a
hydrogel-forming polymer to gel or solidify to form a water soluble
polymer matrix; and (vi) drying the solid.
[0529] Some manufacturing processes comprise steps (A) to (D) below
or, alternatively, a manufacturing process may comprise a single
one or any combination of steps (A) to (D).
[0530] (A) Exemplary Preparation of Aqueous Phase:
[0531] Aqueous phase components are added to water, e.g. purified
water, under agitation e.g. sonication or stirring. The temperature
is gradually increased, for example to 60-70.degree. C. and in
particular 65.degree. C., to achieve complete dissolution of the
solids. The aqueous phase components include a hydrogel-forming
polymer, e.g. gelatin or agar and optionally one or more other
excipients, for example D-sorbitol (a plasticiser) and surfactant
(for example SDS). Possible aqueous phase components are described
elsewhere herein.
[0532] The gelatin may be Type A gelatin. In some less preferred
implementations, the gelatin is Type B. The gelatin may have a
Bloom strength of 125-300, optionally of 200-300, for example of
250-300, and in particular 275. The components of the aqueous phase
may be agitated for a period of, for example, from 1 hour to 12
hours to complete preparation of the aqueous phase (aqueous
premix).
[0533] (B) Exemplary Preparation of Disperse Phase:
[0534] A hydrophobic active ingredient, e.g. cyclosporin A, is
mixed with other disperse phase components (for example an oil,
surfactant and co-solvent) under agitation e.g. sonication or
stirring, suitably at ambient temperature to disperse or preferably
dissolve the active ingredient.
[0535] (C) Exemplary Mixing of the Two Phases
[0536] The aqueous phase and the disperse phase are mixed. The two
phases may be mixed in a desired weight; for example, the weight
ratio of disperse phase to aqueous phase may be from 1:1 to 1:10,
e.g. from 1:4 to 1:9 and optionally from 1:5 to 1:8 such as about
1:5 or about 1:7. The resulting colloid is agitated, e.g. sonicated
or stirred, at a temperature of 60-70.degree. C. and in particular
65.degree. C., to achieve a homogeneous dispersion, then the
homogenous dispersion is formed into beads. In particular, the
homogenous dispersion is ejected through a single orifice nozzle to
form droplets which fall into a cooling medium. The nozzle is
suitably vibrated to facilitate droplet formation. The nozzle may
be vibrated at a frequency of 2-200 Hz and optionally 15-50 Hz.
[0537] The cooling medium may for example be air or an oil; the oil
is suitably physiologically acceptable as, for example, in the case
of medium chain triglycerides e.g. Miglyol 810N. The cooling medium
may be at a cooling temperature often of less than 15.degree. C.,
for example of less than 10.degree. C. but above 0.degree. C. In
some embodiments the cooling temperature is 8-10.degree. C. The
nozzle size (diameter) is typically from 0.5 to 7.5 mm, e.g. from
0.5 to 5 mm and optionally from 0.5 to 4 mm. In some embodiments,
the nozzle diameter is from 1 to 5 mm for example from 2 to 5 mm,
and optionally from 3 to 4 mm, and in particular may be 3.4 mm.
[0538] The flow rate through a 3.4 mm nozzle is 5 to 35 g/min and
optionally 10 to 20 g/min and for nozzles of different sizes may be
adjusted suitably for the nozzle area.
[0539] (D) Exemplary Processing of Beads
[0540] Cooled beads are recovered, for example they may be
recovered from cooling oil after a residence time of 15-60 minutes,
for example after approximately 30 minutes. Beads recovered from a
cooling liquid (e.g. oil) may be centrifuged to eliminate excess
cooling liquid, and then dried. Suitably, drying is carried out at
room temperature, for example from 15-25.degree. C. and optionally
from 20-25.degree. C. The drying may be performed in a drum drier,
for example for a period from 6 to 24 hours, e.g. of about 12 hours
in the case of beads dried at room temperature. The dried beads may
be washed, suitably with a volatile non-aqueous liquid at least
partially miscible with water, e.g. they may be washed with ethyl
acetate. The washed beads may be dried at room temperature, for
example from 15-25.degree. C. and optionally from 20-25.degree. C.
The drying may be performed in a drum drier, for example for a
period from 6 to 48 hours, e.g. of about 24 hours in the case of
beads dried at room temperature. Drying may be achieved by any
suitable means, for example using a drum dryer, suitably under
vacuum; or by simply passing warm air through the batch of beads,
or by fluidising the beads in a suitable equipment with warm air,
for example if a fluid bed dryer. Following drying, the beads are
passed through a 1 to 10 mm, optionally 2 to 5 mm to remove
oversized beads and then through a sieve with a pore size of 0.5 to
9 mm optionally 1 to 4 mm to remove undersized beads.
[0541] It can be appreciated that it is possible to recycle the
beads that are rejected by the sieving process.
[0542] As a further aspect of the invention there is provided a
formulation obtainable by (having the characteristic of) any of the
processes described herein. It is to be understood that the
processes described herein may therefore be used to provide any of
the specific cores described in embodiments herein by dispersing
the appropriate components which form the disperse phase of the
core in the appropriate components which form the aqueous
continuous matrix phase of the core.
[0543] The preceding paragraphs describe the formation of uncoated
cores comprising a pharmaceutically active ingredient in for
example a hydrogel-forming polymer matrix. The cores are suitably
coated to provide the formulation according to the invention. The
cores may be first coated with a subcoat and and then further
coated with a second coating (also referred to as a modified
release coating). Suitable sub coats and modified release coatings
are any of those described herein and any of the first coating (for
the subcoat) or the second coating (for the modified release
coating). Optionally the formulation is further coated with an
optional outer protective coating as described herein The
coating(s) may be applied using well known methods, for example
spray coating as described below to give the desired sub coat and
modified release coating weight gains.
[0544] With regard to one of the methods described above (ejection
of emulsion through an optionally vibrating nozzle) with two
concentric orifices (centre and outer), the outer fluid may form a
coating (outside the bead) as described herein. The Spherex machine
manufactured by Freund (see U.S. Pat. No. 5,882,680 to Freund) is
preferably used (the entire contents of this patent is incorporated
herein by reference). Other similar ejection or extrusion apparatus
may also be used, for example the ejection apparatus described
hereinbefore.
[0545] Use of the Spherex machine achieves very high
monodispersity. For example, in a typical 100 g, batch 97 g of
beads were between 1.4 to 2 mm diameter or between 1 and 2 mm.
Desired size ranges can be achieved by methods known in the art for
rejecting/screening different sized particles. For example, it is
possible to reject/screen out the larger/smaller beads by passing a
batch first through e.g. a 2 mm mesh and subsequently through a 1.4
mm mesh.
[0546] The 1.4 to 2 mm diameter range is a good size if it is
desired to spray coat the beads (if smaller, the spray of the
coating machine may bypass the bead; if too large, the beads may be
harder to fluidise, which is necessary to achieve consistent
coating).
Coating Process
[0547] The coating process can be carried out by any suitable means
such as, for example, by use of a coating machine which applies a
solution of a polymer coat (as described above in particular) to
the formulation. Polymers for coating are either provided by the
manufacturer in ready-made solutions for direct use or can be made
up before use following manufacturers' instructions.
[0548] Coating is suitably carried out using a fluid bed coating
system such as a Wurster column to apply the coating(s) to the
cores. Appropriate coating machines are known to persons skilled in
the art and include, for example, a perforated pan or
fluidized-based system for example the GLATT, Vector (e.g. CF 360
EX), ACCELACOTA, Diosna, O'Hara and/or HICOATER processing
equipment. To be mentioned is the MFL/01 Fluid Bed Coater (Freund)
used in the "Bottom Spray" configuration.
[0549] Typical coating conditions are as follows:
TABLE-US-00003 Process Parameter Values Fluidising airflow (m3/h)
20-60 (preferably 30-60) Inlet air temperature (.degree. C.) 20-65
Exhaust air temperature (.degree. C.) 20-42 Product temperature
(.degree. C.) 20-45 (preferably 40 to 42) Atomizing air pressure
(bar) Up to 1.4 e.g. 0.8-1.2 Spray rate (g/min) 2-10 and 3-25
RPM
[0550] Suitably the coating is applied as a solution or dispersion
of the polymers (and other components) of the coating. Generally
the coatings are applied as an aqueous, solution of dispersion,
although other solvent systems may be used if required. The coating
dispersion is applied to the cored as a spray in the fluid bed
coater to give the required coating weight gain. Generally the
coating process is carried out at a temperature which maintains the
cores at a temperature of from 35 to 45.degree. C., preferably 40
to 42.degree. C.
[0551] After applying the coating, the formulation may be dried,
for example by drying at 40 to 45.degree. C.
[0552] The invention further provides a product having the
characteristics of a formulation obtained as described herein, a
product defined in terms of its characteristics being defined by
the characteristics of the formulation to the exclusion of the
method by which it was made.
[0553] As mentioned herein the processes described may be used to
provide any of the formulations described in the various
embodiments herein. By way of example there is provided a
formulation of the invention comprising a core and a coating
comprising a water-soluble cellulose ether or a water soluble
derivative of a cellulose ether wherein the core comprises a
hydrogel-forming polymer matrix comprising gelatin, cyclosporin A
or another hydrophobic active ingredient, medium chain mono-di-
and/or tri-glycerides, a co-solvent and surfactant, the core having
the characteristics of a core obtained by the process comprising
steps (i) to (vi) described above for forming the core, wherein the
aqueous phase pre-mix in step (i) of the process comprises gelatin
and surfactant (suitably an anionic surfactant), and the oil phase
pre-mix in step (ii) of the process comprises medium chain mono-di-
or tri-glycerides, hydrophobic active ingredient, surfactant
(suitably a non-ionic surfactant) and cosolvent; and the wherein
the core is optionally coated with a coating comprising a
water-soluble cellulose ether or a water soluble derivative of a
cellulose ether and the thus-coated core is optionally coated with
a second coating; wherein the coatings are any of those described
herein. Accordingly, the process may produce a formulation as
described above comprising a first coating. The process may
additionally produce a formulation comprising a first coating and a
second coating being outside the first coating.
[0554] In addition the process to form a formulation of the
invention may comprise the steps of mixing a first population and a
second population, wherein
[0555] the first population has a coating that is or comprises a
water-soluble cellulose ether but having no outer coating, e.g. as
described herein; and
[0556] the second population has a first coating that is or
comprises a water-soluble cellulose ether and a second coating that
is or comprises a delayed release coating, for example as described
herein e.g. a coating that is or comprises a delayed release
polymer.
[0557] In the cores described herein to which the following
characteristics are applicable, e.g. in the immediately preceding
paragraph, the following characteristics may be present:
[0558] gelatin may be present in an amount of in an amount of 300
to 700 mg/g;
[0559] the medium chain mono-, di- or tri-glycerides (for example
caprylic/capric triglyceride) may be present in an amount of 20 to
200 mg/g;
[0560] co-solvent (for example 2-(ethoxyethoxy)ethanol) may be
present in an amount of 150 to 250 mg/g;
[0561] non-ionic surfactant (for example sorbitan-based
surfactants, PEG-fatty acids, or glyceryl fatty acids or poloxamers
or particularly a polyethoxylated castor oil for example Kolliphor
EL) may be present in an amount of 80 to 200 mg/g;
[0562] anionic surfactant (for example, alkyl sulphates,
carboxylates or phospholipids (particularly SDS)) may be present in
an amount of 15 to 50 mg/g; and
[0563] active ingredient, particularly cyclosporin A, may be
present in an amount of from 60 to 180 mg/g, suitably 60 to 150
mg/g or 80 to 100 mg/g, for example 81 to 98 mg/g; wherein all
weights are based upon the dry weight of the core before
coating.
[0564] The core is coated with a first coating (sub-coating) which
is or comprises a water-soluble compound selected from cellulose
ethers and their derivatives, particularly hydroxypropylmethyl
cellulose; the first coating being present in an amount
corresponding to a weight gain due to the first coating in a range
selected from: (i) from 8% to 12%, for example about 10%; or (ii)
from 4% to 6%, for example about 5% or (iii) about 6% to about 10%,
for example about 7%, about 7.5%, about 8%, about 8.5%, about 9% or
about 9.5% by weight based upon the weight of the core prior to
applying the first coating. The first coating may have a modified
release coating (or second coating) applied to it.
[0565] Preferably, any modified release coating, especially in the
embodiments of the immediately preceding paragraphs, is or
comprises a pH independent modified release coating, more
especially the second coating may be a modified release coating
comprising ethyl cellulose (e.g. Surelease) still more particularly
a modified release coating comprising ethyl cellulose and a
water-soluble polysaccharide, pectin (e.g. a Surelease-pectin
coating as described herein); and wherein the modified release
coating is present in an amount corresponding to a weight gain of
the formulation due to the second coating selected from (a) from
10% to 12%, for example about 11% or about 11.5%; or (b) from 16%
to 18%, for example about 17% or (c) from about 8% to about 12%,
for example about 8.5%, about 9%, about 9.5%, about 10%, about
10.5% or about 11% by weight based upon the weight of the
formulation prior to applying the second coating.
Applications
[0566] The formulations of the invention may advantageously be used
for oral delivery pharmaceutically active ingredients by virtue of
the enhanced dissolution profiles achieved.
[0567] The formulations of the invention include modified release
formulations which comprise cyclosporin A as an active ingredient
and a modified release coating, for example comprising a pH
independent polymer, to target cyclosporin release to the lower
intestine. Such formulations result in low systemic exposure to
cyclosporin A, whilst providing high levels of cyclosporin A in the
lower GI tract, particularly in the colon. Such formulations
release the cyclosporin A in an active form for example as a
solution, which provides enhanced absorption of cyclosporin A in
the local tissue of the lower GI tract. When the formulation is
used in the form of minibeads, the minibeads are advantageously
dispersed along large sections of the GI tract following oral
administration and are therefore expected provide a more uniform
exposure to cyclosporin to large sections of for example the colon.
Needless to say, the invention includes such formulations in which
the cyclosporin A is replaced by, or supplemented by, another
active ingredient for local treatment of the lower GI tract, e.g.
colon. The other active ingredient may be another immunosuppressant
or a hydroxylase inhibitor, e.g. DMOG or hydralazine, or it may be
a combination of active ingredients comprising at least one
mentioned in this sentence. Tacrolimus and sirolimus are examples
of other immunosuppressants.
[0568] Accordingly the modified release formulations according to
the invention comprising an active ingredient for local treatment
of the lower GI tract are expected to be useful in the treatment or
prevention of a condition of the GIT. In particular the formulation
of the invention may comprise cyclosporin A and/or another
immunosuppressant and be useful in the prevention or treatment of
inflammatory conditions affecting the lower GI tract, particularly
conditions affecting the colon.
[0569] The formulation of the invention is administered orally. The
dose required will vary depending upon the specific condition being
treated and the stage of the condition. In the case of formulations
containing cyclosporin A, the formulation will generally be
administered to provide a dose of cyclosporin A of from 0.1 to 100
mg, for example a dose of 1 to 500 mg or particularly a dose of 25
to 250 mg cyclosporin A, for example a dose of 37.5 mg, 75 mg or
150 mg. The formulation is suitably administered as a single daily
dose. Optionally the composition may be administered twice per day,
for example 37.5 mg, 75 mg or 150 mg twice per day.
[0570] In one aspect of the invention there is provided a
formulation of the invention that comprises an immunosuppressant as
active ingredient and is for use in the treatment or prophylaxis of
an inflammatory bowel disease, Crohn's disease, ulcerative colitis,
graft-versus-host disease, gastrointestinal graft-versus-host
disease, myasthenia gravis, irritable bowel syndrome (e.g. with
constipation, diarrhea and/or pain symptoms), celiac disease,
stomach ulcers, diverticulitis, pouchitis, proctitis, mucositis,
chemotherapy-associated enteritis, radiation-associated enteritis,
short bowel disease, or chronic diarrhea, gastroenteritis,
duodenitis, jejunitis, peptic ulcer, Curling's ulcer, appendicitis,
colitis, diverticulosis, endometriosis, colorectal carcinoma,
adenocarcinoma, inflammatory disorders such as diversion colitis,
ischemic colitis, infectious colitis, chemical colitis, microscopic
colitis (including collagenous colitis and lymphocytic colitis),
atypical colitis, pseudomembraneous colitis, fulminant colitis,
autistic enterocolitis, interdeminate colitis, jejunoiletis,
ileitis, ileocolitis or granulomatous colitis, the prevention of
rejection following bone marrow transplantation, psoriasis, atopic
dermatitis, rheumatoid arthritis, or nephrotic syndrome, primary
sclerosing cholangitis, familial adenomatous polyposis, or
perinanal Crohn's, including perianal fistulae.
[0571] In one embodiment the formulation of the invention that
comprises an immunosuppressant as active ingredient is for use in
the treatment of an inflammatory bowel disease. The main forms of
inflammatory bowel disease are Crohn's disease and ulcerative
colitis. Accordingly the formulation of the invention may be useful
in the treatment of both of these conditions.
[0572] Crohn's disease may affect the entire GI tract including the
colon. However, ulcerative colitis is a condition which affects
only the colon and the rectum. Accordingly, the release profile
provided by the colon-targeted, immunosuppressant-containing (e.g.
cyclosporin A-containing), formulation according to the invention
is expected to be especially beneficial in the treatment of
ulcerative colitis.
[0573] In one aspect of the invention there is provided a
formulation of the invention that comprises an immunosuppressant as
active ingredient and is for use in the treatment or prophylaxis of
a condition of the GIT, for example an inflammatory condition of
the GIT, optionally wherein the condition of the GIT is selected
from of irritable bowel syndrome celiac disease, stomach ulcers,
diverticulitis, pouchitis, proctitis, mucositis,
radiation-associated enteritis, short bowel disease, or chronic
diarrhea, gastroenteritis, duodenitis, jejunitis, peptic ulcer,
Curling's ulcer, appendicitis, colitis, diverticulosis,
endometriosis, colorectal carcinoma, adenocarcinoma, inflammatory
disorders such as diversion colitis, ischemic colitis, infectious
colitis, chemical colitis, microscopic colitis (including
collagenous colitis and lymphocytic colitis), atypical colitis,
pseudomembraneous colitis, fulminant colitis, autistic
enterocolitis, interdeminate colitis, jejunoiletis, ileitis,
ileocolitis, granulomatous colitis, fibrosis, graft-versus-host
disease, gastrointestinal graft-versus-host disease, or HIV or
enteropathies.
[0574] The colon-targeted, immunosuppressant-containing formulation
of the invention primarily releases immunosuppressant, e.g.
cyclosporin A, in the colon. However, drug may also be released
higher in the GI tract and accordingly the formulation may also
provide therapeutic benefit in conditions which affect other parts
of the lower GI tract.
[0575] Gastrointestinal Graft-Versus-Host-Disease (GI-GVHD) is a
life-threatening condition and one of the most common causes for
bone marrow and stem cell transplant failure. In patients with
GI-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 diarrhoea. 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. Accordingly, in one embodiment the
immunosuppressant-containing formulation is for use in the
treatment or prophylaxis of Gastrointestinal
Graft-Versus-Host-Disease (GI-GVHD).
[0576] In a further embodiment there is provided an
immunosuppressant-containing formulation of the invention for use
in the treatment of celiac disease.
[0577] In one embodiment the formulation of the invention that
comprises an immunosuppressant as active ingredient is for use in
the treatment of neurodegenerative diseases (for example
Parkinson's disease, Alzheimer's disease or vascular dementia) or
paediatric diseases, including, but not limited to ulcerative
colitis, Crohn's disease and GvHD.
[0578] The coating containing the water-soluble cellulose ether of
the present invention may be useful in reducing the variability
between release profiles of different batches of minibeads. The
first coating being beneath the second coating has been shown (see
FIG. 10) to produce beads with similar (.+-.5% release) % release
of the active ingredient at time points in a release profile. This
has the beneficial effect of improving consistency in in-vitro
release profiles but also in in-vivo dissolution and consequently
consistent release of the active along the gastrointestinal
tract.
[0579] A "batch" is a specific quantity of a drug or other material
that is intended to have uniform character and quality, within
specified limits, and is produced according to a single
manufacturing order during the same cycle of manufacture. A "lot"
means a batch, or a specific identified portion of a batch, having
uniform character and quality within specified limits; or, in the
case of a drug product produced by continuous process, it is a
specific identified amount produced in a unit of time or quantity
in a manner that assures its having uniform character and quality
within specified limits. "Lot number", "control number", or "batch
number" means any distinctive combination of letters, numbers, or
symbols, or any combination of them, from which the complete
history of the manufacture, processing, packing, holding, and
distribution of a batch or lot of drug product or other material
can be determined."
EXAMPLES
Example 1: Preparation of a Minibead with a Hydroxypropyl
Methylcellulose Coating
[0580] The minibead was generally prepared by forming a core
according to the following procedure and then coating the core with
a dispersion of Opadry White 20A28380 (supplied by Colorcon).
[0581] Core Manufacture
[0582] The cores in the form of seamless minibeads were prepared
using Spherex process as follows.
[0583] An aqueous phase was prepared by mixing sodium dodecyl
sulphate (SDS) and D-sorbitol with purified water under constant
stirring. Gelatin was then added to this solution and gentle heat
was applied to approximately 60-70.degree. C. to achieve complete
melting of gelatin.
[0584] An oil phase was prepared by mixing together
2-(2-ethoxyethoxy)ethanol (Transcutol HP), polyethoxylated castor
oil (Kolliphor EL) and capric/caprylic triglyceride (Miglyol 810)
with stirring at room temperature to form a solution. Ciclosporin A
was added and mixed until a clear solution was obtained. The oil
phase was mixed with the heated aqueous phase in a ratio of
approximately 1:7 (oil phase:aqueous phase). The resulting mixture
was stirred at 60-70.degree. C. to achieve homogeneity.
[0585] The resulting mixture was then fed (via temperature
controlled tubing) through a vibrating nozzle, with a single nozzle
outlet with a diameter of 3 mm. Seamless minibeads were formed as
the solution flowed through the vibrating nozzle into a cooling
chamber of constantly flowing medium chain triglyceride (Miglyol
810) cooling oil at a temperature of 10.degree. C.
[0586] The minibeads were removed from the cooling oil and placed
in a centrifuge to remove the excess oil. Following centrifugation,
a first drying step was initiated with a set refrigerator
temperature of 10.degree. C. and the heater temperature of
20.degree. C. The dryer was rotated at 15 RPM. When the beads were
observed to be freely rotating in the drying drum, they were
considered to be dry.
[0587] The minibeads were washed with ethyl acetate and then dried
for a further 24 h under the same drying conditions as those
mentioned above in the first drying step. The dried minibeads were
then sieved to remove oversize and undersize beads resulting in
cores 1 mm-2 mm in diameter. This procedure provided cores with the
composition shown in Table 1, the values being the weight percent
of the total weight for each component.
TABLE-US-00004 TABLE 1 Component w/w % Cyclosporin A 10.8 Miglyol
810 N 4.6 Transcutol HP 16.4 Kolliphor EL 9.2 SDS 4.0 Sorbitol 5.7
Gelatin 49.3
[0588] Coating the Core
[0589] The minibead cores were loaded into a fluid bed coater
(Wurster column) and coated with Opadry White 20A28380 (supplied by
Colorcon Limited) as a dispersion. The processing parameters, such
as inlet air temperature and inlet air volume, were adjusted to
keep the minibead temperature between 40.degree. C. and 42.degree.
C. until the required coating weight gain was reached. The
resulting subcoated minibeads were dried for 5 minutes at
40.degree. C. in the coater.
[0590] Composition of the Minibead
[0591] A minibead with the composition shown in Table 2 below was
produced by the above procedure. The minibead has an Opadry weight
gain of 2.7% relative to the weight of the core.
TABLE-US-00005 TABLE 2 Component w/w % Cyclosporin A 10.5 Miglyol
810 N 4.5 Transcutol HP 16.0 Kolliphor EL 9.0 SDS 3.9 Sorbitol 5.5
Gelatin 48.0 Opadry 2.6
Example 2: Preparation of Minibeads with a Hydroxypropyl
Methylcellulose Coating
[0592] Following the procedure described in Example 1, minibeads
coated with hydroxypropyl methylcellulose with the differing %
weight gains of Opadry were produced. The % weight gain of Opadry
are shown in Table 3 below.
TABLE-US-00006 TABLE 3 % weight gain of Opadry Example 2a 6.3%
Example 2b 10% Example 2c 15%
[0593] The minibeads of Examples 2a-c had the composition shown in
Table 4.
TABLE-US-00007 TABLE 4 Example 2a Example 2b Example 2c Component
w/w % Cyclosporin A 10.2 9.8 9.4 Miglyol 810 N 4.3 4.2 4.0
Transcutol HP 15.5 14.9 14.3 Kolliphor EL 8.7 8.4 8.0 SDS 3.8 3.6
3.5 Sorbitol 5.3 5.2 5.0 Gelatin 46.3 44.8 42.8 Opadry 5.9 9.1
13.0
Example 3: In-Vitro Dissolution Profile of Minibeads of Examples 1,
2a, 2b and 2c Up to 4 Hours
[0594] The in-vitro dissolution profiles of a sample of the
minibeads produced in Examples 1, 2a, 2b and 2c were measured in
water. As a reference example, the dissolution profile of the core
with no Opadry coating produced in Example 1 was tested. The
dissolution testing was carried out in accordance with USP
<711> Dissolution using Apparatus II (paddle apparatus)
operated with a paddle speed of 75 rpm and with the dissolution
medium at a temperature of 37.degree. C..+-.5.degree. C.
[0595] Aliquots of the medium were taken for analysis at 1 hour, 2
hours and 4 hours for all of the test media. In addition to these
time points, aliquots were also taken at the following time points
for the indicated minibeads: [0596] minibeads of Examples 1 and
2a-20 mins, 40 mins and 1.5 hours; [0597] minibeads of Examples 2b,
2c and the non-coated core of Example 1-30 mins.
[0598] The aliquots were analysed for cyclosporin A using Reverse
Phase HPLC with UV detection at 210 nm.
[0599] The amount of dissolved cyclosporin A in the dissolution
medium is expressed as a percentage based upon the original
cyclosporin content in the test formulation (the released). The %
release values provide a release profile when plotted against time
and the release profile for each of the samples of minibeads from
Examples 1, 2a, 2b, 2c and the non-coated core of Example 1 is
shown in FIG. 1.
[0600] The release profiles of the tested minibeads clearly show
that an additional subcoat of hydroxypropyl methylcellulose
(Opadry) enhances the dissolution of the active ingredient within
the first 2 hours of the dissolution test. All of the minibeads
with a coating of hydroxypropyl methylcellulose (HPMC) released
cyclosporine into solution much more rapidly than the non-coated
core of Example 1. This is surprising and counterintuitive. Common
sense suggests that adding additional material onto the core, which
coating the core with HPMC does, should increase the time in which
it takes to release the active into solution.
Example 4: In-Vitro Dissolution Profile of Minibeads of Examples 1,
2a, 2b and 2c Up to 24 Hours
[0601] Following the same protocol as that described in Example 3 a
dissolution profile of minibeads of Examples 1, 2a, 2b, 2c and the
non-coated core of Example 1 over 24 hours was generated.
[0602] In addition to the aliquot samples taken at the time points
mentioned in Example 3 each of the dissolution tests were also
sampled at 6 hours, 12 hours, 18 hours and 24 hours. Every sample
taken from the dissolution tests were analysed for cyclosporin A
using Reverse Phase HPLC with UV detection at 210 nm.
[0603] As in Example 3 a graph of the release profile of each
dissolution test was generated and the release profiles are shown
in FIG. 2.
[0604] It is evident from the release profiles of FIG. 2 that the
presence of a HPMC coating significantly improves the cyclosporin
release when compared to a non-coated core. Not only is there a
more rapid release of the cyclosporin within the first 2 hours but
the presence of a HPMC coating also maintains the cyclosporin in
solution in the water dissolution medium.
Example 5: Preparation of a Minibead with a First Coating of
Hydroxypropyl Methylcellulose and a Second Coating of
Ethylcellulose/Pectin
[0605] A core was produced and subsequently coated with Opadry, the
first coating (also referred to as a subcoat), following the
procedure in Example 1. The minibead produced by the procedure of
Example 1 was then further coated with a second coating (also
referred to as an overcoat) of a mixture of Surelease.RTM. (an
ethylcellulose dispersion) and Pectin.
[0606] The Surelease.RTM./pectin overcoat was applied by the
following procedure. Pectin was added to purified water in a
stainless steel vessel and mixed to obtain a solution.
Surelease.RTM. was slowly added to the vessel whilst maintaining
mixing to provide the required Pectin concentration in the
Surelease.RTM. for the overcoat. The resulting coating suspension
was then applied onto the surface of the sub-coated minibeads using
an analogous coating method to that described for the Opadry
coating in Example 1 until the desired weight gain of
Surelease.RTM./Pectin was reached. The over-coated minibeads were
then dried in the coater for an hour at 40-45.degree. C.
[0607] A number of minibeads with differing levels of Opadry and
differing levels of Surelease.RTM./Pectin were produced. Table 5
shows the % weight gain of Opadry and the % weight gain of
Surelease.RTM./Pectin of the minibeads that were produced.
TABLE-US-00008 TABLE 5 % weight gain of % weight gain of Opadry
Surelease/Pectin Example 5a N/A 9% Example 5b 2.7% .sup. 11%
Example 5c 6.3% .sup. 11% Example 5d .sup. 10% .sup. 11% Example 5e
N/A 5% Example 5f 2.6% 4.6% Example 5g 11.9% 5.4% Example 5h N/A
21.3% Example 5i 10.6% 23.3% Example 5j 15.5% 23.1%
[0608] Examples 5a, 5e and 5h have no Opadry coating. They are
produced by coating a core described in Example 1 with
Surelease.RTM./Pectin as described above.
[0609] The minibeads of Examples 5a-j have the compositions shown
in Table 6.
TABLE-US-00009 TABLE 6 Example Example Example Example Example
Example Example 5a 5d 5c 5b 5h 5i 5j Component w/w % Cyclosporin A
9.9 8.8 9.2 9.5 8.9 7.9 7.6 Miglyol 810 N 4.2 3.8 3.9 4.0 3.8 3.4
3.2 Transcutol HP 15.1 13.4 13.9 14.4 13.5 12.0 11.5 Kolliphor EL
8.4 7.6 7.8 8.1 7.6 6.8 6.5 SDS 3.7 3.3 3.4 3.5 3.3 3.0 2.8
Sorbitol 5.2 4.7 4.8 5.0 4.7 4.2 4.0 Gelatin 45.2 40.3 41.8 43.2
40.6 36.1 34.6 Opadry N/A 8.2 5.3 2.4 N/A 7.8 10.9 Surelease (solid
8.1 9.7 9.7 9.7 17.2 18.4 18.5 contents) Pectin 0.2 0.2 0.2 0.2 0.4
0.4 0.4 Example Example Example 5e 5f 5g Component w/w %
Cyclosporin A 10.3 10.1 9.2 Miglyol 810 N 4.4 4.3 3.9 Transcutol HP
15.6 15.3 13.9 Kolliphor EL 8.8 8.6 7.8 SDS 3.8 3.7 3.4 Sorbitol
5.4 5.3 4.8 Gelatin 46.9 45.9 41.8 Opadry N/A 2.4 10.1 Surelease
(solid 4.7 4.3 5.0 contents) Pectin 0.1 0.1 0.1
Example 6: In-Vitro Dissolution Profile of Minibeads of Examples
5a-d
[0610] The in-vitro dissolution profiles of a sample of the
minibeads produced in Examples 5a-d were measured using the
following two stage dissolution test. The dissolution testing was
carried out in accordance with USP <711> Dissolution using
Apparatus II (paddle apparatus) operated with a paddle speed of 75
rpm and with the dissolution medium at a temperature of 37.degree.
C..+-.0.5.degree. C. In the first stage of the test the dissolution
medium was 750 ml of 0.1N HCl simulating the pH of the gastric
environment. At the start of the test (t=0) the sample was placed
in the dissolution medium. After 2 hours an aliquot of the medium
is taken for subsequent analysis and immediately (suitably within 5
minutes) the second stage of the dissolution test is initiated. In
the second stage 250 ml of 0.2M tribasic sodium phosphate
containing 2% sodium dodecyl sulphate (SDS) is added to the
dissolution medium and the pH adjusted to 6.8.+-.0.05 using 2N NaOH
or 2N HCl as required.
[0611] Samples of the dissolution medium were taken at the
following time points during the second stage of the test: 4 hours;
6 hours; 12 hours; and 24 hours from the start of the test (i.e.
from t=0 at the start of the first stage).
[0612] The sample taken at the end of the first stage (2 hours) and
the samples from the second stage were analysed for cyclosporin A
using Reverse Phase HPLC with UV detection at 210 nm.
[0613] The amount of dissolved cyclosporin A in the dissolution
medium is expressed as a percentage based upon the original
cyclosporin content in the test formulation (the % released). The %
release values provide a release profile when plotted against time
and the release profile for each of the samples of minibeads from
Examples 5a-d are shown in FIG. 3.
[0614] It is readily apparent from the release profiles in FIG. 3
that the presence of a HPMC subcoat enhances the release profile
compared to the non-subcoated minibead of Example 5a. The minibeads
comprising a HPMC subcoat give a higher % release of cyclosporin
from the minibeads than the non-subcoated minibeads. The same
relationship between the % release of cyclosporin from subcoated
and non-subcoated minibeads can be seen in the release profiles of
FIG. 4.
Example 7: In-Vitro Dissolution Profile of Minibeads of Examples
5e-g
[0615] Following the procedure described in Example 6 a release
profile for each of the minibeads of Examples 5e-g was generated.
These release profiles are shown in FIG. 4. FIG. 4 shows that the
effect observed in FIG. 3 also occurs when a subcoated bead with a
lower level of Surelease/Pectin is used.
Example 8: In-Vitro Dissolution Profile of Minibeads of Examples
5h-j
[0616] Following the procedure described in Example 6 a release
profile for each of the minibeads of Examples 5h-j was generated.
These release profiles are shown in FIG. 5. FIG. 5 shows that the
effect observed in FIGS. 3 and 4 also occurs when a subcoated bead
with a higher level of Surelease/Pectin is used.
Example 9: Preparation of Further Minibeads with a First Coating of
Hydroxypropyl Methylcellulose and a Second Coating of
Ethylcellulose/Pectin
[0617] Example 5 describes the use of Opadry White to provide the
hydroxylpropyl methylcellulose subcoat. We now describe the
production of further minibeads with a first coating of
hydroxypropyl methylcellulose and a second coating of
ethylcellulose/pectin using Methocel E5 (supplied by Colorcon
Limited) as the hydroxypropyl methylcellulose.
[0618] Minibeads were produced in the same way as in Example 5,
except Methocel E5 was used instead of Opadry White for the first
coating (subcoat).
[0619] A number of minibeads with differing levels of Methocel E5
and differing levels of Surelease.RTM./Pectin were produced. Table
7 shows the % weight gain of Methocel E5 and the % weight gain of
Surelease.RTM./Pectin of the minibeads that were produced.
TABLE-US-00010 TABLE 7 % weight gain of % weight gain of Methocel
E5 Surelease/Pectin Example 9a N/A 9% Example 9b 3% 11% Example 9c
5.3% 11%
[0620] Example 9a has no Methocel E5 coating. It is produced by
coating a core described in Example 1 with Surelease.RTM./Pectin as
described above.
[0621] The minibeads of Examples 9a-c have the compositions shown
in Table 8.
TABLE-US-00011 TABLE 8 Example Example Example 9a 9b 9c Component
w/w % Cyclosporin A 9.9 9.4 9.2 Miglyol 810 N 4.2 4.0 4.0
Transcutol HP 15.1 14.4 14.1 Kolliphor EL 8.4 8.1 7.9 SDS 3.7 3.5
3.4 Sorbitol 5.2 5.0 4.9 Gelatin 45.2 43.1 42.1 Methocel E5 N/A 2.6
4.5 Surelease (solid 8.1 9.7 9.7 contents) Pectin 0.2 0.2 0.2
Example 10: In-Vitro Dissolution Profile of Minibeads of Examples
9a-c
[0622] The in-vitro dissolution profiles of a sample of the
minibeads produced in Examples 9a-c were measured using the
dissolution test method described in Example 6. The release profile
for each of the minibeads of Examples 9a-c is shown in FIG. 6.
[0623] FIG. 6 shows that the same result is obtained when Methocel
is used as the subcoat as when Opadry is used as the subcoat.
Example 11: Comparison of In-Vitro Dissolution Profiles of Examples
5a-d and Examples 9b-c
[0624] FIG. 7 shows the release profile of each of Examples 5a-d
and 9b-c. As mentioned above, FIG. 6 shows the same effect is seen
with Methocel subcoated minibeads as Opadry subcoated minibeads. In
addition, when the release profiles generated by the Methocel
subcoated minibeads are plotted against the release profile of
Opadry subcoated beads, as in FIG. 7, it can be seen that the
Methocel subcoated minibeads and the Opadry subcoated minibeads
give closely matching release profiles.
Example 12: Preparation of Mesalamine Containing Minibeads with a
First Coating of Hydroxypropyl Methylcellulose and a Second Coating
of Ethylcellulose/Pectin
[0625] Minibeads containing mesalamine were prepared as described
in Example 5 except that the cores were not produced by passing the
mixture through a vibrating nozzle but they were produced by hand.
In addition cyclosporin was replaced by mesalamine and the oil
phase formed during the process to make the core (described in
Example 1) did not form a solution; the mesalamine remained as a
suspension.
[0626] By following this procedure a three populations of minibeads
with differing levels of Opadry and differing levels of
Surelease.RTM./Pectin were produced. Table 9 shows the % weight
gain of Opadry and the % weight gain of Surelease.RTM./Pectin of
the minibeads that were produced.
TABLE-US-00012 TABLE 9 % weight gain of % weight gain of Opadry
Surelease/Pectin Example 12a N/A 10.5% Example 12b 5% 12% Example
12c 12% 11.5%
[0627] Example 12a has no Opadry coating. It is produced by coating
a core described in Example 1 with Surelease.RTM./Pectin as
described above.
[0628] The minibeads of Examples 12a-c have the compositions shown
in Table 10.
TABLE-US-00013 TABLE 10 Example Example Example 12a 12b 12c
Component w/w % Mesalamine 9.0 8.4 7.9 Miglyol 810 N 4.7 4.4 4.2
Transcutol HP 13.7 12.9 12.1 Kolliphor EL 7.5 7.0 6.6 SDS 3.5 3.3
3.1 Sorbitol 5.0 4.7 4.4 Gelatin 47.2 44.4 41.8 Opadry N/A 4.3 9.6
Surelease (solid 9.2 10.4 10.1 contents) Pectin 0.2 0.2 0.2
Example 13: In-Vitro Dissolution Profile of Minibeads of Examples
12a-c
[0629] The in-vitro dissolution profiles of a sample of the
minibeads produced in Examples 12a-c were measured using the
dissolution test described below:0.05M pH 7.5 phosphate buffer
prepared by dissolving 6.8 g of monobasic potassium phosphate and 1
g of sodium hydroxide in water to make 1000 mL of solution, and
adjusting with 10N sodium hydroxide to a pH of 7.5.+-.0.05; 900 mL
are used.
USP Apparatus 2 with a paddle speed of 75 RPM. Dissolution medium
temperature: 37.degree. C..+-.0.5.degree. C. The release profile
for each of the minibeads of Examples 12a-c is shown in FIG. 8.
Example 14: Preparation of Hydralazine HCl Containing Minibeads
with a First Coating of Hydroxypropyl Methylcellulose and a Second
Coating of Ethylcellulose/Pectin
[0630] The coated minibeads containing hydralazine HCl were
produced by coating a core comprising the hydralazine HCl.
Hydralazine HCl is a hydrophilic API, its solubility in water is
approximately 8 g/L (i.e. 0.8%); however, it has been found that
the API was fully soluble in the aqueous phase of the formulation
when heated at 60-70.degree. C.
[0631] Core Manufacture
[0632] The cores in the form of seamless minibeads were prepared
manually as follows.
[0633] The aqueous phase was prepared by adding sodium dodecyl
sulphate (SDS) and D-sorbitol to purified water under constant
stirring until a solution was obtained. Hydralazine HCl and Gelatin
were then added to this solution and gentle heat was applied to
approximately 60-70.degree. C. to achieve complete melting of
gelatin. Stirring was continued until a clear solution was
obtained.
[0634] The composition of the aqueous phase is shown in Table
11.
TABLE-US-00014 TABLE 11 Component % w/w Hydralazine HCl 3.5 Gelatin
18.4 Sorbitol 2.0 SDS 1.3 Purified Water 74.7
[0635] An oil phase was prepared by mixing together
2-(2-ethoxyethoxy)ethanol (Transcutol HP), polyethoxylated castor
oil (Kolliphor EL) and capric/caprylic triglyceride (Miglyol 810)
with stirring at room temperature to form a solution. The
composition of the oil phase is given in Table 12.
TABLE-US-00015 TABLE 12 Component % w/w Transcutol HP 55.0
Kolliphor EL 30.0 Miglyol 810 15.0
[0636] The oil phase was mixed to form an emulsion with the heated
aqueous phase in a ratio of approximately 1:12 (oil phase:aqueous
phase). The resulting mixture was stirred at 60-70.degree. C. to
achieve homogeneity. The composition of the emulsion is shown in
Table 13
TABLE-US-00016 TABLE 13 Component % w/w Hydralazine HCl 3.2
Transcutol HP 4.2 Miglyol 810 1.2 Kolliphor EL 2.3 Gelatin 17.0
Sorbitol 1.8 SDS 1.3 Purified water 69.0
[0637] The resulting mixture was then manually ejected through an
orifice into a cooling chamber of medium chain triglyceride
(Miglyol 810) cooling oil at a temperature of 4-10.degree. C. The
minibeads were removed from the cooling oil and dried at room
temperature for 24 hours.
[0638] The composition of the cores is shown in Table 14.
TABLE-US-00017 TABLE 14 Components % w/w Hydralazine HCl 10.4
Transcutol HP 13.7 Miglyol 810 N 3.7 Kolliphor EL 7.4 Gelatin 54.8
D-Sorbitol 6.0 SDS 4.0
[0639] The cores produced by the procedure described in this
example were coated with Opadry White 20A28380 (supplied by
Colorcon) in the same way as described in Example 1, where
appropriate. The cores were directly coated or the Opadry coated
cores, as appropriate, were coated with Surelease/Pectin as
described in Example 5. Six populations of minibeads with differing
levels of Opadry and differing levels of Surelease.RTM./Pectin were
produced by following this procedure. Table 15 shows the % weight
gain of Opadry and the % weight gain of Surelease.RTM./Pectin of
the minibeads that were produced.
TABLE-US-00018 TABLE 15 % weight gain of % weight gain of Opadry
Surelease/Pectin Example 14a N/A 11% Example 14b 6.4% 10.8% Example
14c 11.5% 11.1% Example 14d N/A 17.7% Example 14e 6.4% 17.9%
Example 14f 11.5% 16.6%
[0640] Examples 14a and 14d have no Opadry coating. These Examples
are produced by coating a core described in Example 1 with
Surelease.RTM./Pectin as described above.
[0641] The minibeads of Examples 14a-f have the compositions shown
in Table 16.
TABLE-US-00019 TABLE 16 Example Example Example Example Example
Example 14a 14b 14c 14d 14e 14f Component w/w % Hydralazine 9.4 8.8
8.4 8.8 8.3 8.0 Miglyol 810 N 3.4 11.6 11.1 11.7 10.9 10.5
Transcutol HP 12.3 3.1 3.0 3.1 3.0 2.9 Kolliphor EL 6.7 6.3 6.0 6.3
5.9 5.7 SDS 3.6 46.5 44.2 46.6 43.7 42.1 Sorbitol 5.4 5.1 4.8 5.1
4.8 4.6 Gelatin 49.4 3.4 3.2 3.4 3.2 3.1 Opadry N/A 5.4 9.3 N/A 5.1
8.9 Surelease (solid 9.9 9.8 10.0 15.0 15.1 14.2 contents)
Example 15: In-Vitro Dissolution Profile of Minibeads of Examples
14a-f
[0642] The in-vitro dissolution profiles of a sample of the
minibeads produced in Examples 14a-f were measured using the
dissolution test method described in Example 13. The release
profile for each of the minibeads of Examples 14a-f is shown in
FIG. 9.
[0643] The release profile of FIG. 9 shows the same effect as that
observed in the previous examples--an increased % release of the
active ingredient, hydralazine, from the minibeads with a HPMC
subcoat versus non-subcoated minibeads with comparable levels of
Surelease/Pectin. For example, a comparison between non-subcoated
Example 14a and subcoated Example 14c shows the higher % release
effect of the HPMC subcoat. The same is true of a comparison
between Example 14d and Example 14f.
Example 16: Preparation of Celecoxib Containing Minibeads with a
First Coating of Hydroxypropyl Methylcellulose and a Second Coating
of Ethylcellulose/Pectin
[0644] The coated minibeads containing celecoxib were produced by
coating a core comprising the celecoxib. Celecoxib is a hydrophobic
API.
[0645] Core Manufacture
[0646] The cores in the form of seamless minibeads were prepared
manually as follows.
[0647] The aqueous phase was prepared by adding sodium dodecyl
sulphate (SDS) and D-sorbitol to purified water under constant
stirring until a solution was obtained. Gelatin was then added to
this solution and gentle heat was applied to approximately
60-70.degree. C. to achieve complete melting of gelatin. Stirring
was continued until a clear solution was obtained.
[0648] An oil phase was prepared by mixing together macrogol
hydroxystearate (Kolliphor HS-15) with celecoxib. The mixture was
stirred at room temperature to form a solution.
[0649] The oil phase was mixed to form an emulsion with the heated
aqueous phase in a ratio of approximately 1:3 (oil phase:aqueous
phase). The resulting mixture was stirred at 60-70.degree. C. to
achieve homogeneity.
[0650] The resulting mixture was then manually ejected through an
orifice into a cooling chamber of medium chain triglyceride
(Miglyol 810) cooling oil at a temperature of 10.degree. C. The
minibeads were removed from the cooling oil and dried at room
temperature for 24 hours.
[0651] The cores produced by the procedure described in this
example were coated with Opadry White 20A28380 (supplied by
Colorcon) in the same way as described in Example 1 and then coated
with Surelease as described in Example 5. The cores were also
directly coated (i.e. in the absence of an Opadry coat) with
Surelease in a similar fashion to that described in Example 5.
Table 17 shows the composition of minibeads coated with 27% weight
gain Surelease.RTM. without a subcoat of Opadry (non-subcoated
minibeads). Table 18 shows the composition of minibeads coated with
10% Opadry subcoat and 27% weight gain Surelease.RTM. (subcoated
minibeads).
TABLE-US-00020 TABLE 17 27% wt. g Surelease formulation (w/o
subcoat) Component w/w % Celecoxib 4.8 Kolliphor HS-15 43.0 Gelatin
24.9 SDS 3.3 D-Sorbitol 2.8 Surelease 21.2
TABLE-US-00021 TABLE 18 27% wt. g Surelease formulation (10% Opadry
subcoat) Component w/w % Celecoxib 4.4 Kolliphor HS-15 39.8 Gelatin
23.1 SDS 3.1 D-Sorbitol 2.5 Opadry 7.3 Surelease 19.7
Example 17: In-Vitro Dissolution Profile of Minibeads of Examples
16
[0652] The in-vitro dissolution profiles of a sample of the
minibeads produced in Example 16 were measured using the
dissolution test method described below.
[0653] The in-vitro release was measured using a two stage in-vitro
dissolution test in which a composition is exposed to 0.1 N HCl for
two hours to simulate pH of the gastric environment and is then
exposed to pH 6.8 for twenty two hours (by adding a sufficient
quantity of 0.2M tribasic sodium phosphate solution either with or
without 0.05% sodium dodecyl sulfate (SDS)) to simulate pH in the
small intestine and lower GI tract. The in-vitro test using
Apparatus II (paddle apparatus) was operated with a paddle speed of
75 rpm and with the dissolution medium at a temperature of
37.degree. C..+-.0.5.degree. C. Aliquots of the medium were taken
for analysis at 1 hour, 2 hours, 4 hours, 6 hours, 12 hours and 18
hours. The aliquots were analysed for celecoxib using a high
performance liquid chromatography (HPLC) method. From the area
under the curve (HPLC method), the % of drug released at particular
time points was calculated.
[0654] Both subcoated and non-subcoated minibeads were tested using
the dissolution test described above not containing SDS and
subcoated minibeads were also tested in a using the dissolution
test with 0.05% SDS. The release profile for each of the minibeads
of Example 16 is shown in FIG. 10.
[0655] The release profile of FIG. 10 shows the same effect as that
observed in the previous examples--an increased final % release of
the active ingredient, celecoxib, from the minibeads with a HPMC
subcoat versus non-subcoated minibeads with comparable levels of
Surelease.
Example 18: In-Vitro Dissolution Profile of Minibeads from
Different Batches
[0656] Minibead cores were prepared according to the procedure
described in Example 1. From these cores, 3 populations of
minibeads coated with both an Opadry subcoat and a Surelease/pectin
overcoat were produced and 3 populations of minibeads with only a
Surelease/Pectin coating were produced. The 3 populations with both
an Opadry subcoat and a Surelease/pectin overcoat had an amount of
coating corresponding to a 5% weight gain of Opadry and a 11.5%
weight gain of Surelease/Pectin. The 3 populations with only a
Surelease/pectin coating had an amount of coating corresponding to
a 9% weight gain of Surelease/Pectin. The compositions of the
minibeads with an Opadry subcoat and without an Opadry subcoat are
shown in Table 19.
TABLE-US-00022 TABLE 19 With subcoat W/o subcoat Component (%) (%)
Cyclosporin A 9.2 9.9 Miglyol 810 N 3.9 4.2 Transcutol HP 14.0 15.1
Kolliphor EL 7.9 8.4 SDS 3.4 3.7 Sorbitol 4.9 5.2 Gelatin 42.1 45.2
Opadry 4.3 N/A Surelease (solid contents) 10.1 8.1 Pectin 0.2
0.2
[0657] The dissolution profile of these 6 populations of minibeads
was tested using the dissolution test protocol of Example 6 to give
the dissolution profile shown in FIG. 11.
[0658] FIG. 11 shows a wide variation in the release profiles for
the populations of minibeads lacking a HPMC subcoat; % release
values at 12 hours range from 48% to 63% and at 24 hours they range
from 61% to 83%. In stark contrast to the results obtained for the
minibeads lacking a HPMC subcoat, the minibeads having a HPMC
subcoat have very little variation in the % release of the
different batches.
Example 19: Measurement of Coating Thickness
[0659] A minibead produced according to the procedure disclosed
herein was studied under a scanning electron microscope (SEM). The
minibead had a first coating of Opadry with a weight gain of 10%
and a second coating of Surelease/Pectin (98:2 ratio) with a weight
gain of 11%. The minibead was cut in half at the widest point of
the minibead. The cross sectional surface of the bead was then
studied under the SEM. FIG. 12 shows a SEM image of the cross
section of the minibead and FIG. 13 provides a magnified version of
the image of FIG. 12. FIG. 13 clearly shows the distinct first
coating and second coating. From the SEM image it was possible to
determine that the thickness of the first coating was 41 .mu.m and
the thickness of the second coating was 40 .mu.m.
Example 20: Minibead Compositions
[0660] Minibeads having the compositions shown in Table 21 were
prepared using an analogous method to that described in Example 1
under "Core Manufacture" except the oil phase to aqueous phase
ratio was 1:5 in the compositions of Table 21. Mixing of the oil
phase and the aqueous phase resulted in a liquid mixture with the
composition shown in Table 20. The "surfactant" of Table 20 was one
of the surfactants listed in Table 22. Minibeads with a composition
of Table 21 were prepared for all of the surfactants of Table 22
except for Labrafil M 1944 CS. It is expected that minibeads can be
formed with a liquid composition comprising Labrafil M 1944 CS by
varying the oil to aqueous phase ratio or by increasing the
viscosity of the liquid composition.
TABLE-US-00023 TABLE 20 Component % w/w Cyclosporine 4.1 Transcutol
HP 6.2 Surfactant* 4.3 Miglyol 810 2.1 Type A Gelatin 14.3 Sorbitol
1.7 SDS 1.1 Purified Water 66.2
TABLE-US-00024 TABLE 21 Component % w/w Cyclosporine 12.1
Transcutol HP 18.3 Surfactant* 12.9 Miglyol 810 6.2 Type A Gelatin
42.3 Sorbitol 5.0 SDS 3.2
[0661] Table 22 shows the surfactants of the compositions of Table
20 and 21. The table also shows the results of a crystallisation
test carried out on the liquid compositions comprising each of the
surfactants.
[0662] Crystallisation Test
[0663] Emulsions were obtained with a composition disclosed in
Table 20 for each of the surfactants listed in Table 22 with
stirring at 250-350 rpm. Samples of the emulsion were taken at 30
minute intervals and viewed under a microscope at 50.times. or
100.times. magnification. The time when crystals appeared in the
sample is shown in Table 22.
TABLE-US-00025 TABLE 22 Surfactant HLB Crystallization time (h)
Span 85* 1.8 3 Labrafil M 1944 CS 4 1 Span 40* 6.7 1.5 Plurol
Oleique CC 497 6 1 Labrafil M 2130 CS 4 0.5 Cremophor EL 14 0.5
* * * * *