U.S. patent number RE39,079 [Application Number 10/764,382] was granted by the patent office on 2006-04-25 for film forming compositions comprising modified starches and iota-carrageenan and methods for manufacturing soft capsules using same.
This patent grant is currently assigned to R.P. Scherer Technologies, Inc.. Invention is credited to Stephen W. Burnett, Peter Robert Draper, John J. Getz, Keith Edward Tanner, Elizabeth Youngblood.
United States Patent |
RE39,079 |
Tanner , et al. |
April 25, 2006 |
Film forming compositions comprising modified starches and
iota-carrageenan and methods for manufacturing soft capsules using
same
Abstract
Disclosed herein are compositions comprising a modified starch
and a carrageenan, especially iota-carrageenan, where the
compositions are suitable for use in manufacturing soft
capsules.
Inventors: |
Tanner; Keith Edward (Safety
Harbor, FL), Draper; Peter Robert (LaSalle, CA),
Getz; John J. (Delray Beach, FL), Burnett; Stephen W.
(Clearwater, FL), Youngblood; Elizabeth (Valrico, FL) |
Assignee: |
R.P. Scherer Technologies, Inc.
(Las Vegas, NV)
|
Family
ID: |
22500942 |
Appl.
No.: |
10/764,382 |
Filed: |
January 22, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60142704 |
Jul 7, 1999 |
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Reissue of: |
09608853 |
Jun 30, 2000 |
06340473 |
Jan 22, 2002 |
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Current U.S.
Class: |
424/451; 514/777;
514/782; 514/778; 424/452 |
Current CPC
Class: |
A61K
9/4816 (20130101) |
Current International
Class: |
A61K
9/48 (20060101) |
Field of
Search: |
;424/451,452,453,454,455,489,490 ;514/777,778,482 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0 141 374 |
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May 1985 |
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EP |
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0 547 551 |
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Dec 1992 |
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EP |
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0 592 130 |
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Apr 1994 |
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EP |
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0 714 656 |
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Jun 1996 |
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EP |
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0 882 449 |
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Dec 1998 |
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EP |
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0 592 130 |
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Apr 1999 |
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EP |
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2 214 920 |
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Sep 1989 |
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GB |
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SH060-12943 |
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Jan 1985 |
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JP |
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61-10508 |
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Jan 1986 |
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JP |
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61010508 |
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Jan 1986 |
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JP |
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63-164858 |
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Jul 1988 |
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JP |
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1-143827 |
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Sep 1989 |
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JP |
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4-243818 |
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Aug 1992 |
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JP |
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05065222 |
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Mar 1993 |
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JP |
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HE15-310529 |
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Nov 1993 |
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JP |
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HE19-25228 |
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Jan 1997 |
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JP |
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95/35100 |
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Dec 1995 |
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WO |
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00/10538 |
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Mar 2000 |
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WO |
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00/18835 |
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Apr 2000 |
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WO |
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Other References
"Diffusion Characteristics and Properties of Chitosan Coacervate
Capsules", Process Biochemistry, 26 (1991) pp. 75-81. cited by
examiner .
Chemical Abstracts 63--Pharmaceuticals, vol. 126, No. 15, 1997.
cited by examiner.
|
Primary Examiner: Hartley; Michael G.
Attorney, Agent or Firm: Dippert; William H. Rozycki; Andrew
G. Nickey; Donald O.
Parent Case Text
RELATED APPLICATIONS
This application is a continuation-in-part application and is based
on U.S. Provisional Application Ser. No. 60/142,704; filed Jul. 7,
1999.
Claims
We claim:
1. An edible, soft capsule which comprises a soft, dry shell which
comprises: .[.(v).]. .Iadd.(a) .Iaddend.about 12-24 weight %
iota-carrageenan; .[.(vi).]. .Iadd.(b) .Iaddend.about 30-60 weight
% modified starch; .[.(vii).]. .Iadd.(c) .Iaddend.about 10-60
weight % plasticizer; .Iadd.and .Iaddend. .[.(viii).]. .Iadd.(d)
.Iaddend.about 1-4 weight % sodium phosphate dibasic buffer
system.[.; and.]. .Iadd., .Iaddend.L wherein said shell encloses a
soft capsule fill material.
2. A soft capsule according to claim 1 wherein the plasticizer is
comprised of glycerin or sorbitol or a mixture thereof and the
modified starch is selected from the group consisting of modified
corn starch, acid modified hydroxypropylated corn starch and
hydroxypropylated acid modified tapioca starch.
.Iadd.3. An edible, soft capsule which comprises a soft, dry shell
which comprises: (a) iota-carrageenan; (b) modified starch; and (c)
plasticizer, wherein the weight ratio of iota-carrageenan to
modified starch is at least 1.5:1 and wherein said shell encloses a
soft capsule fill material..Iaddend.
.Iadd.4. An edible, soft capsule which comprises: (a) a soft dry
shell comprising: (i) iota-carrageenan; (ii) modified starch; and
(iii) plasticizer, wherein the weight ratio of iota-carrageenan to
modified starch is at least 1.5:1, and (b) soft capsule fill
material..Iaddend.
.Iadd.5. A soft shell capsule according to claim 4 wherein the
soft, dry shell also comprises buffer..Iaddend.
.Iadd.6. An edible, soft capsule, which comprises a soft, dry shell
which comprises: (a) about 12-24 weight % iota-carrageenan; (b)
about 30-60 weight % modified starch; (c) about 10-60 weight %
plasticizer; and (d) about 1-4 weight % buffer, wherein said shell
encloses a soft capsule fill material..Iaddend.
Description
FIELD OF THE INVENTION
This invention relates to capsules and, more specifically, to soft
capsules typically made using a rotary die apparatus. More
specifically, it relates to novel compositions that are capable of
forming films from which soft capsule shells can be made.
BACKGROUND OF THE INVENTION
Encapsulation within a soft capsule of a solution or dispersion of
a nutritional or pharmaceutical agent in a liquid carrier offers
many advantages over other dosage forms such as compressed, coated
or uncoated solid tablets or bulk liquid preparations.
Encapsulation of a solution or dispersion permits accurate delivery
of a unit dose, an advantage which becomes especially important
when relatively small amounts of the active ingredient must be
delivered, as in the case of certain hormones. Such uniformity is
more difficult to achieve via a tableting process wherein solids
must be uniformly mixed and compressed, or via incorporation of the
total dose of active ingredient into a bulk liquid carrier which
must be measured out prior to each oral administration.
Soft capsules, most commonly, soft gelatin capsules, provide a
dosage form which is more readily accepted by patients, since the
capsules are easy to swallow and need not be flavored in order to
mask the unpleasant taste of the active agent. Soft capsules are
also more easily transported by patients than bulk liquids, since
only the required number of doses need be removed from the
package.
Soft encapsulation of drugs further provides the potential to
improve the bioavailability of pharmaceutical agents. Active
ingredients are rapidly released in liquid form as soon as the
gelatin shell ruptures. Complete disintegration of the capsule is
not necessary for the active ingredients to become available for
absorption, unlike the case of tableted compositions. Also,
relatively insoluble active ingredients can be dispersed in a
liquid carrier to provide faster absorption.
Traditionally, both soft and hard-shell capsules have been
manufactured using mammalian gelatin as the material of choice for
producing the capsule envelope. The rotary die process developed by
Robert Scherer in 1933 for producing one piece soft capsules
utilized the unique properties of gelatin to enable a continuous
soft capsule manufacturing process. The inventive, gelatin-free
composition disclosed in this patent application is especially
useful in the rotary die method of soft capsule manufacture.
Conventional manufacturing of soft capsules using the rotary die
process utilizes mammalian gelatin in a process essentially as
follows. Dry gelatin granules are combined with water and suitable
plasticizers and the combination is then heated under vacuum to
form a molten gelatin mass. The gelatin mass is held in its molten
state while being formed or cast as films or ribbons or casting
wheels or drums. The films or ribbons are fed under a wedge and
between rotary encapsulation dies. Within the encapsulation dies,
capsules are simultaneously formed from the films or ribbons,
filled, cut and sealed. The seals are formed via a combination of
pressure and heat as the capsule is filled and cut. Rotary die
manufacture of soft gelatin capsules is disclosed in detail in The
Theory and Practice of Industrial Pharmacy (Lachman, Lieberman and
Kanig, Editors), 3.sup.rd Edition, published by Lea & Febiger.
A good description of gelatin encapsulation techniques can also be
found in WO 98/42294 (PCT/GB98/00830).
Gelatin formulations used to produce films suitable for making
capsules within the rotary die process typically contain between
25% to 45% by weight mammalian gelatin. Levels below 25% by weight
tend to lead to poor sealing of the capsule. The physical
properties of the gelatin film are critical to the economic
production of soft capsules. For example, the film must be strong
enough to survive manipulation in the encapsulation machine,
provide good sealing properties at temperatures below the melting
point of the film, evidence rapid dissolution in gastric juices,
and have sufficient elasticity to allow for the formation of the
capsule. The wholly non-animal composition of the present invention
meets all of these requirements without the use of mammalian
gelatin, and surprisingly evidences several improved
properties.
The composition according to the present invention, like mammalian
gelatin, has many properties that favor its use in soft capsule
manufacture. One important property of the inventive compositions
with respect to the rotary die process is the ability of the
compositions to be cast to form films that are mechanically strong
and exhibit elasticity sufficient to allow the film to stretch
during filling. In other words, the inventive films have
dimensional stability, elasticity and strength adequate for use in
a continuous commercial process.
Another important and unique property of the inventive compositions
is that the films forming the two halves of the capsule will fuse
together during the filling and cutting process when subjected to
sufficient pressure and elevated temperature. This fusing together
relies on a particular property of the films that allows fusion
under conditions of elevated temperature, supplied by the injection
wedge, and pressure, supplied by the rotary cutting dies. The
temperature at which fusion of two opposing films occurs should be
below the melting point of the film, i.e., the fusion or sealing
temperature is less than the melting point of the film composition.
It has proven difficult to find this combination of properties in
other polymer systems. Thus, most proposed substitutes for
mammalian gelatin have failed due to a lack of one or more of these
properties. This is the main reason why mammalian gelatin has been
used almost exclusively as the shell forming material in soft
capsule manufacture.
The property of fusion temperature being lower than melting
temperature is crucial to the sealing of capsules using the
continuous rotary die process. If the fusion and melting
temperatures are about the same, the film will nearly completely
melt as it passes through the wedge and the rotary die. At this
temperature, the film loses its structure. As a result, capsules
cannot be produced.
Disadvantages of mammalian gelatin includes the cost and continuity
of supply. Gelatin has a variety of other drawbacks. For example,
bovine sources are somewhat unattractive to individuals that prefer
vegetarian food sources. Also, gelatin is prone to cross-linking,
either caused by aging or due to reaction with compounds such as
aldehydes. Cross-linking reduces the gelatin insoluble in gastric
fluids, a generally undesirable quality for soft capsules. Thus,
there is a need in the soft capsule industry for a replacement for
the gelatin based compositions.
Other hydrocolloids form films but they lack the attributes of
mammalian gelatin required to allow their use in the rotary die
process. For example, a variety of modified food starches such as
those available from Grain Processing Corporation as
Pure-Cote.RTM., are low viscosity starches that provide
film-forming and adhesive properties. Such starches form clear,
flexible films that are fast drying and flavor free. These
materials are suitable as binders for seasonings on snacks and
cereals and as smooth, glassy coating agents for confections and
baked goods. However, these materials are unable to form hydrated
films with the requisite strength and elasticity required for use
in the rotary die process. Further, films made entirely from starch
have insufficient elasticity and strength to be transferred from
the casting drum to the rotary dies. Also, the films adhere too
tightly to the casting drum, further diminishing transferability.
Thus, compositions are needed that mimic the behavior and
characteristics of mammalian gelatin while overcoming its
shortcomings.
BACKGROUND ART
Japanese Patent Application Kokai Publication No. 63-164858
discloses a composition for the outer skin of soft capsules that
allows the filling of hydrophilic materials into the capsule. The
composition is a mixture of at least one natural polysaccharide
selected from alginic acid, alginic acid derivatives, agar, locust
bean gum, carrageenan, guaic gum, tamarind seed polysaccharide,
pectin, xanthan gum, glucomannan, chitin, pluran, and cyclodextrin;
and at least one substance selected from polyvalent alcohols, sugar
alcohols, monosaccharides, disaccharides, and oligosaccharides. The
oligosaccharides are described as enzyme and acid decomposition
products of sweet potato, potato, corn and the like. While
carrageenan is disclosed, there is no distinction made between the
various forms of carrageenan (i.e., iota versus kappa). Further,
there is no suggestion that the combination of two gelling agents,
iota-carrageenan and a modified starch having a hydration
temperature below about 90.degree. C. would advantageously produce
a soft capsule having outstanding physical properties. Further,
there is no disclosure or suggestion that a weight ratio of
modified starch to iota-carrageenan of at least 1.5:1 is required
to produce a film that can be used in a rotary die encapsulation
machine to make soft capsules.
International Patent Application No. PCT/FR98/01744 (WO 97/07347)
discloses a composition for the manufacture of soft and hard
capsules that uses iota-carrageenan as the only gelling agent at
concentrations of greater than 5% by weight. This reference does
disclose the use of starches and surfactants in the composition at
levels of up to 20% by weight for the purpose of accelerating the
disintegration of the capsule after contacting gastric juices. No
specific teaching on the type of starch is given, other than
substances such as wheat, rice, maize or manioc starch which may or
many not have been modified, may be used. This reference fails to
suggest or disclose the use of gelling starches and
iota-carrageenan at weight ratios of at least 1.5:1 to form films
useful in making soft capsules, wherein the starch is a modified
starch with a hydration temperature of less than 90.degree. C.
U.S. Pat. No. 5,342,626 to Winston et al. discloses a composition
comprising gellan, carrageenan and mannan gums for producing soft
capsules. This patent further discloses that the tri blend of gums
can be combined with additional ingredients to form a film-forming
polymer composition. This reference, however, fails to disclose the
benefits that can be arrived at through the use of iota-carrageenan
with certain modified starches.
Japanese Patent Application No. HE19-25228 discloses a soft capsule
film having an essential components agar and water-soluble high
polymers, such as the carrageenans. This reference fails to suggest
or disclose the combination of iota-carrageenan with a modified
starch having a hydration temperature below about 90.degree. C. to
form films that have outstanding properties in the preparation of
soft capsules.
In similar fashion, Japanese Patent Application Disclosure No.
HE15-310529 discloses a capsule forming film comprising agar and
carrageenan. The reference points out that kappa carrageenan was
found to be preferable. This reference does not make any mention of
modified starches being incorporated into the film forming
composition.
Japanese Public Patent Disclosure Bulletin No. 61-10508 disclose
capsules made from polysaccharides which contain carrageenan and a
base which contains multivalent alcohols. The multivalent alcohols
include sorbitol, ethylene glycol, glycol, glycerin and the like.
No mention is made of iota-carrageenan nor of modified
starches.
Another reference suggesting the use of kappa-carrageenan to form
capsules is seen in Japanese Patent Application Disclosure No.
SHO60-12943. This reference teaches the exclusive use of kappa
carrageenan in concentrations of about 1 to about 12% by weight.
This reference also suggest that suitable plasticizers or gelatins
can be included for increasing film strength.
PCT Application WO 00/10538 to Banner Pharmacaps discloses a
gelatin free capsule comprising: a) 8-50% by weight of a water
dispersible or water-soluble plasticizer; b) 0.5-12% by weight
kappa carrageenan; c) 0-60% by weight dextrins; and d) 1-95% by
weight water wherein the kappa carrageenan comprises at least 50%
by weight of all gums forming or contributing to formation of
thermo-reversible gels in the composition. This application does
not suggest the combination of a film-forming starch and
iota-carrageenan to produce a film of exceptional properties for
the formation of soft capsules.
U.S. Pat. No. 5,089,307 to Ninomiya et al. discloses a heat
sealable, edible film comprising a film layer consisting
essentially of: 1) a water soluble polysaccharide composed chiefly
of carrageenan; 2) a polyhydric alcohol; and 3) water. The film of
this patent has a water content of not greater than 25% by weight
and a weight ratio of the polyhydric alcohol to the water soluble
polysaccharide being in the range from 1:5 to 1:1. While this
reference does mention all three (3) forms of carrageenan, kappa,
iota and lambda, it fails to suggest or disclose a soft capsule
formulation containing iota-carrageenan and a modified starch, such
as hydroxypropylated tapioca starch.
U.S. Pat. No. 5,817,323 to Hutchison et al. discloses a composition
for use in the shell of a comestible capsule comprising gelatin and
a plasticizer, such as glycerol, together with a further compound
which forms a secondary matrix for the plasticizer. This further
component is disclosed as typically being unbleached potato starch
acetate. This patent makes no suggestion or disclosure of the use
of iota-carrageenan as an elasticizing agent for the film forming
modified starches.
U.S. Pat. No. 4,804,542 to Fischer et al. describes gelatin
capsules comprising a capsule sheath and a filling wherein the
sheath contains a gelatin and at least 1% by weight of an agent
selected from the group consisting of starches, starch derivatives,
celluloses, cellulose derivatives, milk powder, non-hygroscopic
mono-, di- and oligo saccharides, magnesium trisilicate and silicon
dioxide. These agents are described as being capable of absorbing
water in an amount of at least 10% by weight of its own weight.
This patent teaches that the capsule sheath can then be used in
containing water miscible, water soluble, water sensitive or
hydrophilic materials. This patent makes no mention of
iota-carrageenan.
U.S. Pat. No. 3,865,603 to Szymanski et al. relates to modified
starch-extended gelatin compositions. This patent discloses
modified starches with hydration temperatures above 99.degree. C.
for use with mammalian gelatin at weight ratios of about 1:9 to 1:1
(starch to gelatin). No mention is made of iota-carrageenan or the
special need for soft capsule manufacture with sealing temperatures
substantially below the melting point of the film.
SUMMARY OF THE INVENTION
The present invention provides compositions for manufacturing
capsules, in particular, soft capsules, and especially soft
capsules manufactured using the rotary die encapsulation apparatus.
The invention provides compositions that do not employ mammalian
gelatin and, therefore, overcome the disadvantages associated with
collagen-derived material. Compositions of the invention do not
contain any significant amounts of gelatin but, instead, require at
least two (2) agents: 1) a modified starch having a hydration
temperature below about 90.degree. C. and 2) iota-carrageenan.
As those skilled in the art of soft capsule manufacture will
appreciate, the film formed on the drum of the encapsulation
machine is called the "wet film". This film is used in the rotary
encapsulation machine to form the filled capsules. The capsules are
then dried using any number of techniques. During the drying
process, water is removed from the fill material (when the fill
material is hydrophilic) and the capsule shell. The result is a
soft capsule with a "dry film". The dry film comprises the various
components, i.e., carrageenan, plasticizer, modified starch and the
like and "bound water". The bound water, from about 6 to 12% by
weight of the dry film, is not easily removable using conventional
drying techniques and is not considered when describing the
components of the dried film as a percentage of the composition.
The dried film numbers are calculated numbers based upon a assumed
weight percent of the bound water.
Thus, for example, Table I sets out the components of the inventive
film forming composition and representative weight percent ranges
for the wet film and the dry film.
TABLE-US-00001 TABLE I Prototypic Formula Component Weight % of Wet
Film Weight % of Dry Film Iota-carrageenan 6-12 12-24 Modified
starch 12-30 30-60 Plasticizer 5-30 10-60 Buffer 0.5-2 1-4
Preservative 0-0.2 0-0.4
As will be demonstrated in the Examples, one aspect of the present
invention resides in the discovery that the weight ratio of the
modified starch to the iota-carrageenan is crucial to forming a
satisfactory film. The weight ratio of the modified starch to the
iota-carrageenan is at least 1.5:1, with a preferred range being
1.5:1 to 4:1. Another feature useful in characterizing the
inventive film is fusion pressure. The mixture of modified starch,
iota-carrageenan and other components should result in a wet film
that fuses at pressures above 207 kPa.
Thus, there is disclosed, a composition suitable for forming a film
for encapsulating materials, the composition comprising a modified
starch and iota-carrageenan in a ratio by weight of at least 1.5:1;
said film capable of fusion under a pressure of at least about 207
kPa (30 psi). There is further disclosed a composition wherein the
weight ratio of modified starch to iota-carrageenan ranges from
1.5:1 to 4:1, more preferably from 2:1 to 3:1. Further, the
invention relates to a film forming composition that is capable of
fusion, under pressure, in the range of 207 kPa to 2070 kPa (30 to
300 psi) and at temperatures in the range of from 25-80.degree. C.
In a yet more preferred embodiment, the film according to the
present invention has a melting temperature of from 2 to 25.degree.
C., more preferably 3-15.degree. C. and most preferably 4-9.degree.
C. above its fusion temperature.
More specifically, the compositions according to the invention
(expressed as wet film) comprise from 5-50% by weight modified
starch; more preferably 15-40% by weight and the preferred modified
starch is hydroxypropylated acid modified corn starch. The
invention is also most preferably a composition wherein
iota-carrageenan comprises at least 6 and up to 12% by weight of
the composition. The composition according to the present invention
may also contain a plasticizer such as glycerin and the plasticizer
may comprise up to 50% by weight of the composition, more
preferably up to 30% by weight.
There is also disclosed a dried film composition for soft capsules,
the composition consisting essentially of from 42-84% by weight gel
formers comprising a mixture of iota-carrageenan and modified
starch; a plasticizer; and a buffer.
There is further disclosed a composition suitable for forming a
soft capsule, the composition comprising iota-carrageenan and at
least one modified starch selected from the group consisting of
hydroxypropylated tapioca starch, hydroxypropylated maize starch,
acid thinned hydroxypropylated corn starch, potato starch,
pregelatinized modified corn starches, and wherein said starch has
a hydration temperature below about 90.degree. C. and wherein the
weight ratio of modified starch in iota-carrageenan ranges from
1.5:1 to 4.0:1. The invention also relates to a soft capsule
comprising a shell and a fill material wherein the shell is a film
according to the present invention.
In general, the invention provides compositions that function
effectively as replacements for the conventional mammalian gelatin
based compositions. Thus, the compositions of the invention possess
many of the desirable important characteristics of gelatin. The
inventive compositions form films that are mechanically strong and
exhibit elasticity sufficient to allow the film to stretch during
filling (blow-molding). Thus, the invention films have dimensional
stability, elasticity and strength adequate for use in a continuous
process which requires their removal from a casting drum and
subsequent transport to rotary dies. Unexpectedly, the fusion or
sealing temperature is substantially less than the melting point of
the inventive film. Thus, films formed from the compositions of the
invention simultaneously fuse together during the filling and
cutting portion of the rotary die process when subjected to
sufficient pressure and elevated temperature.
An additional unexpected property of the films according to the
invention is that sealing occurs at substantially lower pressures
than those experienced with mammalian gelatin based compositions.
For example, conventional mammalian gelatin based films seal at
pressures of about 1,724 kPa (250 psi) whereas the new films
according to the present invention seal at about 207 kPa, more
preferably about 552 kPa (30-80 psi). This saves energy and reduces
the wear experienced by the rotary die. Also, the inventive film,
when dry, (the film contains about 6 to 12% by weight water) is
durable and impermeable to hydrophobic liquids.
As used herein and in the claims, the term "fusion" is meant to
mean the welding of two (2) films by the use of pressure so as to
result in a bond that is not easily separated. The fusion of the
two films during the rotary die process results in a seal that is
adequate to hold the liquid fill of the soft capsule during its
anticipated shelf life.
In a preferred embodiment, the invention provides compositions
comprising at least one modified starch and iota-carrageenan in a
ratio by weight in the range of 1.5:1 to 4:1; plasticizers; buffers
and optionally preservatives. Such materials can be formed into
films that have sufficient structure, elasticity and strength to be
removed from a temperature-controlled casting surface. It has
unexpectedly been found that a combination of carrageenan,
especially iota-carrageenan, and at least one modified starch,
forms films having characteristics that allow the film to be
reversibly stretched during the capsule filling step. These
compositions, as wet films, preferably comprise water, 6-12 weight
% iota-carrageenan, 12-30 weight % modified starch, 5-30 weight %
plasticizers, 0.5-2 weight % buffers and optionally 0-0.2 weight %
preservatives.
In another embodiment, the invention provides films comprising
water and a solids system. In the films of the present invention,
the solid system comprises modified starch and iota-carrageenan.
The films of the invention are capable of maintaining their form
without being applied to a support; they do not lose their shape
through splitting, lengthening, disintegration or otherwise by
breakdown of the film when unsupported. However, the films may be
stretched when pulled or compressed to a certain extent when an
appropriate external force is applied.
As used herein and in the claims, the term "modified starch"
includes such starches as hydroxypropylated starches, acid thinned
starches and the like. The only native starch determined to be
functional with iota-carrageenan in preparing the films according
to the invention is potato starch, thereby the term "modified
starch" is meant to include native, unmodified potato starch. In
general, modified starches are products prepared by chemical
treatment of starches, for example, acid treatment starches, enzyme
treatment starches, oxidized starches, cross-bonding starches, and
other starch derivatives. It is preferred that the modified
starches be derivatized wherein side chains are modified with
hydrophilic or hydrophobic groups to thereby form a more
complicated structure with a strong interaction between side
chains.
Through the diligent work of the inventors herein, they have
determined that some starches are barely functional in their
inventive compositions and include high amylose starches, native
starches other than potato starch and cross-linked starches.
Hydrogenated starch hydrolysates that have been used to promote the
disintegration of the gelatin capsule would likewise not be useful
in the present invention.
These are two characteristics that help characterize modified
starches that are useful in the present invention and they are 1)
hydration temperatures below about 90.degree. C. and 2) film
forming capabilities. Through a careful study of numerous starches,
it has been determined that the following starches are not useful
in the present invention: tapioca dextrin, high amylose
non-modified corn starch, modified waxy maize starch, non-granular
starch, modified high amylose corn starch and pregelatinized rice
flour.
There is further disclosed an edible, soft capsule which comprises:
a) a soft, dry shell which comprises: (i) about 12-24 weight %
iota-carrageenan; (ii) about 30-60 weight % modified starch; (iii)
about 10-60 weight % plasticizer; (iv) about 1-4 weight % sodium
phosphate dibasic buffer system; and wherein said shell encloses:
b) a soft capsule fill material.
In a further embodiment of the invention, there is disclosed a
capsule wherein the plasticizer is comprised of glycerin or
sorbitol or a mixture thereof and the modified starch is selected
from modified corn starch, acid modified hydroxypropylated corn
starch and hydroxypropylated acid modified tapioca starch.
Carrageenan has been known for decades as a useful food ingredient.
While salt and sugar are rather simple food ingredients,
technologically, carrageenans are rather complex and there are
hundreds of different products available in the market called
carrageenan with highly different price levels and functionalities.
Carrageenan is obtained by aqueous extraction of natural strains of
seaweeds of Gigartinaceae, Solieriaceae, Phyllophoraceae, and
Hypneaceae, families of the class Rhodophyccae (red seaweeds). The
three major forms of carrageenan are known as iota, kappa and
lambda carrageenan. Lambda and kappa carrageenans do not typically
occur together in the same plant, however, since the various
species are harvested together, extraction yields a typical mixture
of kappa and lambda with an average of around 70% kappa and 30%
lambda. Euchema Spinosum is the seaweed source for production of
iota-carrageenan either as an extract or as a processed Euchema
seaweed. During the production of carrageenans, it is common that
no sorting takes place before shipment of the seaweed to the
carrageenan rendering facilities. Seaweeds are typically sold based
on seaweed type and content of sand, salt, stones and humidity and
not based on functional specifications. Thus, carrageenan
manufacturers need to test each seaweed shipment to determine the
quality of the extractable carrageenan in order to see if any
processing adjustments are needed for obtaining the desired
specifications. Carrageenans are available in the market place as
standardized and non-standardized carrageenans. Standardization is
done either by blending different pure carrageenan batches
(cross-blending) or by blending one or more carrageenan batches
with other ingredients such as salts (KCl, NaCl, and CaCl.sub.2)
and/or sugars (saccharose, dextrose, maltodextrins, lactose) in
order to reach the desired specification. As used herein an in the
claims, the recited weight percents for iota-carrageenan include
the standardizing ingredient.
All carrageenans are water soluble gums having the common
structural feature of being linear polysaccharides with a sugar
backbone of alternating units consisting of galactose units linked
by 1,3-.beta.-D-linkages, as well as 1,4-.alpha.-D-linkages. The
fundamental properties of iota, kappa and lambda are a function of
the number and position of the ester sulfate groups.
Iota-carrageenan contains approximately 30% by weight 3,6
anhydro-D-galactose and 32% ester sulfate by weight. In contrast,
kappa carrageenan contains more than 36% by weight 3,6
anhydro-D-galactose and 32% ester sulfate by weight. Molecular
weight ranges from 100,000 to 500,000 Daltons. The gelling
carrageenans (kappa and iota) contain an "internal" ring--the
3,6-anhydro ring. The presence of ester sulfate makes carrageenans
negatively charged at all pH values and is responsible for
carrageenans being highly reactive molecules. Commercially
available carrageenans are typically not well defined chemical
compounds. However, through careful quality control, relatively
pure materials with specified properties are available
commercially.
The gelling carrageenan types (kappa and iota) are biosynthesized
by the living seaweed as a non-gelling precursor, which is then
turned into the gelling form by the action of the enzyme,
dekinkase, which catalyzes the formation of the
3,6-anhydroglacatose ring. As mentioned previously,
iota-carrageenan is only produced from Euchema Spinosum and
produces the strongest gels with calcium ions (Ca.sup.++). The gels
are very elastic and completely syneresis free at the normal
concentrations for food application (i.e., 0.5 to 2% by weight).
Although iota-carrageenan does not gel with Na+, diluted
iota-carrageenan solutions will form thixotropic solutions also
with Na+ as it acts as a stabilizing agent. In the best mode of the
present invention, the Ca.sup.++ content is kept to a minimum.
In iota-carrageenan, the 1,3- and 1,4-linked units are respectively
D-galactose-4-sulfate and 3,6-anhydro-D-galactose-2-sulfate.
However, some of the 3,6-anhydro-D-galactose-2-sulfate rings may be
replaced by D-galactose-6-sulfate, which may reduce considerably
the gelling power of the iota-carrageenan.
The iota-carrageenan useful in the composition according to the
invention should conform to the specification laid down by the USA
and European regulatory authorities. The iota-carrageenan should
not be degraded and should conform to minimum viscosity standards,
which correspond to a molecular weight of about 100K Daltons.
Syneresis is often measured on carrageenan gels to determine
breaking force and characterize the iota from the kappa
carrageenan. After breaking force has been measured, the gel is
transferred to a petri dish and covered to avoid evaporation from
the gels. After typically about four (4) hours, the amount of free
water (the syneresis) is measured. A high value indicates a strong
gelling kappa, whereas no syneresis indicates iota.
Table II sets out typical analytical patterns and values for
iota-carrageenan.
TABLE-US-00002 TABLE II Typical Analytical Parameters and Values
for Iota-carrageenan Typical Values Typical Values Parameter
(Ca-iota) (Na-iota) Gel strength 0-100 g/cm.sup.2 0 (1.5%
carrageenan) pH 7-10 7-10 (i.e. 1.5% gel) Viscosity 10-30 cP 10-30
(1.5% at 75.degree. C.) Chloride 0-1% (as KCl) 0-1% Calcium 2-6%
0-0.5% Sodium .about.1% 3-5% Potassium 3-5% 4-7%
Through extensive investigative efforts, the inventors have
determined that iota-carrageenan alone does not produce an
acceptable film and that the modified starches alone do not produce
a useable film for encapsulation. Without being bound to any theory
or mechanism, it is speculated that the iota-carrageenan and
modified starches interact synergistically to provide films of
sufficient strength and elasticity to be useful in the
encapsulation process.
The films made from the compositions of the invention possess the
desirable properties of the films made from gelatin and function as
effective replacements for gelatin films in virtually all processes
that employ aqueous-gelatin compositions for the production of soft
capsules. Among those processes are rotary die encapsulation
processes, reciprocating die encapsulation processes, concentric
cylinder processes, and processes for film-enrobing tablets. The
film-enrobing process is also a rotary die process, as described in
U.S. Pat. No. 5,146,730, the disclosure of which is incorporated
herein by reference in its entirety. Thus, the compositions of the
present invention provide: i) mechanically strong, elastic films
that set on a temperature-controlled casting drum generally within
from about 15 to about 60 seconds, preferably less than about 20
seconds; ii) films that, when brought into contact with one
another, fuse together at temperatures of from about 25-80.degree.
C. and pressures of from about 207 to about 2070 kPa (30-300 psi);
iii) films that fuse (form seals in the rotary die process) at
temperatures significantly below the melting point of the films;
and iv) strong, durable dried films.
Still other advantages of the inventive compositions include: i)
finished capsules are not prone to cross-linking or
insolubilization due to interaction with materials such as
aldehydes, phenols ketones, that may be present within the capsule
fill or shell, or that are formed over time by oxidization; and ii)
finished capsules exhibit greater stability when exposed to
elevated humidity and temperature than capsules made using
gelatin.
The compositions of the present invention are capable of forming
unsupported wet and/or dry films, i.e., the films do not require a
support to maintain their shape and structure. Further, they do not
disintegrate, tear or fracture unless some significant external
force is applied. The compositions of the invention are formed into
films by any of a variety of suitable methods. While casting or
extruding onto a casting drum is preferred in connection with the
rotary die process, other processes for forming films will be
apparent to those skilled in the art.
Other components may also be incorporated into the compositions
provided they do not alter the melting point/fusion point
characteristics of the inventive film. Representative of these
additional components include flavoring agents, opacifying agents,
preservatives, embrittlement inhibiting agents, colorants and
disintegrants. The inventive compositions are typically in the
molten state when these components are added. Use of conventional
pharmaceutical or food grade ingredients is acceptable.
As used herein and in the claims, the phrase "an amount of modified
starch effective to form a structured film" means an amount of a
modified starch sufficient to form a film or gel that does not
flow, but has dimensional stability. More preferably, the phrase
"effective to form a structured film" means an amount of a modified
starch sufficient to form a dimensionally stable film having a
thickness of at least about 0.01 inches.
The phrase "effective elasticizing amount" means an amount of
iota-carrageenan sufficient to provide a starch based composition
in the form of film with sufficient strength to be removed from a
casting drug during rotary die processing and also sufficient
elasticity to be deformed during the rotary die process when a fill
material is presented between a pair of films of the composition
(blow molded).
The phrase "fusion temperature" means the temperature at which two
opposing films, in contact with each other, will blend at their
contact interface to become one, indistinguishable and inseparable
structure.
The weight ratio of modified starch to iota-carrageenan in this
invention is at least 1.5:1, more preferably from about 1.5:1 to
about 4:1, most preferably, from about 2:1 to about 3:1.
Unexpectedly, the compositions of the invention possess the
important characteristic of having a melting point temperature that
is substantially higher than the fusion temperature. Preferably,
the melting point temperature of a film according to the invention,
is from about 3-15.degree. C., and more preferably from about 4 to
9.degree. C., above its fusion temperature.
While not being bound to any theory or mechanism, it is believed
that the iota-carrageenan functions as an elasticizing agent. In
other words, this elasticizing agent renders an otherwise
in-elastic, modified starch film, elastic. Consequently, the films
of the invention have a "memory" and are capable of returning
substantially to their original size and shape after being
subjected to a deforming force. For example, a film made from the
starch/carrageenan compositions of the invention that is stretched
along its length and/or width will substantially return to its
original length over time.
As discussed previously, the modified starches useful in the
present invention include those starches that have a hydration
temperature below about 90.degree. C. Hydration temperatures for
most starches are available in the literature, such as product data
for commercially available starches. Where they are not available
via the literature, such hydration temperatures may be readily
determined employing techniques well know to those skilled in the
art. Suitable starches also must be capable of forming an aqueous
mixture with water at a concentration of at least from about 20
weight % to give a mixture having a viscosity below about 60,000 to
80,000 centipoise (cps) measured at a 10 sec-1 shear rate at the
temperature at which starch hydration occurs.
Representative of the commercially available starches useful in the
present invention include Pure Cote.TM. B760 and B790 (an
acid-modified hydroxypropylated corn starch), Pure-Cote.TM. B793 (a
pre-gelatinized modified corn starch), Pure-Cote.TM. B795 (a
pre-gelatinized modified corn starch), and Pure-Set.TM. B965 (a
flash-dried acid modified native corn dent starch), all available
from the Grain Processing Corporation of Muscatine, Iowa. Other
useful, commercially available, modified starches include
C*AraTex.TM. 75701 (hydroxypropylated acid modified tapioca
starch), available from Cerestar, Inc. of Hammond, Ind.; M250 and
M180 (maltrins) and Pure-Dent.TM. B890 (modified corn starch) from
Grain Processing Corporation; and Midsol Crisp (modified high
amylose corn starch) from Midwest Grain, Inc. of Atkinson, Kans.
The only native (unmodified) starch suitable for use herein is
potato starch. Such a starch is available from Roquette as Potato
Starch Supra Bacter.
The invention may include genetically (recombinantly) modified and
hybridized starches. Genetically modified and hybridized starches
include those that have been developed to alter the physical
properties and/or the amylose/amylopectin ratios. The preferred
starch is an acid hydrolyzed corn starch modified with
2-hydroxypropyl ether functional groups. This starch is identified
by Chemical Abstracts Service Registry No. 68584-86-1. This
material is commercially available as PURE-COTE.RTM. B760 and B790
from Grain Processing Corporation.
The iota-carrageenan is present in the inventive compositions in an
amount that, in combination with starch, effectively causes the
compositions to have the required gelatin-like functional
properties. As discussed previously, as those skilled in the art
will appreciate, the film has what is known as a wet shell
composition and a dry shell composition. This results from the
evaporation of water from the film during the manufacturing process
of the soft capsule. Preferred amounts of iota-carrageenan range
from about 6 to 12% by weight of the wet shell composition. More
preferred amounts of iota-carrageenan range from about 7-12% by
weight of the wet composition. Particularly preferred compositions
contain from about 9-11 weight % of iota-carrageenan, based on the
weight of the wet composition. Even more preferred compositions
contain about 10 weight % of iota-carrageenan by weight of the wet
composition.
As will be demonstrated in the Examples, not all members of the
carrageenans family can be used herein. Standardized
iota-carrageenans are preferred. A particular preferred
standardized iota-carrageenan is commercial available from the FMC
Corporation of Princeton, N.J., known as VIS-CARIN.RTM. SD389,
standardized with 15% by weight dextrose. Other useful
iota-carrageenans include a non-standardized iota-carrageenan from
SKW BioSystems of Baupt, France known as XPU-HGI and a
non-standardized iota-carrageenan from FMC.
In general, the film forming compositions may consist of the
iota-carrageenan, at least one modified starch with the balance of
the composition being water. However, preferred compositions of the
invention include a plasticizer. Suitable plasticizers include the
materials used for the same purpose in the manufacture of mammalian
gelatin capsules. Representative plasticizers are any of a variety
of polyhydric alcohols such as glycerin, sorbitol, propylene
glycol, polyethylene glycol and the like. Other plasticizers
include saccharides and polysaccharides. The saccharides and
polysaccharides suitable for use herein may be produced by
hydrolysis and/or hydrogenation of a simple or complex
polysaccharides.
Where plasticizers are employed, they can be used in amounts of up
to about 60% by weight of the dry shell composition or 30% of the
wet shell composition. More preferred compositions contain from
about 10 to 25% by weight, based on the weight of the wet shell
composition and 30-50% by weight of the dry shell composition.
Also, the capsule forming composition, i.e., the shell mass
composition, may optionally contain an embrittlement inhibiting
composition. An example of embrittlement inhibiting compositions is
a mixture of sorbitol and one or more sorbitans. See U.S. Pat. No.
4,780,316.
Optionally, the film forming composition may contain preservatives
and stabilizers such as mixed parabens, ordinarily methyl or propyl
parabens, in about a 4:1 ratio. The parabens may be incorporated in
the compositions at levels of 0-0.2 weight % for the wet shell and
0-0.4 weight % for the dry shell. It should be noted that in the
following Examples, preservatives were included in the experimental
formulation to facilitate un-dried sample retention for later
evaluations. Without preservatives, the retained wet ribbons would
be spoiled by microbial growth in a day or two. On a commercial
scale, preservatives would typically note be added to the film
forming composition because the wet ribbon would be quickly
processed through the encapsulation machines and then the dryers.
The dried film does not support microbial growth.
It has been found by the inventors that the use of a buffer system
in the inventive compositions is highly desirable. Any known buffer
can be used with phosphate buffers being preferred. Controlling the
pH of the melt and film is highly important as carrageenans are
rapidly broken down in conditions of high temperature and acidity.
As mentioned previously, the presence of Ca.sup.++ ions should be
kept to a minimum.
Soft capsules may be manufactured in accordance with conventional
techniques as set forth in Ebert, E. W., "Soft elastic gelatin
capsules: a unique dosage form", Pharmaceutical Tech., October
1977; Stanley, J. P., "Soft Gelatin Capsules", in The Theory and
Practice of Industrial Pharmacy, 359-84 (Lea and Febiger ed. 1970);
U.S. Pat. Nos. 1,970,396; 2,288,327; and 2,318,718.
The capsules made using the rotary die process, will typically have
wet shell thicknesses varying from about 0.024 to 0.1778,
preferably from about 0.0508 to 0.127 and more preferably from
about 0.0508 to 0.0762 cm in thickness. The capsules of the
invention may be manufactured in any desired shape using the
above-mentioned rotary die process.
The fill materials for the soft capsules may be any of a wide
variety of materials suitable for encapsulation using the rotary
die apparatus. Among the types of materials that are suitable for
encapsulation include oils, hydrophilic liquids and emulsions. The
active components that may be contained within the oils and
emulsions are hydrophobic and hydrophilic actives. Those skilled in
the art are familiar with and will recognize suitable fill
materials. These fill materials may contain cosmetics, foods
including vitamins, liquids, semi-solids, suspensions, flavorings
and pharmaceuticals. After filling, the capsules are typically
dried according to conventional techniques, e.g., tray drying,
using a drum dryer or other suitable drying methods.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following examples demonstrate certain aspects of the present
invention. However, it is to be understood that these examples are
for illustrative purposes only and do not purport to be wholly
definitive as to conditions and the scope of this invention. It
also should be appreciated that when typical reaction conditions
(e.g., temperature, reaction times) have been given, the conditions
which are both above and below these specified ranges can also be
used, though generally less conveniently.
A further understanding of the invention may be obtained from the
following non-limiting examples. Each of the following compositions
is prepared according to the method described below. All
temperatures are expressed in degrees Celsius (.degree. C.) and all
parts are parts by weight, unless designated otherwise.
EXAMPLE 1
Preparation of the Capsule Shell Material
A mixer, fitted with suitable medium shear mixing blades, and a
side sweep assembly was used to prepare a molten mass for forming
films. The mixing container may be heated or cooled as needed and
optionally may be constructed such that a vacuum can be established
inside the vessel.
Appropriate quantities of each component (except starch and
carrageenan) for each formulation was added to the mixer and
blended. The starch and carrageenan were then added to the mixture
and mixed under vacuum. Heat and continuous stirring were applied
until the mixture became molten and homogeneous. Samples from each
formulation were taken and cast onto a glass plate that was at room
temperature. A blade or draw bar with a notch of about 15 cm in
width and 0.127 cm in height was used to create the casting. After
cooling, the film (about 0.06 cm to 0.08 cm in thickness) was
evaluated for stiffness, elasticity, brittleness and film strength.
Those films that were characterized by the investigator as having
some potential were evaluated for sealing properties. The film was
carefully removed from the glass plate and folded in half and
placed on a preheated bag sealer from Midwest Pacific Corp. The arm
was lowered and contacted the folded film as heat and pressure were
applied. This device is also known as an impulse sealer and was
used to assess the sealability of wet films in the laboratory. This
device provided a good guide as to whether or not an experimental
film would form a seal. The fusion of the two films was then
observed and rated as a weak seal or a good seal. The molten mass
was subsequently charged into a heated, preferably electrically
heated holding tank and maintained in its molten state until needed
for encapsulation, if the formulation was to be used for
encapsulation. Normal rotary die pressures for gelatin films range
from 200-300 lbs. (19-136 kg). It was determined from this work
that sealing pressure reductions of greater than 50% (34-68 kg)
could be realized and still produce a good seal.
The following formulations were prepared as discussed above.
TABLE-US-00003 Formulation 1 Wet Film Dry Film* Ingredient Percent
by Weight Percent by Weight PURE-COTE .RTM. B790 15.0 33.94
VISCARIN .RTM. SD389** 8.0 15.38 Glycerin USP (plasticizer) 20.0
45.25 Sodium phosphate di basic 1.0 2.26 (buffer) Preservative
(parabens) 0.20 0.45 Water USP 55.8 Dextrose 2.71
TABLE-US-00004 Formulation 2 Wet Film Dry Film* Ingredient Percent
by weight Percent by weight PURE-COTE .RTM. B790 15.0 34.32
VISCARIN .RTM. SD389** 10.0 19.45 Glycerin USP (Plasticizer) 17.5
40.05 Sodium phosphate di basic 1.0 2.29 (buffer) Preservative
(parabens) 0.20 0.48 Water USP 56.3 Dextrose 3.43
TABLE-US-00005 Formulation 3 Wet Film Dry Film* Ingredient Percent
by weight Percent by weight PURE-COTE .RTM. B760 22.0 37.29
VISCARIN .RTM. SD389** 10.0 14.41 Glycerin USP 25.8 43.73 Sodium
phosphate di basic 1.0 1.69 Preservative 0.20 0.34 Water USP 41.0
Dextrose 2.54
TABLE-US-00006 Formulation 4 Wet Film Dry Film* Ingredient Percent
by weight Percent by weight PURE-COTE .RTM. B760 28.0 49.56
VISCARIN .RTM. SD389** 11.0 16.55 Glycerin USP 15.8 27.96 Sodium
phosphate di basic 1.5 2.65 Preservative 0.20 0.35 Water USP 43.5
Dextrose 2.92
TABLE-US-00007 Formulation 5 Wet Film Ingredient Percent by weight
PURE-COTE B790 .RTM. 27 Genuvisco TPM-1 .RTM. 10 Glycerin USP 20
Water USP 43
TABLE-US-00008 Formulation 6 Wet Film Ingredient Percent by weight
LYCATAB pregelatinized starch (Roquette) 27.3 VISCARIN .RTM. SD389
10.0 Glycerin USP 15.0 Sodium phosphate di basic 1.0 Preservative
0.20 Water USP 46.5
TABLE-US-00009 Formulation 7 Native Potato Starch Wet Film
Ingredient Percent by weight Potato Starch Supra Bacter (Roquette)
15.8 Iota-carrageenan 8.0 Glycerin USP 15.0 Sodium phosphate di
basic 1.0 Preservative 0.20 Water USP 60.0
TABLE-US-00010 Formulation 8 Wet Film Dry Film Ingredient Percent
by weight Percent by weight PURE-COTE .RTM. B790 23.5 41.96
Iota-carrageenan XPU-HGI 8.5 15.18 (SKW) - (not available) Glycerin
USP 23.0 41.07 Sodium phosphate di basic 3.0 1.79 Water 44.0
TABLE-US-00011 Formulation 9 Kappa only - no iota Ingredient
Percent by weight PURE-COTE .RTM. 20.0 Kappa-carrageenan 6.0
Xanthan gum 2.0 Glycerin USP 20.0 Sodium phosphate di basic 1.0
Preservative 0.20 Water USP 50.8
TABLE-US-00012 Formulation 10 Wet Film Dry Film Ingredient Percent
by weight Percent by weight PURE-COTE .RTM. B760 23.0 40.03
VISCARIN .RTM. SD389** 10.45 15.46 Glycerin USP 23.0 40.03 Sodium
phosphate di basic 1.0 1.74 Water USP 42.55 Dextrose 2.73 *Drive
Film Values Calculated **Standardized with 15% by weight dextrose
Note: In the dry film calculations, the dextrose content, from the
iota carrageenan is set out separately.
Formulations 1, 3, 4, 6, 8 and 10 all produced excellent films that
displayed excellent elasticity and sealing features. Formulation 2
produced a seal, but of a weak character compared to Formulations
1, 3 and 4. This could be the result of the modified starch to
iota-carrageenan ratio of 1.5:1, whereas Formulations 3 and 4 had
starch to carrageenan weight ratios in excess of 2.0:1. Formulation
5 yielded a good film, but the sealing characteristics were poorer
than Formulations 3 and 4; this could be due to the high, 2.7:1,
starch to carrageenan ratio. Formulation 7, the only unmodified
starch that was found to work with iota-carrageenan was found to
cast an acceptable film that evidenced good sealing properties. In
contrast, Formulation 9, kappa carrageenan only--no iota, produced
a brittle film that could not be sealed. This experiment evidences
that kappa carrageenan is not a substitute for iota in the present
invention.
EXAMPLE 2
Rotary Die Process
A standard rotary die machine (see The Theory and Practice of
Industrial Pharmacy, Lachmnan, Lieberman and Kanig, Editors,
3.sup.rd Edition, published by Lea & Febiger, was used to
attempt the manufacture of filled capsules using Formulations 1-4,
6, 8 and 10. The fill material was provided to the hopper connected
to the rotary die encapsulation machine. The hopper was heated and
jacketed. Ribbons of casting material were formed in any of a
variety of conventional methods, including extrusion or gravity
feed of the liquid Formulations 1-4, 6, 8 and 10 onto a revolving
casting drum. The formulations were provided to the drum generally
at a temperature 2-5.degree. C. above the melting point of the
formulation. This temperature varies according to each specific
formulation. Encapsulation of the fill material between two ribbons
of the film was carried out according to conventional
procedures.
Capsules prepared according to conventional rotary die procedures
using Formulations 1, 3, 4 and 10, as set forth in this example,
produced durable capsules that, upon drying, are similar in
appearance to traditional softgels manufactured from mammalian
gelatin.
EXAMPLE 3
Evaluation of Capsule Properties
Capsules produced according to Examples 1 and 2 above were tested
for disintegration and resistance to accelerated storage
conditions. Samples of dried capsules were tested using a standard
USP disintegration apparatus fitted with guided disks. The test
medium was 0.1 M HCl maintained at 37.degree. C. Capsules ruptured
within 3 minutes and the shell disintegrated within 15 minutes.
These results are comparable to those obtained using a conventional
soft mammalian gelatin capsule.
Additional samples were stored in open containers for 3 months at
40.degree. C./75% Relative Humidity ("RH"), which is a standard
condition used to accelerate stability evaluation of pharmaceutical
dosage forms. A mammalian gelatin based softgel filled with mineral
oil was also evaluated using the same conditions as a control. The
modified starch/iota-carrageenan capsules remained structurally
intact and exhibited only softening of the shell. In contrast, the
mammalian based soft capsules had fused together and lost much of
their structural integrity. Thus, the capsules made according to
the invention exhibited superior resistance to humidity and
temperature compared to conventional mammalian gelatin-based soft
capsules.
EXAMPLE 4
Comparative Analysis
The following is a comparison of capsule shell formulation
characteristics and associated rotary die parameters for
conventional mammalian gelatin-based materials, a composition
wherein the film was formed solely from carrageenan, and a modified
starch/iota-carrageenan compositions according to the present
invention. The only carrageenan composition was made essentially
according to the description set forth in published International
Application WO 97/07347, except that 17% carrageenan is used
instead of 9% as described in the International Application. Table
III sets forth the melting point of each composition in addition to
processing conditions specific to each composition for use in the
rotary die process.
TABLE-US-00013 TABLE III CONTROL INVENTION CONTROL Gelatin
Starch/Carrageenan Carrageenans Formulation 30-45% 15-20% starch;
17% iota- gelatin; 8-10% iota- carrageenan 10-30% carrageenan
plasticizer, water q.s. Typical Melt 50-55.degree. C. 80-85.degree.
C. 95-98% Temperature Operational 60-65.degree. C. About
98-100.degree. C. Casting 90-95.degree. C. Fusion 40-42.degree. C.
53-75.degree. C. 98-100.degree. C. Temperature for sealing (Wedge
Temperature) Pressure 100-300 psi 50-200 psi Not determined*
Typical Ribbon 0.28-0.040 0.020-0.025 Not thickness determined*
(inches) Machine speed 2 to 3 rpm 2 to 6 rpm Not (optimum)
determined* *The sealing (wedge) temperature was adjusted to the
temperature at which the material fuses, 98-100.degree. C., which
is also the melting temperature. No fusion takes place at lower
temperatures. Sealing and production of capsules was attempted, but
the ribbon melted at the wedge. No capsules were formed.
This Example supports the conclusion that the starch/carrageenan
compositions of the present invention possess properties similar to
mammalian gelatin and therefore allow for their satisfactory use in
the rotary die process. In contrast, the film forming composition
taught in WO 97/07347 is not acceptable for forming soft
capsules.
Films derived from compositions containing carrageenan as the only
film forming material do not possess the desired properties of
gelatin films and are therefore unsuitable for use in the rotary
die process.
EXAMPLE 5
The following Formulations were prepared as set forth in Example 1,
except that they were prepared on a 500 gm scale. The prepared
formulations, as set forth in Table IV, were cast onto a glass
plate using a draw bar set between 0.10 and 0.127 cm in height
(0.040 to 0.050 inches) to form ribbons as described in Example 1.
The ribbons of film were evaluated wet and then allowed to set/dry
overnight and then revaluated. Ribbon strength, elasticity,
clarity, texture and thermal sealing were measured. All values are
weight % unless noted otherwise.
TABLE-US-00014 TABLE IV Weight Percent Wet Film Component #11 #12
#13 #14 #15 #16 #17 #18 #19 #20 #21 #22 #23 #24 #25 #26 - #27
.sup.1Kappa 5.65 5.65 10.0 10.0 5.0 2.5 1.0 10.0 8.0 10.0 10.0 10.0
carrageenan .sup.1Lambda 5.65 carrageenan .sup.1Iota 5.65 5.0 7.5
9.0 carrageenan .sup.2Pure Cote .TM. 15.0 22.0 27.3 27.3 27.3 13.55
20.0 20.0 20.0 23.0 27.3 20.0 15.- 0 B760 Water 80.2 80.2 56.3 41.0
46.5 46.5 46.5 45.0 45.0 48.3 48.3 42.8 68.8 46.- 5 74.5 50.0 55.0
Glycerin 8.3 8.3 17.5 25.8 15.0 15.0 15.0 30.0 25.8 20.0 20.0 22.0
20.0 15- .0 20.0 20.0 20.0 Preservative 0.2 0.2 0.2 0.2 0.2 0.2 0.2
0.2 0.2 0.2 0.2 0.2 0.2 0.2 Na.sub.2HPO.sub.4 1.0 1.0 1.0 1.0 1.0
1.0 1.0 1.0 1.0 1.0 1.0 1.0 Locust Bean 0.25 0.5 1.0 Gum Xanthan
Gum 0.5 .sup.3XPU-APK 10.0 10.0 Kappa carrageenan .sup.3XPU-CMI 5.5
10.0 10.0 Iota/Kappa blend .sup.1Supplied by FMC Corporation of
Princeton, New Jersey .sup.2Hydroxypropylated maize starch
.sup.3Supplied by SKW Biosystems
The formulations containing kappa carrageenan, F11 to F23, all
produced a brittle and weak film irrespective of the level of the
modified starch (Pure Cote B790). Even the inclusion of lambda
carrageenan (F11) or iota-carrageenan (F12, F15-F17) to the kappa
did not produce a useable film. Even F17 with 1% kappa, 9% iota and
27.3% modified corn starch (Pure Cote B790) produced a non-brittle
film that only formed a weak seal. Thus, the presence of even low
levels of kappa carrageenan is detrimental to the production of a
useable film.
EXAMPLE 6
Using the procedure set forth in Example 5, additional formulations
were prepared and evaluated. The formulations are set forth in
Table V.
TABLE-US-00015 TABLE V Component #28 #29 #30 #31 .sup.1Lambda
carrageenan 10.0 .sup.1Iota-carrageenen 10.0 LC-5 standardized with
sacrose Pure Cote .TM. B790 15.0 27.3 27.3 .sup.2TPH-1
non-standardized iota 10.0 .sup.3XPU-HG1 iota 10.0 Water 56.3 46.5
46.5 68.8 Glycerin 17.5 15.0 20.0 20.0 Na.sub.2HPO.sub.4 1.0 1.0
1.0 1.0 Preservative 0.2 0.2 0.2 0.2 .sup.1Supplied by FMC Corp.
.sup.2Supplied by Hercules Corp. .sup.3Supplied by SKW
Biosystems
F28 (lambda carrageenan plus modified starch) produced a very weak
film that did not seal. In contrast F29 and F30 (iota-carrageenan
plus modified starch) produced very strong films that provided
excellent seals. F31 (iota only) produced a strong film, but would
not seal.
EXAMPLE 7
Using the procedure set forth in Examples 1 and 2, the following
formulations were prepared cast onto a rotary encapsulation machine
and formed into soft capsules filled with vitamin E.
TABLE-US-00016 TABLE VI #32 #33 Wet Dry Wet Dry Component film film
film film Viscarin SD-389 10.25 14.97 0 0 Standardized iota Pure
Cote B760 25.75 44.25 24.0 41.96 Glycerin 21.0 36.08 22.5 39.34
Sodium phosphate buffer 1.0 1.72 1.0 1.75 Parabens 0.2 0.34 0.2
0.35 Water 41.8 42.8 XPU HG1 2.64 9.5 15.61
F32 and F33 were found to be easily processed on the rotary die
encapsulation machine. These formulations represent the inventors
best mode and produced capsules with very few defects. The capsules
were then tested in a simulated gastric fluid and were found to
dissolve or disintegrate in about five (5) minutes, which is about
the time for commercially available mammalian gelatin capsules.
EXAMPLE 8
In this experiment, hydroxypropylated tapioca starch was used in
combination with iota-carrageenan to produce a soft capsule. The
tapioca formulation #34, and a comparative maize formulation are
set forth in Table VII.
TABLE-US-00017 TABLE VII Weight % In Wet Composition Component #34
#35 Iota-carrageenan (Viscarin SD389) 10.25 10.25 Hydroxypropylated
tapioca starch 25.75 0 Glycerin 21.40 21.40 Disodium phosphate
41.60 41.60 Water 1.0 1.0 Hydroxypropylated maize starch 0
25.75
Soft capsules were manufactured successfully using a pilot scale
encapsulation machine using F34 and F35. Yield is a measure of
process effectiveness. It is expressed as the percentage of
capsules that did not leak after drying, out of the number of
capsules produced. The yield, using the hydroxypropylated maize
starch, was slightly better than the modified tapioca starch.
Formulation #35 has been used to produce over 100,000 soft capsules
filled with vitamin E. The yield for this production run was found
to be 99.1%, which is considered excellent.
EXAMPLE 9
Comparative
The formulation set forth in Table VIII investigates the use of
kappa carrageenan as the sole elasticizing agent, as it is less
expensive than iota-carrageenan.
TABLE-US-00018 TABLE VIII Weight % in Wet Composition Component #34
Kappa carrageenan 8.0 Locust Bean Gum 0.5 Xanthan Gum 0.25
Hydroxypropylated maize starch 18.00 Pure Cote B790 Glycerin 30.2
Disodium phosphate 1.0 Water 42.05
Formulation #34 was placed on a pilot scale rotary die
encapsulation machine and was not successful in producing any
intact soft capsules. The formulation would form films, but due to
poor mechanical strength, low elasticity coefficient and inability
to form seals, no soft capsules could be produced.
Industrial Applicability
The economic manufacture of soft capsules requires that the ribbons
used to form the gels possess certain specific properties. While
mammalian gelatin has remained the gelling agent of choice, there
are numerous shortcomings that the pharmaceutical industry would
like to overcome with new, non-gelatin soft capsules.
The present invention, which is founded in a discovery regarding
the synergistic activity between a specific form of carrageenan and
certain modified starches, will provide to the pharmaceutical
industry an alternative to mammalian gelatin. It was through
diligent experimentation and scientific observation that the
inventive compositions were realized.
In the foregoing, there has been provided a detailed description of
preferred embodiments of the present invention for the purpose of
illustration and not limitation. It is to be understood that all
other modifications, ramifications and equivalents obvious to those
having skill in the art based on this disclosure are intended to be
within the scope of the invention as claimed.
* * * * *