Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~324~76 2449-l
PROCESS FOR MAKING A SPRAY-DRIED,
DIRECTLY-COMPRESSI~LE VITAMIM
. POWDER COMPRISI~G UN~YDROLYZED GELATIN
Background of the Invention
~ield of the-Invention
~ ~ The present invention pertains to processes for
'~ making formulations useful for direct-compression powders.
These powders are used in the manufacture of pharmaceutical
tablets. More specifically, the present invention is
concerned with processes for making directly-~ompressible
formulations which also contain a fat-soluble vitamin. It
has been found that the use of a unhydrolyzed gelatin (i.e.
a gelatin having a bloom number between 30 and 300) in these
tabletting formulations imparts satisfactory hardness to
:
tablets made therefrom, and that emulsions made with
unhydrolyzed gelatin do not exhibit off-odor problems.
j Moreover, it has unexpectedly been found that a mixture
comprising an unhydrolyzed gelatin can be spray-dryed by
; conventional means.
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Description of the Prior Art
The closest art known to Applicants is: U.S.
4,395,422; ~.S. 2,824,807, U.S. 4,254,100; U.S. 4,519,961
U.S. ~,914,430; U.S. 3,608,08~, and an article entitled "The
Effects of Using Different Grades PVP and Gelatin as sinders
in the Fl~idized sed Granulation of Tabletting of
Lactose". Pharmazie, 38 (4), 240-3.
The process described in the '422 patent produces
a product comprising Vitamin E and a hydrolyzed (i.e. zero
bloom) gelatin. The '430 and '083 patents describe similar
processes (i.e. both of these patents utilize only zero
bloom gel~tin in their processes).
`~ The '807 p~tent teaches a process for spray-drying
: a solution of an unhydrolyzed gelatin by "atomizing the
solution into a cool air zone prior to introduction ~f the
atomized solution into a drying zone"O (U.S. 2,B24,807,
claim 1). The '807 patent refers to problems encountered in
'~ spray-drying solutions of high bloom gelatins ~Column 1, lu
36 - column 2, 1. 20). As a result o~ these problems, the
'807 patent states that if the high bloom gelatin concentra-
tion is greater than 1 percent, satisfactory spray-drying
cannot be achieved without utilizing the cool air zone
modified spray-drying technique diuclo~ed therein.
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In contrast, the process of the present invention
requires that the spray-drying is carried out in a "conven-
tional" spray-dryer, i.e. without any means to overcome the
J problems described in the '807 patent. Applicants have
unexpectedly found that when utilizing the mixture described
below, no droplet formation problems were encountered during
spray-drying, even though the mixture comprised signifi-
cantly more than 1 percent of a high bloom gelatin.
The article cited above, authorized by
Georgakop~ulos et al, teaches a fluid-bed granulation
process f~r making a tabletting composition comprising a
7 high bloom gelatin, lactose, and a fat soluble vitamin. In
contrast, the process of the present invention pertains to
spray-drying, not fluid-bed granualtion.
The '100 patent, to Keller, teaches processes for
making tabletting compositions which comprise fat-soluble
vitamins and high bloom gelatins. The '100 patent nowhere
refers to ~pray drying, ~ut rather teaches emulsification
followed by filtration and either fluid-bed drying or vacuum
' drying.
; The '961 patent, t~ Schumacher, teaches processes
;~ for making powders which comprise a fat-soluble vitamin and
" ~ high bloom gelatin. The processes referred to in the '961
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patent utilize "spray formulation" followed by 1uid bed
drying. During spray formulation the temperature of the gas
flowing through the spraying chamber is at, or near, room
temperature. In the '961 patent, the "drying" of the powder
is carried out by heating the po~der in a fluid bed for
relatively long periods o~ time. In contrast, conventional
spray drying utilizes a comparatively high temperature gas
in the spray chamber, and the desired amount of drying is
completed quickly, i.e. in less than 10 seconds.
~rie_ Summary of the Invention
The present invention pertains to a process for
making a spray-dried vitamin powder. The spray-dried
vitamin powder is ~ component which can be used in a
formulation suitable for direct-compression into tabletsO
The process of the present invention is carried out by
~ombining a fat-soluble vitamin, a gelatin having a bloom
number between 30 and 300, a water-soluble carbohydrate, and
an effective amount of water to permit spray-drying. Once
combined, the vitamin, ~elatin, carbohydrate, and water
together form a mixture. The relative amounts of vitamin,
gelatin, and carbohydrate in the mixture are selected so
that the resulting spray-dried powder comprises:
(1) 20 to 60 percent by weight of the fat-soluble
vitamins;
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(2) 6 to 46 percent by weight of the gelatîn; and
~3~ an effective amount of the carbohydrate to
, prevent extru~ion.
The mixture i5 spray-dried in a conventional spray dryer.
It is an object of the present invention to
provide a process for producing a spray-dried directly-
.compressible, fat-soluble vitamin powder which comprises an
unhydrolyzed gelatin, while using a conventional spray-
dryer.
It is a further object of the present invention to
provide a process for producing a sipray-dried/ directly-
compressible powder compri~ing vitamin E and unhydrolyzed
gelatin, the powder being suitable as a component in a
formulation which can be directly compressed into a tablet,
the process using a conventional spray dryer.
It is an object of the present invention to enable
one to carry out the conventional spray-drying of a solution
~ :comprising substantially morè than one percent by weight of
;/~ an unhydrolyzed gelatin, without encountering problems with
;11 droplet formation as described by Laster in UOS. 2,824,807.
~: Finally, it is an object of the present invention
to enable the spray-drying of a solution comprising a
substhntial amount of a high bloom gelatin using only
: conventional spray-drying means.
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Detailed Desc~tion of the Preferred Embodiments
The present invention relates to processes for
making spray-dried vitamin powders which comprise a fat-
soluble ~itamin. The four most common fat-soluble vitamins
are: vitamin A (retinol), vitamin D (calciferol), vitamin E
(tocopherol), and vitamin K ~phylloquinone a~d mena-
~uinone). In the process of the present invention, the
vitamin itself, in combination with other ingredients, is
spray-dried in a conventional spray dryer. As used herein,
the term "conventional spray-dryer" is used with reference
to spray-dryers which have no special means for preventing
the formation of the "fluffy web-like mass of ~elatin", and
the gelatin "filaments", referred to in the Laster patent
(U.S. 2,824,207~. The conventional spray-dryer used in the
process of the present invention has no means for preventing
the problems referred to in the Laster patent. It has been
surprisingly found that no such means is required in the
process of the present invention~
Preferably, vitamin E is the vitamin used in the
powder of the present invention. Most preferably, the
vitamin E i9 a tocopherol or an ester thereof. Alpha-
tocopherol has the greatest biological activity while the
isomers beta-, gamma-, and delta-tocopherol have a lesser
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activity. The tocopherols and their esters such as water
tocopherol acetate and tocopherol Ruccinate are normally
water insoluble and either oily, waxy, or have a low melting
point. Therefore, in makinq water-disper~ible powders, an
emulsion is normally prepared and then ~pray dried.
D-alpha-tocopherol and d-alpha-tocophe~ol acetate are of use
in the invention. Preferably used i5 vitamin E acetate.
Most preferably the powder comprises between 50 and 54
percent (by weight~ of dl-alpha-tocopherol acetate.
The resulting spray-dried powder of the present
invention comprises an unhydrolyzed gelatin. The term
"unhydrolyzed" is herein defined as a gelatin having a bloom
number between 30 and 300. The term "bloom" as used herein
and in the appended claims is defined as the weight in grams
re~uired to impress a one-half inch diameter plunger 4 mm
into a gelatin solution containing 6 percent solids gelled
at 10C for 17 hours~ A suitable test procedure for
determining bloom is outlined in Industrial Engineeriny
Chemistry, Analytical Edition~ vol. II, page 348, and vol.
XVII, page 64. The unhydrolyzed gelatin utilized in the
procesq serves as an encapsulator and a binder. Preferably,
the bloom count of the gelatin is approximately 80, and
preferably, the resulting spray-dried powder comprises
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between 7.8 and 46 percent, by weight, gelatin. Most
preferably, the resulting spray-dried powder comprises
approximately 10 percent by weight gelatin having a bloom
number of approximately ~0.
An additional encapsulator may also be utilized in
the present invention. Most preferably, sodium caseinate is
utilized as the additional encapsulator. Furthermore, when
sodium caseinate is utilized in the process, it preferably
comprises between 3 and 20 percent, and more preferably
lo between lo to 15 percent by w~ight of the resulting spray-
dried powder, and most preferably comprises approximately 11
percent by weight, of the powder. Preferably, a spray-
dried sodium caseinate is utilized in tlle process. (See
~.S. Patent 4,395,422, column 2, lines 16-32).
An effective amount of a water-soluble
carbohydrate is necessary in the process of the present
invention. The water-soluble carbohydrate can be lactose,
maltodextrin, corn syrup, mannitol, sorbitol, a modified
r food starch, etc. The water-soluble carbohydrate has been
found to aid the unhydrolyzed gelatin in creating a stable
emulsion, among other desirable effects. The use of the
water-soluble carbohydrate creates a powder which is
resistant to "extrusionO" Extrusion occurs if the oil
separates from the powder during compression of the powder
~5 into a tahlet. Excessive extrusion is highly undesirable
because extrusion results in a loss of vitamin potency. The
"effective amount" of the water-soluhle carbohydrate is an
amount which prevents extrusion from occurring. Generally,
,! the water-soluble carbohydrate comprises 5 to 32 percent, by
weight, of the resulting spray-dried powder. Most
; preferably, the water-soluble carbohydrate comprises
,~ approximately ~ percent by weight of the resulting spray-
dried powder. The water-soluble carbohydrate is most
: preferably lactose present in an amount ranging from 7.B to
.
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13.9 percent by weight of the resulting spray-dried powder.
Occasionally it is desirable to eliminate lactose from the
powder. lsee Example 3, which utilizes maltodextrin in
place of lactose).
The process of the present invention preferably
utilizes a secondary emulsifier and surfactant. The
secondary emulsifier used is preferably a fatty acid
monoglyceride, which is present in an amount between 0.1 and
6 percent, preferably 0.6 percent, by weight of the
resulting spray-dried powder~ Most preferahle is the use of
approximately 1.1 percent, by weight of spray-dried product,
of a monoglyceride which is a mixture of glycerol
monostearate and glycerol derived from hydrogenated tallow
or lard and includes about lo percent by weight diglyceride.
(See U.S. 4,395,422, column 2, lines 40-55).
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The most preferred ~pray-drying process for use in
the manufacture of the improved powder of the present
invention is descri~ed in ~xample 1 below. As stated in
Example 1, silicon dioxide was injected into the spray~
drying chamber during the spray-drying process. The amount
of silicon dioxide utilized should be such that the re-
sulting spray-dried product comprises between 0.1 and 5.6
percent, by weight, silicon dioxide. The preferred amount
of silicon dioxide injected during the spray-drying process
is approximately one percent, by weight~ of the resulting
spray-dried powder. The silicon dioxide improves the
flo~ability of the resu-ting powder.
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Example 1
Monoglyceride (0.6 parts} was added to and
dissolved within vitamin E oil (28 parts). The vitamin E
oil having mono- glyceride dissolved therein was then added
to an emulsion feed tank which contained: 8.5 parts
lactose, 10.9 parts caseinate, 4.8 p~rts 80-bloom gelatin,
and 47 parts water. All of the ingredients were then
homogenized for approximately 30 minutes, or until the
emulsion droplet size reache~ 1 to 2 microns. Generally,
the resulting viscosity was between 460 and 660 cps.
~ he emulsion w~s then spray-dried. In the spray-
drying pxocess, the emulsion was pumped into the spray-
drying chamber. ~he inlet air temperature in the dryer wa5
about 390F, and the outlet air temperature was approxi-
mately 215F. Approximately 2.0 percent silicon dioxide was
also injected into the spray-drying ~hamber.
The spray dryer utilized a conventional arrange-
~ ment o~ components, and had no special means for preventing
I droplet formation as, for example, are discussed in column
1, line 36 through column 2, line 20 of U.S. 2,824,807, to
Laster.
The resulting powder partieles were clear beadletswith,a bulk density o~ approximately 50 grams/100 ml. The
~32~76
powder has good Elow characteristics. ~he powder was
comprised of the following ingredientsr in the following
proportions~
% dry ingredients
in s~ray-dried powder
(1) Vitamin E 51.9
~2) Monoglyceride 1.1
(3) Lacto~e 15.8
(4~ Sodium caseinate20.2
(5) 80-bloom gelatin 8.9
(6) Silicon dioxide 1.0
This powder was then tabletted as described below.
The powder resulting from the process described
above was utilized as a component in a chewable tablet
formulation. The tablet formulation was compressed into
tablets. The formulation consisted of the following
ingredients:
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rams/tablet
(1) Vitamin E powder 0.412
made via Example I
(2) Cab-0-Sil HS-5~ 0.035
(3) Syloid 74m 0.015
(4) Tabletting Sugar 0.295
(5) Flavor 0.005
(6) Magnesium Stearate N.E~. 0.002
The desired tablet weight of approximately 0.76
grams per tablet was achieved. ~he tablet had a good
friability rating ~0.1 percent) as well as acceptable tablet
hardness (12-18 scu). The friability and hardness tests are
, described below.
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Wardness Test
The tablet was tested for hardness on a
Schleuniger-2E hardness tester. A tablet hardness of 7-20
s u ~Strong Cobb Units) was considered acceptable.
Friability Test
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~: Tablet friability ~percent weight loss of 20
l~ tablets) was determined on a Vanderkamp Friabilitor with a
`~ 25 rpm gear driven motor set for five minutes. Hardness and
: friability data indicate tablet integrity and resistance to
capping and chipping.
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: Example 2
. The process described in Example 1 was carried out
again, ~ith the ingredients in the following proportions:
Parts
(1) Vitamin E 26.5
(2) 80-bloom gelatin 17.4
(3) Lactose 5.6
(4) Water 51
(51 Silicon dioxide 1.1
~ his emulsion did not use sodium caseinate ias an
encapsulating agent. Instead, a greater amount of gelatin
was substituted for caseinate and 50me of the lactose.
, Furthermore, the emulsion was stable without the use of
monoglyceride. In addition, no off-odors were detected
`I
~i ~ after holding the emulsion at 60C for several hours, even
though the emulsion contained a relatively high proportion
o~ unhydrolyzed gelatin. The resulting spray-dried powder
.i
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i~ proportions:~
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% dry ingredients
n~spray-dried powder
~1) Vitamin E 54
. (2) 80-bloom gelatin 35.5
'~ ~3~ Lactose 11.4
~` (4) Silic~n dioxide 1.0
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The resulting powder had a bulk density of 45 grams/100 ml,
the powder also exhibited good flowability. The powder was
tabletted as described in Example 1. The tablet had a
hardness of ~-12 scu. The friability rating was 0.0
percent.
Example 3
The process described in Example 1 was carried out
again except that the following ingredients and proportions
were utilized.
Parts
(1) Vitamin E 28.8
(2) Maltodextrin (DE* 5-7;11.5
(3) Sodium caseinate 6.8
(4~ 80-bloom gelatin 5.4
(5) Monoglyceride .58
(b~ Silicon dioxide 1.1
(7) Water 47
*DE is the dextrose equivalent,
This example illustrates a powder which did not
~- contain lactose. In this example, maltodextrin, a poly-
saccharide, is substituted for lactose. For certain
segments of the population, a lactose-free formulation is
desirable, as certain segments of the population are
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deficient in the enzyme lactase which is used to hydrolyze
the disaccharide lacto~e. Lack of ability to hydrolyze
lactose can cause gastrointestinal irritation. For individ-
uals with a lactase deficiency, it is desirable to eliminate
lactose from the diet. The resulting spray-dried powder was
comprised of the following ingredients, in the following
proportions:
% dry ~ edients
in spray-dried powder
(1) Vitamin E 54.3
(2) Maltodextrin (DE 5-7~ 21.7
(3) Sodium caseinate 12.8
(4) 80-bloom gelatin 10.2
(5) Monoglyceride 1.1
(6) Silicon dioxide 1.0
The powder prepared in Example 3 had a density oE
42 9/100 ml and exhibited good flowability. The powder was
tabletted as described in Example 1. The resulting tablet
had a hardness of 5-6 scu. The friability was 0.0 percent.
Example 4
A powder was produced by the process described in
Example 1, except that the ingredients and proportions
utilized were as follows:
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13~576
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Part~
~1) Vitamin E 28.8
~2) Lactose 10.1
(3) Sodium caseinate 2.0
~4) 8~-bloom gelatin 12.1
~5) Monoglyceride 0.64
(6) Silicon dioxide 0.10
(7) Water 47
Example 4 demonstrates that for the most preferred powder, 2
percent caseinate is the lowest propor~ion of caseinate that
can be used to achieve a stable emulsion. At the 2 percent
level~ it was found that the sodium caseinate adequately
encapsulated the vitamin E oil. At still lower caseinate
levels, the emulsion was too viscous for spray-drying.
Thus, 2 percent is believed to be the minimum level of
caseinate for the process of making the most preferred
powder. The resulting spray-dried powder was comprised of
the ollowing ingredients, in the following proportions:
::
. ~ % dry ingredients
,~ i spray-dried powder
:s~ (1) Vitamin E 54.3
(2) Lactose19.0
, (3) Sodium caseinate 3.77
i~ (4) 80-bloom gelatin 22,82
(5~ ~onoglyceride 1.13
-3 ~ ~6) 8ilicon dioxide loO
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The powder had a bulk density of 44 9/lOO ml and
exhibited good flowability. The powder was tabletted
utilizing the ormulation of Example 1, and the resulting
tablet hardness was 7~10 scu. The tablet friability was 0.0
percent.
Example 5
The prooess described in Example 1 was again
carried out, except that the ingredients and proportions
were as follows:
Parts
Il) Vitamin E 28.2
(2) Lactose 9.2
, (3) Sodium caseinate 5.0
(4) 80-bloom gelatin 7.65
,~ (5) Monoglyceride 3.0
.I (6) Silicon dioxide 1,0
(7) Water 47
This example illustrates a powder which utilizes a high
proportion of monoglyceride. Monoglyceride acts as a
:,
surfactant in the formation of the oil-in-water emulsion.
,; The resulting spray-dried powder was comprised o~ the
~, following ingredients, in the following proportions:
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96 drY inQredients
.,
in spray-dried p~wder
11) Vitamin E 53.21
, (2) Lactose 17.36
'1 (3) Sodium caseinate 9-43
(4) 80-bloom gelatin 14.43
3 (5) Monoglyceride 5.66
(6~ Silicon dioxide 1.0
The powder had a tapped density of 37 gram~/100
`. milliliters, and exhibited good flowability. Tablet
,~ hardness was measured at 7-8 scu/ the tablet being made by
the formulation utilized~in Example 1. The tablets had a
~: friability of 0.0 percent.
Example 6
3 ~ Another powder was made by the process described
:j in Example 1, except that the following ingredients and
propoxtlons were utilized:
Parts
(1) Vitamin E 28.6
~;~ (2) Lactose 16.5
~ (3) Sodium caseinate 3076
., (4) 80-bloom gelatin 3.23
5) Monoglyceride 0.58
' : (6) Silicon dioxide ~53
( 7 ) Water 47
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After spray drying, the resulting dry powder had
the following proportions of ingredients:
% dry in Qedients
in spray-dried powder
(1) Vitamin E 54.0
(2) Lactose 31.1
(3) Sodium caseinate 7.1
(4) 80-bloom gelatin 6.7
~5) Monoglyceride 1.1
(6) Silicon dioxide 1.0
This example illustrates a formulation having a relatively
high proporti~n of lactose. Furthermore, this example
.illustrates that a relatively low proportion of sodium
caseinate and gelatin can be utilized. ~he powder had a t~p
density of 48 grams/100 ml, and exhibited good flowability.
The powder was utilized to make a tablet via the
i;formulation given in Example 1. The tablet exhibited a
hardness of 6-7 scu. The tablet friabil.ity was O.O perrent.
t: Example 7
Another powder was made by the process of Example
1, except that the following ingredients and proportions
were utilized:
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Parts
(1) Vitamin E 27.6
~2) 200-bloom gelatin 7.1
~,) Sodium caseinate 9.5
(4) Lactose 7.1
(5) Monoglyceride.60
(6J Silicon dioxide 1.1
( 7 ) Water 48
This exampl,e illustrates a formulation having a gelatin of
higher bloom number than the gelatin utilized in Examples
1-6. The spray-drying process resulted in a formulation
having the following proportions:
: % dry ingredient
in SPray dried ~owder
(1) Vitamin E 27.6
(2) 200-bloom gelatin 7.1
~) Sodium caseinate 9.5
; (4~ Lactose 7 1
(5) Monoglyceride0.59
,: (6) Silicon dioxide 2.1
~7) Water 48
The resulting powder had a tapped density of 48 9/100 ml and
exhibited good flowability. When the powder was utilized to
make a tablet via the formulation of Example 1, the re-
sulting tablet had a hardness of 9-10 scu. The tablet
. ~ friability was OqO percent.
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Example 8
Another powder was made by the process of
Example 1, except that the following ingredients and
proportions were utilized.
Parts
(in emulsion
~,
(1) Vitamin E 28.6
~; (2) 275 Bloom gelatin7.1
(3) Sodium caseinate9.5
' ~4~ Lactose 7.1
(5) Monoglyceride 0.6
(6) Silicon dioxide0.53
. (7) Water 48.0
The resulting spray-dried powder was ~omprised of the
following ingredients, in the following proportions:
dry ingredients
in spray-dried powder
,,1
(1) Vitamin E 55.0
: (2) 275 Bloom~gelatin13.7
~3) Sodium caseinate18.2
~4) Lactose 13.7
, (5) Monoglyceride 1.15
., ~6) Silicon dioxide1.0
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The resulting powder had a tapped density of 39 grams~100
ml. The powder exhibited good flow. A tablet was made
., utilizing this powder in the tablet formulation given in
Example 1. The tablet had a hardness ~f approximately 1
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~cu as measured by the Hardness Test described above. The
table friability was 0.02 percent.
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