Claims:CLAIMS
1. A stable hard capsule shell comprising
a) About 10 to 50% by weight of starch, based on total weight of the capsule shell;
b) About 50 to 90% by weight of pullulan, based on total weight of the capsule shell; and
c) one or more pharmaceutically acceptable excipient.
2. A stable hard capsule shell comprising
a) About 10 to 50% by weight of starch, based on total weight of the capsule shell;
b) About 50 to 90% by weight of pullulan, based on total weight of the capsule shell; and
c) one or more pharmaceutically acceptable excipient,
wherein the capsule shell exhibits enhanced dimensional stability as compared to capsule shell comprising pullulan alone, when exposed to a relative humidity of above 75% RH for a period of at least one week.
3. The stable hard capsule shell according to claim 1 or 2 wherein the starch is organic native starch.
4. The stable hard capsule shell according to claim 3 wherein the organic native starch is selected from the group consisting of potato starch, corn starch, maize starch, cassava starch and tapioca starch or combination thereof.
5. The stable hard capsule shell according to claim 1 or 2 wherein pullulan is organic pullulan.
6. The stable hard capsule shell according to claim 1 or 2 wherein organic pullulan has a viscosity from 60 cps to 180 cps of a 2% solution in water at a temperature of 20°C.
7. The stable hard capsule shell according to claim 1 or 2 wherein capsule shell further comprises a setting system, a surfactant and a smoothening agent.
8. The stable hard capsule shell according to claim 7 wherein the setting system comprises a gelling agent and a salt.
9. The stable hard capsule shell according to claim 8 wherein the gelling agent is selected from the group consisting of alginates, agar gum, guar gum, locust bean gum (carob), kappa carrageenan, tara gum, arabic gum, ghatti gum, khaya grandifolia gum, tragacanth gum, karaya gum, pectin, arabian (araban), xanthan, gellan gum, starch, konjac mannan, galactomannan, funoran, acetan, welan, rhamsan, furcelleran, succinoglycan, scleroglycan, schizophyllan, tamarind gum, curdlan, dextran and mixtures thereof.
10. The stable hard capsule shell according to claim 8 wherein the salt is selected K+, Na+, NH4+, Ca2+, Mg2+ and mixtures thereof.
11. The stable hard capsule shell according to claim 10 wherein the salt is potassium chloride.
12. The stable hard capsule shell according to claim 7 wherein surfactants are selected from the group consisting of sodium lauryl sulphate (SLS), dioctyl sodium sulfosuccinate (DSS), benzalkonium chloride, benzethonium chloride, cetrimide (trimethyltetradecylammonium bromide), fatty acid sugar esters for example like sorbitol esters (SE) and/or sucrose esters like sucrose monolaurate (SML), sucrose cocoate; glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters, polyvinyl alcohol, dimethylpolysiloxan, sorbitan esters, lecithin and mixture thereof.
13. The stable hard capsule shell according to claim 12 wherein the surfactant is sucrose cocoate.
14. The stable hard capsule shell according to claim 8 wherein the gelling agent is present in amount from 0.01% to 5% by weight of the total weight of capsule shell.
15. The stable hard capsule shell according to claim 10 wherein the salt is present in amount from 0.01% to 3% by weight of the total weight of capsule shell.
16. The stable hard capsule shell according to claim 13 wherein sucrose cocoate is present in an amount from 0.05% to 2% by weight of the total weight of the capsule shell.
17. The stable hard capsule shell according to claim 8 wherein the smoothening agent is finely ground rice hull.
, Description:FIELD OF THE INVENTION
The present invention relates to a stable hard capsule shell comprising starch and
pullulan, wherein the capsule shell exhibits enhanced dimensional stability as
compared to capsule shell comprising pullulan alone, when exposed to high
humidity condition.
BACKGROUND OF THE INVENTION
Most of pharmaceutical capsules available in market are made of gelatin, while
many companies are trying to bring non-gelatin based capsules, and some of them
have introduced powdered herbs and dietary supplements in HPMC based
capsules. The crosslinking of gelatin, drug incompatibilities and the strict
regulations regarding the use of animal derived gelatin requiring the absence of
bovine spongiform encephalopathy (BSE) have pushed the manufacturers to look
for alternatives. HPMC capsules has been considered to be a good alternative of
gelatin capsules due to its non-animal source. On the other hand, HPMC being a
semi-synthetic polymer, it exhibits the unfavorable attributes of a synthetic
polymer; this warranted the pursuit of identifying a new polymer of natural origin
for capsule manufacturing.
To overcome the issues associated with HPMC, manufacturers started exploring
pullulan for manufacturing of the hard capsule shell. However, pullulan also poses
challenges to the manufacturers as pullulan capsules are moisture sensitive, and
mechanically weak as compared to gelatin. The super-hydrophilic nature of
pullulan often renders the capsules very sticky and mechanical deformed state
3
when exposed to high relative humidity (RH). Therefore, there is a growing
demand to develop pullulan capsules with higher environmental and mechanical
stability. So, while designing such a capsule product, combination of pullulan with
other polymers have been explored. The combination should be able to provide a
capsule shell which have the desired properties of capsule shell like
pharmacopeially acceptable disintegration and dissolution profile along with good
mechanical strength.
Various attempts have been made in the prior art like US patent 6,887,307 and US
patent 6,635,275 to develop hard capsule shell comprising pullulan alone or in
combination with other polymers. However, there is a long-standing need for
improved hard capsule comprising pullulan that do not have the shortcomings of
prior art capsule shells.
SUMMARY OF THE INVENTION
The inventors of the present composition have developed a stable hard capsule
shell comprising starch and pullulan, while retaining the transparency as that of
pullulan alone capsule shell. Further, the present invention provides a stable hard
capsule shell comprising starch and pullulan, wherein the specific combination of
the polymer provides excellent mechanical stability to the shell even at a relative
humidity above 75%. On the other hand, the particular combination achieves the
desired disintegration and dissolution characteristic.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the comparison of the dimensional stability of the capsule shells of
the present invention vis-à-vis the comparative example when exposed to a relative
humidity of 82% and a temperature of 40oC for a period of one week.
4
FIG. 2 shows the comparison of the dimensional stability of the capsule shells of
the present invention vis-à-vis the comparative example when exposed to a relative
humidity of 93% and a temperature of 25oC for a period of two and half days.
DETAILED DESCRIPTION OF THE INVENTION
In one of the aspects, there is provided a stable hard capsule shell comprising
a) About 10 to about 50% by weight of starch, based on total weight of the
capsule shell; and
b) About 50 to about 90% by weight of pullulan, based on total weight of the
capsule shell;
wherein the capsule shell exhibits dimensional stability when exposed to a high
humidity conditions.
In one of the aspects, there is provided astable hard capsule shell comprising
a) About 10 to about 50% by weight of starch, based on total weight of the
capsule shell; and
b) About 50 to about 90% by weight of pullulan, based on total weight of the
capsule shell;
wherein the capsule shell exhibits dimensional stability when exposed to a relative
humidity of above 75% for a period of at least one week.
Pullulan is a polysaccharide polymer consisting of maltotriose units, also known
as -1,4-;-1,6-glucan as given below. Pullulan is produced from starch or sugars by
the fungus Aureobasidium pullulans. Although pullulan of various molecular
weight and viscosity are available, pullulan with a viscosity from 60 cps to 180 cps
of a 2% solution in water at a temperature of 20°C is preferred.
5
Pullulan
In one of the embodiments, the ratio of starch to pullulan can vary from 0.1:1 to
1:1.
In one of the embodiments, the relative humidity is 80 to 95%.
The term “dimensional stability” as used herein is determined based on the physical
examination of the capsule shells. The capsule shells are physically examined to
find that whether there has been any mechanical deformation of the shell.
In one of the embodiments, starch used in the present invention can be a “native
organic starch”, or a “modified starch”. Native organic starch may be potato starch,
corn starch, maize starch, arrowroot starch, cassava starch and tapioca starch or a
combination of these starch.
In another aspect, there is provided a stable hard capsule shell comprising
a) About 10 to 50% by weight of native starch, based on total weight of the
capsule shell; and
b) About 50 to 90% by weight of pullulan, based on total weight of the capsule
shell;
wherein the capsule shell has dimensional stability when exposed to a relative
humidity of more than 75% for a period of at least one week.
6
In one of the preferred embodiments, native starch is organic native starch.
In one of the preferred embodiments, pullulan is organic pullulan.
In another aspect, there is provided a stable hard capsule shell comprising
a) About 10 to about 50% by weight, based on the total weight of the capsule
shell, of organic native starch selected from the group consisting of potato
starch, corn starch, maize starch, arrowroot starch cassava starch and
tapioca starch or combination thereof; and
b) About 50 to about 90% by weight, based on the total weight of the capsule
shell, of organic pullulan;
wherein the capsule shell has dimensional stability when exposed to a relative
humidity of more than 75% for a period of at least one week.
In one of the aspect, there is provided a stable hard capsule shell comprising
a) About 10 to about 50% by weight, based on the total weight of the capsule
shell, of organic tapoica starch; and
b) About 50 to about 90% by weight, based on the total weight of the capsule
shell, of organic pullulan;
wherein the capsule shell has dimensional stability when exposed to a relative
humidity of more than 75% for a period of at least one week.
According to one of the embodiment, the capsule shell further comprises a setting
system, a surfactant and a smoothening agent.
In another aspect, there is provided a stable hard capsule shell comprising
a) About 10 to 50% by weight, based on the total weight of the capsule shell,
organic tapoica starch
b) About 50 to 90% by weight, based on the total weight of the capsule shell,
of organic pullulan;
7
c) A setting system;
d) A surfactant; and
e) A smoothening agent.
wherein the capsule shell has dimensional stability when exposed to a relative
humidity of more than 75% for a period of at least one week.
Setting systems are conventionally relied upon in the manufacture of hard capsule
shells by providing setting ability to film-forming polymers (like pullulan, HPMC
or starch derivatives) that may have poor gelling properties. The setting system
makes the aqueous composition to set on the dipped mould pins, thus assuring a
uniform capsule shell thickness, a crucial parameter for the capsule shell
manufacturing.
In another embodiment, a setting system comprises a gelling agent and a salt.
In one embodiment, the one or more gelling agent of the setting system are selected
from the group consisting of alginates, agar gum, guar gum, locust bean gum
(carob), carrageenan (preferably kappa and/or iota), tara gum, arabic gum, ghatti
gum, khaya grandifolia gum, tragacanth gum, karaya gum, pectin, arabian (araban),
xanthan, gellan gum, starch, konjac mannan, galactomannan, funoran, acetan,
welan, rhamsan, furcelleran, succinoglycan, scleroglycan, schizophyllan, tamarind
gum, curdlan, dextran and mixtures thereof. Preferably, the setting system polymer
is carrageenan (preferably kappa). The polymer is present in an amount between
about 0.01 and 5% by weight, based on the total weight of the capsule shell.
In another embodiment, the salt is selected K+, Na+, NH4
+, Ca2+, Mg2+ and mixtures
thereof. Preferably, the salts are selected from the group consisting of: K+, NH4
+,
Ca2+ and mixtures thereof. The cations can be added to the setting system in the
form of a pharmaceutically or food acceptable water soluble salt (e.g. chloride,
acetate, citrate or phosphate). The salt is present in an amount between about 0.01
and about 3% by weight of the total capsule shell.
8
In the preferred embodiment, the setting system comprises kappa carrageenan and
potassium chloride (KCl).
In one embodiment, the capsule shell comprises a surfactant in an amount between
about 0.01% and about 3% by weight, in particular about 0.05% and about 2% by
weight, based on the total weight of capsule shell. The surfactant ensures proper
mixing of the ingredients and prevents any polymer chain agglomeration.
In one embodiment, the one or more pharmaceutically or food acceptable
surfactants are selected from the group consisting of: sodium lauryl sulphate (SLS),
dioctyl sodium sulfosuccinate (DSS), benzalkonium chloride, benzethonium
chloride, cetrimide (trimethyltetradecylammonium bromide), fatty acid sugar
esters for example like sorbitol esters (SE) and/or sucrose esters like sucrose
monolaurate (SML), sucrose cocoate; glyceryl monooleate, polyoxyethylene
sorbitan fatty acid esters, polyvinyl alcohol, dimethylpolysiloxan, sorbitan esters
or lecithin. In one preferred embodiment, the one or more pharmaceutically or food
acceptable surfactants comprisessucrose cocoate.
The capsule shell further comprises a smoothening agent, which helps
smoothening of the surface post capsule shell formation. In one of the preferred
embodiment, the capsule shell comprises a smoothening agent, for example finely
grounded rice hulls, silicon dioxide. The smoothening agent is present in an amount
about 0.05% and about 2% by weight, based on the total weight of capsule shell.
In one of the aspect, there is provided a process for the preparation of stable hard
capsule shell comprising the steps of
a) Dissolving starch and pullulan separately in an aqueous solvent at a
temperature of more than 70°C for a suitable amount of time; mixing both
the solutions at a defined combination of concentration and temperature.
9
b) To the solution of step a), a setting system, a surfactant and a smoothening
agent is added and stirred till all the ingredients are uniformly mixed;
c) The solution of step c) was defoamed and poured into dipping dish
maintained at a suitable temperature; and
d) Following the dip moulding process to obtain capsules of desired size.
The capsule shell of the present invention may comprise other pharmaceutically or
food acceptable excipients such as plasticizers, sequestering agents, flavouring
agents, dyes and colouring agents.
In one of the embodiments, capsule shells are manufactured by conventional dip
moulding process as normally used in the production of conventional hard gelatin
capsules.
The capsule shells of the present invention are useful in pharmaceutical,
nutraceutical, veterinary, food, health supplement and cosmetic industry.
In one of the embodiments, the capsule shells are used for composition comprising
oxygen sensitive ingredients or drug substance or drug product.
EXAMPLES
Example T0 - T10
Solution A: Preparation of Pullulan solution.
Typically, 1.9 kg of pullulan powder was dissolved in 7.9 kg of distilled water by
heating at 80°C for 1h under constant mechanical stirring. Thus, obtained solution
was cooled to 50°C at ambient conditions and kept undisturbed to eliminate foam
and bubbles.
Solution B: Preparation of Tapioca Starch solution.
10
Typically, 1.9 kg of tapioca starch powder was dissolved in 7.9 kg of distilled water
by heating at 92°C for 1h under constant mechanical stirring. Thus, obtained
solution was cooled to 50°C at ambient conditions and kept undisturbed to
eliminate foam and bubbles.
Solution C: Preparation of the solution for dip moulding.
The solutions A and B were mixed with respective ratios as given in Table 1, to
result a solution of 18-20 wt% solid content for 1h. To this added kappacarrageenan
and potassium chloride (KCl) and further stirred for 30 minutes.
Further added surfactant compound sucrose cocoate, which ensures proper mixing
of the ingredients and prevent any polymer chain agglomerations. Additionally,
added finely grounded rice hulls, which act as surface smoothening agent for post
capsule formation. Thus, obtained mixture was further mechanically stirred for 30
minutes at 70oC to ensure uniform mixing of the ingredients.
Table 1. Compositions used for capsule manufacturing
Capsule
Pullulan
(in g)
Tapioca
Starch
(in g)
Potassium
Chloride
(in g)
Kappa-
Carrageenan
(in g)
Sucrose
Cocoate
(in g)
Ground
Rice
Hulls
(in g)
Solid
Content
in
Solution
(% w/w)
T-0 1900 0 0 0 0 0 19.1
T-1 1900 0 11.4 32.3 4.75 4.75 19.1
T-2 1647 183 11.0 31.1 4.57 4.57 18.3
T-3 1424 356 10.7 30.3 4.45 4.45 17.8
T-4 1204 516 10.3 29.2 4.30 4.30 17.2
T-5 1008 672 10.1 28.6 4.20 4.20 16.8
T-6 880 720 9.6 27.2 4.00 4.00 16.1
T-7 835 835 10.0 28.4 4.17 4.17 16.7
11
T-8 568 852 8.5 24.1 3.55 3.55 14.2
T-9 417 973 8.3 23.6 3.47 3.47 13.9
T-10 260 1040 7.8 22.1 3.25 3.25 13.1
Manufacturing of the capsules
10 kg solution C was made for each of the formulation as given in Table 1. The
solution was maintained at temperature below 55?C. Typically, the below steps
were followed for manufacturing the capsules.
- The solution was defoamed and transferred into a dipping dish maintained
at 50?C.
- The temperature of the pins was maintained at 25?C +/- 5°C and then
performed the conventional dip moulding process for manufacturing
capsules.
- The pins with wet film were exposed to cold air blast of temperature
between 25 to 40?C.
- The dried shells were then removed from pin, cut to specified length and
joined to form capsules.
- The capsules were then evaluated for appearance, defects, taste, brittleness,
strength etc.
Example T-0, T-1 and T-8 toT-10 represent the comparative examples, wherein T0
only comprises pullulan, T1 comprises all the ingredients except Tapoica starch
and T-8 to T-10 comprises a percentage of tapioca starch and pullulan different
than the claimed value.
STABILITY STUDIES
a. The capsule shells prepared according to comparative example T-1 and
capsule shell of the present invention as prepared according to example T12
3 were subjected to stability studies at a relative humidity of 82% and a
temperature of 40°C for a period of one week. The capsules were physically
examined to check for dimensional stability. The capsules of the present
invention retained their shape and size as compared to capsules of the
comparative example, which became soggy and sticky when exposed to
such high level of humidity.
Evaluation section:
1- Evaluation for capsule formation
The capsules were removed from dip moulds and were evaluated for
good capsule formation by visual observation by qualified process
expert. It was graded as good, OK and not good category.
2- Evaluation for clarity and transparency
The capsules were removed from dip moulds and were observed under
illumination from above first and then below over a frosted glass type
table typically used in capsule manufacturing. It was graded as clear,
slightly hazy and not clear category.
3- Capsule rigidity
100 capsules were subjected to 50g weight falling from 100 mm
distance. Number of broken capsules were measured.
Table 2: Observations on formation, clarity, transparency and broken
capsules
Trial No Capsule
formation
Capsule clarity/
transparency
Broken capsules
(%)
T-0 No formation Not applicable Not applicable
T-1 Good Clear 3
T-2 Good Clear 2
13
T-3 Good Clear 2
T-4 Good Clear 2
T-5 Good Clear 2
T-6 Good Slightly hazy 2
T-7 OK Slightly hazy 4
T-8 OK Hazy 6
T-9 Not good Not clear 8
T-10 Not good Not clear 8
4- Dissolution study of the capsules:
The capsules were filled with 650 mg Acetaminophen formulation and
were subjected to dissolution media of 0.1 N HCl (USP) solution and
percentage drug release was measured after 45 minutes as summarised
in table below.
5- Disintegration study of the capsules:
Disintegration of Capsule filled with 650 mg Acetaminophen
formulation was carried out in disintegration apparatus using water, 0.1
N HCl and 6.8 pH mixed phosphate buffer maintained at 37± 2°C. The
method followed was as per USP monograph. The time for first rupture
and total disintegration was recorded.
Table 3: Observations on disintegration time (DT) and dissolution
Trial No DT in water
(in minutes)
DT in 0.1 N
HCl (in
minutes)
DT in 6.8 pH
buffer (in
minutes)
Dissolution %
after 45
minutes.
T-1 1 1 1 97
14
T-2 1 1 1 93
T-3 1.3 1.3 1.3 88
T-4 1.6 1.6 1.6 85
T-5 2 2 2 82
6- Capsule stability at high temperature and humidity
The capsules produced were exposed at following conditions for 2 to
14 days in desiccator by using appropriate salt solution.
o 25°C and 60 % RH
o 25°C and 85 % RH
o 40°C and 75 % RH
o 40°C and 90 % RH
The capsules were then observed for deformation and softening, the
data is presented in Table 4.
Table 4: Observation on environment stability
Trial
No
25°C& 60 % RH 25°C& 85 % RH 40°C& 75 % RH 40°C& 90 % RH
Deformat
ion
Softnes
s
Deformat
ion
Softnes
s
Deformat
ion
Softnes
s
Deformat
ion
Softnes
s
T-1 No
deformati
on
No
softness
Deforme
d
Soft Deforme
d
Soft Deforme
d
Soft
T-3 No
deformati
on
No
softness
No
deformati
on
No
softness
No
deformati
on
No
softness
No
deformati
on
No
softness
T-4 No
deformati
on
No
softness
No
deformati
on
No
softness
No
deformati
on
No
softness
No
deformati
on
No
softness
T-5 No
deformati
on
No
softness
No
deformati
on
No
softness
No
deformati
on
No
softness
No
deformati
on
No
softness
15
The capsule shells prepared according to comparative example T-1 and capsule
shell of the present invention as prepared according to example T-3 were subjected
to stability studies at a relative humidity of 82% and a temperature of 40°C for a
period of one week. The capsules were physically examined to check for
dimensional stability. The capsules of the present invention retained their shape
and size as compared to capsules of the comparative example, which became soggy
and sticky when exposed to such high level of humidity.
The capsule shells prepared according to comparative example T-1 and capsule
shell of the present invention as prepared according to example T-3 were subjected
to stability studies at a relative humidity of 93% and a temperature of 25°C for a
period of two and half days. The capsules were physically examined to check for
dimensional stability. The capsules of the present invention retained their shape
and size as compared to capsules of the comparative example, which became sticky
and were found to be in mechanically deformed state when exposed to such high
level of humidity.
The above data clearly indicates the capsules of the present invention provide the
desired properties w.r.t mechanical stability, clarity, rigidity, dissolution and
disintegration of the capsule shell. Whereas the comparative example T-0 does not
form the film per se, on the other hand T-1 softens at higher humidity conditions.
Further, capsule shell comprising percentage of pullulan different than the claimed
range did not have the desired transparency and the capsule rigidity was also less
than the capsule shell of the present invention.