U.S. patent application number 15/986584 was filed with the patent office on 2018-09-20 for composition comprising oil drops.
This patent application is currently assigned to Sigmoid Pharma Limited. The applicant listed for this patent is Sigmoid Pharma Limited. Invention is credited to Vincenzo Aversa, Ivan Coulter, Bernard Francis McDonald.
Application Number | 20180264076 15/986584 |
Document ID | / |
Family ID | 43126572 |
Filed Date | 2018-09-20 |
United States Patent
Application |
20180264076 |
Kind Code |
A1 |
Coulter; Ivan ; et
al. |
September 20, 2018 |
COMPOSITION COMPRISING OIL DROPS
Abstract
A composition comprises a water-soluble polymer matrix in which
are dispersed droplets of oil, the composition comprising an active
principle. The invention includes embodiments in which the active
principle is included in at least some of the oil droplets as well
as embodiments in which the oil droplets are released as the matrix
containing them dissolves in an aqueous medium. In one embodiment,
the oil droplets are substantially immobilized in or by the matrix
and the immobilizing feature is lost as the matrix dissolves in
aqueous media. In certain embodiments, the oil drops may
collectively be referred to as the oil phase of the composition of
the invention. The product may be in the form of mini-beads. The
oil phase and/or the polymer matrix may each include a
surfactant.
Inventors: |
Coulter; Ivan; (Dublin,
IE) ; McDonald; Bernard Francis; (Co. Monaghan,
IE) ; Aversa; Vincenzo; (Dublin, IE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sigmoid Pharma Limited |
Dublin 9 |
|
IE |
|
|
Assignee: |
Sigmoid Pharma Limited
Dublin 9
IE
|
Family ID: |
43126572 |
Appl. No.: |
15/986584 |
Filed: |
May 22, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15011372 |
Jan 29, 2016 |
9999651 |
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15986584 |
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13321149 |
Feb 9, 2012 |
9278070 |
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PCT/EP2010/056838 |
May 18, 2010 |
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15011372 |
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61179121 |
May 18, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/44 20130101;
A61K 38/00 20130101; A61K 31/436 20130101; A61P 37/04 20180101;
A61K 9/1635 20130101; A61K 47/14 20130101; A61K 38/13 20130101;
A61K 47/10 20130101; A61P 1/12 20180101; A61K 9/5073 20130101; A61P
1/04 20180101; A61P 1/14 20180101; A61K 9/5036 20130101; A61K
9/5026 20130101; A61K 9/1075 20130101; A61K 9/5047 20130101; A61K
9/1652 20130101; A61K 9/1617 20130101; A61K 9/107 20130101; A61P
31/04 20180101; A61K 9/1658 20130101; A61K 9/1694 20130101; Y02A
50/30 20180101 |
International
Class: |
A61K 38/13 20060101
A61K038/13; A61K 47/44 20170101 A61K047/44; A61K 9/107 20060101
A61K009/107; A61K 47/10 20170101 A61K047/10; A61K 47/14 20170101
A61K047/14; A61K 9/16 20060101 A61K009/16; A61K 31/436 20060101
A61K031/436; A61K 9/50 20060101 A61K009/50 |
Foreign Application Data
Date |
Code |
Application Number |
May 18, 2009 |
IE |
2009/0381 |
Claims
1-46. (canceled)
47. A vaccine or immune-modulating composition for oral
administration comprising a water-soluble polymer matrix material
in which are dispersed droplets of oil, the composition comprising
an active principle.
48. The composition according to claim 47, wherein the active
principle comprises an adjuvant.
49. The composition according to claim 48, wherein the adjuvant is
.alpha.-galactosylceramide.
50. The composition according to claim 48 wherein the active
principle comprises the adjuvant and an immunomodulator.
51. The composition according to claim 50, wherein the
immunomodulator is selected from a vaccine, an antigen, or an
immunotherapeutic agent.
52. The composition according to claim 51, wherein the active
principle is a vaccine.
53. The composition according to claim 52, wherein the vaccine is
to prevent or treat a viral or bacterial infection.
54. The composition according to claim 53, wherein the vaccine is
for the treatment or prevention of a gastro-intestinal infection, a
respiratory infection or a sexually transmitted genital
infection.
55. The composition according to claim 53, wherein the vaccine is
for the treatment or prevention of a gastro-intestinal infection
selected from those caused by Helicobacter pylori, Vibrio cholerae,
enterotoxigenic Escherichia coli (ETEC), Shigella spp., Clostridium
difficile, rotaviruses or calici viruses; or a respiratory
infection selected from those caused by Mycoplasma pneumoniae,
influenza virus, and respiratory syncytial virus; or a sexually
transmitted genital infection selected from those caused by HIV,
Chlamydia trachomatis, Neisseria gonorrhoeae or herpes simplex
virus.
56. The composition according to claim 47 wherein the oil droplets
comprise: i) polyglycol mono- and di-esters of 12-hydroxystearic
acid and about 30% free polyethylene glycol; or ii) linoleoyl
macrogolglycerides (polyoxylglycerides).
57. The composition according to claim 56, wherein part of the
12-hydroxy group of the 12-hydroxystearic acid is etherified with
polyethylene glycol
58. The composition according to claim 47 wherein the active
principle is included in at least some of the oil droplets.
59. The composition according to claim 48, wherein the at least
some of oil droplets comprise droplets of
water-in-oil-emulsion.
60. The composition according to claim 47, wherein the
water-soluble polymer matrix material is selected from: one or more
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 pectin.
61. The composition according to claim 60, wherein the
water-soluble polymer matrix material is gelatin.
62. The composition according to claim 61, wherein the
water-soluble polymer matrix further comprises a plasticizer.
63. The composition according to claim 62 wherein the plasticizer
is a low molecular weight polyol.
64. The composition according to claim 47, which is in the form of
a mini-bead.
65. The composition according to claim 64, wherein the mini-bead
has a diameter of from 0.5 mm to 5 mm.
66. The composition according to claim 65, wherein the mini-bead
has a coat.
67. The composition according to claim 66, wherein the coat
comprises: (i) ethylcellulose; or (ii) a polymeric coating material
which material may comprise methacrylic acid co-polymers, ammonio
methacrylate co-polymers, or mixtures thereof.
68. The composition according to claim 67, wherein the coat
comprises ethylcellulose in association with an emulsification
agent.
69. The composition of claim 67, wherein the emulsification agent
is ammonium oleate
70. The composition according to claim 66, wherein the coat
comprises ethylcellulose in association with a plasticizer.
71. The composition of claim 70, wherein the plasticizer is
selected from dibutyl sebacate or medium chain triglycerides.
72. The composition according to claim 65 wherein the minibead has
a coat which coat comprises i) a combination of ethylcellulose and
a polysaccharide selected from chondroitin sulphate, pectin,
dextran, guar gum and amylose and chitosan; or ii) a polymeric
coating material.
73. The composition according to claim 72 wherein the coat
comprises a polymeric coating material comprising a methacrylic
acid co-polymer, an ammonio methacrylate co-polymer, or a mixture
thereof.
74. The composition according to claim 72, wherein the coat is
outside a first coat which first coat comprises a cellulosic
film-forming polymer.
75. The composition according to claim 74, wherein the cellulosic
film-forming polymer comprises hydroxypropylmethyl cellulose,
hydroxypropyl cellulose, or a combination thereof.
76. The composition according to claim 47, which is a dried
oil-in-water emulsion.
77. The composition according to claim 47, which is in the form of
a plurality of minibeads in a single format.
78. The composition according to claim 77, wherein the single
format is a plurality of minibeads contained in a hard gel capsule,
a sachet or container, or a plurality of minibeads in a tablet
79. A method of making a composition, the method comprising: i)
mixing an oil phase with an aqueous phase comprising a
water-soluble polymer matrix material to form an emulsion, at least
one of the oil phase and the aqueous phase comprising an active
principle, wherein the active principle comprises an adjuvant which
is .alpha.-galactosylceramide; and then ii) causing the emulsion to
solidify by exposing droplets of the emulsion to a solidification
medium to form mini-beads.
80. The method of claim 79, further comprising coating the
mini-beads.
81. The method of claim 79, wherein the mini-beads comprise the
water-soluble polymer matrix material in which are dispersed
droplets of oil.
Description
[0001] This invention relates to compositions for delivering active
principles, in particular active principles in a liquid state. The
composition may be used for example in pharmaceuticals, cosmetics,
healthcare, veterinary, aquaculture, fermentation, diagnostics,
food clean-tech and environmental applications. The invention also
relates to methods of making the compositions, methods of using
them, and other subject matter.
BACKGROUND
[0002] For a variety of reasons, it is desirable in the fields of
pharmaceuticals, cosmetics, food, clean-tech, photography and the
environment to maintain, deliver and administer (or use) active
principles in a fluid state. Fluid or solubilized active principles
generally act faster (eg pass more quickly through or are more
quickly absorbed by membranes especially natural membranes such as
skin, mucous membranes or other cell membranes) than solid or dry
forms of the active principle. For specific applications such as
oral administration of food supplements and pharmaceuticals, it is
desirable to formulate the active principles as solutions or
liquids in order to increase and/or accelerate absorption or effect
and/or to enhance the control and/or predictability of absorption
or effect. However, fluids and liquids tend to be less stable e.g.
to light and air and tend to require special containment for
transport (eg vials, tankers) and for administration (eg syringes).
Further processing of solids (eg applying additional layers or
coats of other materials) is generally easier than further
processing of liquids which at least require a filling step into a
receptacle of predefined geometry such as, for example,
liquid-filled soft-gel capsules, used in the food supplements and
pharmaceuticals industries, which are essentially limited in size
in part by the machinery required to achieve the filling. Thus
fluids are generally more difficult to formulate in discrete
(individual) forms e.g. dosage forms than solids. It would
therefore be desirable to have a form which presents fluid active
ingredients in a way which can be easily and directly manufactured
and shaped while retaining the benefits of fluids described
above.
[0003] Shingel et al. (J Mater Sci: Mater Med 2008) describe a
solid emulsion gel for topical delivery of hydrophilic and
lipophilic drugs. A solid emulsion is normally a type of colloid in
which a solid is dispersed in a liquid. However, Shingel et al. use
the term to denote an oil-in-water (o/w) emulsion in which the
aqueous continuous phase is a solid gel resulting from
cross-linking between protein (acting also as stabilizer) and a
poly ethylene glycol (PEG) derivative (activated PEG synthesised by
reacting the polymer with nitrophenyl chloroformate). The
researchers cast solid emulsion gel between two films to form a 1.2
mm thick sheet. According to Shingel et al., the solid aqueous
phase acts like a hydrogel in its ability to absorb and then impart
water e.g. when placed on skin requiring hydration. The emulsion,
however, is not re-established on rehydration of the solid emulsion
gel. Rather, the cross-linking has created protein-coated oil
droplets (diameter range 5-20 .mu.m) immobilized individually or as
coalesced neighbouring droplets.
[0004] A particular industrial application of the present invention
is in formulation for oral administration of active
pharmaceuticals, nutraceuticals and food additives as well as
immunomodulators, immunomodulating therapeutics and
supplements.
[0005] For successful oral administration in these fields, the
active principle must be in solution for local effect or systemic
absorption, it must usually be stabilized before release (including
protection from degrading stomach acids, pH degradation,
proteolytic enzymes etc) and it must be permeable, with degrees of
necessary permeability depending on whether local or systemic
effect is required.
[0006] Additional requirements which pose problems in developing
oral dosage forms are ease and cost of manufacture including
scaleability, reproducibility and shelf-life.
[0007] If the active principle is to be delivered to the colon, as
may be desireable eg. for local treatment of colonic disease, for
presentation of the active principle to specific immune cells or
for systemic or lymphatic absorption, additional constraints and
requirements arise. Related or separate issues must be overcome if
the active principle (and/or associated excipients) is desired to
sequester, absorb or adsorb toxins, pollutants or other exogenous
agents.
[0008] A variety of solutions to these individual problems have
been identified but it is more challenging to resolve multiple such
problems simultaneously in a single oral dosage form. The above
described formulation issues are often greater for water-insoluble
or poorly water-soluble active entities.
[0009] The above described formulation issues are often greater for
water-insoluble or poorly water-soluble active entities.
[0010] Some of the issues mentioned above can be subdivided into
more specific challenges. For example, the general requirement for
the active principle to be in solution can be addressed by
formulating it in a dissolved state and maintaining that dissolved
state until release so avoiding reliance on dissolution in vivo (a
"pre-dissolved" active principle). The technical challenge then
becomes how to maintain the solubilized state and prevent release
until the target release zone (eg colon) is reached.
[0011] A further specific need within the general requirement for
the active principle to be in solution is the maintenance of the
formulated active principle in a dissolved state as well as
immediately after dispersion/egress from its carrier or matrix.
[0012] A particular problem in formulating active principles in a
dissolved state (eg by encapsulation of solution in minispheres)
arises when such dosage forms are coated with polymers intended to
modify drug release characteristics. The coating may prevent full,
sufficient or predictable release of active principle in the
gastro-intestinal tract (GIT) or, through unpredictable swelling of
or poration (pore formation) in the coating, create excess
variability in release within a population.
[0013] For hydrophobic active principles, it is particularly
desirable to increase water solubility or miscibility as well as to
increase stability and reduce volatility. It is likewise a goal to
control the availability of the active principle, particularly the
bioavailability. One approach to these issues has been to use
cyclodextrins, especially modified cyclodextrins as described e.g.
in US 2006/0148756 A1 (Darcy et al). However, use of cyclodextrins
although valuable in particular situations, can add manufacturing
and quality control complexity to oral drug formulation and
manufacture.
[0014] The oral delivery of combinations of otherwise
physico-chemically incompatible drugs or of drugs (especially
oil-soluble drugs) in soluble ("pre-solubliized") form or to mask
the unpleasant or undesireable taste or smell of active principles,
has been addressed by drug delivery systems having distinct
compartments within a single administrative form--see for example
U.S. Pat. No. 7,431,943 (Villa et al.). In such cases, the
objective is often to prevent a first drug (eg hydrophobic drug
with limited stability in aqueous milieu) from coming into contact
with a second drug (eg hydrophilic drug dissolved in aqueous
milieu) or in the case of a single active principle to maintain it
in liquid form (eg as a liquid core within a capsule) either to
mask taste/smell or to ensure it is delivered in active
("pre-dissolved") form at the desired intestinal location. In such
situations, particularly when an enteric, sustained or delayed
release coating is also applied to the drug form, the spatial
asymmetries in the dosage form potentially lead to unpredictable
release characteristics and/or unacceptable variability of drug
release, bioavailability or dynamic/clinical response. In other
words, distinct kinetic release characteristics apply to each
compartment. This can make it difficult to achieve controlled e.g.
simultaneous release of multiple drugs contained in a single
form.
[0015] A related challenge in co-delivery (following
co-administration) of more than one active principle is control
(avoidance or enhancement, depending on the desired outcome) of
interactions between the two or more active principles (or indeed,
excipients) at the point(s) of release.
[0016] A further complication arising from inclusion of a liquid
core within a capsule or minicapsule format is that for
minicapsules to form, there is a very low threshold for surfactant
in the core and this places a constraint on formulation options
should it be desirable (see below) to include a surfactant in the
liquid core. This is because the need for surface tension to create
and maintain capsules precludes or limits use of surfactants as the
reduction in surface tension caused by the surfactant in the core
can destroy the integrity of the capsule or cause a more monolithic
format where for example a shell or capsular layer may be desired.
Thus it can be difficult to formulate liquid, emulsified or
pre-solubilized active principles with surfactants which, as
mentioned, may for a variety of reasons be desirable.
[0017] US Pharmacopoiea (USP), European Pharmacopoiea (EP),
Japanese Pharmacopoiea (JP) and others are official public
standards--setting authorities for medicines and other health care
products manufactured or sold in the United States, Europe, Japan
etc. Among other things, the Pharmacopoiea set recognized standards
for the quality control of drug formulations to help ensure the
consistency of products made for public consumption. These
standards include dissolution methods, apparatus and media, often
referred to as "compendial" e.g. "compendial media" meaning
standard dissolution media described in USP, EP, JP etc. In the
dissolution testing of sparingly water-soluble drug products,
surfactants may be added to the medium to improve simulation of the
environment in the GI tract--see eg. Noory et al. Dissolution
Technologies, February 2000, Article 3.
[0018] The advantage of compendial methods is their relative
simplicity. Their perceived disadvantage is their relatively poor
predictive value in terms of assessing likely in vivo performance
even with addition of surfactant to the medium. In order to enhance
predictability, various non-compendial media as well as more
elaborate dissolution apparatus and methods achieving improved in
vivo/in vitro correlation (IVIVIC) have been developed particularly
to measure colonic release--see e.g. Klein et al., J. Controlled
Release, 130 (2008) 216-219.
[0019] Surfactants are also known to have been incorporated in oral
pharmaceutical formulations, often as components of (usually)
oil-in-water emulsions or self-emulsifying drug delivery systems
(SEDDS) which are oil-phase-only formulations which spontaneously
form emulsions on addition to water (sometimes therefore referred
to as pre-emulsions). Where the oil droplets in these emulsions are
very small, they are referred to as microemulsions (and their
precursors as SMEDDS).
[0020] In general, the presence of surfactants in pharmaceutical
formulations can be said to be an attempt to mimic the effect of
bile salts and others, the natural surfactants synthesised in the
liver and present in the GI tract. One of the main functions of
bile salts is to solubilise fats in the GI tract and to facilitate
their absorption into the systemic circulation and this gives an
indication as to why it can be advantageous to use emulsion systems
to enhance the systemic absorption of oil soluble and/or
hydrophobic drugs. However, the goal of oral drug delivery is not
always (or not solely) systemic absorption. If systemic absorption
was not wanted, for example if local delivery with reduced, limited
or negligible systemic absorption was the objective, the
requirement or role, if any, for surfactants may be different.
[0021] With the rapid progress in biotechnology, peptide drugs are
becoming important as therapeutic agents. A wide variety of
peptides have been used as drugs, including hormones, nucleic
acids, synthetic peptides, enzyme substrates and inhibitors.
Although they are highly potent and specific in their physiological
functions, most of them are difficult to administer orally because
of the unique physicochemical properties of peptides including
molecular size, poor solubility, short plasma half-life,
requirement for specialised mechanisms for membrane transport and
susceptibility to enzymatic breakdown (intestinal, pre-systemic and
systemic). Many different approaches have been used to improve the
oral absorption and enhance the bioavailability of peptide drugs.
In recent years, enhanced bioavailability after oral administration
has been reported by using microemulsion systems which are
thermodynamically stable, isotropically clear dispersions of two
immiscible liquids such as oil and water stabilized by an
interfacial film of surfactant molecules. The advantages of
microemulsions as drug delivery systems is the improvement of drug
solubilization and protection against enzymatic hydrolysis, as well
as the potential for enhanced absorption (eg from the jejunum but
also the colon) due to surfactant-induced permeability changes.
[0022] However, there are a large number of technical variables
which must be understood in order to design a microemulsion system
suitable for a particular purpose or drug. The physicochemical
properties such as drug stability, proportions of oil and water
phases and the size of microemulsion droplets all affect outcome.
If one or more surfactants are used, additional uncertainties arise
such as the influence of surfactant to co-surfactant ratio, a
consideration which is itself affected by the choice of oil in the
oil phase and/or choice of surfactant or surfactant type.
[0023] A peptide drug which has been widely studied for the
optimisation of microemulsion systems is ciclosporin A
(International Non-Proprietary Name or INN) also known as
cyclosporin(e) A.
[0024] In a microemulsion system of ciclosporin A obtained by using
polyoxyethylated castor oil (Cremophor EL.RTM.) as a surfactant,
Transcutol.RTM. as a co-surfactant and caprylic/capric tryglyceride
(Captex 355.RTM.) as an oil, Gao et al (1998) in International
Journal of Pharmaceutics 161 (1998) 75-86 achieved microemulsion
stability with high ciclosporin A solubility, small droplet size
and fast dispersion rate when selecting a Cremophor
EL.RTM.:Transcutol.RTM.:Captex 355.RTM. ratio of 10:5:4. No further
formulation of these microemulsions was described.
[0025] UK patent application 2,222,770 (SANDOZ LTD) describes
galenic formulations which contain cyclosporines in the form of
microemulsions (comprising a hydrophilic phase, a lipophilic phase
and a surfactant) or microemulsion preconcentrates (no hydrophilic
phase) also known as premicroemulsion concentrates. Such
preconcentrates spontaneously form microemulsions in an aqueous
medium for example in water or in the gastric juices after oral
administration. With a maximisation of systemic absorption with
good inter-subject variability being the objectives, this British
patent application did not describe or address the challenges and
problems of formulating cyclosporine A (also spelt cyclosporin A or
ciclosporin A) for delivery to the colon and/or to sections of the
GIT where absorption of cyclosporin is limited.
[0026] Kim et al. (Pharmaceutical Research, Vol 18, No 4, 2001)
describe a combined oral dosing regimen of premicroemulsion
concentrates (as in UK patent application 2,222,770) and enteric
coated solid-state premicroemulsion concentrates with the objective
of achieving high systemic absorption following oral
administration. In both cases, microemulsions are formed on
addition to water/aqueous media. The enteric coated solid state
preconcentrates are powders made by mixing the oil phase
(premicroemulsion concentrate) with polymer dissolved in acetone.
Removal of acetone leaves a film which is then powdered.
[0027] For colonic disease or to achieve absorption of drugs from
the colon, colon-specific delivery systems must prevent the release
of the drug in the upper part of the GIT yet release it on reaching
the colon. Apart from pro-drugs activated by contact with the
colonic milieu (eg specific bacteria or their enzymes), pure
formulation approaches include pH and time-dependent
polymer-mediated technologies. However, while variations in pH
between the small intestine and the colon are well documented, the
differences can be small and can vary between individuals. This can
make pH-dependent systems unreliable in obtaining a predictable
drug release profile. Time-dependent systems depend on the transit
time of the delivery system in the GIT. A major limitation with
these systems is that in vivo variation in the small intestinal
transit time may lead to release of the bioactive (active
principle) in the small intestine (too early) or in the terminal
part of the colon (too late). The patho-physiological state of the
individual recipient of such oral drug delivery systems also has a
significant effect on the performance of these time-dependent
systems--patients with irritable bowel syndrome and inflammatory
bowel disease (including Crohn's disease and ulcerative colitis)
often exhibit accelerated transit through the colon. Independently
of these considerations, the size of the dosage form at the point
of entry into the small intestine (pylorus) can have a significant
effect on GI transit time and/or variability of response.
[0028] A number of other colon targeted delivery systems have been
investigated. These systems include: intestinal
presssure-controlled colon delivery capsules which rely on
peristaltic waves occurring in the colon but not in the stomach and
small intestine; combination of pH-sensitive polymer coatings
(remaining intact in the upper GIT) with a coating of
polysaccharides degradable only by bacteria found in the colon;
pectin and galatomannan coating, degraded by colonic bacteria; and
azo hydrogels progressively degraded by azoreductase produced by
colonic bacteria. The preceding four systems are reviewed by Yang
et al., International Journal of Pharmaceutics 235 (2002) 1-15, the
entirety of which is incorporated herein by reference.
Polysaccharide based delivery systems are of particular
interest--see e.g. Kosaraju, Critical Reviews in Food Science and
Nutrition, 45:251-258 (2005) the entirety of which is incorporated
herein by reference. Nevertheless, for systems solely reliant on
specific enzymatic activity in the colon, disease state can once
again cause variability in the drug release profile as a result of
pathological derangements in colonic flora (eg resulting from pH
changes and changing amounts/activity of bacterial enzymes).
[0029] Beads of oil-in-water (o/w) emulsions are known. PCT
application WO/2008/122967 (Sigmoid Pharma Limited) describes an
oral composition comprising minicapsules having a liquid,
semi-solid, or solid core and FIG. 2 therein is a schematic of a
semi-solid- or solid-filled minicapsule/minisphere wherein the
active principle is solubilised or in a suspension form, with
controlled release polymer coatings. Example 20 describes beads of
an extruded emulsion drug suspension made from mixing an aqueous
solution with an oil solution made up of squalene (a natural
unsaturated hydrocarbon), Gelucire 44/14 and Labrafil MS 1944 C S.
The water-soluble active principle hydralazine is in the aqueous
phase and the oil phase is 1.12 dry wt % of the formulation.
[0030] Dried oil-in-water (o/w) emulsions are known. U.S. Pat. No.
4,045,589 (Petrowski et al) describes a stable, dry, non-dairy fat
emulsion product suitable for use as a coffee whitener. Such
whiteners are prepared as dry emulsion concentrates which, on
addition to an aqueous media such as coffee or tea, form a
reconstituted oil-in-water emulsion which whitens and flavours the
beverage. A first emulsifier is included in the liquid emulsion
concentrate to promote the stability of the liquid emulsion and a
second emulsifier (modified starch) is added to stabilize the
emulsion through the drying step. Before drying, the fat particles
in the emulsion average 1-3 .mu.m in diameter. This liquid emulsion
concentrate is dried to a moisture content not in excess of about
3%. In addition to spray drying, various other drying methods are
described as possible including freeze drying, drying on heated
drums etc.
[0031] U.S. Pat. No. 4,615,892 (Morehouse et al.) describes a dry
imitation margarine or butter product which can be easily
reconstituted to form a butter-like spread by slowly stirring the
dry product into water accompanied by mixing with kitchen blenders.
The dry product is made from an oil-in-water emulsion of an edible
fat and a starch hydrolyzate and water. This emulsion is then dried
e.g. by freeze or spray drying to reduce the moisture content to
less than about 6%. During drying, agitation must be minimised and
temperatures maintained above about 30.degree. C. to prevent phase
inversion prior to drying. The result is a protective film of
starch hydrolyzate around the fat droplets in powder form.
[0032] U.S. Pat. No. 4,540,602 (Motoyama et al.) describes an
activated pharmaceutical composition containing a solid drug that
is scarcely soluble in water. When the composition is administered
orally, the drug is readily absorbed to attain its high blood
concentration quickly. To achieve this, the drug is dispersed in
water in the presence of a water-soluble high-molecular weight
substance to form finely divided particles not greater than 10
.mu.m in diameter and then the water is removed to generate a
finely divided drug coated with the water-soluble high-molecular
substance in the form of a powder or granules. Emphasis is placed
on achieving powders or granulates of particle size in the
sub-micron range to optimise absorption from the intestinal mucosa.
The water-soluble high-molecular weight substance can be a
polymeric substance such as gelatin or gum arabic (Example 8
illustrates a combination of these two) or a cellulose derivative
such as hydroxymethyl cellulose, methyl cellulose, hydroxyethyl
cellulose, hydroxypropyl methylcellulose, hydroxypropyl
ethylcellulose, carboxymethyl cellulose sodium and the like. Where
the scarcely soluble drug is first dissolved in a hydrophobic
organic solvent, the dispersion can be an emulsion. The solvent can
be low-boil or non-volatile in which case it remains after drying
and can be orally administered without harmful effect (eg
glycerides, liquid paraffin, squalane, squalene, lecithin,
pristine, etc).
[0033] LiuXing et al in J. Controlled Release 93 (2003) 293-300
describe entrapment of peptide-loaded liposomes in calcium alginate
gel beads ranging from 0.95 to 1.10 mm in size. The goal was to
obtain a colonic release form of the entrapped peptide (bee venom)
and to protect the peptide from enzymic degradation and to disrupt
the mucosal membrane to increase peptide absorption. The objective
was to address the low drug incorporation efficiency arising from
the porosity of alginate beads.
[0034] Other problems with use of alginate results from loss of
active principle during gelation due to diffusion from the
concentrated gel to a less concentrated large volume cross-linking
solution--see e.g. Wells et al., Eur J. of Pharmaceutics and
Biopharmaceutics 65 (2007) 329-335.
[0035] Toorisaka et al. (J. Controlled Release 107 (2005) 91-96)
addressed the problem of physical-chemical instability of a
solid-in-oil-in water (S/O/W) emulsion. The instability led to a
need for storage at low temperatures, a major impediment to
pharmaceutical development. The researchers resolved this by
creating a dry S/O/W emulsion in which the active principle
(insulin) coated with a surfactant was the solid phase dispersed in
soybean oil (oil internal phase). This was then homogenized with
aqueous hydroxypropylmethylcellulose phthalate (HPMCP) to form the
S/O/W emulsion. This was then dropped into hydrochloric acid to
gellify the HPMCP and the resultant spherical microparticles were
lyophilized to yield 1 .mu.m diameter oil droplets coated with
HPMCP. This process has many steps and is therefore complex to
industrialize.
BRIEF SUMMARY OF THE DISCLOSURE
[0036] In accordance with the present invention there is provided a
composition comprising a water-soluble polymer matrix in which are
dispersed droplets of oil, the composition comprising an active
principle. The invention includes embodiments in which the active
principle is included in at least some of the oil droplets as well
as embodiments in which the oil droplets are free of active
principle. The oil droplets are released as the matrix containing
them dissolves in an aqueous medium. In one embodiment, the oil
droplets are substantially immobilized in or by the matrix and the
immobilizing feature is lost as the matrix dissolves in aqueous
media. In certain embodiments, the oil drops may collectively be
referred to as the oil phase of the composition of the
invention.
[0037] In one embodiment, the invention provides a composition
comprising a water-soluble polymer matrix in which are dispersed
droplets of oil, the matrix including a surfactant and the
composition comprising an active principle. In another embodiment,
the invention provides a composition comprising a water-soluble
polymer matrix in which are dispersed droplets of oil, the oil
comprising a surfactant and the composition comprising an active
principle. In a further embodiment, the invention provides a
composition comprising a water-soluble polymer matrix in which are
dispersed droplets of oil, the matrix including a surfactant, the
oil comprising a surfactant, and the composition comprising an
active principle.
[0038] The extent to which dissolution may affect the composition's
physical form and features depends on the initial shape, size and
make-up of the composition. Where the composition bears a coat, the
rate and manner of dissolution can be modified (see below).
[0039] In one aspect, the present invention can be described as a
dried oil-in-water (o/w) emulsion, one embodiment of which is
non-powdered. Another embodiment is moulded and/or shaped e.g. in
the form of beads, especially mini-beads e.g. spherical mini-beads.
The composition of the invention generally comprises multiple oil
drops or droplets within a moulded or shaped form e.g. a
mini-bead.
[0040] Another aspect of the present invention provides a
composition (suitable e.g. for pharmaceutical or nutraceutical use)
comprising a plurality of optionally coated mini-beads of a
water-soluble polymer matrix. In a particular embodiment, the
present invention provides a composition comprising a plurality of
mini-beads of dried oil-in-water emulsion.
[0041] In either case, at least some of the mini-beads (eg a first
population) may comprise an active principle (or more than one) and
optionally other beads (eg a second population) which comprise an
active principle (or more than one) or one population may be free
of active principles or include "deactivating" principles e.g.
enzyme or toxin sequesters or include active excipients, such as,
for example, permeability enhancers, which may enhance, moderate or
potentiate the effect of an active principle in another population.
In related embodiments, the composition of the invention may
comprise multiple populations of mini-spheres. The active
principles may be the same or different as between populations.
[0042] In a specific embodiment, one or more active principle(s) is
(are) incorporated in the oil phase of the composition or dried
emulsion. In another specific embodiment, one or more active
principle(s) is (are) incorporated in the aqueous phase of the
composition or dried emulsion. In another embodiment, the beads may
be coated with a polymer to alter the release profile or to protect
the bead and/or the active principle within the bead from
degradation or oxidation or hydrolysis or proteolysis or
degradation mediated by high or low pH.
[0043] The composition of the invention is of particular interest
for active principles of low aqueous solubility and/or liposoluble
compounds (active principles) where incorporation into the oil
phase brings particular advantages.
[0044] Thus in one aspect, the relation relates to formulating
active principles for oral administration as mini-beads of dried
oil-in-water emulsions in which the active principle can be
incorporated in the oil phase of the emulsion and with the beads
being optionally coated with a polymer.
[0045] The water-soluble immobilizing polymer matrix (or in one
aspect, the aqueous phase of a dried emulsion) comprises, in one
embodiment, a cross-linked water-soluble polymer e.g. resulting
from chemical or physico-chemical (eg drying) solidification of a
fluid aqueous continuous phase such that, in the matrix or dried
emulsion, water is substantially absent and the oil droplets are
immobilized. In this embodiment, the dried aqueous phase can
therefore be referred to as an immobilization matrix.
[0046] The term "dried emulsion" generally means an emulsion whose
internal (discontinuous) phase has been immobilized in a
substantially solid or solidified external phase. The solid
external phase dissolves on contact with an aqueous medium.
[0047] The term "matrix" is a term well-known in the art and
generally means, according to context, a solid, semi-solid,
undissolved or not-yet-dissolved material which provides structure
and volume to a composition. In some contexts, the term "matrix"
may mean a scaffold.
[0048] Solidification of the external phase may have arisen through
various means including chemically (eg by cross-linking) or
physically (eg by cooling or heating). By use of the term "dried",
it is not sought to imply that a drying step is necessary to
produce the dried emulsion (although this is not excluded) rather
that the solid or solidified aqueous external phase is
substantially free of water or free of available water. In this
respect, the term "aqueous phase" is nevertheless employed in this
document to denote the external (continuous) phase of the
composition of the invention even though water, in certain
embodiments, is largely absent from (or trapped within the
cross-linked matrix of) the composition of the invention,
particularly when in the form of mini-beads. The external phase of
the composition of the invention is however water-soluble and
dissolves in aqueous media. In one embodiment, the oil droplets are
released when the aqueous phase dissolves or is exposed to aqueous
media.
[0049] The term "released" in relation to the oil droplets means
free to move, egress, coalesce, dissolve, (re)emulsify etc.
although actual movement, egression, coalescence, association or
(re)emulsification is not a requirement ie. may not occur and
indeed may intentionally be constrained e.g. by presence of a coat
or coating and/or by incorporation of certain constraining or
retarding substances into the water-soluble polymer matrix.
[0050] It has additionally been found, to the inventors' surprise,
that within the broad invention described herein, i.e. in certain
embodiments, the constituents of the oil phase can be chosen to
produce particular advantages in relation to certain active
principles, particularly hydrophobic and/or lipophilic active
principles. In particular it has been found that judicious choice
of oil components one of which may be a surfactant allows certain
lipophilic active principles to be solubilized in such a way as to
maintain the solubilized state until the target release zone of the
GI tract (eg colon) is reached. Indeed, selection of a particular
kind of oil e.g. with surfactant properties, can in certain
embodiments yield compositions whose oil phase is otherwise free of
surfactant and in other embodiments yield compositions in which the
aqueous phase is free of surfactant. In this group of embodiments,
the inclusion of a surfactant in the aqueous phase is however
preferred, particularly if it is desired to obtain a microemulsion
according to the invention.
[0051] Another surprising development from the work leading to the
present invention is that, for certain embodiments, the inclusion
in the aqueous phase of a surfactant (described below) leads to
improved dissolution of the active principle. In particular, it has
been found that, when the composition of the invention is in the
form of beads bearing a polymeric coating, inclusion of a
surfactant in the aqueous phase enhances dispersion/egress through
pores or other openings in the polymer coat (or other local
removal, swelling or weakening of the polymer coat). Where the oil
phase comprises a surfactant, the surfactant included in the
aqueous phase may be different from any surfactant included in the
oil phase.
[0052] For certain of the mini-bead embodiments, a further
unexpected benefit arising from the work leading to the present
invention is that selection of the appropriate combination of
surfactants for the aqueous and oil phases leads to the maintenance
of the API in a dissolved (or semi-dissolved or pre-dissolved)
state on or immediately after dispersion/egress from the
water-soluble matrix and (if present) polymer coating on the beads.
For certain active principles, a particular choice of surfactant
combination (described below) ensures immediate or early activity
(or absorption) of the active principle at the site of release from
the mini-bead.
[0053] Against the background of increasing sophistication and
complexity of dissolution methods, media and apparatus, the present
applicant and inventors have also surprisingly found that USP/EP/JP
etc (compendial) methods and media can, contrary to expectations,
provide for certain embodiments a valuable guide to in vivo
performance--for example the time required for a given proportion
of sample (composition or dosage form) to dissolve and/or release
active principle. This surprising finding applies in a particular
embodiment to poorly water-soluble drugs where the
inventors/applicants have found that no surfactant need be added to
the medium to achieve full dissolution/dispersion within a
reasonable time frame noting, however, that low levels of
surfactant in the medium may be desirable to maintain dissolution
for longer periods.
[0054] In relation to specific embodiments, the present
applicants/inventors have found that the advantages of compendial
methods and media are particularly applicable to the development of
novel compositions which incorporate a colonic release component.
In addition, the present applications/inventors have found in
relation to certain embodiments that the use of surfactants in
compendial dissolution media, while aiding full dissolution for
testing purposes, do not reflect in vivo conditions, particularly
in the colon.
[0055] According to certain embodiments, complete or substantially
complete dissolution of active principle (API) in USP/EP/JP etc
dissolution apparatus using standard media can be achieved without
addition of surfactant to the dissolution medium (and that
maintenance of dissolution can be achieved with addition of very
low quantities of surfactant to the dissolution medium) by
incorporating in the composition according to this embodiment of
the invention one or more surfactants even when the quantity of
surfactant incorporated into the composition is much smaller than
would have been required in the medium to achieve a comparable
degree of dissolution of a composition (or formulation) containing
no surfactant. In fact, one aspect of the present invention
(described in more detail below) is the incorporation of
surfactants in the composition of the invention, particularly in
the mini-bead embodiment of the invention.
[0056] In particular, it has surprisingly been found in relation to
certain embodiments that the composition according to the invention
leads to complete or substantially complete dissolution of active
principle (API) in USP/EP/JP etc dissolution apparatus using
standard media without addition (or with addition of only small
amounts of) surfactant to the dissolution medium (sufficient to
maintain rather than establish dissolution) by incorporating in to
the formulation or composition (preferably the aqueous phase
thereof) one or more surfactants which facilitate complete or
substantially complete dissolution/egress of API such that the
quantity of surfactant incorporated into the composition is much
smaller than would have been required in the medium to achieve a
comparable degree of dissolution of a composition containing no
surfactant. In essence, the invention provides in this embodiment a
composition which dissolves in standard dissolution medium
independently of the medium's surfactant content.
[0057] Another surprising feature emerging from experiments leading
to the present invention is the make up of the optional polymeric
coating. For instance, it has been discovered that judicious
combination of different types of polymeric coating (described in
more detail below) can produce unexpected advantages in relation to
the in vitro dissolution and in vivo performance of the composition
of the invention. In particular, it has now been discovered for
these embodiments that inclusion of a polymer which degrades in the
presence of bacterial enzymes present in the colon (and/or a
polymer which encourages the formation of pores in the coating--a
"pore-former") with a pH-independent polymer leads to release of
active principle substantially in the colon or other pre-determined
site of the GI tract. In a particular embodiment, the above
mentioned polymer degradable by bacterial enzymes is water-soluble.
At least in embodiments, the invention ameliorates or solves one or
more of the shortcomings of the prior art. In particular, the
invention comprises formulations or compositions which enable
multiple problems of the prior art to be solved.
[0058] 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.
[0059] 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.
[0060] 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.
DETAILED DESCRIPTION
[0061] As previously described, the present invention relates to a
water-soluble polymer matrix composition in which are dispersed
droplets of oil, the composition comprising an active
principle.
[0062] The invention will now be described in detail by reference
to the various components which the composition of the invention
may comprise. The term "excipient" may be used occasionally to
describe all or some of the components other than the active
principle(s) bearing in mind that some excipients can be active and
that some active principles can have excipient character.
[0063] If not otherwise stated, ingredients, components, excipients
etc of the composition of the invention are suitable for one or
more of the intended purposes discussed elsewhere herein e.g. are
cosmetically acceptable, environmentally acceptable,
pharmaceutically acceptable, acceptable as food additives etc.
Surfactants
[0064] 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:
anionic, cationic, nonionic, and amphoteric (zwitterionic). The
nonionic 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.
[0065] 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-00001 HLB Value Expected properties 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 10 to
18 solubiliser or hydrotrope
[0066] Although HLB numbers are assigned to surfactants other than
the non-ionic, for which the system was invented, HLB numbers for
anionic, cationic, nonionic, 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.
Surfactants in Aqueous Phase
[0067] Surfactants which may be included in the aqueous phase of
the inventive composition are preferably readily diffusing or
diffusible surfactants to facilitate manufacturing and processing
of the composition of the invention. Such surfactants can be of any
particular type (ionic, non-ionic, zwitterionic) and may comprise
as a proportion of dry weight of the composition 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%.
[0068] Unless otherwise stated or required, all percentages and
ratios are by weight.
[0069] Preferred anionic surfactants for inclusion in the aqueous
phase include perfluoro-octanoate (PFOA or PFO),
perfluoro-octanesulfonate (PFOS), sodium dodecyl sulphate (SDS),
ammonium lauryl sulphate, and other alkyl sulfate salts, sodium
laureth sulphate, also known as sodium lauryl ether sulphate (SLES)
and alkyl benzene sulphonate. A preferred anionic surfactant in the
aqueous phase is SDS. Mixtures of anionic surfactants are also
contemplated.
[0070] The physical form of the surfactant at the point of
introduction into the aqueous phase during preparation plays a role
in the ease of manufacture of the composition according to the
invention. As such, although liquid surfactants can be employed, it
is preferred to utilize a surfactant which is in solid form (eg
crystalline, granules or powder) at room temperature, particularly
when the aqueous phase comprises gelatin.
[0071] Possible non-ionic surfactants for the aqueous phase include
perfluorocarbons, polyoxyethyleneglycol dodecyl ether (eg Brij such
as, for example, Brij 35), Myrij, Tween 20 or 80 (also known as
Polysorbate), Span 80 or 85. Brij, Myrj and Tween products are
available commercially from Croda, formerly ICI.
[0072] In general, mixtures of surfactants can be utilised eg. to
achieve optimum long term stability of the composition 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.
[0073] Instead of (or as complement to) the surfactant in the
aqueous phase, the invention also contemplates use of
surfactant-like emulsifiers (also known as crystalisation
inhibitors) such as, for example, HPMC (also known as hypromellose)
although their use is generally contemplated in relatively smaller
amounts to avoid high viscosity which may constrain processing
options.
[0074] Other non-ionic surfactants which may be included in the
aqueous phase include 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)). Poloxamers are
available commercially under the trade name Pluronics.TM.. Such
surfactants or similar larger polymeric surfactants are aqueously
soluble and are therefore presented here as optional components of
the aqueous phase. However, they may be used to reduce the amount
of or to replace a higher HLB polymeric component of the oil phase
(see also separate section) such as, for example, polyethoxylated
castor oils (polyethylene glycol ethers) exemplified commercially
as Cremophor.TM.. Diblock, tetrablock, multiblock, etc copolymers
(poloxomers) are also included.
[0075] Another type of polymeric aqueous soluble surfactant which
may be used in a similar way are anionic copolymers based on
methacrylic acid and methyl methacrylate in which the ratio of the
free carboxyl groups to ester groups is approx. 1:1 and with
average molecular weight is approx. 135,000. Such a polymeric
surfactant is available from Degussa under the trade name
EUDRAGIT.RTM. L 100.
[0076] The surfactant included in the aqueous phase is preferably
present within ranges noted above. In the mini-bead embodiment,
avoidance of excess surfactant is desirable to avoid the "golf ball
effect" whereby mini-beads when dried have a plurality of
point-sized dimples in their surface (visible under the
microscope). While not necessarily a major concern, such dimples
can lead to variability in coating if it is desired to apply for
example a polymer coat to the mini-beads. Although higher values
within the preferred range generally increase the rate of
egress/dissolution of mini-beads, the present inventors/applicants
have surprisingly found that in certain circumstances higher levels
of surfactant included in the composition of the invention can
cause a counterintuitive drop in the in vitro dissolution profile
including a drop in the total amount dissolved of the composition
according to the invention. Based on the work leading up to this
invention, it was established that the concentration of surfactant
above which the dissolution profile dropped (or total amount of
dissolved composition dropped) was approximately 5% by dry weight
of the composition for example when SDS is selected as the
surfactant. In certain embodiments, it is therefore preferred to
have in the aqueous phase a surfactant, e.g. SDS, in an amount of
less than 5% by dry weight of the total composition (for example,
the composition may be in the form of beads or mini-beads, wherein
the aqueous phase contains SDS or another surfactant in an amount
of less than 5% by dry weight of the beads/mini-beads). In
embodiments of the invention, the composition, e.g. in the form of
beads or mini-beads, comprises in the aqueous phase surfactant in
an amount of no more than 5%, no more than 4.5%, no more than 4% or
no more than 3% by dry weight of the beads or mini-beads. In one
class of embodiments, the surfactant is in an amount of at least
0.1% by dry weight of the beads or mini-beads. In another class of
embodiments, the surfactant is in an amount of at least 1% by dry
weight of the beads or mini-beads. In a further class of
embodiments, the surfactant is in an amount of at least 2% by dry
weight of the beads or mini-beads. Higher levels of surfactant in
the aqueous phase (e.g. above 5% by weight of the total
composition) restrict the processing parameters for manufacturing
when certain manufacturing approaches are followed.
[0077] It is noteworthy that surfactants are used in dissolution
testing media when complete dissolution of the composition being
studied is otherwise not achievable. In respect of the amount of
surfactant included in the aqueous phase of the composition of the
present invention as described above, the inventors/applications
have surprisingly found that such (small) quantities included in
the composition have a much greater effect than larger quantities
included in the dissolution medium.
[0078] In the case of the mini-bead embodiment, the present
inventors hypothesise that the local concentration of surfactant in
and around the mini-bead as it dissolves or disperses is more
effective than an otherwise greater concentration in the medium as
a whole. It is also believed, although the inventors/applicants do
not necessarily intend to be bound by this or other hypotheses
advanced in this text, that the surfactant in the beads assists API
egress from within the polymer coat (if a coat is afterwards added
to the mini-beads) and also possibly to shield the API from
crystalisation and/or precipitation after release from the
bead.
[0079] Thus it was a surprise for the present applicant/inventors
to find that in certain embodiments complete or substantially
complete dissolution of active principle (API) in USP/EP/JP etc
dissolution apparatus using standard media can be achieved, using
no or only minor amounts of surfactant in the dissolution medium,
by incorporating in to the composition of the invention (eg dosage
form) one or more surfactants even when the quantity of surfactant
incorporated into the formulation is much smaller than would have
been required in the medium to achieve a comparable degree of
dissolution of a formulation containing no surfactant. The one or
more surfactants may be comprised in the aqueous phase (the polymer
matrix) or the oil phase, or both, and are in particular comprised
in at least the aqueous phase and optionally also in the oil
phase.
[0080] These observations are particularly relevant to the class of
mini-bead embodiments of the invention, in particular where an
oil-soluble API such as, for example, ciclosporin is incorporated
in the oil phase and the mini-bead comprises a surfactant, e.g. in
at least the aqueous phase (polymer matrix). On full dissolution of
the composition of the invention in standard 900-1000 mL
dissolution pots using compendial medium, the concentration of
surfactant in an exemplary embodiment would be of the order of
0.001% ie. much lower than the amount (around 0.5%-1%) typically
added to the dissolution medium. Putting it another way, very
significantly greater amounts of surfactant would need to be
included in this embodiment of the composition of the invention in
order to achieve a fully diluted equivalent concentration of
surfactant typically used in 900-1000 mL dissolution pots.
[0081] High surfactant concentrations in the dissolution medium can
generate very good in vitro data but which is not necessarily
predictive of in vivo performance (eg pharmacokinetic profile). In
contrast, incorporation of (much lower overall quantities of)
surfactant in one embodiment of the mini-beads of the invention
produces unexpectedly superior in-vivo performance. The
inventors/applicants hypothesise (without wishing to be bound by
the hypothesis) that surfactant in the dissolution medium is more
playing the role of a dispersing agent (bringing other components
into the dissolution medium) rather than its classical role as an
aid to dissolution and that it is the surfactant included in the
aqueous phase of this embodiment of the composition of the
invention which ensures or enables dissolution. In this setting,
the small amount of surfactant included in the dissolution medium
therefore makes the test more a dispersion test than a dissolution
test and achieves dissolution/dispersion maintenance for the
purposes of compendial methods.
Oil Phase
[0082] Any pharmaceutically suitable oil or oil acceptable for food
use (or other chosen application) may be used to constitute the oil
phase (oil drops) according to the invention. In terms of dry
weight of the composition of the invention, the oil phase generally
comprises a proportion from 10% to 85%, preferably 15% to 50%, more
preferably 20% to 30% or from 35% to 45% e.g. for vaccine
formulations. 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 (eg neem oil), petrochemical oils, and volatile essential
oils.
[0083] 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.
[0084] 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. Oils which are particularly
preferred include 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 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 particularly when they have a
surfactant activity. In this embodiment, suitable oils include
polyglycol mono- and di-esters of 12-hydroxystearic acid
(=lipophilic part) and of about 30% of free polyethylene glycol
(=hydrophilic part). A small part of the 12-hydroxy group can be
etherified with polyethylene glycol. Such waxy oils are available
commercially e.g. from BASF under the trade name Solutol.TM.. An
example is Solutol.RTM. HS 15.
[0085] Alternative or additional oils which may be included in the
oil phase according to the invention are medium chain tryglycerides
such as for example Labrafac.TM. Lipophile manufactured by
Gattefosse in particular product number WL1349.
[0086] Other possible (alternative or additional) oils include
linoleoyl macrogolglycerides (polyoxylglycerides) such as, for
example, Labrafil (eg product number M2125CS by Gattefosse) and
caprylocaproyl macrogolglycerides such as, for example, Labrasol by
Gattefosse.
[0087] The oil phase may also include a solubilizer (which may also
be referred to as anamphiphilic oil or a surfactant) and examples
include polyethoxylated castor oils (polyethylene glycol ethers)
which can be prepared by reacting ethylene oxide with castor oil.
Commercial preparations may also be used as the solubilizer of the
composition of the invention 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. The preferred example is
Cremophor by BASF Corp. also known as Cremophor EL. Alternative or
additional solubilizers include phospholipids such as, for example,
phosphatidylcholine. In embodiments of the composition of the
invention which comprise a phospholipid solubilizer, the
phospholipid solubilizer may be incorporated either in the aqueous
phase or in the oil phase or both. If at least one phospholipid
solubilizer is incorporated in each phase, it may be the same
phospholipid solubilizer in both phases or different in each.
[0088] In one embodiment of the invention, the oil phase comprises
more than one component. For example, as just mentioned, the oil
phase may comprise a solubilizer.
[0089] Within this preferred embodiment, it is further preferred
that the HLB of the oil be in the range 0-10 (preferably 1-5) and
the HLB of the solubilizer be in the range 10-20 and optionally
11-20 (preferably 11-15).
[0090] Particularly preferred oils in the lower HLB category
include medium chain tryglycerides, 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 (eg 1349 WL), Labrafil, Labrasol, Captex 355 and and
Miglyol 810.
[0091] Particularly preferred solubilizers in the higher HLB
category include polyethoxylated castor oils (polyethylene glycol
ethers). The preferred commercial product for example is
Cremophor.
[0092] While higher HLB solubilizers can be considered surfactants,
the invention also contemplates, additionally or alternatively,
inclusion of any other appropriate (non-ionic or other) surfactant
in the oil phase.
[0093] For certain active principles, particularly
hydrophobic/lipophilic agents such as cyclosporine A for example,
the present inventors/applicants have observed to their surprise
that incorporation into the oil phase of a solubilizer 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
composition in vitro.
[0094] By "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.
[0095] The oil phase preferably also comprises a co-solvent for the
active principle (particularly in the case of poorly-soluble active
principles such as for example cyclosporine or celecoxib). Examples
of suitable co-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. PEG of molecular
weight 190-210 (eg. PEG 200) or 380-420 (eg. PEG 400) are preferred
in this embodiment. Suitable PEG can be obtained commercially under
the name "Carbowax" manufactured by Union Carbide Corporation
although many alternative manufacturers or suppliers are
possible.
[0096] A particularly preferred oil phase according to the
invention is made up of an oil (low HLB), a solubilzer (high HLB)
and a co-solvent. For example the following three commercial
products: Transcutol P (as co-solvent), Myglyol 810 (as oil) and
Cremophor (as solubilizer) is particularly preferred. Miglyol has a
low HLB and Cremophor has a high HLB. This particularly preferred
oil phase is preferably used to prepare (and is preferably a
component of) a composition of the invention comprising
cyclosporine. Another preferred oil phase comprises a waxy oil e.g.
polyglycol mono- and di-esters of 12-hydroxystearic acid and free
polyethylene glycol such as, for example, Solutol in which up to 1%
of oil-soluble or hydrophobic antioxidant e.g. hydralazine or BHT
is included. This second particularly preferred oil phase is
preferably used to prepare (and is preferably a component of) a
composition of the invention comprising tacrolimus. In specific
embodiments, compositions according to the invention (and which
comprise the aforementioned preferred oil phases) are free of other
oily and/or hydrophobic components. In one embodiment, the
composition comprises an oil-soluble or hydrophobic antioxidant
e.g. hydralazine or BHT or carnosic acid or vitamin E.
[0097] The oil phase may also be a water-in-oil (w/o) emulsion so
that the composition of the invention becomes a
water-in-oil-in-water (w/o/w) emulsion.
[0098] The oil phase may include one or more active principles as
discussed in more detail elsewhere herein particularly in the
section entitled "Active Ingredients" et seq and may also include
one or more volatile or non-volatile solvents, which may be the
same or different from the co-solvent or solubilizer previously
mentioned. Such solvents may for example remain in the composition
of the invention following processing e.g. initial dissolution of
the active principle, and have no particular function in the final
composition. Alternatively, such solvents if present may function
to maintain the active principle in 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 aqeuous phase of the
composition according to the invention. An example of such a
solvent is ethanol. Another example is transcutol which is already
mentioned as a co-solvent.
[0099] It will be appreciated, therefore, that the invention
provides inter alia a bead or mini-bead comprising a water-soluble
polymer matrix material in which are dispersed droplets of oil, the
composition comprising an active principle and the oil comprising a
combination of a high HLB compound, e.g. a solubilizer, and a low
HLB compound, e.g. an oil, and optionally including a
co-solvent.
Aqueous Phase
[0100] The principal component of the aqueous phase of the
composition according to the invention (preferably between 20% and
70%, more preferably between 30% and 60%, still more preferably
between 35% and 55%, by dry weight thereof) is a water-soluble
polymer matrix material although other components may also be
included as described below. The inventors/applicants have
surprisingly found that inclusion of too little of the
water-soluble polymer matrix material can for certain active
principles lead to non-incorporation or leaching of the active out
of the composition, particularly when in the form of mini-beads.
For certain embodiments, for example vaccine compositions and
compositions comprising solutol or a retardant (see below), it is
preferred that the aqueous phase comprise from 55% and 65% of the
dry weight of the composition.
[0101] While mixtures of water-soluble polymer matrix materials are
contemplated by the invention, preferably the composition of the
present invention comprises a matrix material which is
substantially a single material or type of material among those
described herein and/or a matrix which can be solidified without
inclusion of specific additional polymeric components in the
aqueous phase. However, mixtures may be preferred to achieve
certain performance characteristics. Thus it may be desired to
incorporate certain constraining or retarding substances
(retardants) into the water-soluble polymer matrix. In certain
embodiments, such incorporation permits a coat (or coating) to be
dispensed with. In other embodiments where a constraining or
retarding agent is included into the water-soluble polymer matrix,
a coat (or coating) may be present and desirable. For example,
incorporation of a retarding agent which is insoluble in acid
milieu (such as the stomach) is selected to prevent or retard
release in the stomach and a coating may not be needed ie. the
composition may be free of a coat/coating. Alternatively,
incorporation of a retarding agent which is soluble in acid media
may be selected to retard release in the intestine distal to the
stomach. Again a coating may not be needed ie. the composition may
be free of a coat/coating. However, a composition according to the
invention which incorporates a retarding agent soluble in acid
media may optionally be coated e.g. with an acid-resistant polymer
to achieve particular advantage. Such a composition is protected
from (complete) gastric release (or gastric release is retarded)
owing to the effect of the acid-resistant polymer coat. Distal to
the stomach, following loss of the coat, the acid-soluble agent
retards release because the milieu of the small and large intestine
is no longer acid. Retarding or constraining agents insoluble in
acid mileu include polymers whose solubility is pH-dependent ie
soluble at higher pH. Such polymers are described in detail in the
section below entitled "Coating" and such polymers may be used
either as coats/coatings or as retarding agents incorporated into
the water-soluble polymer matrix. An example of a suitable
retarding agent mentioned in the section below entitled "Coating"
is HPMCP (hydroxy-propyl-methyl-cellulose-phthalate also known as
hypromellose phthalate) which is used to prevent release in the
gastric environment since it is soluble above pH 5.5--see that
section for other examples of polymers soluble in non-acid (basic)
media. HPMCP may also be used as a pore-former. Retarding or
constraining agents soluble in acid mileu include polymers whose
solubility is pH-dependent ie. soluble at lower pH. Such polymers
include cationic polymers such as for example copolymers based on
dimethylaminoethyl methacrylate, butyl methacrylate, and methyl
methacrylate. An example of such a cationic co-polymer which may be
used according to the invention is Eudragit E PO commercially
available from Evonik Industries.
[0102] In one embodiment, the water-soluble polymer matrix material
may be of one or more of those selected from gelatine, agar, a
polyethylene glycol, starch, casein, chitosan, soya bean protein,
safflower protein, alginates, gellan gum, carrageenan, xanthan gum,
phtalated gelatine, succinated gelatine, cellulosephtalate-acetate,
oleoresin, polyvinylacetate, hydroxypropyl methyl cellulose,
polymerisates of acrylic or methacrylic esters and
polyvinylacetate-phtalate and any derivative of any of the
foregoing. Mixtures of one or more water-soluble polymers
comprising the matrix are also contemplated. In specific
embodiments binary or tertiary etc combinations of any of the above
substances are foreseen. An unexpected advantage of combining
certain water-soluble polymers to form the matrix is that it allows
for a reduction in the total amount of water-soluble polymer
employed. This may have cost advantages or may allow greater
loading of other materials such as, for example, one or more active
principles. Inclusion of (addition of) a second water-soluble
polymer to form the matrix may also give more strength to the
composition of the invention e.g. beads.
[0103] In a preferred embodiment, the polymer matrix material is a
hydrocolloid ie. a colloid system wherein the colloid particles are
dispersed in water and depending on the quantity of water available
can take on different states, e.g., gel or sol (liquid). It is
preferred to use reversible hydrocolloids (eg agar, gelatin etc) as
opposed to irreversible (single-state) hydrocolloids. Reversible
hydrocolloids can exist in a gel and sol state, and alternate
between states with the addition or elimination of heat. Gelatin is
a thermo-reversible, rehydratable colloid and is particularly
preferred. Gelatin derivatives such as, for example, succinated or
phtalated gelatins are also contemplated. Hydrocolloids which may
be used according to the invention 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) 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.
[0104] The immobilized aqueous phase of the composition according
to one embodiment of the invention is preferably a gel ie. a
substantially dilute crosslinked system, which exhibits no flow
when in the steady-state. The internal network structure of the
solidified aqueous phase may result from physical or chemical
bonds, as well as crystallites or other junctions that remain
intact within an extending fluid e.g. water.
[0105] In an alternative preferred embodiment, the polymer matrix
is 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.
[0106] In an alternative preferred embodiment, the 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.
[0107] In the embodiment in which gelatin is the polymer matrix of
the invention, 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.
[0108] According to the invention, in the embodiment in which
gelatin is the polymer matrix, it is preferred to use gelatin with
bloom strength between 200 and 300, preferably between 210 and
280.
[0109] According to the invention, in the embodiment in which
gelatin is the water-soluble polymer matrix material, 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 mini-bead manufacture.
[0110] Commercially gelatin can be obtained from the Sigma Chemical
Company, St. Louis, Mo. USA or from Nitta
(http://www.nitta-gelatin.com).
[0111] 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 (eg sodium
alginate described above) are preferred for example when the active
principle to be incorporated in the composition of the invention is
temperature-labile or whose activity may be affected by exposure to
higher temperatures.
[0112] According to the invention, in the embodiment in which
gelatin is the polymer, 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 composition 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 include glycerin (1,2,3-propanetriol), D-sorbitol
(D-glucitol), sorbitol BP (a non-crystallizing sorbitol solution)
or an aqueous solution of D-sorbitol and sorbitans (eg Andidriborb
85/70). Other or similar low molecular weight polyols are also
contemplated. Polyethylene glycol may also be used although this is
less preferred and indeed particularly preferred compositions of
the invention are free or substantially free of PEG or derivatives
thereof. Glycerin and D-sorbitol may be obtained from the Sigma
Chemical Company, St. Louis, Mo. USA or Roquette, France.
[0113] As noted above, some constituents of the present invention
may play more than one role. For example when one of the active
principles (see below) is ibuprofen, it may also act as a
plasticiser owing to its particular physico-chemical properties.
Choice of ibuprofen has particular advantages in relation to higher
loading as "conventional" plasticiser, for example dibutyl sebacate
or DBS, may be reduced in quantity. Alternatively it is
contemplated that the surfactants discussed above may be selected
for their plasticiser characteristics to achieve particular
advantage.
[0114] Softeners, 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 composition of the invention, even
more preferably between 3 and 8%, and most preferably between 4%
and 6%.
[0115] As noted in more detail above in the section on surfactants,
it is preferred to include one or more surfactants in the aqueous
phase. Certain surfactants may also act as plasticisers or
softeners or vice versa.
[0116] Although not essential, the aqueous phase may also
optionally contain a disintegrant where it is particularly desired
to enhance the rate of disintegration of the composition of the
invention.
[0117] Examples of disintegrants which may be included are alginic
acid, croscarmellose sodium, crospovidone, low-substituted
hydroxypropyl cellulose and sodium starch glycolate.
[0118] A crystalisation inhibitor (eg approximately 1% by dry
weight of the composition) may also be included in the composition
of the invention, preferably in the aqueous phase. An example is
hydroxy propyl/methyl cellulose (HMC or HPMC, hypromellose etc)
which may play other roles such as, for example, emulsifier (see
above). In addition, the aqueous phase may include some or all of a
solvent used during processing to dissolve, or facilitate
dissolution of, an active principle e.g. an active principle
comprised in the oil phase. An example is ethanol (see discussion
above on use of solvents in oil phase).
[0119] The invention includes compositions comprising a solid phase
comprising a water-soluble polymer matrix material and an oil phase
dispersed in the solid phase.
Shape, Size and Geometry
[0120] The composition of the invention can be formed into a
limitless number of shapes and sizes. In the section below
describing the process for making the composition, various methods
are given including pouring or introducing a fluid emulsion into a
mould where it hardens or can be caused to harden. Thus the
composition can be created in whichever form is desired by creating
an appropriate mould (eg in the shape of a disc, pill or tablet).
However, it is not essential to use a mould. For example, the
composition may be in the form of a sheet e.g. resulting from
pouring a fluid emulsion onto a flat surface where it hardens or
can be caused to harden.
[0121] Alternatively, the composition may be in the form of spheres
or spherical-like shapes made as described below. Preferably, the
composition of the invention is in the form of substantially
spherical, seamless beads, especially mini-beads. The absence of
seams on the mini-bead 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 mini-beads
also enhances consistency of dissolution of the mini-beads.
[0122] The preferred size or diameter range of mini-beads according
to the invention can be chosen to avoid retention in the stomach
upon oral administration of the mini-beads. 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 prediction of therapeutic effect post-dosing
more accurate. Compared to a single large monolithic oral format
such as, for example, a traditional compressed pill, a plurality of
mini-beads released into the GI tract (as foreseen by the present
invention) permits greater intestinal lumen dispersion so enhancing
absorption via exposure to greater epithelial area, prevents
irritation (e.g as otherwise seen with NSAIDs) and achieves greater
topical coating (e.g. as may be desired for local drug effect in
certain parts of the GI tract for example the colon). Reduction of
residence time in the ileo-caecal junction is another
advantage.
[0123] The composition of the invention is preferably monolithic
meaning internally (ie. cross-sectionally) homogeneous. This is
particularly preferred for the mini-bead embodiment.
[0124] In the embodiment of the present invention which is in the
form of mini-beads, the mini-beads generally range in diameter from
0.5 mm to 10 mm with the upper limit preferably 5 mm. A
particularly convenient upper limit is 2 mm with 1.7 mm being
particularly preferred. The lower limit can be e.g. approximately 1
mm, preferably from 1.2 mm, more preferably from 1.3 mm, most
preferably from 1.4 mm. While the invention may be practiced in
relation to the above size ranges, it is preferred to have a bead
population which is substantially homogeneous as to bead size
(diameter). In this respect, a given bead population may comprise
beads of diameter substantially equal to the figures just given.
More than one population of beads, differing as to bead size
(diameter) may be combined within a single formulation. Thus the
invention includes embodiments in which populations of beads have
substantially homogeneous diameters of approximately 0.5 mm, 1.2
mm, 1.3 mm, 1.4 mm, 1.7 mm, 2 mm or 5 mm.
[0125] Another possible form of the composition of the invention is
as hemispherical beads two of which may optionally be joined at the
flat face to create a single mini-bead with two distinct halves,
each having a distinct composition, if that is desired, e.g. each
containing different active principles or the same active
principles but different excipients e.g. to achieve differing
permeability, solubilization or release profiles as between the two
hemispheres.
[0126] The embodiment in which the composition of the invention
takes the form of mini-beads can be further developed to create a
larger mass of mini-beads e.g. via compression (with appropriate
oil or powder-based binder and/or filler known to persons skilled
in the art of pharmaceutical formulation and with the option of
including additional quantities of the same API as in the
composition of the invention or a different API a preferred example
being where the composition of the invention takes the form of
beads which comprise immediate or controlled release cyclosporine
and the binder or filler comprises MMF, mycophenolate mofetil, an
immunosuppressant) of a plurality of mini-beads which disintegrate
at a different rate in different conditions than a unitary moulded
form of the same shape. The larger (eg 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
mini-bead embodiment solves is the "dead space" (above the settled
particulate contents) and/or "void space" (between the particulate
content elements) typically found in hardgel 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 mini-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 minibeads 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 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 oil phase constituents
described herein or it may be one or more surfactants, or one or
more solubilizers. Particularly preferred but non-limiting examples
are corn oil and the commercial products known as Span 85,
Labrafac, Trancutol P and Tween 80. An example of a liquid medium
which may be used in this embodiment and which contains an active
principle is the commercially available cyclosporin
pre-microemulsion Neoral.TM.. It is particularly preferred to
formulate beads according to the invention in Neoral and to fill a
hard gel capsule.
[0127] Another possible form of the composition of the invention is
as a capsule in which the core of the composition is a solid (eg
gastro-retentive float material such as, for example, biocarbonate
salts) or a fluid (a gas or a liquid). If the core is a liquid, it
may contain an active principle and/or excipients which may be the
same or different from those described above. Like the
hemispherical beads described above, such capsules may have two
halves of different constitution and sealed hermetically to retain
the internal fluid. An internal layer e.g. internal film layer of
non-aqueous material on the inner face of the sphere, may be
included if it is desired that the core be an aqueous liquid such
that the internal layer prevents the aqueous core from coming into
contact with the inner surface of the capsule. With or without an
intermediate layer, the core may be a variant of the composition of
the invention so that the composition of the invention, in the
mini-bead embodiment, comprises a core made from a first
composition according to the invention and a capsule made from a
second composition according to the invention.
[0128] The mini-bead embodiment of the invention, while by itself
offering a range of solutions to the issues identified above, may
also be used as a starting point for creation of further eg.
pharmaceutical or nutraceutical forms for example by using the
mini-bead as a nonpareil seed on which additional layers of
material can be applied as is well known to a person skilled in the
art e.g. of pharmaceutical science. The material of the additional
layers may comprise the same or different active principle and/or
the same or different excipients as are described in this document.
Such variants allow differential release of the same or different
active principles and facilitate inclusion of multiple fixed-dose
combination products as for example discussed in connection with
the popularly termed "polypill" which denotes a single pill
comprising more than one active principle in a fixed dose
combination, an idea of particular relevance to cardiovascular
medicine.
[0129] The composition of the invention may have a coat of
additional material on its outer surface. This coat may be applied
in a number of ways, including drug layering, as described more
particularly in the section below entitled "coating". In one such
embodiment, the composition of the invention comprises an acid
within the bead e.g. included within the water soluble polymer
matrix or as a liquid core in mini-capsular format and bicarbonate
applied as a coat e.g. by drug layering. If the bead has a
polymeric coat, e.g. to control release into the colon, the
bicarbonate may optionally or additionally be included in or be
absent from the coating polymer. This composition is intended to
release carbon dioxide in the GI tract e.g. to reduce pain or to
reduce inflammation. In a related embodiment, the core or the bead
comprises an acid to enhance the solubility of active principles of
various pKa (acid dissociation constant) in the small intestine or
colon. Alternatively, the core or the bead comprises a base to
enhance the solubility of active principles of various pKa in the
stomach.
Other Characteristics
[0130] The composition of the invention, in certain embodiments,
comprises one or more elements, components, excipients, structural
features, functional features or other aspects of the prior art
described above.
[0131] To summarise a limited number of embodiments of the
invention, the composition as described above and elsewhere herein
may additionally be one or more of the following: substantially
water-free, in a gel state, in a solid state, undissolved,
non-powdered, formed, shaped, and not in solution.
[0132] Unless geometrically designed to comprise inner aqueous
compartments (eg w/o/w format or capsular format with liquid core),
it is desirable that the composition of the invention is
essentially or substantially dry, e.g. contains less than 5%,
preferably less than 1% of free water by weight. The mini-beads are
preferably homogeneous although processing conditions may be varied
(see below) to achieve for example heterogeneity such as, for
example, a harder skin and softer core with less than complete
immobilization of oil droplets towards the core as opposed to the
surface of the bead. Larger (eg non-beaded) forms or shapes of the
composition according to the invention may particularly be
engineered to embody such heterogeneity.
[0133] The low free-water content is a distinguishing feature of
certain embodiments of the compositions of the present invention.
The free-water content can be measured using thermogravimetic
analysis (TGA), for example with commercially available
instrumentation, e.g. using a TGA Q 500 of TA 0 series instrument.
TGA measures changes in weight in relation to a change in
temperature. For example, a TGA method can comprise a temperature
scan, e.g. from 20 to 400.degree. C. at 20.degree. C. per minute,
where the moisture content is obtained from the sample weight loss
at about 100 degrees Celsius.
[0134] In one embodiment, the oil droplets in the composition of
the invention are homogeneously dispersed in the solidified aqueous
phase (or in some embodiments the water-soluble polymer matrix
material) with substantial absence of coalescence between adjacent
oil droplets. Thus the emulsion is preferably maintained during
solidification. Coalescence of neighbouring oil droplets,
preferably only does so, if at all, on rehydration of the
composition of the invention.
[0135] Depending on process parameters, droplet size can vary
broadly e.g. from 10 nm to 10 .mu.m (diameter). However, the
inventors/applicants have found that it is beneficial to maintain
droplet size in the range from 100 nm to 1 .mu.m, e.g. from 300-700
nm. The term "emulsion" therefore includes microemulsions and
nanoemulsions.
[0136] The composition of the invention generally comprises
multiple oil drops or droplets within a moulded or shaped form e.g.
a mini-bead which might typically contain many hundreds or
thousands of droplets as distinct from a powder which generally
derives from micron-sized particles incorporating a single or a
small number of oil drops or droplets often following coalescence
of smaller droplets during spray-drying. While powder embodiments
are not excluded, the composition of the invention, if particulate,
preferably comprises particles larger than powder particles such
that the composition is in a non-powdered form.
[0137] In the embodiment in which the invention is in the form of
minibeads, a plurality of minibeads may be presented in a single
format e.g. contained in a single hardgel capsule which releases
the mini-beads eg. in the stomach. Alternatively the minibeads may
be presented in a sachet or other container which permits the
minibeads 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 mini-beads may be
administered as a tablet for example if a plurality of mini-beads
are compressed into a single tablet as described elsewhere herein.
Alternatively, the mini-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
mini-beads are released into a fluid or other contents of the
bottle or vial such that the beads are dispersed (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. A related or similar approach is also
contemplated for e.g. timed release of mini-capsules into a
reactor, feeding environment e.g. tank, incubator etc.
[0138] The mini-beads so-presented may be of a single type (or
population) or may be of multiple types (or populations) differing
between populations in relation to one or more features described
herein e.g. different API or different excipients or different
physical geometry, coated, multiply coated, uncoated etc.
[0139] In one embodiment, the invention allows for mini-beads
having immediate release (IR) characteristics e.g. bearing no coat,
enteric-only coat or coat designed to prevent release and/or
dissolution of the bead only for a limited time or lacking a
retardant in the aqueous phase. In another embodiment, the
invention allows for mini-beads having delayed or sustained release
(SR) characteristics e.g. bearing a coat (or more than one coat) as
described in more detail elsewhere herein, particularly in the
section entitled "coating". The invention also provides for an
embodiment in which immediate release mini-beads are produced in
combination with a Sustained Release or Controlled Release (CR)
mini-beads in varying ratios of IR:SR/CR. The immediate release
mini-beads can be combined with a Sustained or Controlled release
mini-bead component in the following ratios (w/w by potency) e.g.
10% Immediate Release (IR)+90% Sustained (SR)/Controlled Release
(CR) minicapsules; 20% IR+80% SR/CR; 30% IR+70% SR/CR; 40% IR+60%
SR/CR and 50% IR+50% SR/CR.
Active Ingredients
[0140] The present invention provides a vehicle for delivery of
active principles which can be of various types including cosmetic,
food, food supplements, nutraceuticals, pharmaceuticals,
aquaculture, etc. It can also include active principles used in
sterilisation or purification of contaminated liquids e.g. water
contaminated with pathogens for example bacteria. The composition
of the invention can be used also to absorb active principles in
order for example to remove pollutants from the environment
including air or water or from the intestine or specific part
thereof e.g. colon.
[0141] In addition, the composition of the invention may be used to
deliver active principles which deactivate, inhibit, sequester or
down-regulate enzymes e.g. in the intestinal lumen (for example
lipases, proteinases etc) which may be desirable to abate the
effects of a bacterial infection and or to facilitate the
absorption of other active principles whose absorption may
otherwise be affected by such enzymes.
[0142] The composition of the invention may also be used to remove
fats from the intestine for example by inclusion of a fat absorber
or fat sequestrant (or other agent susceptible of binding,
reversibly or otherwise to fats present in the intestinal
lumen).
[0143] Separately or in conjunction with one of the preceding
functions, the composition of the invention may also include an
active principle able to interact with bacteria in the gut for
example by delivery of antibiotics (including lantibiotics or
bacteriocins) to a specific portion of the gut so as to reduce side
effects or, in the case of a peptide as active principle, its
survival from degradation as it passes through the upper GI
tract.
[0144] Other active principles contained in the same or a separate
composition may sequester antibiotics e.g. in the lower small
intestine, ileum or colon. Thus in one embodiment, the composition
of the invention delivers antibiotics relatively proximally and
reabsorbs them relatively distally to reduce the amount of excess
antibiotic remaining in the colon and/or excreted. In a related
embodiment, the composition of the invention comprises enzymes to
break down or neutralize or deactivate antibiotics e.g.
beta-lactams and delivers and/or releases these to target locations
in the GI tract e.g. in the colon.
[0145] Active ingredients may also be included in the composition
of the invention to enhance absorption of nutrients e.g. in the
small intestine or to provide nutrition or nutritional
supplementation. In a related embodiment, the composition of the
invention comprises functional oils in combination with a natural
plant or marine extract. An example of a natural plant extract is
berberine which is a quaternary ammonium salt from the group of
isoquinoline alkaloids. An example of functional oils (the term
also includes "designer" oils) are medium chain triglycerides
(MCTs) derived from tropical oils which have had longer chain and
"bad" palmitic acid removed to leave medium chain "good" fatty
acids behind. "Good" oils, such as, for example, omega-3-rich
flaxseed oil may then be added to achieve variant functional
oils.
[0146] The compositions of the present invention may be
administered to an animal e.g. fish or mammal by any appropriate
route including oral, anal, rectal, vaginal, urethral, intravenous,
subcutaneous, transcutaneous, intraperitoneal etc or may be added
to the environment e.g. food, drink, water etc for absorption by
the animal. The invention also relates to a method of treating one
or more animals just described by administering such a composition
via the oral, anal, rectal, vaginal, urethral, intravenous,
subcutaneous, transcutaneous or intraperitoneal route or by adding
the composition to the environment e.g. food, drink, water etc for
absorption by the animal.
[0147] A particular focus of the present invention is the delivery
of pharmaceuticals. This applies particularly to the embodiment in
which the composition takes the forms of mini-beads e.g. for oral
administration. The composition may comprise one or more active
principles (also referred to as active pharmaceutical ingredients
or APIs) and it is preferred to incorporate lipophilic APIs (if
any) in the oil phase and hydrophilic APIs (if any) in the aqueous
phase. More than one active principle may be incorporated in a
single mini-bead and/or in distinct populations of mini-beads
within a single dosage form, e.g. hardgel capsule, and specific
binary fixed dose combinations are discussed in a separate section
below (although this section is not to be taken as a limitation on
the full extent of possible binary combinations). Ternary,
quaternary etc combinations are also contemplated.
[0148] In relation to its pharmaceutical applications, the
invention applies to a wide range of drug types e.g. as classified
according to the Biopharmaceutics Classification System (BCS) which
comprises 4 classes:
Class I--High Permeability, High Solubility
Class II--High Permeability, Low Solubility
Class III--Low Permeability, High Solubility
Class IV--Low Permeability, Low Solubility
[0149] In relation to the APIs incorporated in the oil phase of the
invention, Classes II and IV are of particular relevance.
[0150] For the purposes of this description and claims, a drug
substance is considered highly soluble when the highest dose
strength is soluble in .ltoreq.250 ml water over a pH range of 1 to
7.5 (and of low solubility if not meeting these criteria) and
highly permeable when the extent of absorption in humans is
determined to be .gtoreq.90% of an administered dose, based on
mass-balance or in comparison to an intravenous reference dose (and
of low permeability if not meeting these criteria).
[0151] Again, for the purposes of this description and claims, a
drug product is considered to be rapidly dissolving when
.gtoreq.85% of the labeled amount of drug substance dissolves
within 30 minutes using USP apparatus I or II in a volume of
.ltoreq.900 ml buffer solutions. Usually the buffer is phosphate
buffer (PBS) of pH 7.4.
[0152] Regarding solubility determination, further details are
provided below and in relation to specific examples. However, in
general terms, solubility determination is carried out by one of
four methods: [0153] Visual disappearance of drug [0154]
pH-solubility profile of test drug in aqueous media with a pH range
of 1 to 7.5. [0155] Shake-flask or titration method. [0156]
Analysis by a validated stability-indicating assay.
[0157] Permeability determination can be carried out by assessing
the extent of absorption in humans or other in vivo permeability
methods. Approaches include: [0158] Mass-balance pharmacokinetic
studies. [0159] Absolute bioavailability studies. [0160] In vivo
intestinal perfusion studies in humans. [0161] In vivo or in situ
intestinal perfusion studies in animals [0162] In vitro permeation
experiments with excised human or animal intestinal tissue [0163]
In vitro permeation experiments across epithelial cell
monolayers
[0164] Permeability determination methodology is not standardised
and results can therefore depend on experimental conditions. For
example, some APIs e.g. cyclosporine A (CyA) can be classed as
either Class II (high permeability, low solubility) or Class IV
(low permeability, low solubility). Chiu et al in Pharmaceutical
Research Volume 20, 5 2003 assign CyA to Class II, while Sharma et
al in Farmaco. 2005 60 (11-12):884-93 assign it to Class IV.
Although there is agreement on low solubility, there is apparent
disagreement on permeability and this is believed to be because
permeability changes with the formulation and/or tissue site under
study with Chiu et al. for example apparently discussing jejunal
permeability.
[0165] For pharmaceutical applications, the composition of the
invention may be applied to a very wide range of active principles
with a particular focus being on hydrophobic/lipophilic active
principles for incorporation in to the oil phase bearing in mind
that hydrophilic active principles may also be included in the
aqueous phase (including in the inner aqueous phase if the oil
phase is a w/o emulsion).
[0166] For example the composition of the invention can be used in
the case of insoluble active ingredients such as, for example,
nifedipine, lipid soluble active ingredients such as, for example,
gemfibrizol, and pH sensitive active ingredients such as, for
example, captopril.
[0167] The composition of the invention in the mini-bead embodiment
is also suitable for the administration of active ingredients which
are sensitive to the pH environment in the stomach, such as, for
example, omeprazole and other proton pump inhibitors used in
anti-ulcer treatment. Active ingredients for the treatment or
prevention of H. pylori infection are particularly
contemplated.
[0168] The formulation according to the invention can also be used
to improve the bioavailability of active ingredients such as, for
example, terfenadine which have a low oral bioavailability.
Moreover, the composition according to the invention can also be
used to dramatically increase the absorption of active ingredients
which are poorly absorbed from or are destroyed in the
gastrointestinal tract such as, for example, captopril,
cyclosporin, calcitonin, heparins and heparinoids. Certain
antibiotics, including some lantibiotics e.g. lacticin are
destroyed in the gastrointestinal tract by the action e.g. of
enzymes such as, for example, .alpha.-chymotrypsin and pepsin or by
acid. One embodiment of the invention relates to compositions which
prevent or reduce such destruction and release such an active
principle at a target site e.g. distal to the stomach or small
intestine. Thus, in distinct embodiments, the invention provides
compositions comprising captopril or cyclosporin or calcitonin or
heparin or low molecular weight heparin or pentasaccharide heparin
derivative or heparinoids or lacticin. Nucleic acids such as, for
example, siRNAs, may also be formulated in this way and the
invention includes embodiments in which the composition comprises
one or more nucleic acid.
[0169] Suitable classes of therapeutic agents which can be
delivered using this invention include but are not limited to
poorly water soluble drugs such as, for example, cardiovascular
agents, lipid lowering agents, anti-diabetic agents e.g. PPAR-gamma
activators, anti-epileptics, anti-infectives (including antibiotics
such as, for example, lantibiotics and bacteriocins), anti-fungal
agents, anti-viral agents, antipsychotic agents,
immunosuppressants, protease inhibitors and cyclic peptides. In a
related embodiment, the composition of the invention comprises an
active principle capable of activating PPAR-gamma e.g.
rosiglitazone or pioglitazone. The invention relates also to a
method of treating inflammatory bowel disease by administering such
a formulation to a mammal, e.g. a human patient, in need
thereof.
[0170] Suitable classes of therapeutic agents which can be
delivered using this invention include but are not limited to
peptides, proteins, vaccines, and oligonucleotides, including
non-covalent or covalent modified versions thereof including --NO,
--HS and --CO2 derivatives.
[0171] It is to be further appreciated that the present invention
may be used to deliver a number of drugs, singly or in various
combinations, as well as nutritional supplements or various
nutritional or pharmaceutical adjuvants. The term "drug" used
herein includes but is not limited to peptides or proteins (and
mimetics as well as covalent, non-covalent or chemical analogues
thereof), antigens, vaccines, hormones, analgesics, anti-migraine
agents, anti-coagulant agents, medications directed to the
treatment of diseases and conditions of the central nervous system,
narcotic antagonists, immunosuppressants, immunostimulators, agents
used in the treatment of AIDS, chelating agents, anti-anginal
agents, chemotherapy agents, sedatives, anti-neoplastics,
prostaglandins, antidiuretic agents, DNA or DNA/RNA molecules to
support gene or other nucleic acid-based therapeutics and entities
leading to various immunotherapies, including antigenic and nucleic
acid-based vaccines or immunotherapies, primers and adjuvants of
such as well as organisms that synthesize and secrete therapeutic
or health modulating entities. The present invention may also be
used to deliver NSAIDs and in one embodiment relates to a
composition of an NSAID in particular for preventing and/or
treating bowel cancer and/or polyps and/or to block PGP to enhance
the effect of anti-cancer agents. The present invention may also be
used to deliver bile salts or other active principles or primary
bile acids e.g. chenodeoxycholic acid (CDCA), or derivatives e.g.
salts thereof which are capable of binding to and activating the
nuclear farnesoid X receptor (FXR). The invention also relates to a
composition comprising such active principles and also to a method
of treating or preventing hypercholesterolemia or diarrhea or
chemotherapy-induced diarrhea or constipation-predominant irritable
bowel syndrome (IBS-C) by administering such a formulation to a
mammal, e.g. a human patient, in need thereof.
[0172] Moreover, the active pharmaceutical agent(s) included in the
composition of the invention may be in a solubility-modified form
so that when released in the colon or other target part of the GI
tract, it (they) is (are) more or less readily absorbed (depending
on the extent to which absorption is or is not desired).
[0173] As noted above, the active pharmaceutical agent(s) may be a
small molecule, a macromolecule or biopharmaceutical and includes
any variant, derivative or conjugate designed to enhance
permeability, increase lipophilicity, and/or increase
hydrophilicity or the like (or reduce immunogenicity and increase
stability in the case of a biopharmaceutical such as a peptide,
protein, nucleic acid or carbohydrate). The active pharmaceutical
agent may alternatively be an amino acid such as, for example,
glycine. Glycine is of particular interest given its ability to
protect human intestinal Caco-2 and HCT-8 cells against oxidative
agents and its ability to reduce the intracellular concentration of
reactive oxygen species and its ability to preserve intracellular
glutathione concentration. The invention therefore includes a
composition of the disclosure comprising glycine. In a related
embodiment, the invention provides a composition for use in
protecting human intestinal cells against oxidative agents or to
reduce the intracellular concentration of reactive oxygen species
of such cells or to preserve intracellular glutathione
concentration or to prevent/treat inflammatory bowel disease or
ischemia-reperfusion (IR) injury. The invention also provides an
embodiment comprising a method of maintaining intracellular
glutathione content or treatment of inflammatory bowel disease or
protection of mammalian intestine against oxidative damage caused
by IR injury wherein a composition of the invention is administered
to a mammal in need thereof.
[0174] The pharmaceutical active may be an immunosuppressive, for
example cyclosporine A or tacrolimus or sirolimus or derivatives
thereof. The pharmaceutical active may be a hydroxylase inhibitor,
for example a propyl hydroxylase inhibitor or an asparaginyl
hydroxylase inhibitor. Particular examples are: DMOG, hydralazine,
FG-4497 and FG4095. The pharmaceutical active may modulate oral
tolerance. For example, the active entity may be gluten or a gluten
derivative. The pharmaceutical active may be an ion channel blocker
such as, for example, nimodipine. The pharmaceutical active may be
an opioid. For example the pharmaceutical active may be morphine or
morphine sulphate or may be an opioid-induced constipation
modulator for example a peripheral opioid receptor antagonist such
as for example methylnaltrexone, naltrexone or naloxone. The active
principle may be an antibody e.g. a polyclonal antibody. Thus the
present invention may be used to deliver one or more antibodies to
the GI tract, e.g. the colon, to inactivate viruses or bacteria
such as, for example, enterotoxigenic Escherichia coli (ETEC). The
invention relates to a composition comprising such active
principles and also to a method of treating viral or bacterial
infections of the GI tract by administering such a formulation to a
mammal, e.g. a human patient, in need thereof. The present
invention may also be used to deliver one or more antibodies e.g.
infliximab or natalizumab or bevacizumab to the GI tract, e.g. the
colon, for therapeutic or prophylactic benefit e.g. to treat
inflammatory bowel disease or prevention or treatment of
colo-rectal cancer (CRC). The invention also relates to a
composition comprising such active principles and also to a method
of preventing or treating inflammatory bowel disease or of
preventing or treating CRC by administering such a formulation to a
mammal, e.g. a human patient, in need thereof. The present
invention may also be used to deliver other types of active
principles, especially anti-cancer active principles, such as, for
example, tyrosine kinase inhibitors e.g. erlotinib or targeted
receptor tyrosine kinase (RTK) inhibitors such as, for example,
sunitinib malate, or pyrimidine analogues such as, for example,
fluorouracil (5-FU or f5U). The invention relates to a composition
comprising such active principles and also to a method of
preventing or treating inflammatory bowel disease or CRC by
administering such a formulation to a mammal, e.g. a human patient,
in need thereof.
[0175] Where the active principles are for vaccination, the vaccine
may for example be to prevent or treat gastro-intestinal infections
including those caused by Helicobacter pylori, Vibrio cholerae,
enterotoxigenic Escherichia coli (ETEC), Shigella spp., Clostridium
difficile, rotaviruses and calici viruses; or respiratory
infections including those caused by Mycoplasma pneumoniae,
influenza virus, and respiratory syncytial virus; and sexually
transmitted genital infections including those caused by HIV,
Chlamydia trachomatis, Neisseria gonorrhoeae and herpes simplex
virus. Adjuvants (one or more in admixture) may be chosen for
example from the group consisting of .alpha.-galactosylceramide
(also known as alphaGalCer), chitosan, cholera toxin e.g. rCTB
(recombinant B subunit of cholera toxin), E. coli heat labile
enterotoxin e.g. mLT, oligodeoxynucleotides such as, for example,
CpG, monophospholipid (MPL) e.g. MPLA, BCG, saponins including
those derived from the soap bark tree (Quillaja saponaria) such as,
for example, QS21 and QuilA, Poly I:C (polyinosinic:polycytidylic
acid or polyinosinic-polycytidylic acid sodium salt), various oils
such as, for example, cholesterol-related or cholesterol-derived
oils such as, for example, squalene (IUPAC name:
(6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexa-
eneoils. Such a vaccine or immuno-modulating composition may
optionally also contain one or more emulsifiers e.g. mannide
monooleate. If it is desired to utilise both squalene and mannide
monooleate as components of the composition, it is possible to
introduce both components into the composition of the invention
during manufacturing by using a commercially available water-in-oil
emulsion which includes squalene and mannide monooleate (Montanide
ISA 720 by Seppic Inc, France).
[0176] The composition of the invention may also or instead
comprise one or more active principle(s) selected from any of the
combinations described in the next section (single APIs from this
list are contemplated as are any combinations of such single APIs
such that for example, the combination described below of an
antibiotic susceptible to enzymatic or acidic degradation and a
degradative enzyme, is also intended to include a composition
according to the invention which comprises an antibiotic
susceptible to enzymic or acidic degradation not combined with a
degradative enzyme and also a composition according to the
invention which comprises a degradative enzyme not combined with an
antibiotic susceptible to enzymic or acidic degradation).
[0177] The present invention also provides methods of treatment of
an animal e.g. fish or mammal e.g. a human, and/or of one or more
of the above diseases comprising administering to the animal the
composition described herein.
[0178] Nourishment, medication or vaccines for non-mammalian
animals including fish or other aquatic life forms is also
contemplated.
[0179] The composition of the invention may be formulated in
capsules, suppositories, pessaries or may be used in extracorporeal
devices or other health-related e.g. medical or other devices.
Combinations of Active Ingredients
[0180] As noted above, more than one active principle may be
incorporated in a single mini-bead and/or in distinct populations
of mini-beads within a single dosage form, e.g. hardgel capsule.
The composition of the invention lends itself to fixed dose
combinations of particular drugs.
[0181] In one such embodiment the formulation of the invention
comprises a methylxanthine and a corticosteroid. The methylxanthine
may be selected from theophylline, pentoxifylline, and A802715 and
the corticosteroid may be selected from dexamethasone,
prednisolone, prednisone and budesonide.
[0182] Other preferred fixed dose combinations include:-- [0183] a
combination comprising a methylxanthine and an anticancer agent
(such as, for example, cisplatin, paclitaxel, daubomycin or
vincristine); [0184] a combination comprising a methylxanthine and
a Vitamin A analogue (such as, for example, valproaic acid,
valproate or isotretinoin); [0185] a combination comprising a
methylxanthine and a nitric oxide donor such as, for example,
nitroprusside, 02-acyl diazenium dipole or NO-NSAIDs such as, for
example, NO-aspirin; [0186] a combination comprising a
methylxanthine and a reactive oxygen species scavenger such as, for
example, stephenhenanthrine or uvariopsine; [0187] a combination
comprising an immunostimatory agent such as, for example, inosine
or other adjuvants and an anticancer agent such as, for example,
cisplatin, paclitaxel, daubomycin or vincristine; [0188] a
combination comprising various antiretroviral agents for the
treatment of HIV/AIDS, selected from sequinivir, stavudine,
ritonivir, lipinavir, amprenevir; [0189] a combination comprising
various antiretroviral agents for the treatment of HIV/AIDS
together with immunostimulatory agents; [0190] a combination for
the treatment of malaria comprising Artemisinin-based actives,
including artesunate plus sulfadoxine/pyrimethamine or artesunate
and amodiaquine; [0191] a combination for the treatment of
tuberculosis comprising isoniazid, rifampin and pyrazinamide;
[0192] a combination for the co-treatment of HIV/AIDS, Malaria and
TB, comprised of, from one of the following: HIV: Sequinivir,
Stavudine, Ritonivir, Lipinavir, or Amprenevir; Malaria:
Sulfadoxine/Primethamine/Artesunate; and Tuberculosis:
Isoniazid/Rifampin/Pyrazinamide; [0193] a combination comprising
various cardiovascular agents, selected from one or more of ACE
inhibitors, antidiuretics, statins, anticholesterol agents,
anti-coagulants, beta-blockers and anti-oxidants; [0194] a
combination comprising immunomodulators including vaccines,
antigens and immunotherapeutic agents with immunostimulatory agents
and/or adjuvants; [0195] a combination comprising a proton pump
inhibitor (PPI) [which may be selected from omeprazole,
lansoprazole, rabeprazole, esomeprazole, pantoprazole], an
anti-H-Pylori antibiotic [which may be selected from metronidazole,
tetracycline, clarithromycin, amoxicillin], H-blockers [which may
be selected from cimetidine, ranitidine, famotidine, nizatidine]
and stomach lining protectants [such as, for example, bismuth
subsalicylate], the PPI and H-blockers being released following
transit through the stomach, the antibiotic release in the stomach
and the stomach lining protectant being released in the stomach;
[0196] a combination comprising agents susceptible to efflux pump
activity or metabolism via cytochrome P450 subtypes, including 3A,
together with inhibitors of such; [0197] a combination comprising
an antibiotic susceptible to enzymatic degradation and a
degradative enzyme, the antibiotic have a controlled release
profile in the stomach and small intestine and the enzyme being
released in the distal small intestine and colon; [0198] a
combination comprising a narcotic, anti-psychotic or other
potentially addictive agent with an antidote or irritant, the
former drug classes being released in the stomach and small
intestine with the antidote, an innocuous or non-systemically
absorbed agent, being released in the colon, the irritant may be
irritating when injected but innocuous when taken orally; [0199] a
combination for the treatment of Alzheimer's Disease comprising a
cholinesterase inhibitor (such as, for example, donepezil,
rivastigmine, galantamine) and a N-Methyl-D-Aspartame (NMDA)
antagonist such as, for example, memantine; [0200] a combination
for the treatment of Alzheimer's Disease comprising a
cholinesterase inhibitor (such as, for example, donepezil,
rivastigmine, galantamine) and one or more from the following
classes: vitamins, statins, estrogen, nootrophic agents, ginkgo
biloba, anti-inflammatory agents, anti-depressants,
anti-psychotics, vasodilators, mood stabilizers and calcium channel
blockers, including Nimodipine; [0201] a cholesterol lowering
combination comprised of a HMG-CoA inhibitor and a intestinal
cholesterol uptake inhibitor; [0202] a combination for the
treatment of diabetes comprising insulin and an insulin sensitizer;
[0203] a combination for the treatment of diabetes comprising
insulin and an oral antihyperglycemic agent; [0204] a combination
for the treatment of diabetes comprising insulin and a sulfonylurea
agent or metformin; [0205] a combination for the treatment of
diabetes comprising insulin and an oral PTP-1B inhibitor; [0206] a
combination for the treatment of diabetes comprise an oral mimetic
agent with an appetite suppressant or fat uptake inhibitor such as,
for example, orlistat; [0207] a combination comprising an
anti-cancer agents and a potency enhancers, including
isoflavanoids, polyphenols and anti-cancer agent derivatives;
[0208] a combination containing a potency enhancer such as, for
example, an isoflavonoid and either a heart disease therapy,
osteoporosis therapy, autoimmune disease treatment or inflammatory
bowel disease treatment; [0209] a combination containing an opioid
(such as, for example, morphine or morphine sulphate) combined with
an opioid-induced constipation modulator (for example a peripheral
opioid receptor antagonist such as, for example, methylnaltrexone,
naltrexone or naloxone; [0210] a ternary combination containing an
opioid and peripheral opioid receptor (as exemplified above)
combined with an ion-channel blocker for example a calcium channel
blocker (eg nimodipine). [0211] PUFA (polyunsaturated fatty acid)
with other natural extracts, including antioxidants and/or
pharmaceutical actives [0212] diuretics and aldosterone inhibitors
with differential release profiles [0213] an anti-inflammatory
agents with a steroid [0214] an immunosuppressant with
acetylsalicylic acid (ASA) [0215] a methylxanthine with a
corticosteroid; e.g. for use in the treatment of chronic
obstructive pulmonary disease (COPD) and/or asthma or inflammatory
bowel disease (IBD) [0216] a COX-2 inhibitor with vitamin D.
[0217] The present invention also provides methods of treatment of
one or more of the above diseases using the composition described
herein.
Other Active Excipients
[0218] The heading of this section is for convenience only and does
not imply strict categorization. For example, a category, substance
or active principle described within this "other active excipients"
may also be considered to fall within another section or category
in this patent application. One (non-limiting) example is the group
of substances known as phospholipids which, according to the
invention may be excipients, permeability enhancers or active
principles (eg phosphatidylcholine which is useful for instance in
the treatment of inflammatory bowel disease).
[0219] However, in general terms, the invention foresees
incorporation into the composition of one or more of the following
substances or categories of substances in addition to the primary
active principle. For example, the composition may contain a
protectant such as, for example, a proteolytic enzyme inhibitor or
a protector against acid degradation or both (eg an alkali for
example sodium hydroxide); an adhesive entity such as, for example,
a muco- or bio-adhesive; excipients to maximize solubility of
active pharmaceutical compound(s); excipients to maximize
permeability of the active pharmaceutical compound(s) in the small
intestine; an antigen(s) and/or an adjuvant(s) to induce an
intestinal mucosal or a systemic immune response.
[0220] Regarding permeability enhancement, the typical excipients
include but are not limited to sodium caprate, sodium dodecanoate,
sodium palmitate, SNAG, chitosan and derivatives thereof, fatty
acids, fatty acid esters, polyethers, bile salts, phospholipids,
alkyl polyglucosides, hydroxylase inhibitors, antioxidants (eg
ascorbic acid) and/or nitric oxide donors, including nitric oxide
donor groups covalently attached to various active pharmaceutical
ingredients. The preceding list is of particular interest to
enhance permeability in the ileum.
[0221] To enhance permeability in the colon, typical excipients
including, but not limited to sodium caprate, sodium dodecanoate,
sodium palmitate, SNAG, 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 active pharmaceutical ingredients.
[0222] The composition may further comprise excipients to enhance
the therapeutic potential of active pharmaceutical agents 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, fumeric acid, citric acid and others,
as well as modifications thereof.
[0223] The composition may further comprise excipients or other
active pharmaceutical or other ingredients to enhance systemic
bioavailability following absorption in the small intestine
including efflux pump inhibitors, including, but not limited to PgP
pump inhibitors, and metabolism inhibitors, including, but not
limited to, cytochrome P450 3A inhibitors.
[0224] The composition may further comprise excipients to reduce
systemic side effects associated with absorption in 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.
[0225] The composition 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 (eg hydrophilic antioxidants) or in the oil phase (eg
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.
[0226] The composition may further or separately include an
adhesive to ensure that if desired eg. for the mini-bead
embodiment, that the mini-beads remain, or remain for longer, in
the gastric environment. Mini-beads according to the invention may
also comprise materials facilitating or enabling floating or
density reduction e.g. as a means of localising mini-beads in
desired GI sites. The invention may also, in the mini-bead
embodiment, have the means to swell and/or aggregate in the stomach
or other GI site.
Cyclosporine
[0227] The composition of the present invention is applicable to a
wide range of active principles with a range of industrial
applications as described above. Within its pharmaceutical
applications, the present invention is particularly suitable for
the formulation for oral delivery of low solubility drugs as
described above. The following section describes by way of extended
example, how the present invention can be applied to one such drug,
cyclosporine (also known by its International Non-Proprietary Name
of ciclosporin).
[0228] Cyclosporines form a class of polypeptides commonly
possessing immunosuppressive and anti-inflammatory activity. The
most commonly known cyclosporin is cyclosporin-A. Other forms of
cyclosporines include cyclosporin-B, -C, -D, and -G and their
derivatives. It should be understood that herein the terms
"cyclosporin" or "cyclosporins" refers to any of the several
cyclosporins, derivatives or prodrugs thereof, or to any mixture of
any of the above.
[0229] Cyclosporin A, available in soft gelatin capsule or oral
suspension form, is indicated for the prevention of organ rejection
in kidney, liver and heart transplants, for the treatment of severe
active rheumatoid arthritis (RA) and severe recalcitrant plaque
psoriasis. Other potential indications include Bechet's disease,
anemia, nephrotic syndrome and Graft Versus Host Disease (GVHD),
including Gastro-Intestinal Graft Versus Host Disease (GI-GVHD),
myasthenia gravis, psoriases etc. Furthermore, a range or other
diseases may benefit from treatment with cyclosporin A (Landford et
al. (1998) Ann Intern Med; 128: 1021-1028) the entirety of which is
incorporated herein by reference.
[0230] The present invention also provides methods of treatment of
one or more of the above diseases using the composition described
herein.
[0231] Among other things, the composition of the invention enables
successful colonic delivery of active principles. This is of
particular interest in the case of cyclosporin formulated in the
composition of the invention as mini-beads, particularly when the
beads bear a polymeric coat of the sort described elsewhere herein.
The coat prevents or limits absorption of cyclosporin in the
environment of the upper gastrointestinal tract (GIT) but allows
abrupt and/or sustained release into the proximal colon, which is
the optimum site for colon-targeted delivery of cyclosporin for
certain diseases. Such colon targeting is particularly of value for
the treatment of diseases of the colon such as, for example,
Crohn's disease, ulcerative colitis, and GVHD, including GI-GVHD.
It is particularly preferred to have a composition of the invention
adapted to release drug, especially cyclosporin, for absorption
from the small intestine (for systemic bioavailability) and in the
colon (for local effect) in a single format.
[0232] Loading of cyclosporine in the mini-beads of the invention
is preferably such that a sufficient quantity of mini-beads can be
loaded into a hardgel capsule (size 0 or size 1) to achieve 25 mg
of CyA in each size zero capsule.
Process for Making the Composition of the Invention
[0233] The reader is notified that it is important to refer to this
section in relation to the Examples.
[0234] The basic method for making the composition of the invention
is to mix a fluid form (preferably a solution) of the polymer (or
mixture of polymers) chosen to be the water-soluble polymer matrix
material (eg gelatin, gum, alginate etc as described more generally
elsewhere herein and in any event optionally in admixture with
other components described above) with an oil phase to form an
homogeneous fluid emulsion. Taking account of the final composition
required (as described elsewhere herein), the oil phase and the
aqueous phase may be mixed in a proportion in the range 1:6-10,
preferably approximately 1:7 or 1:8. 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 emulsification. Continuous
stirring is preferred. 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.
[0235] In the embodiment where the polymer matrix substantially
comprises 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 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 15-25% (preferably
17-18%) gelatin; 75%-85% (preferably 77-82%) of water plus from
1-5% (preferably 1.5 to 3%) sorbitol.
[0236] The choice of temperature at which the emulsion is formed
depends however on various factors include the temperature lability
of the active pharmaceutical ingredient and the amount of
plasticiser included in the gelatin, the type of gelatin, as well
as other factors. Generally however, the gelatin solution
(especially in the case of standard or normal gelatin) is
maintained at 60.degree. C.-70.degree. C. to maintain it in a fluid
state.
[0237] The processing temperature can however 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 for example when the
active principle to be incorporated in the composition of the
invention is temperature-labile. Alternatively, temperature-labile
active principles may be processed at higher temperatures by using
appropriate apparatus or machinery which limits the time during
which the temperature-labile active principle is in contact with
the higher temperature medium. For example, 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 temperature-sensitive active principle into the 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
active principle to the higher temperature gelatin is limited so
reducing the degree of any heat-dependent degradation of the active
principle. 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.
[0238] Surfactant, if included, is added to the aqueous phase
conveniently at the same time the other components are added e.g.
polymer matrix material and plasticiser if included e.g. at the
beginning of the processing session. The physical form of the
surfactant at the point of introduction into the aqueous phase
during preparation may play a role in the ease of manufacture of
the composition according to the invention. As such, although
liquid surfactants can be employed, it is preferred to utilize a
surfactant which is in solid form (eg crystalline or powder) at
room temperature, particularly when the aqueous phase comprises
gelatin. Surfactant is added in the appropriate amount required to
achieve the proportion desired and as described above. In general
this leads to presence of surfactant in an amount between 0.8% and
1% (by weight) of the aqueous phase.
[0239] Generally, the oil phase need not be heated and active
principle and in this case other oil phase components are added at
room temperature with stirring until clear. These other components
may include a volatile (or non-volatile) solvent in addition to the
co-solvent and/or solubilizer if selected. The appropriate amount
of oil phase active principle (if any) is added to achieve the
target proportion as described elsewhere herein and in the
examples. In the case of cyclosporine for example, incorporation of
too much CyA (35-40%) in the oil phase can lead to precipitation on
mixing with the gelatin solution and 25-27% is a reasonable target
if for example a dry weight CyA target of 10% is the objective.
Stirring can continue for a few minutes to a few hours, even
overnight, depending on the active principle (for example,
cyclosporine takes several hours to be fully solubilized). Where it
is desired to use or include an oil e.g. a wax oil which is not
liquid or fully liquid at room temperature (eg Solutol or Cremophor
RH40) as the oil phase slight warming e.g. to 40-50.degree. C. is
appropriate.
[0240] The emulsion is formed by addition of the oil phase to the
heated aqueous phase with stirring as described above. The
resultant emulsion then has the composition of the solidified
mini-beads described above but with water still present.
[0241] The emulsion 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.
[0242] Alternatively to moulding, specialised machinery can be
employed for example to create the hemispherical beads described
above (see section above entitled "Shape, Size and Geometry") in
which the invention takes the form of hemispherical beads. It is
possible to manufacture a single bead made from joining two such
hemispheres (ie. a single bead having two distinct halves) by using
specialist apparatus in which two tubes through which two different
emulsions are flowing, normally of circular cross section, are
joined shortly before an extrusion point or nozzle (which may be
vibrating) into a single dual lumen tube with a flat wall
separating the two emulsion flows and which prevents the two
emulsions from coming into contact until the point of extrusion.
The cross-section of the joined dual-lumen tube up to the point of
extrusion therefore appears as two semicircles. In operation, the
two hemispherical emulsion flows combine to form a single,
substantially spherical, bead on extrusion such that normal
droplets are ejected/extruded for solidification.
[0243] Solidification 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.
[0244] In the preferred embodiment in which the composition of the
invention takes the form of mini-beads, the mini-beads may be
formed for example by dropping the fluid emulsion dropwise into a
fluid which effects solidification. Where the viscosity of the
emulsion to be beaded reaches a certain point, drop formation
becomes more difficult and specialised apparatus is then
preferred.
[0245] 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 at the desired rate.
For example, when gelatin is used as the polymer matrix, the
solidification fluid is at a lower temperature than the temperature
of the emulsion thus causing solidification of the polymer matrix.
In this case, the solidification fluid is termed a cooling
fluid.
[0246] 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 (eg dispersed) 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 mini-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 polymer matrix, the solidification fluid can
be initially gaseous (eg droplets passing through cooling air) and
then subsequently liquid (eg 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.
[0247] In the case of gelatin or other water-soluble polymer
destined to form the 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 emulsion as they solidify to form beads. Use of a
non-aqueous liquid allows greater flexibility in choice of the
temperature at which cooling is conducted.
[0248] 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 polymer matrix. If a triglyceride
is chosen as the cooling fluid in the cooling bath, a preferred
example is Miglyol 810 from Sasol.
[0249] If gelatin is selected as the polymer matrix, respect for
appropriate temperature ranges ensures solidification of the
gelatin at an appropriate rate to avoid destruction e.g. of
tertiary protein structure in the case where the active principle
is a protein.
[0250] If alginate is selected as the polymer matrix, a typical
method of making mini-beads involves dropwise addition of a 3%
sodium alginate solution in which oil droplets are dispersed 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 mini-beads to effect cross-linking or
setting). Using a syringe pump, or Inotech machine, droplets can be
generated or extruded (eg 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
mini-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.
[0251] An alternative approach when using alginate is internal
gelation in which the calcium ions are dispersed 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.
[0252] Following shape-forming, moulding or beading, the resultant
shapes or forms may be washed then dried if appropriate. In the
case of mini-beads solidified in a solidification fluid, an
optional final step in the method of production described above
therefore comprises removal of the solidified mini-beads from the
solidification fluid. This may be achieved e.g. by collection in a
mesh basket through which the solidification fluid (eg MCT) 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 (eg using ethyl
acetate) and a subsequent "drying" step to remove excess solvent
(eg 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 (eg 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. Use of gelatin as the polymer
matrix (eg as principal constituent of the aqueous immobilisation
phase) in most cases requires a drying step and for mini-beads this
is preferably achieved by drying in air as above described. The
resultant composition (the composition of the invention) is
essentially dry as described in more detail above.
[0253] In terms of the way in which emulsion droplets may be formed
in the first step of the beading process described above,
variations of the above described method are possible including
introducing droplets into a variety of solidification fluids.
[0254] In general, the mini-beads may be generated by the
application of surface tension between the fluid o/w emulsion 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.
[0255] Alternatively, the mini-beads may be produced through
ejection or extrusion of the fluid o/w emulsion through an orifice
or nozzle with a certain diameter and optionally subject to
selected vibrational frequencies and/or gravitational flow.
Examples of machines which may be used are the Freund Spherex,
ITAS/Lambo, Globex or Inotech processing equipment. Operation of
the Spherex machine manufactured by Freund as may be desired to
manufacture mini-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 10-15 RPM although
the ultimate choice (and separately the amplitude of vibration
selected) depends on the viscosity of the emulsion 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.
[0256] The Spherex machine (and others) may be adapted to make use
of a dual concentric lumen nozzle to ensure simultaneous extrusion
of two fluids, the fluid in the inner lumen forming a core and the
fluid of the outer lumen forming a capsule. The fluid forming the
capsule is solidified according to one of the methods described. It
may or may not be desirable for the fluid forming the core to be
susceptible of solidification to yield a particular embodiment of
the composition of the invention.
[0257] The above machinery adapted in this way can be used to
manufacture the composition of the invention in the form of a
capsule in which the core of the composition is filled with a fluid
(a gas or a liquid) as described in the section above entitled
"Shape, Size and Geometry" (noting that the core, like the capsular
material, may be a composition, albeit optionally a distinct
composition, according to the invention ie. susceptible of
solidification according to one of the methods described above). A
three-lumen nozzle and appropriate tubing may be employed if it is
desired to include an intermediate internal layer e.g. internal
film layer of non-aqueous material on the inner face of the sphere
with the intermediate layer conveniently being solid at room
temperature. Thus, in terms of the softness/hardness of successive
layers, the composition may for example be described as solid:solid
in the case of two layers or solid:solid:solid in the case of 3
layers or liquid/semi-liquid:solid:solid in the case of 3
layers.
[0258] The preceding paragraphs describe the formation of uncoated
beads. It is a preferred embodiment of the present invention to
have coated beads which are described in more detail elsewhere
herein. Such coatings may be single or multiple and may be applied
in a number of ways (see separate section).
[0259] 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
coat (outside the mini-bead) of e.g. polymeric material (polymeric
coating) which may contain an active principle or may impart
controlled release characteristics to the mini-bead and the inner
layer (core) may be a composition according to the invention. 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).
[0260] Use of the Spherex machine achieves very high
monodispersity. For example, in a typical 100 g, batch 97 g of
mini-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.
[0261] The 1.4 to 2 mm diameter range is a good size if it is
desired to coat the mini-beads (if smaller, the spray of the
coating machine may bypass the mini-bead; if too large hard, the
beads may be harder to fluidise which is necessary to achieve
consistent coating).
[0262] The mini-beads are preferably internally (ie.
cross-sectionally) homogeneous ie. monolithic although processing
conditions may be varied for example by altering the temperature of
the fluid emulsion, the solidification fluid and the concentration
of components in these fluids and the time allowed for certain
processing steps to occur including drying. Although not currently
preferred, such variations may be applied in the case of mini-bead
manufacture to achieve heterogeneity such as, for example, a harder
skin and softer core with less than complete immobilization of oil
droplets towards the core as opposed to the surface of the bead.
Larger (eg non-beaded) forms or shapes of the composition according
to the invention may particularly be engineered to embody such
heterogeneity. However, it is currently preferred to have
internally homogenous compositions according to the invention and
within the mini-bead embodiment, this can be favoured by conducting
the beading/dropletting using a homogeneous medium eg. a well
dispersed emulsion. Such homogeneity in the emulsion to be beaded
can help avoid the drying conditions affecting symmetry.
Coating
[0263] The composition of the invention may be used for a number of
applications as discussed elsewhere herein. When used for oral
delivery of active principles, the principles may be advantageous
released immediately (immediate release profile) or be released
after some delay and/or over an extended period (delayed and/or
extended release profile). For immediate release, the mini-beads
may be uncoated or coated enterically to protect against stomach
acid for immediate release in the small intestine.
[0264] Alternatively, if controlled release is desired (ie.
delayed, extended or site-targeted release etc), or if
media-independent release is desired, it is possible, according to
the invention to apply a coat to the mini-beads. Application of the
appropriate coat may, for example if colonic release is required,
allow for say less than 10% of the active principle to be dissolved
(in dissolution medium) at 4 hours and then a burst (sudden
release) towards a maximum dissolution (approaching 100%) in the
subsequent 24 hours. Many alternative target profiles are possible
and this example is purely for illustration.
[0265] Thus according to one embodiment of the present invention,
the composition is in the form of mini-spheres at least some of
which bear a coat (ie. are coated) in order to control release of
active principle from the mini-bead. In one embodiment, the coat is
a film and in another embodiment, it is a membrane. The coat, film
or membrane comprises one or more substances preferably of a
polymeric nature (eg methacrylates etc; polysaccharides etc as
described in more detail below) or combination of more than one
such substance, optionally including other excipients or active
principles, such as, for example, plasticizers, described e.g. in
the sections above on active principles. Preferred plasticizers, if
they are used, include hydrophilic plasticizers for example
triethyl citrate (TEC) which is particularly preferred when using
the Eudragit family of polymers as coatings as described below.
Another preferred plasticiser, described in more detail below in
relation to coating with ethyl cellulose, is 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 family of polymers as coatings.
[0266] In the case of combinations of polymers, combinations may be
selected in order to achieve the desired delay (or other change) in
the release of the drug and/or poration of the coating and/or
exposure of the mini-bead within the coating to allow egress of
drug and/or dissolution of the immobilization matrix. In one
embodiment, two types of polymers are combined into the same
polymeric material, or provided as separate coats that are applied
to the mini-beads.
[0267] It has previously been stated that the composition of the
invention may comprise more than one population of mini-beads.
Within the coating embodiment, the differences between populations
may lie in the coat ie. two (or more) populations of mini-beads may
differ in a number of respects one of which is the coating.
[0268] The coat 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 dried composition (eg
mini-bead) of the invention. 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%.
[0269] The polymeric coating material 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.
[0270] The trademark "EUDRAGIT" is used hereinafter to refer to
methacrylic acid copolymers, in particular those sold under the
EUDRAGIT.TM. by Evonik.
[0271] The coating 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.
[0272] 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 (TAMCl) groups in the polymer. For example,
those polymers having EA:MMA:TAMCl ratios of 1:2:0.2 (EUDRAGIT.TM.
RL) are more permeable than those with ratios of 1:2:0.1
(EUDRAGIT.TM. RS). Polymers of EUDRAGIT.TM. RL are insoluble
polymers of high permeability. Polymers of EUDRAGIT.TM. RS are
insoluble films of low permeability. A particularly preferred
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.
[0273] 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 mini-bead allowing
pre-dissolved pharmaceutical actives to escape in a controlled
manner.
[0274] 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
poration of the coating and/or exposure of the mini-bead 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 mini-beads.
[0275] 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.
[0276] 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.
[0277] Several derivatives of hydroxypropyl methylcellulose (HPMC)
also exhibit pH dependent solubility and may be used in the
invention for coating. These include hydroxypropyl methylcellulose
phthalate (HPMCP), which rapidly dissolves in the upper intestinal
tract and hydroxypropyl methylcellulose acetate succinate (HPMCAS)
in which the presence of ionizable 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 coatings, HPMC and derivatives may
be combined with other polymers e.g. EUDRAGIT RL-30 D.
[0278] It is particularly preferred according to the invention to
use a polymeric coating substance which is pH-independent in its
dissolution profile and/or in its ability to release active
principles incorporated in the mini-beads of the invention.
Examples have already been given (e.g., Eudragit RS and RL).
Another example of a pH-independent polymeric coating substance is
ethylcellulose, in particular a dispersion of ethylcellulose in a
sub-micron to micron particle size range, e.g. from about 0.1 to 10
microns 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, for
example dibutyl sebacate (DBS) or medium chain triglycerides. 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.
[0279] 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 microns 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.
[0280] Surelease.RTM. dispersion is an example of a combination of
film-forming polymer, plasticizer and stabilizers which may be used
as a 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 mini-bead. 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. E-7-19020 comprises
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. E-7-19030 additionally comprises colloidal
anhydrous silica dispersed into the material. E-7-19040 is like
E-7-19020 except that it comprises medium chain triglycerides
instead of dibutyl sebacate. E-7-19050 derives 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,
E-7-19040 is preferred.
[0281] The invention also contemplates using combinations of
Surelease with other coating components, for example sodium
alginate, e.g. sodium alginate available under the trade name
Nutrateric.TM..
[0282] In addition to the EUDRAGIT.TM. and Surelease.RTM. polymers
discussed above, other enteric, or pH-dependent, polymers can be
used. Such polymers can include phthalate, butyrate, succinate,
and/or mellitate groups. Such polymers include, but are not limited
to, cellulose acetate phthalate, cellulose acetate succinate,
cellulose hydrogen phthalate, cellulose acetate trimellitate,
hydroxypropyl-methylcellulose phthalate,
hydroxypropylmethylcellulose acetate succinate, starch acetate
phthalate, amylose acetate phthalate, polyvinyl acetate phthalate,
and polyvinyl butyrate phthalate. Additionally, where compatible,
any combination of polymer may be blended to provide additional
controlled- or targeted-release profiles.
[0283] The coating can further comprise at least one soluble
excipient to increase the permeability of the polymeric material.
Suitably, the at least one soluble excipient is selected from among
a soluble polymer, a surfactant, an alkali metal salt, an organic
acid, a sugar, and a sugar alcohol. Such soluble excipients
include, but are not limited to, polyvinyl pyrrolidone,
polyethylene glycol, sodium chloride, surfactants such as, 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. In some embodiments, polyvinyl pyrrolidone,
mannitol, and/or polyethylene glycol can be used as soluble
excipients. The at least one soluble excipient can be used in an
amount ranging from about 1% to about 10% by weight, based on the
total dry weight of the polymer.
[0284] 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.
[0285] As noted above, Surelease is a particularly preferred
polymer coating owing to its pH-independent dissolution character.
However, the inventors/applicants have found that it is difficult
to select the appropriate amount (weight gain) of Surelease to
achieve optimal dissolution. It has been found that too much
Surelease leads to incomplete (or over slow) dissolution while too
little leads to over fast dissolution.
[0286] The inventors/applicants have now surprisingly found in a
particular embodiment that by addition to Surelease.TM. of a second
polymer (eg a polysaccharide, especially a heteropolysaccharide)
which is normally degraded by bacterial enzymes (and optionally or
alternatively by pancreatic or other relevant enzymes) unexpectedly
resolves this problem and provides flexibility in modulating the
amount of polymer added to the mini-beads of the invention in order
to achieve optimal dissolution profiles.
[0287] The invention therefore also provides a novel coating for
compositions (whether of the invention or not) intended to release
their active payload in the colon which is a combination of
ethylcellulose (preferably 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 is
particularly preferred in connection with obtaining a
colon-specific release profile. The invention also includes a
composition comprising a combination of ethylcellulose (preferably
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; the composition may include a liquid vehicle, e.g.
water.
[0288] The use of polysaccharides by themselves for 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 polymers like,
ethyl cellulose and acrylates into the amylose film. Amylose
however is not water-soluble and although water-soluble
polysaccharides are not excluded, the present inventors have found
that 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 ie 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 ie for compositions intended to release
active principles in the colon.
[0289] It has been found that 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 mini-bead, rather areas of weakness or
absence of coating occurring stochastically on and within the
coating of the invention.
[0290] Pore formers have been described before in connection with
Surelease (see e.g. US 2005/0220878) but in relation to
"gastro-insoluble" substances such as, for example, alginate.
[0291] According to a particular embodiment of the invention, where
the water-soluble polysaccharide (WSP) is pectin, the proportion of
Surelease.TM. to pectin is ideally in the range 90:10 to 99:1,
preferably, 95:5 to 99:1, more preferably 98:2 to 99:1.
[0292] In this particularly preferred combination (Surelease.TM.
WSP e.g. pectin) the weight gain and ratio between Surelease.TM.
and WSP can be varied to refine the behaviour of the coating and
the composition of the invention when it bears such a coat. Thus to
the inventors/applicant's surprise, the advantages of this
preferred combination of coating polymers were further pronounced
by selecting a weight gain in the range 0 to 30% (preferably 5 to
10%) and a Surelease to pectin ratio in the range 95:5 to 99.5:0.5
preferably 97:3 to 99:1 inclusive. Particularly favoured weight
gains using Surelease are those in the range 5-12% or in the range
8-12%.
[0293] Although the focus above has been on extending and/or
sustaining release of active principles from mini-beads according
to the invention, also contemplated are uncoated or simple enteric
coated mini-beads providing early, small intestinal API release
with sufficient enteric coating merely to protect the minibeads
from dissolution in the stomach.
[0294] It is preferred to dry the mini-beads before they are coated
with a suitable polymeric coat (as described in more detail
above/below). It is also preferred, in certain embodiments to apply
a first coat before applying a second. In general the first coat
and the second coat may be of the same or different materials and
be chosen from any of the classes of coating material described
herein. In specific embodiments, the first coat optionally protects
the core (bead) from interaction with the second coat and/or
prevents leaching of bead contents into the second coat. For
example, the first coat may be made of a mixture of hypromellose,
titanium dioxide and polyethylene glycol and the second (outer)
coat made of the surelease-pectin mixture described above. If it is
desired for the first coat 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,
various products commercialised under the trade name Opadry and
Opadry II. Further nonlimiting examples include Opadry YS-1-7706-G
white, Opadry Yellow 03B92357, Opadry Blue 03690842). These
compositions are available as dry film coating compositions 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). Alternative (non-Opadry) products
for initial protective coats include polyvinyl alcohol-polyethylene
glycol graft copolymers such as is available commercially under the
name Kollicoat IR and methyl metacrylate ammonium-based copolymers
such as are available commercially under the name Eudragit E.
Another preferred example is low molecular weight HPMC. The
optional inner coat is applied in the same manner as is the outer
(or sole) coat (or coating layer).
[0295] 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 mini-beads. 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.
[0296] Appropriate coating machines are known to persons skilled in
the art and include, for example, a perforated pan or
fluidized-baed system for example the GLATT, Vector (eg CF 360 EX),
ACCELACOTA, Diosna, O'Hara and/or HICOATER processing equipment.
Most preferred is the MFL/01 Fluid Bed Coater (Freund) used in the
"Bottom Spray" configuration.
[0297] Typical coating conditions are as follows:
TABLE-US-00002 Process Prameter Values Fluidising airflow (m3/h)
20-60 (preferably 30-60) Inlet air temperature (.degree. C.) 20-65
Exhaust air temperature (.degree. C.) 38-42 Product temperature
(.degree. C.) 38-42 Atomizing air pressure (bar) Up to 1.4 e.g.
0.8-1.2 Spray rate (g/min) 2-10 and 3-25 RPM
[0298] Whether as part of the polymeric coat or independently
thereof, the mini-beads of the invention may be coated with
additional drug layers using methods conventional in the art of
pharmaceutical science (such as for example using coating machines
as just described) to produce a composition having one or more
layer(s), each layer containing one or more active pharmaceutical
or other ingredient/excipient as described elsewhere herein. Drug
layering means the deposition of at least one or successive layers
of drug entities from solution, suspension or dry powder on nuclei
e.g. minibeads as described herein. Drug layering includes
solution/suspension layering, powder layering and powder drug
layering. In solution/suspension layering, drug particles are
dissolved or suspended in a binding liquid. In powder layering,
complete dissolution does not occur, due to low liquid saturation,
irrespective of the solubility of the active agent in the binding
liquid. In powder drug layering, a binder solution is first sprayed
onto previously prepared inert seeds e.g. minibeads as described
herein, followed by the addition of powder. Conventional pan
coaters may be used as described above for polymer coating although
modified forms of pan coaters are preferred including fluidised-bed
and centrifugal rotary granulators. Examples of suitable
granulators include the Rotor granulator. (Glatt), the
Rotor-processor (Aeromatic), the Spir-a-Flow (Freund) and the
CF-granulator (Freund). The use of mini-beads as seeds for drug
layering according to the present invention is superior to using
traditional non-pareils as initial substrates in the preparation of
pellets by a drug layering process. One reason is the optimal size
of the mini-beads of the current invention. Another reason is that
sucrose, the main component of traditional non-pareils, has
well-known drawbacks including harmful effects on diabetics and
potential cariogenicity. According to the prior art,
microcrystalline cellulose (MCC) has also been tested as a
substrate for drug layering although the inventors/applicants are
not aware of successful use of MCC for the preparation of initial
cores/beads in a centrifugal granulating process as may be used in
embodiments of the present invention. Thus in one embodiment, the
invention provides a process for the manufacture of drug-coated
pellets comprising using the mini-beads described herein as seeds
or as non-pareils (i.e. instead of non-pareils) on which the drug
is coated. In a related embodiment, a composition of the invention
comprises a mini-bead of the disclosure coated with one or more
drug layers. Another embodiment is a process of enhancing the
solubility of poorly water-soluble active principles by using one
or more of the above described methods of drug layering, including
spray-drying-based processes. The polymeric coat, described in
detail above, may or may not be applied to a drug-layered
mini-bead. However, if desired, it may be applied after such drug
layering. In applying a drug layer, the drug to be layered onto the
mini-bead may optionally first be admixed with appropriate
excipients such as, for example, binders as described elsewhere
herein. A particularly preferred binder in this context is
polyvinyl pyrrolidone (also spelt polyvinylpyrrolidone and also
known as PVP or povidone). PVPs of various K-values may be used.
The K-value of PVP is a function of its average molecular weight,
the degree of polymerization, and the intrinsic viscosity. It is
particularly preferred to use PVP K-32. Up to 5% of the dry weight
of the composition of the invention in this embodiment may be made
up of such binders. Approximately 1% or less is preferred. Other
suitable binders which may be used in drug-layering include
gelatin, carboxymethyl cellulose, hydroxypropyl methylcellulose and
hydrolysed starches e.g. maltodextrins. Compositions embodying drug
layering may also optionally be coated with a polymer coating, or
include a polymer layer, to control release as described more
generally above including the option to include the same or a
different active principle in this polymer coat.
[0299] The invention therefore includes a layered bead or minibead
comprising
[0300] a core comprising, or consisting of, a water-soluble polymer
matrix material in which are dispersed droplets of oil, the core
comprising an active principle; and
[0301] a layer surrounding the core and comprising an active
principle, which may be the same as or different from the active
principle comprised in the core.
[0302] The layered bead or minibead may have a plurality of layers,
e.g. 2, 3, 4 or 5 layers, comprising an active principle, wherein
the active principle of each layer is selected independently from
the active principle of each other layer. In one embodiment, each
layer comprises the same active principle as each other layer; in
another embodiment, no two layers comprise the same active
principle. The term "active principle" in this paragraph embraces
both a single active entity and a combination of active entities.
The layered bead or minibead may comprise one or more polymer
layers, to control release as described more generally above. Such
a polymer layer may contain an active principle and therefore
constitute a drug layer as well as a release control layer.
Alternatively, a polymer layer may be free of active principle. A
polymer layer, whether or not it contains an active principle, may
be located between the core and a drug layer outside the polymer
layer, or between two drug layers, or may form an outer layer,
[0303] The invention therefore includes a layered bead or minibead
comprising
[0304] a core comprising, or consisting of, a water-soluble polymer
matrix material in which are dispersed droplets of oil, the core
comprising an active principle;
[0305] an active principle layer surrounding the core and
comprising an active principle, which may be the same as or
different from the active principle comprised in the core; and
[0306] a polymer layer free of active principle.
The polymer layer may be located between the core and the active
principle layer. The polymer layer may be located externally of the
active principle layer. The layered bead or minibead may comprise a
plurality of active principle layers and, additionally or
alternatively, it may comprise a plurality of polymer layers. In
some embodiments, there is at least one active principle layer
which comprises a release-controlling polymer. In some embodiments,
the outermost layer comprises a release-controlling polymer, which
may contain an active principle or, in another implementation, be
free of active principle.
[0307] The optionally coated mini-beads of the invention may be
formulated directly following their manufacture in the ways
described above. In an alternative embodiment, it may be desired to
impart different properties to the mini-beads and/or to a final
solid dosage product. One way of achieving this according to the
invention is through granulation eg. to improve the flow of powder
mixtures of mini-beads with other components as e.g. described
above in relation to binders. Granules of intact or broken
mini-beads may be obtained by adding liquids (eg binder or solvent
solutions) and effecting a granulating step as described in the
prior art. Larger quantities of granulating liquid produce a
narrower particle size range and coarser and harder granules, i.e.
the proportion of fine granulate particles decreases. The optimal
quantity of liquid needed to get a given particle size may be
chosen in order to minimise batch-to-batch variations. According to
this embodiment, wet granulation is used to improve flow,
compressibility, bio-availability, homogeneity, electrostatic
properties, and stability of the composition of the invention
presented as a solid dosage form. The particle size of the
granulate is determined by the quantity and feeding rate of
granulating liquid. Wet granulation may be used to improve flow,
compressibility, bio-availability, and homogeneity of low dose
blends, electrostatic properties of powders, and stability of
dosage forms. A wet granulation process according to this
embodiment may employ low or high shear mixing devices in which a
low viscosity liquid (preferably water) is added to a powder blend
containing binder previously dry mixed with the rest of the
formulation including mini-beads. Alternative granulation
approaches which may be utilized include high-shear, extrusion and
conventional wet granulation.
EXAMPLES
[0308] As noted in the introduction, it is desirable to have a
solid composition which presents fluid active ingredients in a way
which can be easily and directly manufactured and shaped while
retaining the benefits of fluids. Individual examples below show,
in one or more embodiments of the invention, a solid composition
comprising a fluid which meets this object.
[0309] For successful oral administration e.g. in the fields of
active pharmaceuticals, the active principle must be in solution
for local effect or systemic absorption, it must be usually be
stabilized before release and it must be permeable, it must ideally
demonstrate ease and cost of manufacture including scaleability,
reproducibility and shelf-life and e.g. deliverable and/or
releasable in the colon. As noted in the introduction above,
"stabilized before release" includes protection from degrading
stomach acids, proteolytic enzymes etc. Individual examples below
show, in one or more embodiments of the invention, that it is
possible to resolve multiple such problems simultaneously in a
single oral dosage form.
[0310] The above described formulation issues are often greater for
water-insoluble or poorly water-soluble active entities. Individual
examples below show, in one or more embodiments of the invention,
that it is possible to provide a dosage form which resolves some or
all of these issues for such difficult-to-solubilize molecules or
active agents or principles.
[0311] As discussed, it can be desirable for an active principle to
be in solution ie. a dissolved state and maintaining that dissolved
state until release thus avoiding the need for dissolution in vivo
(a "pre-dissolved" active principle) and to maintain the
solubilized state and prevent release until the target release zone
(eg colon) is reached. Individual examples below show, in one or
more embodiments of the invention, e.g. on the basis of in vitro
dissolution that it is possible to solve this problem.
[0312] A further specific need within the general requirement for
the active principle to be in solution is the maintenance of the
formulated active principle in a dissolved state as well as
immediately after dispersion/egress from its carrier or matrix.
Individual examples below show, in one or more embodiments of the
invention, that it is possible to address this requirement.
[0313] Individual examples below show, in one or more embodiments
of the invention, that it is also possible to obtain a dosage form
from which substantially all of the active principle is solubilized
and dispersed (without necessarily maintaining dissolution) in
vitro in a compendial medium (without adding surfactant to the
medium) following a standard USP/EP/JP etc method.
[0314] In relation to the problem of how to formulate active
principles in a dissolved state when it is also desired to coat
such dosage forms with polymers intended to modify drug release
characteristics without the coating preventing full, sufficient or
predictable release of active principle in the gastro-intestinal
tract (GIT) and without excess variability in release, the
individual examples below show, in one or more embodiments of the
invention, that it is possible (eg on the basis of in vitro
experiments) to obtain an oral dosage form which achieves full,
substantial or sufficient release of active principle in the GIT
and/or with appropriate inter- and intra-patient variability in a
clinical setting or in vitro surrogate thereof.
[0315] For hydrophobic active principles, it is particularly
desirable to increase water solubility or miscibility as well as to
increase stability and reduce volatility and to control the
availability of the active principle, particularly the
bioavailability. At the same time it is desireable to avoid or
reduce manufacturing and quality control complexity. Individual
examples below show, in one or more embodiments of the invention,
that it is possible in a simple way to obtain an oral drug
formulation which addresses one or more of these goals especially
an increase in water solubility/miscibility; increase in stability;
reduction in volatility; control of bioavailability.
[0316] As mentioned in the introduction, in drug delivery systems
having distinct compartments within a single administrative form,
it can be difficult to achieve controlled e.g. simultaneous release
of multiple drugs contained in a single form. Individual examples
below show, in one or more embodiments of the invention, that it is
possible to obtain oral delivery formulations which address these
challenges.
[0317] As noted previously, it can be desirable but difficult to
formulate liquid, emulsified or pre-solubilized active principles
with surfactants. Individual examples below show, in one or more
embodiments of the invention, that it is possible to obtain oral
delivery formulations which allow the incorporation of surfactants
(or sufficient quantities of surfactants) therein.
[0318] As discussed, peptide drugs such as, for example, for
example, cyclosporin, calcitonin, niacin or lacticin, are difficult
to administer orally or formulate for oral administration because
of the unique physicochemical properties of peptides including
molecular size, poor solubility, short plasma half-life,
requirement for specialised mechanisms for membrane transport and
susceptibility to enzymatic breakdown (intestinal, pre-systemic and
systemic). Individual examples below show, in one or more
embodiments of the invention, that it is possible to provide a
solution to these problems. For example, the invention provides, in
one embodiment, a composition comprising a peptide drug susceptible
of enzymic, acidic or hydrolytic breakdown wherein the composition
prevents or reduces such breakdown from occuring. This may be
physicochemical e.g. barrier means inherent to the composition of
the invention or chemical e.g. base/alkali (eg NaOH) or acid (eg
citric acid) to create a protective milieu around the peptide
drug.
[0319] Moreover, individual examples below show, in one or more
embodiments of the invention, that it is possible to address the
challenges and problems of formulating ciclosporin A for delivery
to the colon and/or to sections of the GIT from where absorption of
cyclosporin is limited.
[0320] Individual examples below also show, in one or more
embodiments of the invention, that it is possible to provide, e.g.
on the basis of in vitro experiments, a composition comprising an
active principle for release in the colon with release prevented in
the more proximal GI tract; to avoid or reduce the variability of
release profile resulting from pure pH-based and time-based
systems; to avoid or reduce variability between healthy and
diseased bowel; and with a particle size which prevents or reduces
delay in passing the pylorus and/or reduces residence time in the
ileo-caecal junction.
[0321] Individual examples below also show, in one or more
embodiments of the invention, that it is possible to obtain an oral
dosage form which can be manufactured relatively easily.
Examples
[0322] In the following examples 1 to 13 inclusive, mini-beads are
produced as generally described. Unless otherwise specified, the
units used to describe the compositions are provided in weight 0/00
(per thousand).
[0323] One important test conducted on the resultant mini-beads is
the content assay. This test relates to the active principle and
establishes the proportion of active principle which has
successfully been incorporated in the mini-bead following its
manufacture. A representative sample of the batch is used to carry
out this analysis. Typically a given amount of the sample is
weighed out and extracted in a suitable diluent. Standard
techniques and methodologies are utilized as would be known to
persons skilled in the art e.g. in relation to established
Pharmacopoeia. For example, in the case of CyA, the diluent used is
acetonitrile/purified water/methanol/ortho-phosphoric acid in the
following ratio 64%/32%/3.5%/0.5%. The extraction is carried out by
sample sonication for 2 hours, at ambient temperature, followed by
filtration and dilution to a predetermined concentration, equal to
that of the reference standard against which the sample is
quantified. Once the sample has been prepared, it is analysed via
HPLC, whereby the sample is passed through a steel column packed
with silica and then detected via UV absorbance at a preset
wavelength. This generates a chromatogram, which delivers a peak
and a peak area. The peak areas are then used to calculate the %
active ingredient present in the sample.
[0324] It is ideal to achieve 100% incorporation in the content
assay although in practice lower levels of incorporation are
acceptable (note that occasional measurement error can lead to
figures slightly above 100%). The content assay (sometimes referred
to as CA) is also therefore one measure of the "quality" of the
formulation in the sense that a formulation which fails to
incorporate sufficient active principle is of lower quality than
one able to incorporate a higher proportion. The present
inventors/applicants have used this measure along with others to
define the parameters of the composition of the invention for
example the type of components the composition may comprise and in
which quantities.
[0325] Another test conducted on the examples below is the
dissolution test which garners a dissolution profile for the
composition of the invention. Typically this test is conducted
using a U.S.P. Type II apparatus (paddles) at 37 degree C. and 50
rpm, in pH 6.8 buffer. Various time points are recorded e.g.
proportion dissolved in the period from start (0 hours) up to 4
hours, then up to 6 hours, then up to 8 hours etc. In general (but
this depends on specific objectives), the longer the time the
experiment is continued, the more active principle is dissolved
with each successive proportion being a cumulative assessment of
dissolution at that time point. It is useful if 100% dissolution is
achieved but the time in which that is achieved is also important
and depends on the therapeutic objectives for the formulation.
Diminishing (or a sudden drop in) dissolution over time signifies
precipitation. Full dissolution is usually more important for
quality control than for prediction of in-vivo performance.
Example 1
[0326] Cyclosporine A (CyA) beads were made as described above
(please also refer to Example 48 for additional experimental
detail). The resulting CyA bead formulation had the following
composition (mg/g, on a dry basis):
TABLE-US-00003 Cyclosporin A 92.87 Gelatin 551.93 D-Sorbitol 74.61
Transcutol 144.95 Cremophor EL 75.43 Labrafac Lipophile 1349 WL
60.21
CyA at 25% (w/w); was dissolved in the oil phase which was made
from 4 parts oil (Labrafac Lipophile 1349 WL), 5 parts Cremophor EL
and 10 parts Transcutol. The resulting oil phase was afterwards
added to the gelatin solution in a 1/8 weight ratio. After drying,
beads were robust and not sticky. The content assay gave nearly 95%
of CyA incorporation. The dissolution profile in water was:
TABLE-US-00004 0.5 h 62.16 1 h 61.49 3 h 61.05 4 h 46.65 6 h
34.26
Example 2
[0327] The following composition was prepared as before:
TABLE-US-00005 Cyclosporin A 182.07 Gelatin 544.39 Transcutol
158.98 Cremophor EL 54.63 Labrafac Lipophile 1349 WL 59.93
[0328] No D-Sorbitol was added in the gelatin solution, since
Transcutol and Cremophor EL also act as plasticizers. In the oil
phase, the weight ratio between Transcutol and Cremophor EL was
increased from 2:1 (Example 1) to 3:1 it was possible to obtain an
oil phase containing 40% of CyA. Some CyA precipitation was
observed when the oil phase and gelatin solution were mixed. The
content assay was 91%. The release profile was:
TABLE-US-00006 0.5 h 12.03 1 h 21.52 3 h 29.71 4 h 31.22 6 h
32.83
Example 3
[0329] The beads of this example were prepared by dissolving CyA in
EtOH (ethanol), then adding Cremophor EL and MCT oil, and finally
letting EtOH evaporate overnight. The resulting CyA solution was
very viscous, and so it remained also after mixing with the gelatin
solution. Example 3 had the following composition:
TABLE-US-00007 CyA 139.83 Cremophor EL 111.30 Labrafac Lipophile
1394 WL 89.22 Gelatin 560.12 D-Sorbitol 75.82 SDS 23.71
Content assay was 48% with the following release profile:
TABLE-US-00008 0 0 1 h 48.31 2 h 50.26 3 h 50.59 6 h 51.13
Example 4
[0330] In this example, CyA was dissolved in EtOH, then a mixture
of Tween 80 and Labrafil M 1944 CS was added; EtOH was evaporated
overnight. The composition was as follows:
TABLE-US-00009 CyA 145.30 Gelatin 539.39 D-Sorbitol 74.11 SDS 23.04
Labrafil M 1944 CS 126.70 Tween 80 91.46
[0331] The content assay was 75% and dissolution profile was:
TABLE-US-00010 0 0 0.5 h 15.79 1 h 22.13 2 h 23.58 3 h 23.52
Example 5
[0332] In this example, CyA was again dissolved in EtOH (evaporated
overnight), while the other components of the oily phase were
Labrafil M 1944 CS and Epax 6000 TG (omega-3 oil). No problem was
encountered during preparation.
TABLE-US-00011 CyA 83.56 Gelatin 538.46 D-Sorbitol 72.66 SDS 22.96
Labrafil M 1944 CS 141.39 Epax 6000 TG 140.97
CyA incorporation was 92.5% and the release profile was:
TABLE-US-00012 0 0 0.5 h 90.17 1 h 104.55 2 h 103.48 3 h 108.24
The CyA loading was 8% w/w.
Example 6
[0333] Compared to Example 1, CyA loading was increased by
decreasing the weight ratio between the oily phase and gelatin
solution from 1:8 to 1:7.
TABLE-US-00013 CyA 103.23 Gelatin 504.16 D-Sorbitol 58.21 SDS 23.00
Transcutol HP 160.91 Cremophor EL 84.98 Labrafac Lipophile 1349 WL
65.51
This example 6 contained 91% of theoretical CyA, and showed the
following release profile:
TABLE-US-00014 0 0 0.5 h 79.60 1 h 88.04 2 h 90.22 3 h 89.76 6 h
86.28
Example 7
[0334] Similar to example 5, the following composition was
manufactured. The content assay result was 87%:
TABLE-US-00015 CyA 82.85 Gelatin 538.67 D-Sorbitol 72.86 SDS 23.08
Epax 6000 TG 140.85 Labrafil M 1944 CS 141.69
Example 8
[0335] Similar to example 7, the following composition was
manufactured. The content assay result was 75%:
TABLE-US-00016 CyA 86.80 Gelatin 610.08 SDS 25.41 Epax 6000 TG
138.33 Labrafil M 1944 CS 139.36
Example 9
[0336] Similar to example 8, the following composition was
manufactured. The content assay result was 79%:
TABLE-US-00017 CyA 74.80 Gelatin 600.63 SDS 25.28 Epax 6000 TG
149.91 Labrafil M 1944 CS 149.93
Example 10
[0337] Similar to example 9, the following composition was
manufactured. It was possible to increase the CyA concentration and
incorporation in the beads. Issues during manufacturing included
viscosity of solution and shape of beads, which were long-tailed.
The content assay result was 97%:
TABLE-US-00018 CyA 106.59 Gelatin 605.06 SDS 24.36 Epax 6000 TG
128.58 Labrafil M1944 CS 135.39 Dissolution 0 0 0.5 h 93.93 1 h
94.55 2 h 96.13 3 h 95.7 4 h 94.15
Example 11
[0338] The beads of this example are similar to the beads of
Example 6. The CyA content was increased to 11% by excluding
D-Sorbitol from the formulation. The content assay data was 98% and
dissolution profile was:
TABLE-US-00019 CyA 109.40 Gelatin 537.20 SDS 24.51 Transcutol HP
169.85 Cremophor EL 89.82 Labrafac Lipophile 1349 WL 69.22
Dissolution 0 0 0.5 h 93.93 1 h 94.55 2 h 96.13 3 h 95.7 4 h
94.15
Example 12
[0339] Similar to Example 11, this Example contained approximately
12.5% CyA, a lower content of gelatin and a higher content of SDS.
Content assay was 99.5% and dissolution profile:
TABLE-US-00020 CyA 124.30 Gelatin 507.76 SDS 50.26 Transcutol HP
172.02 Labrafac Lipophile 1349 WL 59.26 Cremophor EL 86.33.
Dissolution 0 0.00 0.5 h 39.80 1 h 46.96 2 h 56.89 3 h 56.75 4 h
56.08
Spherex CyA Examples
[0340] The following examples (Examples 14 to 17) were made using
the Spherex machine described above equipped with a single lumen
nozzle with a diameter of 3 mm. Unless otherwise specified, the
mini-beads were produced through ejection of the fluid o/w emulsion
through the single orifice (nozzle) subject to vibration at a
frequency of 15-40 Hz. The temperature of the emulsion was in the
range 60.degree. C. to 80.degree. C. and dropped into a cooling
bath of medium chain triglyceride oil kept at around 10.degree. C.
See also Example 49 for additional experimental detail relevant to
these examples.
Example 14
[0341] This example had a content assay of 98% with the following
composition and dissolution profile:
TABLE-US-00021 CYA 116.26 Labrafac Lipophile 1349 WL 61.90
Cremophor EL 88.42 SDS 30.84 Gelatin 525.48 Transcutol HP 177.10
Dissolution 0 0.00 0.5 h 37.43 1 h 41.74 2 h 41.57 3 h 41.77 4 h
41.92
It was observed that it was difficult to obtain good beads
(spherical shape, size uniformity).
Example 15
[0342] This example was similar to Example 14 but with the addition
of D-sorbitol. The beads had improved morphology and dissolution
profile compared to those of Example 14 and achieved a content
assay of 100%:
TABLE-US-00022 CYA 109.91 Migyol 810 46.78 Cremophor EL 93.98 SDS
25.21 Gelatin 499.16 Transcutol HP 167.37 D-Sorbitol 57.59
Dissolution 1 h 79.63 2 h 78.78 3 h 78.30 4 h 78.91
Example 16
[0343] This example is similar to Example 15 but with a different
oil phase resulting in a different weight ratio between MCT oil and
Cremophor EL. The content assay was 95% and the composition and
dissolution profile were as follows:
TABLE-US-00023 CYA 110.39 Labrafac Lipophile 1349 WL 58.83
Cremophor EL 83.77 SDS 23.53 Gelatin 498.13 D-Sorbitol 57.46
Transcutol HP 167.88 Dissolution 0 0.00 0.5 h 53.32 1 h 51.91 2 h
53.64 3 h 53.26 4 h 54.98
Example 17
[0344] This example is similar to that of Example 15 the only
difference being the increased SDS content. In this run, more than
90% of beads were in the range 1.4-2.0 mm. The composition and
release profile were as follows:
TABLE-US-00024 Cyclosporin A 107.91 Miglyol 810 46.06 Cremophor EL
92.40 SDS 40.21 Gelatin 492.38 Transcutol HP 164.36 D-Sorbitol
56.69 Dissolution 0 0.00 0.5 h 64.80 1 h 71.48 3 h 73.79 4 h
78.04
Tacrolimus Examples
[0345] Beads exemplified in Examples 18 to 23 were made in the
manner of Examples 1 to 13.
Example 18a
[0346] In this example, the oil phase was made from Labrafil M
1944CS (40% w/w), Tween 80 (30% w/w) and Transcutol P (30% w/w).
The oil phase weight ratio was 1:8 and this yielded good quality
beads (beads prepared with the same oil phase to gelatin solution
ratio of 1:6 weight ratio were sticky). Drug incorporation was
93.5% and the composition and release profile were as follows:
TABLE-US-00025 Composition mg/g Tacrolimus 11.10 Gelatin 506.80
D-Sorbitol 70.64 Ascorbic Acid* 48.40 Transcutol 108.77 Tween 80
106.19 Labrafil M 1944 CS 148.09 Dissolution (two media) Time (hrs)
Water 0.15% SDS(aq.) 0 0 0 1 47.22 73.26 3 49.00 76.76 4 44.39
68.86 6 50.91 70.20 8 53.52 71.02 12 66.75 70.15 16 52.67 79.90
*Ascorbic Acid is used as antioxidant.
Example 18b
[0347] In this Example, Transcutol was not used and the API was
dissolved in EtOH, then Labrafil M 1944 CS and Tween 80 were added,
finally EtOH was evaporated overnight. Gelatin solution was added
keeping the 1:8 weight ratio. The content assay was 81.55% while
the composition and dissolution profile were as follows:
TABLE-US-00026 Composition mg/g Tacrolimus 15.78 Gelatin 496.88
D-Sorbitol 67.33 Ascorbic Acid 47.35 Tween 80 146.26 Labrafil M
1944 CS 202.66
Dissolution in Three Media:
TABLE-US-00027 [0348] Time (h) Water 0.15% SDS 0.3% SDS 1 40.72
66.4 78.73 3 42.24 61.01 72.46 4 44.23 59.95 79.39 6 45.59 64.24
77.96
Example 19
[0349] In this Example it was decided to use Transcutol HP as
solubilizer and SDS as surfactant in the gelatin solution. The
content assay was 98% while the composition and dissolution profile
were:
TABLE-US-00028 Composition mg/g Tacrolimus 14.57 Gelatin 496.03
D-Sorbitol 67.60 SDS 23.70 Ascorbic Acid 47.33 Transcutol 104.87
Tween 80 105.45 Labrafil M 1944 CS 140.45 Time (hrs) Water 0.15%
SDS 0.3% SDS 1 67.68 no sampling 91.09 2 67.71 67.35 90.98 3 66.10
69.63 90.71 6 63.50 63.86 90.15
Example 20
[0350] In this example, HPMC E 100 (100 is the viscosity in mPa/s
of a 1% HPMC solution) was introduced as crystallization inhibitor.
More vigorous stirring was required as HPMC is not fully soluble in
gelatin solution. Content assay was 102% and composition and
dissolution profiles as follows:
TABLE-US-00029 Tacrolimus 14.95 Gelatin 506.10 Transcutol HP 107.06
Labrafil M 1944 CS 142.77 Tween 80 106.60 SDS 23.95 HPMC 29.76
D-Sorbitol 68.82
Dissolution Profile:
TABLE-US-00030 [0351] DIH20 0.15% SDS 0.3% SDS 0 h 0 0 0 1 h 66.06
84.03 98.35 3 h 68.55 84.70 98.54 6 h 68.55 82.60 94.85 12 h 56.68
81.16 94.49 18 h 56.65 83.25 98.19 24 h 55.67 84.09 97.86
Example 21
[0352] This example is of a formulation very similar to that of
Example 20 except that the gelatin solution/oil phase ratio was
decreased to 6.5:1. The CA was 96.5% with the composition and
dissolution profiles as follows:
TABLE-US-00031 Tacrolimus 16.76 Gelatin 469.90 Transcutol HP 120.02
Labrafil M 1944 CS 160.05 Tween 80 119.51 SDS 22.23 HPMC 27.63
D-Sorbitol 63.89
Dissolution Profile:
TABLE-US-00032 [0353] DIH20 0.15% SDS 0.3% SDS 0 h 0 0 0 1 h 50.20
73.23 96.32 3 h 44.24 72.17 96.59 6 h 53.54 71.52 97.23 12 h 55.10
79.45 98.39 18 h 55.70 80.16 98.80 24 h 56.45 79.90 96.28
Example 22
[0354] In this Example, the SDS content was increased to 4% (on dry
basis) and dissolutions were conducted in media containing
increasing amount of HPMC. C.A.=110%.
TABLE-US-00033 Tacrolimus 14.81 Gelatin 497.67 Transcutol HP 105.72
Labrafil M 1944 CS 141.18 Tween 80 105.64 SDS 40.00 HPMC 27.39
D-Sorbitol 67.59 DIH20 0.25% HPMC 0.50% HPMC 0.75% HPMC 0 h 0 0 0 0
1 h 31.27 42.13 53.72 24.17 4 h 58.03 43.99 47.28 49.38 8 h 57.50
31.38 43.97 61.08 12 h 61.00 32.39 39.19 54.10 18 h 56.29 47.28
35.41 48.69 24 h 58.65 49.14 44.72 46.83
Example 23
[0355] In this Example, as in Example 22, the SDS content was
increased to 4% (on dry basis) and dissolutions were conducted in
media containing increasing amount of HPMC. C.A.=107%.
TABLE-US-00034 Tacrolimus 15.27 Gelatin 510.82 Transcutol HP 108.97
Labrafil M 1944 CS 145.51 Tween 80 108.89 SDS 41.75 D-Sorbitol
68.78 DIH20 0.25% HPMC 0.50% HPMC 0.75% HPMC 0 h 0 0 0 0 1 h 32.19
63.76 18.23 35.06 4 h 59.57 50.91 39.45 49.99 8 h 45.73 39.68 40.26
48.91 12 h 57.68 48.78 50.03 48.83 18 h 62.30 52.13 60.10 47.12 24
h 67.49 53.46 57.52 54.55
Coated CyA Beads
[0356] The following Examples illustrate the embodiment of the
invention in which the mini-beads bear a coat (are coated). In all
this group of examples, coating is conducted following the
manufacturer's instructions using the MFL/01 Fluid Bed Coater
(Freund) used in the "Bottom Spray" configuration. Typical coating
conditions are as described in the table above of process
parameters. Where Surelease is used, this refers to Surelease
E-7-19040.
Example 24
[0357] The mini-beads of Example 1 were coated with 5.82% Surelease
and dissolution were carried out in 3 media (water, 0.15% SDS in
water, 0.30% SDS in water) and gave the following results:
TABLE-US-00035 H2O 0.15% SDS 0.3% SDS 0.5 h 0.00 2.50 1.62 1 h 0.00
1.60 1.38 3 h 0.00 1.81 29.15 4 h 0.00 1.84 44.12 6 h 1.27 2.46
65.49 12 h 9.73 4.18 88.59 18 h 16.82 6.11 98.11 24 h 22.69 7.77
101.35
Example 25
[0358] The mini-beads of Example 1 were coated to get a 10% w/g but
as expected release profile was slower (data not shown).
Example 26
[0359] The mini-beads of Example 6 were coated with 2.43% Surelease
and gave the following dissolution profile:
TABLE-US-00036 H2O 0.15% SDS 0.3% SDS 0 h 0.00 0.00 0.00 1 h 7.77
25.73 45.03 3 h 34.85 58.39 85.75 4 h 43.61 67.23 89.75 6 h 55.24
78.30 90.02 12 h 67.09 89.55 91.76 18 h 20.92 90.40 92.47 24 h
11.22 91.80 93.32
In water, the decrease of CyA release between 12 and 24 hours was
due to API precipitation over time. In order to estimate the actual
amount of drug dissolved, the drug content in the coating shell
after the dissolution (ghosts) was analyzed and found to be 11.5%
ie. nearly 90% of CyA was released in water after 24 hours.
Example 27
[0360] Coated beads of Example 26 were further coated to get 4.89%
Surelease weight gain overall coating to give the following
dissolution profiles:
TABLE-US-00037 H2O 0.15% SDS 0.3% SDS 0 h 0.00 0.00 0.00 1 h 6.23
2.10 3.92 3 h 14.51 12.70 38.10 4 h 23.97 23.07 48.87 6 h 38.23
36.53 63.30 12 h 57.33 61.17 85.69 18 h 30.18 76.78 91.33 24 h
13.65 84.35 93.08 GHOST SAMPLE 12.55%
Example 28
[0361] The beads of Example 11 were coated with 3.5% weight gain
Surelease) and gave the following release profile:
TABLE-US-00038 H2O 0.15% SDS 0.3% SDS 0 h 0.00 0.00 0.00 1 h 0.00
4.01 8.93 3 h 36.69 45.10 83.04 4 h 52.61 62.44 91.12 6 h 69.33
80.54 92.77 12 h 82.19 92.74 93.66 18 h 70.12 93.50 94.17 24 h
26.50 94.00 95.33 GHOST SAMPLE 4.46%
Example 29
[0362] The beads of Example 11 were coated with 5.45% weight gain
Surelease and gave the following release profile:
TABLE-US-00039 H2O 0.15% SDS 0.3% SDS 0 h 0 0 0 1 h 0 0 1.09 3 h
11.22 8.48 54.35 4 h 24.48 17.06 75.38 6 h 43.24 30.22 89.88 12 h
68.85 52.79 92.93 18 h 71.23 60.34 93.66 24 h 73.37 65.61 94.25
GHOST SAMPLE 5.68% 26.08%
Example 30
[0363] The mini-beads of Example 14 were coated with 2.44% weight
gain Surelease and gave the following dissolution profile:
TABLE-US-00040 H2O 0.15% SDS 0.3% SDS 0 h 0.00 0.00 0.00 1 h 14.02
51.46 86.14 3 h 27.42 69.39 96.26 4 h 30.18 70.37 96.32 6 h 32.08
70.34 96.54 12 h 30.01 71.27 97.90 18 h 22.48 71.65 98.84 24 h
15.22 72.71 99.12 ghost anal. 12.68% 30.87%
Example 31
[0364] The beads of Example 16 were coated with 4.5% weight gain
Surelease and gave the following dissolution profiles:
TABLE-US-00041 H2O 0.15% SDS 0.3% SDS 0 0.00 0.00 0.00 1 2.64 3.78
4.92 3 8.93 13.48 36.21 4 13.17 17.43 45.15 6 21.51 23.32 58.87 12
33.60 34.75 83.07 18 15.59 40.72 90.16 24 7.08 44.32 93.21 ghost
38.60% 48.01%
Example 32
[0365] Beads similar to those of Example 16 were coated with 6.55%
weight gain Surelease to give the following dissolution
profile:
TABLE-US-00042 37.5 mg H2O 0.15% SDS 0.3% SDS 0 0.00 0.00 0.00 1
1.02 1.36 2.83 3 3.43 9.11 30.13 4 5.94 13.01 37.39 6 10.91 19.24
48.18 12 12.14 33.00 70.88 18 8.72 41.77 81.42 24 7.50 47.11 84.88
ghost 48.41 43.62
Example 33
[0366] The beads of Example 17 were coated with 3.6% weight gain
Surelease to give the following dissolution profile:
TABLE-US-00043 H2O 0.15% SDS 0 h 0.00 0.00 1 h 36.50 67.11 3 h
65.64 92.00 4 h 70.23 93.70 6 h 62.61 94.64 12 h 28.65 95.04 16 h
11.94 94.56 18 h 9.66 94.50 20 h 7.50 94.76 24 h 6.86 95.08 GHOST
12.86%
Example 34
[0367] The beads of Example 17 were coated with 5.4% weight gain
Surelease to give the following dissolution profile:
TABLE-US-00044 (5.4% Surelease) 37.5 mg H2O 0.15% SDS 0 h 0.00 0.00
1 h 3.40 13.37 3 h 21.98 45.52 4 h 26.07 53.54 6 h 24.15 64.08 12 h
13.11 80.17 16 h 8.69 82.81 18 h 7.47 82.27 20 h 6.64 81.04 24 h
8.74 78.47 Ghost 32.82% 13.76%
Example 35
[0368] The beads of Example 17 were coated with 8.7% weight gain
Surelease to give the following dissolution profile:
TABLE-US-00045 (8.7% Surelease) 37.5 mg H2O 0.15% SDS 0 h 0.00 0.00
1 h 1.86 4.28 3 h 6.01 24.54 4 h 9.82 29.86 6 h 14.23 40.15 12 h
10.84 48.73 16 h 7.69 49.98 18 h 6.27 49.74 20 h 5.19 49.64 24 h
5.22 49.70 Ghost 48.27 42.80
Example 36
[0369] The beads of Example 17 were coated with Nutrateric, that is
an association of Surelease and Na Alginate, at 4.6% weight gain
using Surelease/Alginate in a ratio of 85/15. This gave the
following dissolution profiles: (4.6% Nutrateric 85/15)
TABLE-US-00046 H2O 0.15% SDS 0 h 0 0 1 h 36.33 91.88 3 h 40.6 96.27
4 h 39.95 96.3 6 h 37.15 96.68 12 h 23.42 96.83 16 h 14.39 96.17 18
h 11.23 95.46 20 h 9.03 95.29 24 h 6.82 94.77 GHOST 22.40 1.86
Example 37
[0370] The beads of Example 17 were coated with Nutrateric, that is
an association of Surelease and Na Alginate, at 11.3% weight gain
using Surelease/Alginate in a ratio of 85/15. This gave the
following dissolution profiles:
TABLE-US-00047 (11.3% Nutrateric 85/15) H2O 0.15% SDS 0 h 0 0 1 h
30.95 90.13 3 h 38.79 95.04 4 h 38.81 95.35 6 h 37.61 95.51 12 h
22.81 96.21 16 h 14.18 96.47 18 h 10.86 96.1 20 h 8.64 96.11 24 h
6.39 96.14 GHOST 23.33 2.23
Example 38
[0371] The beads of Example 17 were coated with Nutrateric, that is
an association of Surelease and Na Alginate, at 6.2% weight gain
using Surelease/Alginate in a ratio of 95/5. This gave the
following dissolution profiles:
TABLE-US-00048 (6.2% Nutrateric 95/5) H2O 0.15% SDS 0 h 0 0 1 h
22.76 52.23 3 h 38.71 77.13 4 h 40.09 84.44 6 h 37.64 92.43 12 h
12.3 93.94 16 h 8.23 92.98 18 h 7.72 92.36 20 h 7.47 92.36 24 h
7.47 92.36 GHOST 36.33 --
Example 39
[0372] The beads of Example 17 were coated with Nutrateric
(Surelease and Na Alginate) at 11.2% weight gain using
Surelease/Alginate in a ratio of 95/5. This gave the following
dissolution profiles:
TABLE-US-00049 (11.2% Nutrateric 95/5) 37.5 mg H2O 0.15% SDS 0 h 0
0 1 h 5.93 31.39 3 h 24.42 61 4 h 25.44 66.75 6 h 21.94 74.28 12 h
11.13 83.24 16 h 7.5 83.24 18 h 6.51 83.5 20 h 5.64 82.8 24 h 5.65
82.8 GHOST 43.66 --
Example 40
[0373] The mini-beads of Example 17 were coated with FS 30 D
(Eudragit polymer based on methyl acrylate) for a 22% weight gain
to give the following dissolution profiles:
TABLE-US-00050 (22% FS 30 D) 0 0.00 0.00 0.00 1 10.46 10.92 11.44 2
33.87 32.39 32.89 3 46.34 55.81 54.16 4 52.86 66.98 66.07 6 55.35
73.72 78.28 12 46.71 80.17 85.35 16 42.48 81.31 86.72 18 41.62
81.64 87.19 20 40.86 81.79 87.68 24 39.89 81.76 89.04 ghost 14.37%
5.91% 1.18% *First 2 hours were carried in PBS (pH = 7.4), then
samples were transferred in water, 0.15% SDS and 0.3% SDS.
Example 41
[0374] The mini-beads of Example 17 were coated with RS 30 D
(Eudragit polymer based on methyl acrylate) for a 5% weight gain to
give the following dissolution profiles:
TABLE-US-00051 (5% RS 30 D) H2O 0.15% SDS 0 h 0 0 1 h 0.91 2.23 3 h
13.1 7.66 4 h 22.53 10.97 6 h 34.21 16.47 12 h 35.04 28.32 16 h
17.13 35.37 18 h 15.26 38.06 20 h 12.31 40.17 24 h 13.42 43.52
GHOST 31.42 63.14
Example 42
[0375] The mini-beads of Example 17 were coated with a combination
of Surelease and Pectin in a ratio of 98/2 for a total weight gain
of 16.57% to give the following dissolution profile in three media:
deionised water with pectinase, phosphate-buffered saline and Hanks
buffer solution with SDS and pectinase:
TABLE-US-00052 (16.57% Surelease/Pectin 98/2) DiH2O c. 0.5% 50/50
Hanks/H2O; 0.1% Pectinase PBS pH 7.4 SDS; 0.5% Pectinase 0 h 0.00
0.00 0.00 1 h 4.81 7.88 8.75 3 h 17.07 37.55 40.00 4 h 19.52 46.15
48.90 6 h 19.26 56.90 62.15 12 h 12.35 71.13 79.03 16 h 10.45 73.61
84.29 18 h 11.06 72.40 86.03 20 h 14.80 65.29 88.32 24 h 35.37
54.74 83.66 GHOST 28.11% 14.36% 11.23%
[0376] Dissolution was Carried Out with the Addition of
Pectinase
Example 43
[0377] The mini-beads of Example 17 were coated with a combination
of Surelease and Pectin in a ratio of 98/2 for a total weight gain
of 22.5% to give the following dissolution profile in a medium
varied over the course of the dissolution experiment (middle column
is time in hours) starting with hydrochloric acid and switching to
phosphate-acetate (PA) buffer initially with SDS:
TABLE-US-00053 (22.5% Surelease/Pectin 98:2) 0.1N HCl 0 0.00 0.1N
HCl 1 3.50 0.1N HCl 2 10.11 P-A Buffer 0.1% SDS pH = 7 3 15.97 P-A
Buffer 0.1% SDS pH = 7 4 24.28 P-A Buffer pH = 7 6 42.54 P-A Buffer
pH = 7 12 66.43 P-A Buffer pH = 7 16 70.74 P-A Buffer pH = 7 18
70.94 P-A Buffer pH = 7 20 70.57 P-A Buffer pH = 7 24 67.05 GHOST
15.41
Example 44
[0378] The mini-beads of Example 17 were coated with a combination
of Surelease and Pectin in a ratio of 99/1 (pectin content
decreased over Example 43 from 2 to 1% in terms of solid weight
ratio to Surelease) for a total weight gain of 10% to give the
following dissolution profile:
TABLE-US-00054 (10% Surelease/Pectin 99:1) 0 h 0.1N HCl 0.00 1 h
0.1N HCl 8.31 2 h 0.1N HCl 9.59 3 h P-A Buffer 0.1% SDS pH = 7
13.61 4 h P-A Buffer 0.1% SDS pH = 7 30.04 6 h P-A Buffer pH = 7
47.22 12 h P-A Buffer pH = 7 65.31 16 h P-A Buffer pH = 7 72.67 18
h P-A Buffer pH = 7 70.50 20 h P-A Buffer pH = 7 72.51 24 h P-A
Buffer pH = 7 76.71 Ghost 2.79
Example 45
[0379] This Example is similar to Example 44 except that the weight
gain was increased to 15%. This gave the following dissolution
profile:
TABLE-US-00055 (15% Surelease/Pectin 99:1) 0 h 0.1N HCl 0.00 1 h
0.1N HCl 0.00 2 h 0.1N HCl 0.00 3 h P-A Buffer 0.1% SDS pH = 7 1.05
4 h P-A Buffer 0.1% SDS pH = 7 4.72 6 h P-A Buffer pH = 7 16.81 12
h P-A Buffer pH = 7 17.71 16 h P-A Buffer pH = 7 21.94 18 h P-A
Buffer pH = 7 25.25 20 h P-A Buffer pH = 7 25.94 24 h P-A Buffer pH
= 7 55.11 GHOST 10.31
[0380] The low amount of ghost sample suggested that the actual
dissolution after 24 hours was higher than the 55% recorded, so the
0.1% SDS was maintained from 3.sup.rd to 24.sup.th hour to achieve
the following profile:
TABLE-US-00056 0 h 0.1N HCl 0.00 1 h 0.1N HCl 0.00 2 h 0.1N HCl
0.00 3 h P-A Buffer 0.1% SDS pH = 7 1.28 4 h P-A Buffer 0.1% SDS pH
= 7 5.91 6 h P-A Buffer 0.1% SDS pH = 7 32.17 12 h P-A Buffer 0.1%
SDS pH = 7 64.87 16 h P-A Buffer 0.1% SDS pH = 7 70.83 18 h P-A
Buffer 0.1% SDS pH = 7 77.71 20 h P-A Buffer 0.1% SDS pH = 7 79.90
24 h P-A Buffer 0.1% SDS pH = 7 89.18
[0381] Thus, in this Example, 89% of API was released after 24
hours, which is in accordance to the ghost results obtained.
Example 46
[0382] The beads of Example 18 were coated with 4.9% Surelease to
give the following dissolution profile:
TABLE-US-00057 Time (hrs) AV water AV 0.15% SDS AV 0.3% SDS 1 0 0
10.195 3 3.765 1.74 29.425 4 4.535 4.675 41.12 6 7.99 10.745 55.875
8 10.98 6.895 69.2 12 16.69 17.095 82.535 16 22.715 18.235 85.97 20
26.54 9.7 87.87 24 29.395 21.325 87.69
Example 47 (a) and (b)
[0383] The beads of Example 19 were coated with Surelease at 2
different weight gains: 2.47% (Example 47a) and 4.89% (Example
47b); dissolution profiles are shown below:
TABLE-US-00058 Time (hrs) Water 0.15% SDS 0.3% SDS Dissolution
(Example 47a) 1 19.25 29.00 55.64 3 56.66 51.95 95.38 4 65.42 64.82
98.16 6 69.99 77.03 104.18 8 71.34 80.08 103.12 12 67.02 76.28
101.38 16 66.18 78.42 101.50 20 63.16 80.31 106.47 24 63.77 82.99
99.46 Dissolution (Example 47b) 1 0 0 0 3 0 0 31.14 4 4.33 12.78
46.06 6 18.43 21.08 56.89 8 27.61 31.89 65.52 12 39.49 43.13 75.88
16 46.38 51.44 82.56 20 51.91 57.23 87.39 24 55.86 59.78 91.45
Ghost 19.28% 38.25%
Example 48
[0384] In the following example the oil phase and the aqueous phase
are mixed in a proportion in the range 1:6-10, preferably
approximately 1:7 or 1:8 with gentle continuous stirring of the
components using a Magnetic Stirrer (manufactured by Stuart). The
aqueous phase (gelatin with sorbitol) was prepared by adding the
appropriate quantities of sorbitol (and SDS as surfactant) to
water, heating to approximately 60-75.degree. C. until in solution
and then adding gelatin. The "gelatin solution" comprised 15-25%
(preferably 17-18%) of gelatin; 75%-85% (preferably 77-82%) of
water plus from 1-5% (preferably 1.5 to 3%) sorbitol. The gelatin
solution was maintained at 60.degree. C.-70.degree. C. to maintain
it in a fluid state. In a slightly variant method, the SDS was
added to the aqueous phase at the same time the other components
are added ie. gelatin and sorbitol at the beginning of the
processing session. SDS (surfactant) was present in an amount
between 0.8% and 1% (by weight) of the aqueous phase. The oil phase
was made at room temperature with stirring until clear. The
appropriate amount of CyA (see table below) was added to achieve
the target proportion. Stirring was continued overnight. The
emulsion was formed by addition of the oil phase to the heated
aqueous phase with stirring as described above. The resultant
emulsion then had the composition of the solidified mini-beads but
with water still present. Once the emulsion was formed, the beading
step was begun without delay by dropping the fluid emulsion into
MCT (cooling fluid) maintained in the range 8-12.degree. C. which
effected solidification of the droplets. Beads were then collected
in a mesh basket through which the oil was drained and the beads
retained, excess oil removed by centrifugation then dried and
washed with ethyl acetate then dried again. Drying was with the
Freund Drum dryer with warm air at between 15.degree. C. and
25.degree. C. Uncoated mini-beads having the following composition
were generated:
TABLE-US-00059 Mg/g CYA 80-120 Transcutol HP 150-190 Cremophor EL
80-120 Migyol 810 20-60 SDS 15-50 D-Sorbitol 30-80 Gelatin
450-550
Example 49
[0385] The beads of this Example were produced initially as for
Example 48 then through ejection of the fluid o/w emulsion through
a vibrating 3 mm diameter single lumen nozzle applied to the Freund
Spherex machine. Operation of the Spherex machine manufactured by
Freund was in accordance with the manufacturer's instructions. The
lines to the orifice/nozzle were maintained at 65-85.degree. C. to
maintain the fluidity of the solution. Use of the Spherex machine
achieved high monodispersity--out of a 100 g batch, 97 g of
mini-spheres were between 1.4 to 2 mm diameter. Larger and smaller
beads were rejected by passing the batch first through a 2 mm mesh
and subsequently through a 1.4 mm mesh. The resulting beads had the
following composition:
TABLE-US-00060 Components Lower limit (mg/g) Upper limit (mg/g) CyA
80 140 Gelatin 490 610 D-Sorbitol 55 75 SDS 20 40 Transcutol P 100
180 Cremophor EL 50 110 MCT oil* 45 180 Labrafil M 1944 CS 40 150
Epax 6000** 80 150 *MCT brands used include: Mygliol 810, Labrafac
Lipophile 1349 WL, Captex 355, etc . . . **Omega-3 oil having a EPA
(eicosapentanoic acid)/DHA (docosohexaenoic acid) ratio ~1.5
Example 50
[0386] Uncoated beads in this Example were made in accordance with
Example 48 except that the active ingredient was tacrolimus instead
of CyA and the other components were as stated in the table
below.
TABLE-US-00061 Components Lower limit (mg/g) Upper limit (mg/g)
Tacrolimus 11 17 Gelatin 470 510 D-Sorbitol 63 70 SDS 22 42
Transcutol P 104 119 Tween 80 106 146 HPMC E 100 27 30 Labrafil M
1944 CS 140 203 Ascorbic Acid 47 48
Vaccine Examples
[0387] The following three examples illustrate formulations
according to the invention which are made by following the process
described in Example 48 but using the ingredients (eg using
ovalbumin instead of CyA as main active principle) and quantities
mentioned in the tables below.
Example 51
TABLE-US-00062 [0388] Composition mg/g Ovalbumin 6-10 alphaGalCer
0.1-0.5 Montanide ISA 720 70-120 Labrafil M 1944 CS 280-320 Span 85
1-5 Tween 80 1-5 Gelatin 450-550 D-Sorbitol 50-80 NaOH 1-10 HPMCP
30-80
[0389] The aqueous phase was composed of gelatin, D-sorbitol,
ovalbumin, alphaGalCer, HPMCP and NaOH. The other components,
Montanide ISA 720, Labrafil M 1944 CS, Tween 80 and Span 85)
constituted the oil phase.
[0390] HPMCP (hydroxy-propyl-methyl-cellulose-phtalate or
hypromellose phthalate) was used to prevent release in the gastric
environment, since it is a polymer soluble above pH 5.5 The ratio
used between oil phase and aqueous phase was 1:7.
Example 52
TABLE-US-00063 [0391] Composition mg/g rCTB 1-5 alphaGalCer 1-5
Montanide ISA 720 80-120 Labrafil M 1944 CS 250-300 Span 85 10-20
Tween 80 25-35 Gelatin 450-550 D-Sorbitol 30-60 NaOH 5-10 HPMCP
30-60
[0392] rCTB is the recombinant subunit B of Cholera Toxin (it
replaces Ovalbumin of Example 51). Composition of aqueous and oil
phase are the same of Example 1, the only difference being the
addition of part of Tween 80 to the aqueous phase.
Example 53
TABLE-US-00064 [0393] Composition mg/g rCTB 1-5 alphaGalCer 1-5
Montanide ISA 720 60-100 Labrafil M 1944 CS 200-260 Span 85 5-20
Tween 80 20-50 Gelatin 500-600 D-Sorbitol 50-70
[0394] In this Example, neither HPMCP nor NaOH was used in the
aqueous phase. The beads prepared were then coated with 5.5% of L
30-D 55, an Evonik polymer soluble above pH 5.5. Also in this
example (as per Ex. 52) Tween 80 was dissolved partially in the
aqueous phase. The ratio employed between the 2 phases was
increased to 1:9.
Further Tacrolimus Formulations
Example 54
[0395] The following three examples illustrate formulations
according to the invention which are made by following the process
described in Example 48 but using the quantities of ingredients
mentioned in the tables below and using tacrolimus instead of CyA.
However, the oil phase (Solutol) was warmed to 40-50.degree. C.
before adding and dissolving the tacrolimus and the BHT
therein.
TABLE-US-00065 Composition mg/g Tacrolimus 21.21 Solutol HS 15
402.62 BHT 0.15 Gelatin 517.08 D-Sorbitol 58.95
[0396] Solutol HS 15 is Polyethylene glycol 660 12-hydroxystearate
in which the polyglycol ester of 12-hydroxystearic acid makes up
70% of the Solutol and is the hydrophobic component and in which
the polyethylene glycol makes up 30% of the Solutol and is the
hydrophilic component. BHT is butyl hydroxy toluene, a hydrophobic
antioxidant.
Mean Dissolution of 3 Runs was as Follows:
TABLE-US-00066 [0397] Time/h 1 2 3 4 5 6 Mean 115.93 118.27 121.38
122.25 123.23 119.96
Dissolution Method:
TABLE-US-00067 [0398] Apparatus USP Type II (Paddles) Media Na3PO4
pH 6.8 RPM 75 Temperature 37'C.
Example 55
[0399] This example was made by following the process of Example 55
but using the proportions of materials indicated in the table
below.
TABLE-US-00068 Composition mg/g Tacrolimus 20.54 Solutol HS 15
390.02 BHT 0.14 Gelatin 493.05 D-Sorbitol 56.26 SDS 39.98
[0400] With the addition of SDS in the gelatin phase, the emulsion
resulting by mixing the oil phase and gelatin phase was transparent
(microemulsion --) as were the beads subsequently produced
(solidified microemulsion).
Example 56
[0401] This example was made by following the process described in
Example 48 but using the quantities of ingredients mentioned in the
table below and using tacrolimus instead of CyA.
TABLE-US-00069 Composition mg/g Tacrolimus 21.68 Transcutol 188.66
BHT 0.12 Gelatin 452.86 D-Sorbitol 51.57 Eudragit EPO 128.66
Cremophor EL 104.96 Miglyol 810N 51.5
[0402] Eudragit EPO is a polymer soluble in acidic media. It was
added to the aqueous phase (gelatin and sorbitol) during
preparation as a solution in acetate buffer (approximately
pH3.5).
TABLE-US-00070 Time/h 1 2 3 4 5 6 Mean 90.68209 102.841 104.3954
101.6017 100.8962 103.3445
Dissolution Method:
TABLE-US-00071 [0403] Apparatus USP Type II (Paddles) Media 0.2M
Na3PO4 pH 6.8 RPM 75 Temperature 37'C.
Lacticin Formulations.
Example 57
[0404] The method of preparation was as for Example 54 except for
the change in active ingredient and that SDS was substituted for
BHT. The amounts used were as shown in the following table:
TABLE-US-00072 Composition mg/g Lacticin 35.93 Solutol HS 15 332.17
SDS 42.91 Gelatin 529.42 D-Sorbitol 59.57
Example 58
[0405] This is the same as example 57 except that the beads were
coated with a Surelease/pectin mixture (98:2 ratio by weight) as
described in Example 17. The weight gain was 11.8%.
Example 59
[0406] This example is similar to that of Example 15 the only
difference being the increased SDS content. In this run, more than
90% of beads were in the range 1.4-2.0 mm. The composition and
release profile were as follows:
TABLE-US-00073 Lacticin 40.01 Miglyol 810 55.69 Cremophor EL 109.01
SDS 40.41 Gelatin 498.62 Transcutol HP 200.15 D-Sorbitol 56.10
Example 60
[0407] This is the same as example 59 except that the beads were
coated with a Surelease/pectin mixture (98:2 ratio by weight) as
described in Example 17. The weight gain was 7%.
Two Water-Soluble Polymers Form the Matrix
Example 61
TABLE-US-00074 [0408] Composition mg/g Cyclosporin A 179 Transcutol
P 272 Cremophor EL 152 Miglyol 810 76.5 Agar 178 Gelatin 142
[0409] This formulation was made in the same way as were Examples 1
to 13. The agar was first dissolved in water heated to about 90 deg
C. Once the solution becomes clear the temperature was reduced to
around 70 deg C. and gelatin is added. In the meanwhile the oil
phase was made by mixing all the components together (CyA,
Transcutol, cremophor and mygliol). The two phases were mixed
together in a ratio of 1:10 (oil:aqueous phases). The gelatin/agar
mixture of this Example yielded a stronger bead than agar alone.
Also the mixture allowed for a reduction of the total amount of
gelling polymers present from around 500 mg/g to 320 mg/g
(=178+142). This also allowed higher incorporation of Cyclosporin A
(from around 100 mg/g to 179 mg/g).
Void/Dead Space Filled with Fluids
Example 62
Uncoated Bead Formulation (A):
TABLE-US-00075 [0410] Composition mg/g Cyclosporin A 109 Transcutol
P 165 Cremophor EL 93 Miglyol 810 46 Sorbitol 56 SDS 40 Gelatin
490
[0411] The above beads (formulation A--uncoated) were made by the
process used for Examples 14-17. Using the Diosna machine, these
beads were then coated with 4.6% (B), 7.4% (C) and 15.0% (D) weight
gain of Surelease and Pectin at the ratio of 98:2 in the manner
described in Examples 14-17. Hard gelatin capsules then filled with
a liquid media combined with each of the above uncoated and coated
beads, as per the table below.
TABLE-US-00076 Liquid Media Beads Neoral A B C D Span 85 A B C D
Corn oil A B C D Labrafac A B C D Trancutol P A B C D Tween 80 A B
C D
Dissolution Experiments
TABLE-US-00077 [0412] Replicate 1 Replicate 2 Time (H) (%) (%) Mean
Span85 1 0 0 0 2 0 0 0 3 4.1 0 2.05 4 18.3 27.6 22.95 6 47.8 67
57.4 12 69.1 85.4 77.25 16 74.3 88.4 81.35 18 76.5 91.9 84.2 20
77.7 87.3 82.5 24 79.9 92.7 86.3 Corn Oil 1 1 7.8 4.4 2 0 16.5 8.25
3 16.8 49.4 33.1 4 29.2 61.7 45.45 6 63 73.3 68.15 12 69.6 83.6
76.6 16 73.5 85.8 79.65 18 75.3 86.6 80.95 20 77.2 70 73.6 24 79.4
88.4 83.9 Labrafac 1 0 0 0 2 0 6.7 3.35 3 13.9 34.4 24.15 4 32.4
58.1 45.25 6 56.7 72.1 64.4 12 69.2 83.1 76.15 16 72.4 85.6 79 18
74.9 86.9 80.9 20 75.8 82.6 79.2 24 79.1 89.7 84.4 Transcutol 1 0
12 6 2 13.1 15.7 14.4 3 12.7 26.7 19.7 4 17.7 28.2 22.95 6 24.7 30
27.35 12 24.3 35.7 30 16 27.8 40.9 34.35 18 32.9 43.9 38.4 20 32
45.6 38.8 24 37.5 51.2 44.35 Tween 1 1.5 23.21 12.355 2 3.6 34.01
18.805 3 26.3 62.7 44.5 4 55.7 69.3 62.5 6 62.8 77.9 70.35 12 77.1
90.6 83.85 16 80.7 91.3 86 18 81.2 92 86.6 20 83.3 92.7 88 24 83.4
93.51 88.455
Formulations Comprising Salmon Calcitonin (sCT)
Example 63
[0413] sCT was added to the gelatin solution and it was mixed at
60.degree. C. over night by following the process used
previously.
TABLE-US-00078 Components mg mg/g % Salmon Calcitonin 18.70 4.05
0.41 Transcutol HP 1068.78 231.64 23.16 Cremophor EL 462.56 100.25
10.03 Miglyol 810 342.36 74.20 7.42 SDS 182.90 39.64 3.96
D-Sorbitol 272.80 59.13 5.91 Gelatin 2265.80 491.08 49.11 Total
4613.90 1000.00 100.00
Example 64
[0414] A solution of sCT in water was added to the emulsion and it
was mixed at 60.degree. C. for .about.5 min otherwise following the
process of Example 54.
TABLE-US-00079 Components mg mg/g % Salmon Calcitonin 9.40 4.08
0.41 Transcutol HP 533.96 231.79 23.18 Cremophor EL 229.32 99.55
9.95 Miglyol 810 172.22 74.76 7.48 SDS 65.70 28.52 2.85 D-Sorbitol
125.60 54.52 5.45 Gelatin 1167.40 506.77 50.68 Total 2303.60
1000.00 100.00
Example 65
[0415] A solution of sCT in water was added to the emulsion and it
was mixed at 60.degree. C. for .about.5 min. otherwise following
the process of Example 54. This Example is like Example 65 except
that citric acid was used.
TABLE-US-00080 Components mg mg/g % Salmon Calcitonin 9.40 3.92
0.39 Transcutol HP 535.69 223.23 22.32 Cremophor EL 234.71 97.81
9.78 Miglyol 810 173.89 72.47 7.25 SDS 69.90 29.13 2.91 D-Sorbitol
119.00 49.59 4.96 Citric Acid 120.00 50.01 5.00 Gelatin 1137.10
473.85 47.39 Total 2399.70 1000.00 100.00
Example 66
[0416] sCT was added to the oil phase and it was mixed with the
gelatin solution at 60.degree. C. for .about.5 min. otherwise
following the process of Example 54.
TABLE-US-00081 Components mg mg/g % sCT 13.00 4.17 0.42 Transcutol
HP 632.60 202.88 20.29 Cremophor EL 320.90 102.92 10.29 Miglyol 810
221.50 71.04 7.10 SDS 86.25 27.66 2.77 D-Sorbitol 130.25 41.77 4.18
Citric Acid 156.70 50.26 5.03 Gelatin 1556.83 499.30 49.93 Total
3118.03 1000.00 100.00
Example 67
[0417] This formulation was prepared as for previous sCT
formulations.
TABLE-US-00082 Dried Beads mg mg/g % Salmon 9.63 4.18 0.42
Calcitonin Transcutol HP 542.18 235.28 23.53 Cremophor EL 238.64
103.56 10.36 Miglyol 810 175.68 76.24 7.62 SDS 64.70 28.08 2.81
D-Sorbitol 114.70 49.77 4.98 Gelatin 1158.90 502.90 50.29 Total
2304.43 1000.00 100.00
Example 68
[0418] This formulation was prepared as for previous sCT
formulations.
TABLE-US-00083 Dried Beads mg mg/g % Salmon 9.55 3.71 0.37
Calcitonin Transcutol HP 555.29 215.60 21.56 Cremophor EL 237.85
92.35 9.23 Miglyol 810 180.96 70.26 7.03 SDS 71.00 27.57 2.76
D-Sorbitol 115.60 44.88 4.49 Citric Acid 120.00 46.59 4.66 Gelatin
1285.30 499.04 49.90 Total 2575.55 1000.00 100.00
Example 69
[0419] This formulation was prepared as for previous sCT
formulations.
TABLE-US-00084 Dried Beads mg mg/g % Salmon 9.55 3.76 0.38
Calcitonin Transcutol HP 556.72 219.42 21.94 Cremophor EL 238.46
93.98 9.40 Miglyol 810 181.42 71.50 7.15 SDS 76.90 30.31 3.03
D-Sorbitol 130.70 51.51 5.15 NaTDC 120.00 47.30 4.73 Gelatin
1223.50 482.21 48.22 Total 2537.25 1000.00 100.00
Example 70
[0420] This formulation was prepared as for previous sCT
formulations.
TABLE-US-00085 Dried Beads mg mg/g % Salmon 9.55 3.98 0.40
Calcitonin Transcutol HP 542.13 226.03 22.60 Cremophor EL 232.21
96.82 9.68 Miglyol 810 176.67 73.66 7.37 SDS 80.80 33.69 3.37
D-Sorbitol 118.90 49.57 4.96 C10 120.00 50.03 5.00 Gelatin 1118.20
466.22 46.62 Total 2398.45 1000.00 100.00
Example 70
[0421] This formulation was prepared as for previous sCT
formulations.
TABLE-US-00086 Dried Beads mg mg/g % Salmon 9.75 4.07 0.41
Calcitonin Transcutol HP 541.45 225.78 22.58 Cremophor EL 232.61
97.00 9.70 Miglyol 810 175.64 73.24 7.32 SDS 71.30 29.73 2.97
D-Sorbitol 116.80 48.70 4.87 Plantacare 818 130.90 54.58 5.46
Gelatin 1119.70 466.90 46.69 Total 2398.15 1000.00 100.00
Example 71
[0422] Tacrolimus beads were made containing 2.5% tacrolimus dry
weight and then coated with ibuprofen by drug layering using the
Vector CF 360 EX granulator following the method described in the
body of the specification above. Materials were used in amounts
sufficient to obtain the final weights given in the table below.
The ibuprofen was first mixed with PVP (a binder) in the
appropriate ratio before layering was conducted (duration: less
than 1 hour). The ibuprofen-layered tacrolimus beads were then
coated in the manner described in previous examples with a mixture
of ethylcellulose (EC 10) and a plasticiser, dibutyl sebacate (DBS)
over approximately 2 hours in the appropriate ratio.
TABLE-US-00087 Dried Beads g % Tacrolimus bead 800 62.39 Ibuprofen
200 15.60 PVP K-32 9.4 0.73 DBS 24.8 1.93 EC 10 248 19.34 Total
1282.2 100.00
[0423] The coated beads were tested by standard USP dissolution
methods and had the following release profile:
Example 72
[0424] This is the same as example 71 except that the
ibuprofen-layered tacrolimus beads were coated in the manner
described in previous examples with 10%, 15% and 20% total weight
gain of a mixture of Eudragit RL-30D, talc (as glidant) and DBS
(Examples 72a, 72b and 72c respectively).
Example 72b (20% RL-30D)
TABLE-US-00088 [0425] Dried Beads g % Tacrolimus bead 920 56.53
Ibuprofen 230 14.13 PVP K-32 11.7 0.72 DBS 30.8 1.89 RL-30D 308
18.92 Talc 127 7.80 Total 1627.5 100.00
[0426] Examples 72a and 72c were similar (same weight ratios
between ingredients) except for the different amounts of
RL-30D.
[0427] The release profile of the coated beads were tested by
standard USP dissolution methods. Tests for ibuprofen and
tacrolimus were run on separate samples of beads. Ibuprofen was
tested in add media only (24 h). Tacrolimus was tested firstly 2
hour add 8, 22 hour buffer ph 6.8 (24 hours total). The USP Type II
(Paddles) apparatus was used at 75 RPM and a temperature of 37'C.
Media was 0.1N HCL except that for tacrolimus, after 2 hours in
acid media, 0.2M Na3PO4 pH 6.8 was added.
Release Profile of Example 72a (10% RL-30D)
TABLE-US-00089 [0428] % Dissolved Time/h Tacrolimus Ibuprofen 1
7.68 2 40.57 14.88 3 32.62 4 66.36 53.6 5 67.15 6 94.95 75.45 8
82.2 12 90.85 86.29 24 80.79 85.39
Release Profile of Example 72b (15% RL-30D)
TABLE-US-00090 [0429] % Dissolved Time/h Tacrolimus Ibuprofen 1
6.76 2 24.82 11.27 3 26.03 4 54.51 48.92 5 60.81 6 83.62 69.29 8
77.69 12 81.17 81.83 24 76.88 81.72
Release Profile of Example 72c (20% RL-30D)
TABLE-US-00091 [0430] % Dissolved Time/h Tacrolimus Ibuprofen 1
0.36 2 24.69 6.72 3 19.56 4 52.6 36.59 5 47.98 6 75.51 55.15 8
63.61 12 71.29 71.17 24 76.02 73.1
Example 73
[0431] This is the same as Example 72 except that the tacrolimus
beads were first layered in the manner described in previous
examples with ibuprofen and subsequently coated with theophylline
by spray drying. The resulting ibuprofen-plus-theophylline-layered
tacrolimus beads were then coated, as in Example 72, but with
Eudragit L-30D to provide an enteric coat. The L-30D was first
mixed with talc (as glidant), TEC (triethyl citrate) and HPMC E5
(Methocel).
TABLE-US-00092 Dried Beads g % Tacrolimus bead 920 47.21 Ibuprofen
230 11.80 Theopylline 100 5.13 PVP K-32 11.7 0.60 TEC 29 1.49
RL-30D 288 14.78 HPMC E5 20 1.03 Talc 350 17.96 Total 1948.7
100.00
[0432] Release profile of Example 73 determined, in relation to
tacrolimus and ibuprofen, as for Example 72.
TABLE-US-00093 Tacrolimus Ibuprofen 1 2.73 2 0.55 5.58 3 6.72 4 0
7.66 5 8.6 6 0 9.48 8 11.26 12 0 14.95 24 0 27.39
* * * * *
References