CA1324576C - Process for making a spray-dried, directly- compressible vitamin powder comprising unhydrolyzed gelatin - Google Patents
Process for making a spray-dried, directly- compressible vitamin powder comprising unhydrolyzed gelatinInfo
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- CA1324576C CA1324576C CA000578997A CA578997A CA1324576C CA 1324576 C CA1324576 C CA 1324576C CA 000578997 A CA000578997 A CA 000578997A CA 578997 A CA578997 A CA 578997A CA 1324576 C CA1324576 C CA 1324576C
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Abstract
ABSTRACT OF THE DISCLOSURE:
A process for making a directly-compressible vitamin powder comprising: (A) combining: (1) a fat-soluble vitamin; and (2) a gelatin having a bloom number between 30 and 300; and (3) a water-soluble carbohydrate; and (4) an effective amount of water to permit spray-drying; so that a mixture is formed; (B) spray-drying the mixture in a conventional spray-dryer whereby a directly-compressible powder is formed, the relative amounts of vitamin, gelatin, and carbohydrate in the mixture being selected so that the resulting spray-dried powder comprises: (1) 20 to 60 percent by weight of the fat-soluble vitamin; and (2) 6 to 46 percent by weight of the gelatin; and (3) an effective amount of the carbohydrate to prevent extrusion. The resulting powder is useful in the manufacture of pharmaceutical tablets.
A process for making a directly-compressible vitamin powder comprising: (A) combining: (1) a fat-soluble vitamin; and (2) a gelatin having a bloom number between 30 and 300; and (3) a water-soluble carbohydrate; and (4) an effective amount of water to permit spray-drying; so that a mixture is formed; (B) spray-drying the mixture in a conventional spray-dryer whereby a directly-compressible powder is formed, the relative amounts of vitamin, gelatin, and carbohydrate in the mixture being selected so that the resulting spray-dried powder comprises: (1) 20 to 60 percent by weight of the fat-soluble vitamin; and (2) 6 to 46 percent by weight of the gelatin; and (3) an effective amount of the carbohydrate to prevent extrusion. The resulting powder is useful in the manufacture of pharmaceutical tablets.
Description
~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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~32~76 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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. 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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~32~76 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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~32~a76 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 ~32~7~
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 ~ .
~: 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 .,j was comprised of the following ingredients, in the following 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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~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:
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. ~ % 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 I;!
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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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.
: 5 ~2~7~
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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~32~a76 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 ~32~7~
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 .
~32~
.
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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11 32~i~7~
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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-~32457G
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.
,:
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 ~ .
~: 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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~L32~7~
: 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 .,j was comprised of the following ingredients, in the following i~ proportions:~
:,, '!
% 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 ~,:
i~ - 14 -~.
~32~7~
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 - :: : .
~32~7~
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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~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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~32~7~
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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~32~7~
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.
.
~32~7~
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 I;!
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 ~,' , ;, :.
.:~
~32~7~
~cu as measured by the Hardness Test described above. The table friability was 0.02 percent.
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Claims (11)
1. A process for making a spray-dried fat-soluble vitamin powder suitable for the preparation of direct-compression vitamin tablets, comprising:
(A) combining:
(1) a fat-soluble vitamin; and (2) a gelatin having a bloom number between 30 and 300; and (3) a water-soluble carbohydrate; and (4) an effective amount of water to permit spray-drying;
so that a mixture is formed;
(B) spray-drying the mixture in a conventional spray-dryer whereby a directly-compressible powder is formed, the relative amounts of vitamin, gelatin, and carbohydrate in the mixture being selected so that the resulting spray-dried powder comprises:
(1) 20 to 60 percent by weight of the fat-soluble vitamin; and (2) 6 to 46 percent by weight of the gelatin;
and (3) an effective amount of the carbohydrate to prevent extrusion.
(A) combining:
(1) a fat-soluble vitamin; and (2) a gelatin having a bloom number between 30 and 300; and (3) a water-soluble carbohydrate; and (4) an effective amount of water to permit spray-drying;
so that a mixture is formed;
(B) spray-drying the mixture in a conventional spray-dryer whereby a directly-compressible powder is formed, the relative amounts of vitamin, gelatin, and carbohydrate in the mixture being selected so that the resulting spray-dried powder comprises:
(1) 20 to 60 percent by weight of the fat-soluble vitamin; and (2) 6 to 46 percent by weight of the gelatin;
and (3) an effective amount of the carbohydrate to prevent extrusion.
2. The process as described in claim 1 wherein the relative amounts of vitamin, gelatin, and carbohydrate in the mixture are selected so that the resulting spray-dried powder comprises between 5 and 32 percent, by weight, of the carbohydrate.
3. The process as described in claim 1 wherein sodium caseinate is combined with the vitamin, gelatin, carbohydrate, and water, whereby the mixture comprises the vitamin, the gelatin, the carbohydrate, the water, and the caseinate, the relative amount of caseinate in the mixture being selected 90 that the resulting spray-dried powder comprises between 3 and 20 percent, by weight, of the caseinate.
4. The process as described in claim 2 wherein the water-soluble carbohydrate is a member selected from the group consisting of lactose, maltodextrin, corn syrup, mannitol, sorbitol, and a modified food starch.
5. The process as described in claim 4 wherein the water-soluble carbohydrate is selected from the group consisting of lactose and maltodextrin.
6. The process as described in claim 4 wherein the resulting spray-dried vitamin powder comprises approxi-mately 11 percent, by weight, sodium caseinate and approxi-mately 9 percent, by weight, lactose.
7. The process as described in claim 4 wherein the process further comprises the step of spraying silicon dioxide into the spray-dryer during the spray-drying of the mixture, the spraying of silicon dioxide being at a rate so that the resulting spray-dried powder comprises between 0.1 to 5.6 percent silicon dioxide.
8. The process as described in claim 4 wherein a fatty acid monoglyceride is combined with the vitamin, gelatin, carbohydrate and water, whereby the mixture comprises the vitamin, the gelatin, the carbohydrate, the water, and the fatty acid monoglyceride, the relative amount of the fatty acid monoglyceride in the mixture being selected so that the resulting spray-dried powder comprises between 0.1 and 6 percent, by weight, of the fatty acid monoglyceride.
9. The process a described in claim 7 wherein a fatty acid monoglyceride is combined with the vitamin, gelatin, carbohydrate and water, whereby the mixture comprises the vitamin, the gelatin, the carbohydrate, the water, and the fatty acid monoglyceride, the relative amount of the fatty acid monoglyceride in the mixture being selected so that the resulting spray-dried powder comprises between 0.1 and 6 percent, by weight, of the fatty acid monoglyceride.
10. The process as described in claim 9 wherein the amount of vitamin in the mixture is selected so that the resulting spray-dried vitamin powder comprises between 50 and 54 percent by weight of vitamin.
11. The process as described in claim 10 wherein the resulting spray-dried vitamin powder comprises 7.8 to 46 percent by weight gelatin having a bloom number of approxi-mately 80, 10 to 15 percent by weight sodium caseinate, 7.8 to 13.9 percent lactose, approximately 0.6 percent by weight fatty acid monoglyceride and approximately one percent by weight silicon dioxide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/104,446 US4892889A (en) | 1986-11-18 | 1987-10-02 | Process for making a spray-dried, directly-compressible vitamin powder comprising unhydrolyzed gelatin |
| US104,446 | 1987-10-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1324576C true CA1324576C (en) | 1993-11-23 |
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ID=22300524
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000578997A Expired - Fee Related CA1324576C (en) | 1987-10-02 | 1988-09-30 | Process for making a spray-dried, directly- compressible vitamin powder comprising unhydrolyzed gelatin |
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| Country | Link |
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| CA (1) | CA1324576C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112040793A (en) * | 2018-04-27 | 2020-12-04 | 帝斯曼知识产权资产管理有限公司 | Powder formulation |
-
1988
- 1988-09-30 CA CA000578997A patent/CA1324576C/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112040793A (en) * | 2018-04-27 | 2020-12-04 | 帝斯曼知识产权资产管理有限公司 | Powder formulation |
| CN112040793B (en) * | 2018-04-27 | 2023-06-20 | 帝斯曼知识产权资产管理有限公司 | Powder formulations |
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