U.S. patent application number 13/362429 was filed with the patent office on 2012-08-02 for pharmaceutical formulations.
This patent application is currently assigned to Capsugel Belgium BVBA.. Invention is credited to Adrian Brown, Daniel M. Margetson, Wayne M. Matthews, Stephen Mark McAllister, Ronald K. Raby.
Application Number | 20120196940 13/362429 |
Document ID | / |
Family ID | 34993424 |
Filed Date | 2012-08-02 |
United States Patent
Application |
20120196940 |
Kind Code |
A1 |
Brown; Adrian ; et
al. |
August 2, 2012 |
PHARMACEUTICAL FORMULATIONS
Abstract
The present invention is directed to novel pharmaceutically
acceptable polymeric compositions suitable for melt extrusion and
injection molding of single or multi-component pharmaceutical
dosage forms comprising a plurality of drug substance containing
sub-units, being capsule compartments and/or solid sub-units
comprising a solid matrix of a polymer which contains a drug
substance, the sub-units being connected together in the assembled
dosage form.
Inventors: |
Brown; Adrian; (Harlow,
GB) ; Matthews; Wayne M.; (Harlow, GB) ;
Margetson; Daniel M.; (Harlow, GB) ; McAllister;
Stephen Mark; (Harlow, GB) ; Raby; Ronald K.;
(Collegeville, PA) |
Assignee: |
Capsugel Belgium BVBA.
|
Family ID: |
34993424 |
Appl. No.: |
13/362429 |
Filed: |
January 31, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11078077 |
Mar 11, 2005 |
8147871 |
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13362429 |
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60552499 |
Mar 12, 2004 |
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Current U.S.
Class: |
514/772.4 |
Current CPC
Class: |
A61K 9/1617 20130101;
A61K 47/32 20130101; A61K 9/5047 20130101; A61K 9/5026 20130101;
A61K 9/1652 20130101; A61K 9/1647 20130101; A61K 9/1623 20130101;
A61K 9/4816 20130101 |
Class at
Publication: |
514/772.4 |
International
Class: |
A61K 47/32 20060101
A61K047/32 |
Claims
1-47. (canceled)
48. A multi-component pharmaceutical dosage form which comprises a
plurality of sub-units, and wherein at least one sub-unit is: a) a
drug substance-containing capsule compartment which is soluble or
disintegrable in a patient's gastro-intestinal environment for
release of the drug substance contained in the capsule compartment,
and at least a second sub-unit is: b) a solid matrix comprising
Ammonio methacrylate Copolymer Type A or Ammonio methacrylate
Copolymer Type B present in an amount ranging from about 10% to
about 80% w/w; and a blend of hydroxypropylcelluloses having
different molecular weights in an amount ranging from about 20% to
about 65% w/w, and in which the plurality of sub-units are welded
together or mechanically joined in an assembled dosage form.
49. The dosage form according to claim 48 wherein the copolymer is
Ammonio methacrylate Copolymer Type A.
50. The multi-component pharmaceutical dosage form according to
claim 48, wherein the blend of hydroxypropylcelluloses comprises a
low molecular weight hydroxypropylcellulose and a high molecular
weight hydroxypropylcellulose.
51. The dosage form according to claim 50 wherein the blend of
hydroxypropyl cellulose polymers comprises a hydroxypropylcellulose
having a molecular weight of about 80,000 and a
hydroxypropylcellulose having a molecular weight of about
140,000.
52. The dosage form according to claim 50 wherein the blend of
hydroxypropyl cellulose is a hydroxypropylcellulose having a
molecular weight of about 80,000 and a hydroxypropylcellulose
having a molecular weight of about 370,000.
53. A multi-component pharmaceutical dosage form according to claim
48, in which the solid matrix further comprises a lubricant present
in an amount ranging from about 5% to about 25% w/w.
54. The multi-component dosage form according to claim 53, wherein
the lubricant is stearyl alcohol.
55. The dosage form according to claim 48 further comprising a
dissolution modifying excipient selected from the group consisting
of non-reducing sugars, low molecular weight solutes, and water
soluble fillers.
56. The dosage form according to claim 55 wherein the dissolution
modifying excipient is selected from the group consisting of
xylitol, mannitol, lactose, starch, sodium chloride, and
combinations thereof.
57. The dosage form according to claim 48 further comprising a
disintegrant, wherein the disintegrant is selected from the group
consisting of sodium starch glycollate, croscarmellose sodium,
crospovidone (cross-linked polyvinyl pyrrolidone), copovidone,
polyvinyl pyrrolidone, and combinations or mixtures thereof.
58. The dosage form according to claim 48, further comprising a
plasticizer wherein the plasticizer is selected from the group
consisting of triethyl cifrate (TEC), tributyl cifrate, acetyl
triethyl citrate (ATEC), acetyl tributyl citrate (ATBC), dibutyl
phthalate, dibutyl sebacate (DBS), diethyl phthalate, vinyl
pyrrolidone glycol triacetate, polyethylene glycol, polyoxyethylene
sorbitan monolaurate, propylene glycol, castor oil; and
combinations or mixtures thereof.
59. The dosage form according to claim 48 further comprising a
processing agent in an amount ranging from about 1% to about 5%
w/w.
60. The dosage form according to claim 48 further comprising an
absorption enhancer, wherein the absorption enhancer is selected
from the group consisting of chitosan, lecithin, lectin, a sucrose
fatty acid ester, Vitamin E-TPGS, and combinations or mixtures
thereof.
61. The dosage form according to claim 48 comprising a dissolution
modifying excipient which is a wicking agent.
62. The dosage form according to claim 61 wherein the wicking agent
is lactose.
63. The dosage form according to claim 62 wherein the lactose is
present in an amount of about 13% w/w.
64. The dosage form according to claim 48, further comprising a
surfactant.
65. The dosage form according to claim 64, wherein the surfactant
is selected from sodium dodecyl sulphate or a block copolymer of
ethylene oxide and propylene oxide.
66. The multi-component pharmaceutical dosage form according to
claim 48, wherein the solid matrix further comprises a dissolution
modifying excipient selected from the group consisting of a
disintegrant present in an amount ranging from about 10% to about
40% w/w; a water soluble filler present in an amount ranging from
about 5% to about 70% w/w; a low molecular weight solute present in
an amount ranging from about 2.5% to about 70% w/w; and a
non-reducing sugar present in an amount ranging from about 2.5% to
about 15% w/w.
67. The multi-component dosage form according to claim 48 wherein
each sub-unit has different release characteristic.
68. The multi-component dosage form according to claim 67, in which
at least one of the sub-units is a substantially immediate release
sub-unit.
Description
[0001] This application claims the benefit of priority from
provisional U.S. Ser. No. 60/552,499 filed 12 Mar. 2004.
FIELD OF THE INVENTION
[0002] This invention relates to the preparation of injection
molded single or multi-component dosage forms using novel
pharmaceutically acceptable polymeric blends.
BACKGROUND OF THE INVENTION
[0003] Various types of pharmaceutical dosage forms are known for
oral dosing. Pharmaceutical capsules are well known, generally
being intended for oral dosing. Such capsules generally comprise an
envelope wall of a pharmaceutically acceptable, e.g. orally
ingestible, polymer material such as gelatin, although other
materials for capsule walls, e.g. starch and cellulose based
polymers are also known. Such capsules generally have soft walls
made by making a film on a capsule former, which is then allowed to
dry. Rigid walled capsules made by injection molding are also
known, see for example U.S. Pat. Nos. 4,576,284; 4,591,475;
4,655,840; 4,738,724; 4,738,817 and 4,790,881 (all to Warner
Lambert). These disclose specific constructions of capsules made of
gelatin, starch and other polymers, and methods of making them by
injection molding of hydrophilic polymer--water mixtures. U.S. Pat.
No. 4,576,284 specifically discloses such capsules provided with a
cap which closes the capsule, and which is formed in situ on the
filled capsule by molding. U.S. Pat. No. 4,738,724 discloses a wide
range of rigid capsule shapes and parts.
[0004] Multi-compartment capsules, including those of the type
where each compartment has different drug release characteristics,
or for example, contains a different drug substance or formulation
are also known, for example in U.S. Pat. No. 4,738,724
(Warner-Lambert); U.S. Pat. No. 5,672,359 (University of Kentucky);
U.S. Pat. No. 5,443,461 (Alza Corp.); WO 95/16438 (Cortecs Ltd.);
WO 90/12567 (Helminthology Inst.); DE-A-3727894, and BE 900950
(Warner Lambert); FR 2524311, and NL 7610038 (Tapanhony NV); FR
1,454,013 (Pluripharm); U.S. Pat. No. 3,228,789 (Glassman); and
U.S. Pat. No. 3,186,910 (Glassman) among others. U.S. Pat. No.
4,738,817 discloses a multicompartment capsule with a similar
construction to those of U.S. Pat. No. 3,228,789 and U.S. Pat. No.
3,186,910, made of a water-plasticized gelatin. U.S. Pat. No.
4,738,817 ('817) Witter et al., U.S. Pat. No. 4,790,881 ('881),
Wittwer et al., and EP 0 092 908, Wittwer, F., all discloses
injection molded capsules prepared with gelatin and other
excipients. Wittwer et al. '817 and '881 also prepare capsules with
other hydrophilic polymers, such as hydroxypropylmethyl-cellulose
phthalate (HPMCP), methylcellulose, microcrystalline cellulose,
polyethylene glycol, cellulose acetate phthalate (CAP) and with
polyvinylpyrrolidone. Both U.S. Pat. No. 4,790,881 and EP 0 091 908
propose other polymers having enteric properties suitable for use,
including generally acrylates and methacrylates (Eudragits)
although none are demonstrated and no specific details are
provided.
[0005] Pharmaceutical dosage forms are also known which comprise a
matrix of a solid polymer, in which a drug substance is dispersed,
embedded or dissolved as a solid solution. Such matrixes may be
formed by an injection molding process. This technology is
discussed in Cuff G, and Raouf F, Pharmaceutical Technology, June
(1998) pages 96-106. Some specific formulations for such dosage
forms are disclosed in U.S. Pat. No. 4,678,516; U.S. Pat. No.
4,806,337; U.S. Pat. No. 4,764,378; U.S. Pat. No. 5,004,601; U.S.
Pat. No. 5,135,752; U.S. Pat. No. 5,244,668; U.S. Pat. No.
5,139,790; U.S. Pat. No. 5,082,655; U.S. Pat. No. 5,552,159; U.S.
Pat. No. 5,939,099; U.S. Pat. No. 5,741,519; U.S. Pat. No.
4,801,460; U.S. Pat. No. 6,063,821; WO 99/27909; CA 2,227,272; CA
2,188,185; CA 2,211,671; CA 2,311,308; CA 2,298,659; CA 2,264,287;
CA 2,253,695; CA 2,253,700; and CA 2,257,547 among others.
[0006] U.S. Pat. No. 5,705,189, is directed to a group of
co-polymers of methacrylic acid, methyl methacrylate and methyl
acrylate, for use as thermoplastic agents in the production of
drugs coatings, and capsules. No information is presented on the
quality of the capsule formation with respect to warping or other
distortions produced by the injection molding process. Nor is shear
rate data presented for the viscosity/temperature figures of the
emulsions presented therein.
[0007] It would also be desirable to prepare a pharmaceutical
dosage form in which a pharmaceutically acceptable polymeric blend
is extruded by hot melt into a suitable dosage form, or is
injection molded into suitable dosage forms, which may be
multicompartmental, such as in a capsule. This pharmaceutical
polymeric composition as the dosage form may provide differing
physio-chemical characteristics for each segment containing an
active agent, such that a convenient dosage form can be optioned
which may include a rapid dissolve, immediate, delayed, pulsatile,
or modified release which can be produced by simply selecting the
appropriate polymer(s) to be molded for each section.
SUMMARY OF THE INVENTION
[0008] The present invention provides for novel pharmaceutical
compositions, and their use in melt extrusion technologies, and in
the making of injection molded capsule shells, linkers, spacers,
multicomponent injection molded capsule shells, linkers or spacers,
multicomponent pharmaceutical dosage forms, and other aspects as
defined in the claims and description of this application.
[0009] Another embodiment of the invention is to provide an
alternative and improved pharmaceutical dosage form which provides,
inter alia, greater flexibility in the dosage form adapted to a
patient's specific administration requirement, using the novel
formulations, or compositions, of pharmaceutically acceptable
polymers and suitable excipients in said dosage forms.
[0010] Another embodiment of the invention is to provide a process
of producing the multicomponent dosage forms comprising the novel
pharmaceutically acceptable polymeric blends by injection molding.
These multi-component dosage forms are suitable for containing a
pharmaceutically acceptable active agent, or agents, for release
thereby.
[0011] In accordance with the invention, a melt extrusion
composition, and an injection molded capsule shell, and/or linker
is provided for, with a composition, preferably including Eudragit
RL 100 or Eudragit RS 100 or a combination thereof.
[0012] The capsule or linker, comprises a solid matrix, and
preferably comprises Eudragit RL 100 present in an amount of about
10 to 80% w/w, and a hydroxypropyl cellulose derivative, or blend
of hydroxypropyl celluloses, from about 30 to about 70% w/w.
[0013] The composition may optionally further comprises
dissolution-modifying excipients present in an amount of about 0%
w/w to about 30% w/w; a lubricant present in an amount up to about
30% w/w; a plasticizer present in an amount up to about 10% w/w,
and a processing agent present in an amount up to about 10%
w/w.
[0014] In an alternative embodiment, the pharmaceutical dosage form
comprises a plurality of sub-units, each being a drug
substance-containing capsule compartment. In this case, each
compartment is physically separated from at least one adjacent
compartment, preferably by a wall made of a pharmaceutically
acceptable polymer material. In the case in which at least one of
the sub-units is a drug substance-containing capsule compartment
its wall thickness is in the range of about 0.1-0.8 mm. In another
embodiment the wall thickness is in the range of about 0.3-0.8
mm.
[0015] The multi-component dosage form of the invention affords a
high degree of versatility in that it can be composed of various
combinations of different dosage forms having different release
characteristics. For example, the sub-units can be a substantially
immediate release sub-unit, a sustained release sub-unit, or a
pulsed release sub-unit.
[0016] Other objects and advantages of the invention will be
apparent from the following description.
DETAILED DESCRIPTION OF THE INVENTION
[0017] The present invention is directed to novel compositions of a
pharmaceutically acceptable polymer and excipients, which polymeric
composition may be injection molded into one or more components
which can optionally be utilized together, such as in a stacked or
multi-component dosage form. It is recognized that the polymeric
blends may be injection molded into a single component that may
also contain the active agent for oral administration.
[0018] The present invention also relates to the application of a
pharmaceutically acceptable film coating over a component
comprising the novel pharmaceutically acceptable polymeric blends
as described herein. The film coating may be a delayed release
formulation, or a pH control formulation as are well known in the
art. One suitable coating is Opradry, and/or Eudragit L30D-55. The
enteric coatings, represented by application of L30D-55 for
instance, may be applied using standard equipment such as a GMP
Aerocoater column coater. The component weight gain is nominally
from about 3% to about 5% w/w.
[0019] The pharmaceutically acceptable polymeric blends herein are
designed to provide consistent dissolution profiles.
[0020] A suitable multicomponent dosage form is disclosed in
PCT/EP00/07295, filed Jul. 27, 2000, published as WO 01/08666 on
Feb. 8, 2001, the contents of which are incorporated by reference
herein in its entirety.
[0021] The parts of the dosage form of this invention, e.g. a
capsule compartment wall, a solid sub-unit, or a closure or linker,
comprise a pharmaceutically acceptable polymeric blend (and
adhesive material if adhesive welds are formed) which is generally
regarded as safe, e.g. for oral ingestion and is capable of being
formed into the required shape of a capsule compartment wall, a
solid sub-unit, or a closure or linker as described above. A
preferred method of forming the polymer material into the desired
shape is injection molding, which may be a hot or cold runner
injection molding process. Suitable injection molding machines for
such a process are known.
[0022] The pharmaceutical dosage form may comprises a plurality of
capsule compartments each bounded and physically separated from at
least one adjacent compartment by a wall made of a pharmaceutically
acceptable polymer material, such as described herein, adjacent
compartments being connected together in the assembled dosage form,
and being retained together by the connection at least prior to
administration to a patient, one or more of the compartments
containing a drug substance. Suitably in the assembled dosage form
of this first embodiment there are at least two, for example three,
such capsule compartments. Three or more such compartments may be
linearly disposed in the assembled dosage form, e.g. in an
arrangement comprising two end compartments at opposite ends of the
line, and one or more intermediate compartments. Suitably there may
be two such capsule compartments. Suitably one of such two capsule
compartments may be made of a material which is a sustained release
component, i.e. so that the capsule compartment wall dissolves,
bursts or is otherwise breached to release its contents after a
time delay, e.g. when the compartment has reached the intestine.
Suitably the other of such two capsule compartments may be made of
a material which is an immediate release component, i.e. so that
the capsule compartment wall dissolves, bursts or is otherwise
breached to release its contents immediately or effectively
immediately, e.g. when the compartment is in the mouth or
stomach.
[0023] One or more, e.g. all, of the capsule compartments may for
example be substantially cylindrical, which term includes shapes
which have a circular, oval or oblate circular cross section across
the longitudinal axis, and shapes which have parallel or tapering
e.g. with side walls which taper conically over at least part of
their extent. Such substantially cylindrical capsule compartments
may be provided with connectable parts at one or both of their
longitudinally disposed ends so that the assembled dosage form may
also be overall of a substantially cylindrical shape.
[0024] Suitably, methacrylic acid copolymers (such as Eudragit
E.RTM., Eudragit E100.RTM. Eudragit.RTM. L and/or Eudragit.RTM. S),
poly(meth)acrylate copolymers (such as Eudragit.RTM. 4135F, and
4155F), and ammonium methacrylate copolymers (such as Eudragit.RTM.
RL and/or Eudragit.RTM. RS), are used for hot melt extrusion and
injection molding. The group of poly(meth)acrylate copolymers, such
as Eudragit.RTM. RS 100 or RL100 are an embodiment of this
invention.
[0025] Acrylic and/or methacrylic acid-based polymers which are
soluble in intestinal fluids and which can be formed into capsules
are for example disclosed in U.S. Pat. No. 5,705,189 (Roehm GmbH)
the content of which is incorporated herein by reference in its
entirety. These poly(meth)acrylate copolymers were extrudable and
injection molded into capsule half's wherein the ratio of acrylic
and/or methacrylic acid was generally 20% w/w or more of the
copolymer (Examples 1-8). In these Examples, glycerol monostearate
was added on a 1-6% wt base of the polymer as the sole
mold-releasing agent. The Lehmann patent teaches that unblended
polymers alone are not suitable for injection molding, but must be
blended with a lubricant to produce a capsule shell therein.
[0026] In order to produce injection molded, non-distorted,
unwarped capsule/sub-unit components for assembly into either
single capsule or multicompartment dosage forms using Eudragit RS
100 or RL 100, it has been determined that at least one lubricant
and dissolution modifying agent are useful to obtain release from
the injection molds.
[0027] The polymer Eudragit RL100 is described by the manufacturer,
Rohm Pharma, as being a highly permeable pH independent polymer
which granules are insoluble in water. Eudragit RS 100 is also
described as being a pH independent polymeric granule with low
permeability, and insoluble in water. In contrast, Eudragit
4135F/4155F dissolves only above pH 7, e.g. in the colon, therefore
suitable for use as a sustained or delayed release component, and
the polymer Eudragit E100 dissolves in acid and is suitable for use
as an immediate release component.
[0028] These and other pharmaceutically acceptable polymers are
described in detail in the Handbook of Pharmaceutical excipients,
published jointly by the American Pharmaceutical association and
the Pharmaceutical society of Britain.
[0029] The RL100 polymer is blended with additional excipients
which include, but are not limited to, swelling agents, such as
HPMC, HPC, etc.; surfactants, such as SDS or the Pluronic group of
agents; pore-forming/chanelling agents, such as lactose or PEG;
additional polymers for co-blending such as RS 100; and additional
buffering agents for adjust of microclimate pH conditions.
[0030] In one embodiment of the invention is a co-blend of RL100
with the polymer HPC, such as that marketed by Aqualon, a division
of Hercules Incorporated, as Klucel.RTM.. Klucel HPC is produced in
various grades, determined by their intended use. Suitable Klucel
polymers are Klucel EF, Klucel JH, Klucel LF, and Klucel GF. Klucel
E has a viscosity in the range of 150-700 (a 300-6--mPas for EF
pharm/EXF Pharm), and a molecular weight of about 80,000; J has a
viscosity of 150-400 and a molecular weight of about 140,000, L has
a viscosity in the range of 75-150, and a molecular weight of about
95,000; and G has a viscosity in the range of 75-400, and a
molecular weight of about 370,000.
[0031] Addition of these thermoplastic polymers to the blend
provides for reduced sensitivity to welding conditions, improved
tensile properties both pre and post hydration, and a more robust
swelling of the polymer at pH of 1 to 6.
[0032] It is recognized that the formulations of co-blends still
require additional excipients as herein described. One such
excipient is a lubricant, such as stearyl alcohol.
[0033] It has been determined that these coblended polymers
produces shells which hydrate and swell considerably more than the
non-blended polymeric composition under a number of conditions.
This produces a formulation which has significant improvements in
dissolution reproducibility; the release of the capsule shells is
influenced less by the weld settings; an enhanced hydration
profile, which results in less structural integrity upon
dissolution; and superior appearances, and tensile properties of
the resulting shells.
[0034] The Eudragit RL100 co-blended components have further been
found to be stable after prolonged storage conditions.
[0035] It is recognized that the polymeric compositions are first
melted in a melt extrusion process, and may also contain additional
additives or excipients to assists in melt flow, strength,
brittleness, and other molding characteristics, these additional
excipients include but are not limited to, plasticizers, absorption
enhancers, additional surfactants, flavouring agents, dyes, etc.
Therefore, another aspect of the present invention is a
pharmaceutical composition for melt extrusion comprising Eudragit
RL100 or RS 100 and a lubricant, such as stearyl alcohol.
[0036] While the compositions herein may be molded in varying
wall-thickness, it is preferably that capsules or components have a
wall-thickness of about 0.3 to about 0.8 mm, suitably 0.5 mm.
However, dissolution performance will more appropriately tailor the
wall thickness depending upon the release profiles desired.
Increases in wall thickness may be necessary to reduce warping of
the components, or modification of the additional excipients in
addition to this may be necessary.
[0037] The polymer polymethacyrlate, Eudragit RL100 or RS 100 is
present in the formulation in an amount of about 10 to about 80%
w/w. In another embodiment Eudragit RL100 or RS 100is present in an
amount of about 20 to about 50% w/w. In another embodiment Eudragit
RL100 or RS 100 is present in an amount of about 20 to 40% w/w.
[0038] As noted, the polymeric material(s) may include other
substances to modify their properties and to adapt them to various
applications, including but not limited to surfactants, absorption
enhancers, lubricants, plasticizers, dissolution modifying agents,
processing aids, colouring agents, flavouring agents and sweetening
agents. Incorporation of a surfactant into the formulation may be
necessary or desired to lower the viscosity and surface tension of
the formulation/blend, however, in higher amounts it may adversely
effect the quality of the resulting dosage form. The surfactant
selection may be guided by HLB values but is not necessarily a
useful criterion. While HLB surfactants have been utilized herein,
such as Tween.RTM. 80 (HLB=10), Pluronic F68 (HLB=28), and SDS
(HLB>40), lower HLB value surfactants, such as Pluronic F92 and
F127 may also be used. Pluronic, made by BASF, USA has a synonym of
POLOXAMER. Pluronic F68 for instance has a molecular weight of
8,400. Pluronic F127 has a molecular weight of 12,600. Pluronics
are polyoxypropylene-polyoxyethylene block copolymers.
[0039] A surfactant may also be called an oligomeric surface
modifier and includes, but is not limited to: Pluronics.RTM. (block
copolymers of ethylene oxide and propylene oxide, and are also
referred to as polyoxypropylene-polyoxyethylene block copolymers);
lecithin, Aerosol OT.RTM. (sodium dioctyl sulfosuccinate), sodium
lauryl sulfate, Polyoxyl 40.RTM. hydrogenated castor oil,
polyoxyethylene sorbitan fatty acid esters, i.e., the polysorbates
such as Tween.RTM., such as Tween 20, 60 & 80, the sorbitan
fatty acid esters, i.e., sorbitan monolaurate, monooleate,
monopalmitate, monostearate, etc. such as Span.RTM. or
Arlacel.RTM., Emsorb.RTM., Capmul.RTM., or Sorbester.RTM., Triton
X-200, polyethylene glycol's, glyceryl monostearate, Vitamin
E-TPGS.RTM. (d-alpha-tocopheryl polyethylene glycol 1000
succinate), sucrose fatty acid esters, such as sucrose stearate,
sucrose oleate, sucrose palmitate, sucrose laurate, and sucrose
acetate butyrate, etc.; and combinations and mixtures thereof.
[0040] Suitably, the formulation may optionally contain from about
0 to about 10% w/w surfactant(s). Suitable surfactants for use
herein include, sodium lauryl sulfate, also referred to as sodium
dodecyl sulfate (SDS) or a block copolymers of ethylene oxide and
propylene oxide, or mixtures thereof. In one embodiment, suitable
surfactants are Vitamin E-TPGS.RTM., sodium lauryl sulfate, sucrose
fatty acid esters, lecithin, and the Pluronic groups. In another
embodiment, if SDS (Texapon K-12.RTM.) or a block copolymers of
ethylene oxide and propylene oxide is used in the formulation, they
are present in an amount less than 2% by weight, suitably, less
than 1% w/w.
[0041] The polymeric carriers or oligomeric surface modifiers, if
appropriately chosen, may themselves act as absorption enhancers.
Suitable absorption enhancers for use herein, include but are not
limited to, chitosan, lecithin, lectins, sucrose fatty acid esters
such as the ones derived from stearic acid, oleic acid, palmitic
acid, lauric acid, and Vitamin E-TPGS, and combinations or mixtures
thereof. Suitably, these absorption enhancers are present in a
range of about 0 to about 20% w/w.
[0042] Plasticizers may be employed to assist in the melting
characteristics of the composition. Exemplary of plasticizers that
may be employed in this invention are triethyl citrate (TEC),
triacetin, tributyl citrate, acetyl triethyl citrate (ATEC), acetyl
tributyl citrate (ATBC), dibutyl phthalate, dibutyl sebacate (DBS),
diethyl phthalate, vinyl pyrrolidone glycol triacetate,
polyethylene glycol, polyoxyethylene sorbitan monolaurate,
propylene glycol, or castor oil; and combinations or mixtures
thereof. The polymeric material will determine which plasticizer is
suitable for use. Suitably, the plasticizer is present in an amount
of about 0 to about 20% w/w. In one embodiment of the invention the
plasticizers are present in an amount from about 0 about 5% w/w.
One embodiment of the present invention is the ability to form an
injection molded shell of a Eudragit RL 100 or RS 100 formulation
without the addition of a plasticizer such as those noted
above.
[0043] Dissolution modifying agents, or substances that assist in
release modification, alter the erosion and/or swelling
characteristics of the capsule shell/linker/component. Many
different classes of agents may be used, such as the known
disintegrants represented by "Explotab" (sodium starch glycollate),
"Kollidon-CL", (cross-linked PVP), Kollidon VA 64 (copovidone)
commercially available from BASF, Starch 1500, swelling agents such
as polyvinyl pyrrolidone (PVP, also know as POVIDONE, USP),
manufactured by ISP-Plasdone or BASF-Kollidon, primarily Grades
with lower K values (K-15, K-25, but also K-30 to K-90), cellulosic
derivatives such as hydroxypropyl methyl cellulose (HPMC), wicking
agents such as low molecular weight solutes, e.g. mannitol,
lactose, and starch; inorganic salts such as sodium chloride
(typically at 5-10%).
[0044] Kollidan VA 64, or copovidone, is also known as
copolyvidone, copovidonum, copovidone or copovidon, is ratio of two
monomers, vinylpyrrolidone and vinyl acetate.
[0045] Another class of agents of dissolution modification agents
for use herein are known as swellable solids, and include but are
not limited to poly(ethylene)oxide, the cellulosic derivatives,
such as ethyl cellulose and cellulose acetate phthalate;
hydroxypropylcellulose (HPC), such as the lower molecular weights,
e.g., KLUCEL EF and LF grades, and mixtures of the lower molecular
weights with higher molecular weight grades such as JF or GF;
hydroxypropylmethyl cellulose (HPMC), and other
hydroxyalkylcellulose derivatives. Suitably, the swellable solids
used as dissolution modifying excipients are in the range of about
10% to about 70% w/w. In another embodiment the swelling agents is
present in an amount from about 20 to about 65% w/w, suitably about
50% w/w.
[0046] Other suitable dissolution modifying excipients include, but
are not limited to the class of non-reducing sugars, such as
xylitol, or mannitol, present in the range of about 2.5 to about
15% w/w. Also included herein are a class of water soluble fillers,
such as lactose, lactitol, maltitol, sorbitol or alternatively
organic acids such as malic acid, citric acid or succinic acid,
suitably present in the range of about 5 to about 70% w/w. In
another embodiment of the present invention the water soluble
fillers may be present from an amount of about 5 to about 20%
w/w
[0047] Another group of suitable dissolution modifying excipients
are the agents generally referred to as disintegrants, such as
sodium starch glycolate, croscarmellose sodium NF (Aci-Di-Sol.RTM.
produced by FMC), copovidone, and crospovidone (cross-linked
polyvinyl pyrrolidone); and combinations or mixtures thereof.
Suitably, the class of disintegrants are present in the range of
about 10 to 40%, more preferably about 20 to 30% w/w. It is
recognized that the one of more classes of dissolution modifying
excipients may be used alone, or in combination as mixtures with
each other, resulting in a range from about 2.5 to about 70%
w/w.
[0048] One such combination is hydroxypropylcellulose and lactose.
Additional regents, generally classified as processing aids,
include strengthening agents, such as talc. Suitably, the
processing aids are present from about 0 to about 10% w/w. In
another embodiment, the processing aids are present from about 0 to
about 5% w/w.
[0049] Suitable mold processing lubricants or glidants for use
herein, include but are not limited to, stearyl alcohol, stearic
acid, glycerol monostearate (GMS), talc, magnesium stearate,
silicon dioxide, amorphous silicic acid, and fumed silica; and
combinations or mixtures thereof. The lubricant functions primarily
as a flow promoter for the composition. One embodiment of the
present invention is the use of stearyl alcohol as a suitable
lubricant. Suitably, a commercial grade of stearyl alcohol, such as
Crodacol S95 (Croda Oleochemicals) is used herein. The lubricant
materials should also be suitable for milling. The amount of
lubricant present in the formulation is from about 0 to about 30%
w/w. In another embodiment the lubricant is present from about 10
to about 25% w/w. In another embodiment, the lubricant is present
from about 10 to 15% w/w.
[0050] Stearyl alcohol has been found to act as a mold processing
lubricant but and causes no mold distortion, i.e. crumpling of the
multidosage compartment shell when the hot soft shell is taken out
of the mold. Another alternative material useable as a
lubricant/flow promoter is lecithin (a natural product). Suitably,
the lubricants for use herein do not introduce any metal ion
contamination.
[0051] One embodiment of the present invention is the combination
of stearyl alcohol, at least one swellable solid, and the polymer
Eudragit RL100. Optionally, the formulation may further comprise a
surfactant, such as SDS at 2% w/w or less, or 1% or less. The
swellable solid may be the polymer hydroxypropylcellulose or a
blend of hydroxypropylcellulose.
[0052] The final products of this invention, i.e. the capsules, and
or components or sub-units may additionally include materials in
the polymer materials of which they are made to enhance the ease
with which they can be welded together. The sub-units may
additionally be provided with constructional features and/or
include materials in the polymer materials of which they are made
to enhance the ease with which they can be joined together, either
by simple mechanical joints, or welded together. A suitable
material for assisting such are opacifier materials such as carbon
(e.g. 0.2-0.5%), iron oxides or titanium dioxide (e.g. 0.5-1.0%)
which help the polymer to absorb laser energy. Such opacifier
materials are generally regarded as safe.
[0053] For example each of a plurality of sub units, e.g. of the
capsule compartments, solid sub-units, or combinations thereof may
comprise the same or different polymer(s). For example each of a
plurality of sub units, e.g. of capsule compartments, solid
sub-units, or combinations thereof may comprise the same or
different drug substance. For example each sub-unit may contain the
same drug substance but release the contents into the
gastro-intestinal tract of the patient at a different rate, at
different times after administration to the patient or at different
places in the patient's gastro-intestinal system. Alternatively
each sub-unit may contain a different drug substance, each of which
may be released at the same or a different rate or time after
administration or place in the patient's gastro-intestinal
system.
[0054] For example two or more sub-units, e.g. two capsule
compartments, may each contain different drug substances, and/or
different drug substance formulations, and/or the same drug in
different formulations, so that a combination of two or more drug
substances or formulations may be administered to a patient.
[0055] The dosage form of this invention enables the assembly
together of sub-units which differ in their drug content and/or
drug content release characteristics to provide a dosage form
tailored to specific administration requirements.
[0056] The dimensions and shape of each of the sub-units and hence
of the overall assembled dosage form may be determined by the
nature and quantity of the material to be contained therein and the
intended mode of administration and intended recipients. For
example a dosage form intended for oral administration may be of a
shape and size similar to that of known capsules intended for oral
administration.
[0057] The dosage form is particularly suitable for presentation as
an oral dosage form containing one or more drug substances suitable
for oral administration, and appears to be suitable for all types
of such drug substance.
[0058] The drug substance(s) contained in any capsule compartment
may be present in any suitable form, e.g. as a powder, granules,
compact, microcapsules, gel, syrup or liquid provided that the
capsule compartment wall material is sufficiently inert to the
liquid content of the latter three forms. The contents of the
compartments, e.g. drug substances, may be introduced into the
compartments by standard methods such as those used conventionally
for filling capsules, such as dosating pins or die filling.
[0059] The sub-units may differ from each other in their drug
content release characteristics, and this may be achieved in
various ways. For example one or more solid sub-units and/or
capsule compartments may be substantially immediate release, i.e.
releasing their drug contents substantially immediately upon
ingestion or on reaching the stomach. This may for example be
achieved by means of the matrix polymer or the capsule compartment
wall dissolving, disintegrating or otherwise being breached to
release the drug content substantially immediately. Generally,
immediate-release sub-units are preferably provided by being
capsule compartments.
[0060] For example one or more solid sub-units and/or capsule
compartments may be sustained-release sub-units. Preferably these
are solid sub-units, as a bulk matrix of polymer is likely to
dissolve or disperse more slowly to release its drug content that a
thin walled capsule.
[0061] For example one or more solid sub-units and/or capsule
compartments may be pulsed-release sub-units for example releasing
their drug content at a specific predetermined point in a patient's
gastro-intestinal system. This may be achieved by the use of
polymer materials which dissolve or disperse only at defined pH
environments, such as the above mentioned Eudragit.RTM. polymers.
For instance, E100 is acid labile.
[0062] For example in the above-described capsule
compartment-linker-capsule compartment dosage form one capsule
compartment may be effectively immediate release and the other may
be sustained, delayed or pulsed release. To achieve this for
example one capsule compartment may be made of polymer materials
which cause the capsule compartment to release its drug content in
the stomach or upper part of the digestive tract, and the linker
(acting as a closure for the second compartment) and the second
compartment itself may be made of materials e.g. the above
described enteric polymers, which release their drug content only
in the intestinal environment.
[0063] Determination of the time or location within the
gastro-intestinal tract at which a sub-unit releases its drug
substance content may be achieved by for example the nature of the
sub-unit material, e.g. a solid sub-unit matrix polymer or a
capsule compartment wall material, or in the case of an end
compartment which is closed by a closure, by the nature of the
closure material. For example the wall of different, e.g. adjacent,
compartments may be made of polymers which are different or which
otherwise differ in their dissolution or disintegration
characteristics so as to endow different compartments with
different drug release characteristics. Similarly for example the
polymer matrix material of different, e.g. adjacent, solid
sub-units may be made of polymers which are different or which
otherwise differ in their dissolution or disintegration
characteristics so as to endow different solid sub-units with
different drug release characteristics.
[0064] For example the matrix, wall or closure material may be a
polymer which dissolves or disperses at stomach pH to release the
drug substance in the stomach. Alternatively the wall material of
different compartments may differ so that different compartments
have different release characteristics.
[0065] For example a solid sub-unit or a capsule compartment may
have respectively a matrix or a wall or a closure comprising an
enteric polymer which dissolves or disperses at the pH of the small
or large intestine to release the drug substance in the intestine.
Suitable such polymers have been described above, for example, with
reference to U.S. Pat. No. 5,705,189.
[0066] Additionally or alternatively the wall material may differ
in thickness between compartments so that thicker walled
compartments disrupt more slowly than thinner walled
compartments.
[0067] Additionally or alternatively the compartment walls or the
closure may have areas or points of weakness which preferentially
dissolve and may thereby determine the time of onset and/or rate of
release of the drug substance content. For example such points of
weakness may comprise holes, e.g. small holes, e.g. laser-drilled
holes in the compartment wall or the closure, these holes being
closed and/or covered with a film of a polymer material that
dissolves at a pre-determined point in the digestive tract, for
example an enteric polymer material. For example such points of
weakness may comprise thinned parts in a capsule compartment wall
formed during the molding operation in which the capsule
compartment is formed.
[0068] The sub-units may additionally or alternatively have surface
or other constructional features that modify their drug release
characteristics. For example solid sub-units may be provided with
internal cavities or channels to create a large surface area. For
example solid sub-units may be in the form of hollow cylinders,
donuts, or toroids, which shapes are known to tend towards
first-order dissolution or erosion in liquid media and
correspondingly to tend toward first-order release of drug content
dispersed therein.
[0069] "Pharmaceutically acceptable agents" includes, but is not
limited to, drugs, proteins, peptides, nucleic acids, nutritional
agents, as described herein. This term includes therapeutic active
agents, bioactive agents, active agents, therapeutic agents,
therapeutic proteins, diagnostic agents, or drug(s) as defined
herein, and follows the guidelines from the European Union Guide to
Good Manufacturing Practice. Such substances are intended to
furnish pharmacological activity or other direct effect in the
diagnosis, cure, mitigation, treatment, or prevention of a disease
or to affect the structure and function of the body. The substance
may also include a diagnostic agent, such as an imaging agent
and/or a radioactive labeled compound. Their use may be in a
mammal, or may be in a human. The pharmacological activity may be
prophylactic, or for treatment of a disease state. The agents
herein include both small molecule therapeutics, as well as
peptides and proteins. The pharmaceutical compositions described
herein may optionally comprise one or more pharmaceutically
acceptable active agent, bioactive agent, active agent, therapeutic
agent, therapeutic protein, diagnostic agent, or drug(s) or
ingredients distributed within.
[0070] As used herein the term's "active agent", "drug moiety" or
"drug" are all used interchangeably.
[0071] Water solubility of an active agent is defined by the United
States Pharmacoepia. Therefore, active agents which meet the
criteria of very soluble, freely soluble, soluble and sparingly
soluble as defined therein are encompassed this invention.
[0072] Suitable drug substances can be selected from a variety of
known classes of drugs including, but not limited to, analgesics,
anti-inflammatory agents, anthelmintics, anti-arrhythmic agents,
antibiotics (including penicillin's), anticoagulants,
antidepressants, antidiabetic agents, antiepileptics,
antihistamines, antihypertensive agents, antimuscarinic agents,
antimycobactefial agents, antineoplastic agents,
immunosuppressants, antithyroid agents, antiviral agents,
anxiolytic sedatives (hypnotics and neuroleptics), astringents,
beta-adrenoceptor blocking agents, blood products and substitutes,
cardiac inotropic agents, corticosteroids, cough suppressants
(expectorants and mucolytics), diagnostic agents, diuretics,
dopaminergics (antiparkinsonian agents), haemostatics,
immunological agents, lipid regulating agents, muscle relaxants,
parasympathomimetics, parathyroid calcitonin and biphosphonates,
prostaglandins, radiopharmaceuticals, sex hormones (including
steroids), anti-allergic agents, stimulants and anorexics,
sympathomimetics, thyroid agents, PDE IV inhibitors, NK3
inhibitors, CSBP/RK/p38 inhibitors, antipsychotics, vasodilators
and xanthines.
[0073] Preferred drug substances include those intended for oral
administration and intravenous administration. A description of
these classes of drugs and a listing of species within each class
can be found in Martindale, The Extra Pharmacopoeia, Twenty-ninth
Edition, The Pharmaceutical Press, London, 1989, the disclosure of
which is hereby incorporated herein by reference in its entirety.
The drug substances are commercially available and/or can be
prepared by techniques known in the art.
[0074] The polymeric blends can be preferably selected from known
pharmaceutical polymers. The physico-chemical characteristics of
these polymers, as well as the thickness of the ultimate injection
molded component, will dictate the design of the dosage form, such
as rapid dissolve, immediate release, delayed release, modified
release such as sustained release, controlled release, or pulsatile
release. etc.
[0075] The polymer blends are made by well-known methods for
producing hot melt extrusions in which the selected ingredients are
fed into a feed hopper of an extrusion machine. Suitable well known
equipment is readily available for producing a hot melt extrusion
of the blends herein.
[0076] For production of an early release capsule or component in a
multidosage capsule, (such as in a 2 hour window or less), the
polymer Eudragit RL 100 (Rohm), may be extruded into a thin walled
component shell (such as those indicated herein), by blending with
the excipients as noted herein. As will be seen by the experimental
section, formulation with a lubricant, and hydroxypropylcellulose,
or a coblend of HPC has now been shown to produce a stable,
injection molded component which can be reliably reproduced and
injected from the mold with reduced, or no warpage of the
shell.
[0077] Experiments with Klucel HPC at various percentages, ranging
from 30 to 70% have been formulated and tested for the variance in
dissolution times. Formulations containing approx. 26% to 63%
Klucel's have been found to have similar dissolution times (<2
hours) in both simulated gastric fluid and simulated intestinal
fluids.
[0078] To ensure a consistent release, the pharmaceutical
formulations include various hydrophilic excipients. Preferably,
the hydrophilic excipient is one which does not melt at the
extrusion temperature, e.g. the lactose, inorganic salts, HPC,
HPMC, such as Pharmacoat 603 (an HPMC with a glass transition
temperature 175.degree. C.). As noted, these swellable solids are
available commercially in a number of grades by molecular weight,
for examples 95K, or 80K grades of HPC. A change in the molecular
weight of HPC, for instance, should retain the ability to hydrate
the shell, but the hydration rate may be slower, i.e. the rate of
expansion will be reduced. Hence, a longer dissolution time of the
shell and release of the components therein may result. Experiments
with Klucel.RTM. HPC at various percentages, have been formulated
and tested for the variance in dissolution times. Formulations
containing 40 to 70% Klucel.RTM. have been found to have similar
dissolution times.
[0079] Inclusion of a lubricant, such as stearyl alcohol enhances
flow. It is also found that higher proportions of stearyl alcohol
increase the flowability so as to enable molding of thinner walls.
The formulation may optionally include surfactants, and
disintegrating agents.
EXAMPLES
[0080] The invention will now be described by reference to the
following examples, which are merely illustrative and are not to be
construed as a limitation of the scope of the present invention.
All temperatures are given in degrees centigrade; all solvents are
highest available purity unless otherwise indicated.
Example 1
[0081] Manufacture of multicomponent pharmaceutical dosage forms
with pharmaceutically acceptable polymeric compositions as
described herein. Example 1 will describe a general process used to
mold the various multicomponent capsules and appropriate subunits.
Additional pharmaceutical compositions are shown and described
below.
TABLE-US-00001 Item number Material % w/w 1. Ammonium methacrylate
copolymer (Eudragit 25.0 RL100) 2. Hydroxypropyl Cellulose (Klucel
GF) 50.0 3. Lactose monohydrate 13.0 4. Stearyl alcohol, milled
12.0 Total 100.0
[0082] Using a suitable blender mix together: [0083] Item 2.
Hydroxypropyl Cellulose (Klucel GF) [0084] Item 3. Lactose
monohydrate [0085] Item 4. Stearyl alcohol, milled
[0086] to form a homogeneous powder blend.
[0087] Set up a suitable co-rotating twin screw hot melt extruder
with both a pellet feeder and a powder feeder together with strand
cooling equipment and a pelletizer. Fit the selected mold in the
injection molding machine. Example processing parameters are as
follows:
[0088] Extruder:
TABLE-US-00002 Screw speed 150 rpm (range 100-500 rpm) Temperature
of zone 1 (feed zone) 50.degree. C. (range 30-75.degree. C.)
Temperature of zone 2 95.degree. C. (range 85-130.degree. C.)
Temperature of zone 3 100.degree. C. (range 90-135.degree. C.)
Temperature of zone 4 110.degree. C. (range 95-140.degree. C.)
Temperature of zone 5 115.degree. C. (range 100-145.degree. C.)
Temperature of strand die 120.degree. C. (range 105-150.degree. C.)
Pellet feeder 0.25 kg/hour (0.2-1.8 kg/hour) Powder feeder 0.75
kg/hour (0.2-1.8 kg/hour)
[0089] Strand cooling equipment: Appropriate for extrusion rate
used [0090] Pelletiser: Appropriate for extrusion rate used [0091]
Injection molder: Appropriate injection/cooling times, temperature
and injection pressure, dependent on machine type and pellet
formulation.
[0092] Pre-heat the extruder to the appropriate temperature. Load
the pellet feeder with the Ammonium methacrylate copolymer
(Eudragit RL100) and the powder feeder with the blend. Start the
extruder screws rotating and then start the two feeders. Process
the extruded strand along the cooling equipment into the pelletiser
and collect the pellets formed.
[0093] Input appropriate machine settings and pre-heat the
injection molder. Load the hopper with the pellets and mold the
multi-components units.
[0094] Additional examples or embodiments of this example have been
prepared, using the same process steps but with variant
formulations as shown below.
[0095] The resulting shells from these examples are welded together
with a linker unit, as previously described herein, having a
composition comprising Eudragit 4135F, 10% hypromellose
(HPMC)--Pharmacoat 603, Shin-etsu Chemical Company, and 12% Stearyl
alcohol using a maximum weld strength. Unless otherwise indicated a
standard weld for RL100 shells is 31 2.50 mm, 100% amplitude.
[0096] With regards to the shell thickness, if no reference to the
wall thickness is given, the shell is of 0.5 mm thickness.
[0097] The welded capsules, where applicable were tested using
either a USP2 or a USP3 dissolution apparatus.
Example 2
TABLE-US-00003 [0098] Formulation % w/w Eudragit RL100 25.00 Klucel
GF 50.00 Lactose 13.00 Stearyl alcohol 12.00
[0099] Process Conditions
[0100] Extrusion/Injection moulding: Extrusion--1 kg/hr die temp.
120.degree. C., 150 rpm screw, torque 46%, die pressure 5 bar;
Injection Moulding--partially filled 2/4 0.5 mm wall section
shells, complete mouldings from other pins; 185 C. probe temp.
Additional Shell Observations: many cracked or incompletely moulded
shells, and a polymer knit line was present on all shells. There
was also a high degree of breakage on welding.
[0101] Dissolution Testing using USP 2, 0.5 mm capsule shells
containing an active ingredient, welded at -2.50 mm; a 100% run at
50 rpm in pH 1.2 SGF using Disc sinkers demonstrated a release
profile which was fairly reproducible and had a detachment ranging
from 34-64 minutes for 6 samples tested.
Example 3
TABLE-US-00004 [0102] Formulation % w/w Eudragit RL100 35.00 Klucel
EF 40.00 Lactose 13.00 Stearyl alcohol 12.00
[0103] Process Conditions
[0104] Extrusion/Injection moulding: Extrusion--1.1 kg/hr die temp.
110.degree. C., 200 rpm screw, torque 53%, die pressure 2 bar;
Injection Moulding--crack in 1/4 of the 0.5 mm wall section shells,
complete mouldings from other pins, 175 C. probe temp.
[0105] Dissolution Testing using USP 2, 0.5 mm capsule shells
containing an active ingredient, welded at -2.50 mm; a 100% run at
75 rpm in pH 1.2 SGF using Disc sinkers demonstrated a release
profile which was very reproducible and had a detachment ranging
from 38-50 minutes for 6 samples tested.
Example 4
TABLE-US-00005 [0106] Formulation % w/w Eudragit RL100 25.00 Klucel
EF 63.00 Stearyl alcohol 12.00
[0107] Process Conditions
[0108] Extrusion/Injection moulding: Extrusion--1.2 kg/hr die temp.
110.degree. C., 200 rpm screw, torque 35%, die pressure 1 bar;
Injection Moulding--satisfactory 0.5 mm wall section shells, Small
knit line on some 0.3 mm shells, 180 C. probe temp.
[0109] Additional Shell observations: Good mouldings, very little
cracking.
[0110] Dissolution Testing using USP 2, 0.5 mm capsules, welded at
-2.50 mm; a 100% run at 50 rpm in pH 1.2 SGF using Disc sinkers
demonstrated a variable release times from 58 to 100 minutes.
[0111] In an alternative embodiment, using the molded 0.5 mm shells
from this example, a film coat was added of Eudragit L30D-55. An
Aeromatic Aerocoater was used for applying the coating, with
standard procedures, at a 6% film coat by weight gain.
[0112] The coated shells have not been tested for their release
profile in a USP2 or USP3 dissolution apparatus.
Example 5
TABLE-US-00006 [0113] Formulation % w/w Eudragit RL100 25.00 Klucel
EF 31.50 Klucel JF 31.50 Stearyl alcohol 12.00
[0114] Process Conditions
[0115] Extrusion/Injection moulding: Extrusion--1.2 kg/hr die temp.
115.degree. C., 200 rpm screw; torque 41%, die pressure 4 bar;
Injection Moulding--satisfactory 0.5 mm wall section shells, 185 C.
probe temp.
[0116] Additional Shell Observations: Very good mouldings, shells
are completely clear, no cracking on welding.
[0117] Dissolution Testing using USP 2, 0.5 mm capsules, welded at
-2.50 mm; a 100% run at 50 rpm in pH 1.2 SGF using Disc sinkers
demonstrated a very reproducible detachment ranging between 36-40
minutes for 6 samples tested.
Example 6
TABLE-US-00007 [0118] Formulation % w/w Eudragit RL100 25.00 Klucel
EF 50.00 Lactose 13.00 Stearyl alcohol 12.00
[0119] Process Conditions
[0120] Extrusion/Injection moulding: 0.5 mm shells film were made
using the conditions noted above, and coated with an Opadry clear
sub coat then coated with an Eudragit L30D-55 enteric coat. The
coating was done with an Aeromatic Aerocoater and the film coat
weight gain was divided into two groups as follows: A=1.5% w/w sub
coat; B=2.5% w/w enteric coat; and C=6.0% w/w enteric coat.
[0121] Dissolution Testing using USP 3, 0.5 mm capsule shells with
a 1.5% sub coat (A) and a 2.5% enteric coat (B) containing an
active ingredient, welded at -2.60 mm; a 100% run at 10 dpm in pH
1.2 SGF demonstrated a release profile which was very reproducible
and had a detachment ranging from 40-55 minutes for 6 samples
tested.
[0122] In an alternative embodiment, the 0.5 mm shells of this
example were film coated with an Opadry clear sub coat. The coating
was done with an Aeromatic Aerocoater, and the capsules were
divided into two groups with a film coat weight gain as follows:
A=3.8% w/w sub coat; B=7.0% w/w sub coat.
[0123] Using USP3 Dissolution testing conditions, the 7% Methocel
coated shells of group B, ultrasonically welded at -2.60 mm, 100%
amplitude, produced very reproducible release profiles between
45-55 minutes for 6 samples tested.
[0124] In another alternative embodiment, the 0.5 mm shells of this
example were film coated with Opadry clear sub coat & then over
coated with a Eudragit L30D-55 enteric coat. An Aeromatic
Aerocoater was used, and the capsules were divided into two groups
with a film coat weight gain as follows: A=2.5% w/w sub coat;
B=7.5% w/w enteric coat; and C=10.0% w/w enteric coat
[0125] Using USP3 dissolution testing conditions, a 2.5% subcoat
and a 10% L30D55 enteric coat, 6 sample shells ultrasonically
welded at -2.50 mm, 100% amplitude at 10 dpm were tested. Their
release profile was considered good with a reproducible release (1
outlier) between 80-125 minutes.
[0126] In another alternative embodiment the 0.5 mm shells of this
example film were coated with an Opadry clear sub coat using an
Aeromatic Aerocoater. The resulting film coat weight gain was as
follows: A=1.7% w/w sub coat; B=15.3% w/w enteric coat; C=21.3% w/w
enteric coat.
[0127] Dissolution Testing using USP 3, 0.5 mm capsule shells with
a 1.7% sub coat (A) and a 15.3% enteric coat (B) containing an
active ingredient, welded at -2.60 mm; a 100% run at 10 dpm in pH
1.2 SGF demonstrated a release profile which was very reproducible
and had a detachment ranging from 160-190 minutes for 6 samples
tested.
[0128] In another alternative embodiment, 0.3 mm shells produced
using this formulation were film coated with an Opadry clear sub
coat then over coated with a Eudragit L30D-55 enteric coat (about
24 hrs between applications). An Aeromatic Aerocoater was used, and
the film coat weight gain was as follows A=2.5% w/w sub coat;
B=13.3% w/w enteric coat.
[0129] Dissolution Testing using USP3, 0.3 mm capsule shells with a
2.5% w/w sub coat (A) and a 13.3% enteric coat (B) containing an
active ingredient, welded at -2.50 mm; a 100% run at 10 dpm in pH
1.2 SGF (1.5 hrs), pH 5.5 SIF (0.5 hrs) then pH 6.8 SIF (2 hrs)
demonstrated release ranging from 85-130 minutes for 6 samples
tested.
Example 7
TABLE-US-00008 [0130] Formulation % w/w Eudragit RL100 25.00 Klucel
EF 61.00 Stearyl alcohol 12.00 Titanium dioxide 2.00
[0131] Process Conditions:
[0132] Extrusion/Injection moulding: Extrusion--1.00 kg/hr die
temp. 105.degree. C., 200 rpm screw torque 41%, die pressure 1 bar;
Injection Moulding--satisfactory 0.5 mm wall section shells; 180 C.
probe temp.
[0133] Dissolution Testing using USP 3, 0.5 mm capsule shells
containing an active ingredient, welded at 2.40 mm; at 100% run at
10 dpm in pH 1.2 SGF demonstrated a release profile which was
variable and had a detachment ranging from 34-95 minutes for 6
samples tested.
Example 8
TABLE-US-00009 [0134] Formulation % w/w Eudragit RL100 24.00 Klucel
EF 50.00 Stearyl alcohol 12.00 Succinic acid 13.00
[0135] Process Conditions:
[0136] Extrusion/Injection moulding: Extrusion 1.00 kg/hr die temp.
110.degree. C., 200 rpm screw torque 46%, die pressure 1 bar,
smooth `glassy` strand. Injection Moulding--0.5 mm; persistent
sticking in cavities. A 0.3 mm shell was not attempted.
Example 9
TABLE-US-00010 [0137] Formulation % w/w Eudragit RL100 24.00 Klucel
EF 50.00 Lactose 13.00 Stearyl alcohol 12.00 SDS 1.00
[0138] Process Conditions:
[0139] Extrusion/Injection moulding: Extrusion--0.73 kg/hr die
temp. 110.degree. C., 200 rpm screw torque, 41%, die pressure 2
bar; Injection Moulding--satisfactory 0.5 mm shells at 150 C.
probe.
[0140] Shells of this example have not been tested for their
release profile in a USP2 or USP3 dissolution apparatus.
Example 10
TABLE-US-00011 [0141] Formulation % w/w Eudragit RL100 21.60
Eudragit RS100 2.40 Klucel EF 32.00 Klucel JF 32.00 Stearyl alcohol
12.00
[0142] Process Conditions:
[0143] Extrusion/Injection moulding: Extrusion--1.5 kg/hr; die
temperature 120.degree. C., 150 rpm screw; torque 38%.; Injection
Moulding--satisfactory 0.5 mm shells at 180.degree. C. probe;
occasional sticking in mould.
[0144] Dissolution Testing using USP 2, 0.5 mm capsule shells
containing an active ingredient, welded at -2.50 mm; at 100% run at
75 rpm in pH 1.2 SGF using Disc sinkers demonstrated a release
profile which was very reproducible and had a detachment ranging
from 34-48 minutes for 6 samples tested.
Example 11
TABLE-US-00012 [0145] Formulation % w/w Eudragit RL100 2.40
Eudragit RS100 21.60 Klucel EF 32.00 Klucel JF 32.00 Stearyl
alcohol 12.00
[0146] Process Conditions:
[0147] Extrusion/Injection moulding: Extrusion--1.5 kg/hr; die
temperature of about 120.degree. C., 153 rpm screw; torque 35%.;
Injection Moulding--satisfactory 0.5 mm shells at 180.degree. C.
probe; Occasional sticking in mould.
[0148] Dissolution Testing using USP 2, 0.5 mm capsule shells
containing an active ingredient, welded at -2.50 mm; a 100% run at
75 rpm in pH 1.2 SGF using Disc sinkers demonstrated a release
profile which was fairly reproducible and had a detachment ranging
from 46-50 minutes for 4 samples and 84 and 94 minutes for 2
samples tested.
[0149] Dissolution Testing using USP3, 0.5 mm capsule shells
containing an active ingredient, welded at -2.45 mm; a 100% run at
10 dpm in pH 1.2 SGF (1.5 hrs) then pH 6.8 SIF (4.5 hrs)
demonstrated a release profile which was very reproducible and had
a detachment ranging from 55-80 minutes for 6 samples tested.
Example 12
TABLE-US-00013 [0150] Formulation % w/w Eudragit RL100 10.00 Citric
acid 20.00 Klucel EF 58.00 Stearyl alcohol 12.00
[0151] Process Conditions:
[0152] Extrusion: Extrusion--1.0 kg/hr; with a die temperature of
about 110.degree. C.; a 200 rpm screw; and torque 35%.
[0153] All publications, including but not limited to patents and
patent applications, cited in this specification are herein
incorporated by reference as if each individual publication were
specifically and individually indicated to be incorporated by
reference herein as though fully set forth.
[0154] The above description fully discloses the invention
including preferred embodiments thereof. Modifications and
improvements of the embodiments specifically disclosed herein are
within the scope of the following claims. Without further
elaboration, it is believed that one skilled in the area can, using
the preceding description, utilize the present invention to its
fullest extent. Therefore, the Examples herein are to be construed
as merely illustrative and not a limitation of the scope of the
present invention in any way. The embodiments of the invention in
which an exclusive property or privilege is claimed are defined as
follows.
* * * * *