CA1054520A - L-ascorbic acid tablets - Google Patents
L-ascorbic acid tabletsInfo
- Publication number
- CA1054520A CA1054520A CA249,080A CA249080A CA1054520A CA 1054520 A CA1054520 A CA 1054520A CA 249080 A CA249080 A CA 249080A CA 1054520 A CA1054520 A CA 1054520A
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- CA
- Canada
- Prior art keywords
- ascorbic acid
- weight percent
- granules
- weight
- binder
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Abstract of the Disclosure L-Ascorbic acid tablets which contain more than about 90 weight percent of L-ascorbic acid and have a satisfactory mechanical strength can be obtained by spray-coating L-ascorbic acid powder capable of passing through a 200-mesh screen, with a solution of a binder under constant agitation in fluidized-bed granulating apparatus, until the amount of the binder has reached about 2 to about 4 weight percent relative to L-ascorbic acid, and compressing the resultant granules mixed with a lubricant into tablets.
Description
1~54520 The present invention relates to ~he production of L-ascorbic acid granules of excellent fluidity and homogeniety, and to improved L-ascorbic acid-containing tablets made therefrom.
High L-ascorbic acid content and satisfactory hardness or strength of product have been the essential requirements for L-ascorbic acid tablets.
In the past, however, these two requirements have been considered antagonis-tic to each other because for the enhancement of the strength of the tablet, the atdition of a large amount of adjuvant or excipient is necessary, which results in the necessity of imposing an upper limit on the L-ascorbic acid content of the tablet. This upper limit arises from the fact that the large amounts of L-ascorbic acid required in high potency tablets require large amounts of adju~ant, thus making the tablets too large to be comfortably swallowed.
United States Patent No. 3,453,368 is directed towards solving the aforementioned problems, but its solution is not altogether satisfactory. The patent relates to a process for producing L-ascorbic acid tablets by mixing 85 to 95 weight percent of L-ascorbic acid with 5 to 15 weight percent of modified starch or pregelatinized starch, followed by massing, crushing and drying in that order to give L-ascorbic acid-containing granules, and then mixing the resultant granules with a lubricant and compressing the mixture into tablets (hereafter briefly called the wet-granulation process).
Hbwever, it is difficult to provide granules of good fluidity and homogeniety from such a wet granulation process and, as a result, L-ascorbic acid tablets which are compressed from such granules are far from satisfaction in their mechanical strength (i.e. tensile strength or hardness).
The present invention is based on the disco~ery that drawbacks of the kno~n art can be overcome largely or completely, and L-ascorbic acid gra-nules suitable for tabletting can be producedJ by coating L-ascorbic acid powder with a binder in a fluidizet bed technique.
According to the invention, there is provided a process for producing L-ascorbic acid granules, whichco~prisesspray-coating minus 200-~esh (Tyler) L-ascorbic acid powder with a solution of a pharmaceutically acceptable binter under constant agitation in fluidized-bed granulating zone until the a~ount of binder coating the powder has reached about 2 to about 4 weight percent rela-tive to the weight of the L-ascorbic acid, and recovering dry, coated L-ascor-bic acit granules from said zone.
The invention also provides L-ascorbic acid granules produced by spray-coating minus 200-mesh L-ascorbic acid powder with a solution of a phar~aceutically acceptable binder unter constant agitation in a fluidized-bed granulating zone until the a~ount of the binter has reached about 2 to about 4 weight percent relati~e to the weight of the L-ascorbic acid.
Finally, the invention provides an L-ascorbic acid tablet consisting essentially of L-ascorbic acit and phanDaceutically acceptable binder and tab-letting lubricant, and having the following characteristics;
a) L-ascorbic acid contont: about 100 to about 2000 mg. per tablet and forming about 90 to about 97.1 percent by weight of the tablet;
b) binder content: about 2 to about 4 woight percent relative to the weight of the L-ascorbic acid:
c) lubricant content: about 1 to about 7 weight percent relative to the weight of the L-ascorbic acid;
t) tensile strength: not lower than 12.5 kglcE2.
In the process of the present in~ention, L-ascorbic acid granules are prepared in tho following manner. ~inus 200-mesh L-ascorbic acid powder (i.e. powdor which passes through a 200-mesh screen) is spray-coatet with a solution of a binder under continuously fluitizing conditions.
Preferably, use is nate of L-ascorbic acit powder, not less than 50 woight percont of which is ~inus 325-~esh (i.e. passes through a 325-~esh screen). Here "mesh" ~eans W.S. Tyler Standard mesh. Tho "powder" may be preparet by grinding or otherwise.
As the binder, there may be ~entionet water-soluble binters such as pregolatinized starch (e.g. pregelatinized corn starch, pregelatinized white
High L-ascorbic acid content and satisfactory hardness or strength of product have been the essential requirements for L-ascorbic acid tablets.
In the past, however, these two requirements have been considered antagonis-tic to each other because for the enhancement of the strength of the tablet, the atdition of a large amount of adjuvant or excipient is necessary, which results in the necessity of imposing an upper limit on the L-ascorbic acid content of the tablet. This upper limit arises from the fact that the large amounts of L-ascorbic acid required in high potency tablets require large amounts of adju~ant, thus making the tablets too large to be comfortably swallowed.
United States Patent No. 3,453,368 is directed towards solving the aforementioned problems, but its solution is not altogether satisfactory. The patent relates to a process for producing L-ascorbic acid tablets by mixing 85 to 95 weight percent of L-ascorbic acid with 5 to 15 weight percent of modified starch or pregelatinized starch, followed by massing, crushing and drying in that order to give L-ascorbic acid-containing granules, and then mixing the resultant granules with a lubricant and compressing the mixture into tablets (hereafter briefly called the wet-granulation process).
Hbwever, it is difficult to provide granules of good fluidity and homogeniety from such a wet granulation process and, as a result, L-ascorbic acid tablets which are compressed from such granules are far from satisfaction in their mechanical strength (i.e. tensile strength or hardness).
The present invention is based on the disco~ery that drawbacks of the kno~n art can be overcome largely or completely, and L-ascorbic acid gra-nules suitable for tabletting can be producedJ by coating L-ascorbic acid powder with a binder in a fluidizet bed technique.
According to the invention, there is provided a process for producing L-ascorbic acid granules, whichco~prisesspray-coating minus 200-~esh (Tyler) L-ascorbic acid powder with a solution of a pharmaceutically acceptable binter under constant agitation in fluidized-bed granulating zone until the a~ount of binder coating the powder has reached about 2 to about 4 weight percent rela-tive to the weight of the L-ascorbic acid, and recovering dry, coated L-ascor-bic acit granules from said zone.
The invention also provides L-ascorbic acid granules produced by spray-coating minus 200-mesh L-ascorbic acid powder with a solution of a phar~aceutically acceptable binder unter constant agitation in a fluidized-bed granulating zone until the a~ount of the binter has reached about 2 to about 4 weight percent relati~e to the weight of the L-ascorbic acid.
Finally, the invention provides an L-ascorbic acid tablet consisting essentially of L-ascorbic acit and phanDaceutically acceptable binder and tab-letting lubricant, and having the following characteristics;
a) L-ascorbic acid contont: about 100 to about 2000 mg. per tablet and forming about 90 to about 97.1 percent by weight of the tablet;
b) binder content: about 2 to about 4 woight percent relative to the weight of the L-ascorbic acid:
c) lubricant content: about 1 to about 7 weight percent relative to the weight of the L-ascorbic acid;
t) tensile strength: not lower than 12.5 kglcE2.
In the process of the present in~ention, L-ascorbic acid granules are prepared in tho following manner. ~inus 200-mesh L-ascorbic acid powder (i.e. powdor which passes through a 200-mesh screen) is spray-coatet with a solution of a binder under continuously fluitizing conditions.
Preferably, use is nate of L-ascorbic acit powder, not less than 50 woight percont of which is ~inus 325-~esh (i.e. passes through a 325-~esh screen). Here "mesh" ~eans W.S. Tyler Standard mesh. Tho "powder" may be preparet by grinding or otherwise.
As the binder, there may be ~entionet water-soluble binters such as pregolatinized starch (e.g. pregelatinized corn starch, pregelatinized white
- 2 -, .
potato starch), pregelatinized modified starch (see Code of Federal Regulation tU.S,A,) 5 121,1031, a,b,c,d,e,f,g and h), water soluble cellulose derivatives ~e.g. hydroxypropyl-cellulose, hydroxymethyl-cellulose hydroxypropylmethyl-cellulose, carboxymethyl-cellulose), polyvinylpyrrolidone, polyvinyl alcohol, dextrin, gum arabic and gelatin; and organic solvent-soluble binders, such as cellulose derivatives (e.g. cellulose acetate phthalate, hydroxypropylmethyl-cellulose phthalate, ethyl-cellulose).
As the solvent for preparing the solution for spray-coating, there may be ~entioned, for exa~ple, water, alcohols (e.g. methyl slcohol, ethyl alcohol, isopropyl alcohol), and acetone.
The concentration of the binder in the solution ~or spray-coating is not particularly critical but practically ranges from about 1 to about 10 weight pcrcent, ~nd preferably about 2 to about 8 weight percent.
The n uidizet-bed granulating zone ay be provided by a fluitized-bed trying tevice fitted with spray means to inject a ~ist of a binder solution in such a ~anner that the granulating ant drying sperations are accomplishet in a 5~ single s~age. By way of exa~ple, Glatt (made by Glatt AG, West Germany), Aero-matic (mate by Aero~atic AG, Switzerlant), Cal~ic (~ade by Calmic Engineering Co., Englant), Growmax ~mate by Fuji Powtal Co., Japan) or Plo~coater (Dade by Freund Industrios Co., Japan) aro mentioned as suitable types of apparatus.
The granulating process co~tinues until ~he amount of the binder has roached about 2 to about 4 woight percent relative to the weight of the L-ascorbic acid.
As an optional second step of the process of tho present invention, tho thus-coated L-ascorbic acid granules are mixed with a phar~aceutically acceptable tabletting lubric3nt and compresset into tabIets.
As the lubricant use may be made, $or instance, of stearates (e.g.
magnesium stearate, calciu~ stearate, stearic acid), corn starch and so on, the amouDt of lubricant used i5 ~ore or less conventional, but as a~ounts about 1 to about 7 woight percent relative to ~he ~eight of L- ascorbic acid TrAI~ ~arl~5 _ 3 _ ", . . . . . . . ..
are preferred, the stearates offer the best pcrformance at this level.
In ~he process of this invention minus 200-mesh L-ascorbic acid pow-der is homogeneouslr coated with only 2 to 4 perccnt of binder, a rather small amount of binder compared to conventional practice, ant the thus coated L-ascorbic acid granules are substantially free from fine dust and possess excel-lent fluidity, being easy to mix with other components. Besides, the L-ascor-bic acid component in the granules are more stable since whereas moisture is highly teterimental to L-ascorbic acid, the granules preparet by the present process are coated with only a small a~ount of moisture-absorbing binder.
The granules obtained by the present process are distinguishable from granules obtained by wet-granulating methods in electron microsopic photographs.
Tho atvantages of the granules of the in~ention combino to contri-bute to the impro~e~ent in the final L-ascorbic acid tablets. Thus, the tab-lets prepared fro~ the coatet L-ascorbic acid granules excel in ter~s of L-ascorbic acit content and mechanical strength. Shus, the tablets can contain as high as about 90 to about 97,1 weight percent of L-ascorbic acid while aintaining a tensile strength not lower than 12.5 kg/cm2. In terms of L-ascorbic acit content per tablet the range is from about 100 to about 2000 mg., preferably about 400 to about 600 mg. Hardness is generally 8.5 kg. or grea-ter.
In terms of disintegsation, the tablets are satisfactory in that the disintcgration time of the tablets falls within the require~ent of the standard in the Japanese Phar~acopoeia, 8th dition.
The following exa~ples and tests~are further illustrative of this invention. In the examples ant tests, "partts)" and "percent(s)" are based on weight, unless otherwise speci~ied.
The relationship between hartness and tensile strength of a tablet is shown by the following equation;
2P t~g/cm2) ~DT
~ .
wherein a stands for tensile strength, P for hardness, D for diameter, T for thickness and ~ for circular constant, respecti~ely. For the practical use tablets having not lower than 12.5 kg/cm2 of tensile strength is satisfactory.
Example 1 a) 97 parts of finely ground L-ascorbic acid, 100 weight percent of which was minus 200-mesh, 4.5 weight percent of which was plus 250-mesh but 82.8 weight percent of which was minus 325-mesh, were sprayed under constant agitation in a fluidized-bed granulator with a paste which had been prepared by gelatinizing a 5.0 weight percent aqueous suspension of corn starch at 85C
and cooling to 50C, until the amount of starch coating had reached 3 parts, followed by drying in situ. The product was then comminuted in a Fitz-mill equipped with a 1.0 mm-screen to obtain L-ascorbic acid granules.
b)-l To 515 parts of the granules prepared as above there were added S
parts of magnesium stearate and 15 parts of corn starch, and after mixing, the composition was co~pressed into a 535 mg. tablet.
L-Ascorbic acid content: 93.5 weight percent Hardnoss: 12.1 kg.
Tensilo strength: 18.4 kg/cm2 b)-2 To 515 parts of the granules prepared as above (a) there were added 5 parts of magnesium stearate, and after mixing, the composition was conpres-set into a 520 mg. tablet.
L-Ascorbic acid content: 96.2 weight percent Hardness: 11.5 kg.
Tensile strength: 17.5 kg/cm2 b)_3 To 515 parts of the granules prepared as above (a) ~here were added 5 parts of magnesium stearate and 30 parts of corn s~arch, and after mixing, the composition was compressed into a 550 mg. tablet.
L-Ascorbic acid content: 90.9 weight percent Hardness: 11.8 kg.
Tensile strength: 18.0 kg/cm2 .
: .
lOS45ZO
Example 2 a) 98 parts of finely ground L-ascorbic acid 100 weigh~ percent of which was minus ~00-mesh, 4.5 weight percent of which was plus 250-mesh but 82.8 weight percent of which was minus 325-mesh, were sprayed under constant agitation in a fluidized-bed granulator with a paste which had been prepared by gelatinizing a 2.5 weight percent aqueous suspension of white potato starch at 85C and cooling to 50C, until the amount of white potato starch coated on the L-ascorbic acid hat reached 2 parts, followed by drying in situ. The product was then comminutet in a Fitz-nill equipped with a 1.5 mm-screen to obtain L-ascorbic acid granules.
b) To 510 parts of the granules prepared as above there were added 5 parts of magnesium stearate and 15 parts of corn s~arch, and after mixing, the composition was compressed into a 530 mg. tablet.
L-Ascorbic acid content: 94.3 weight percent Hardness: 10.0 kg.
Tensile strength: 15.2 kg/c~2 Example 3 a) 96 parts of fin~ly ground L-ascorbic acid, 100 ~eight percent of which was minus 200-mesh, 4.5 weight percent of which was plus 250-mesh but 82.8 woight percent of which was minus 325-mesh, were sprayed under constant ; agitation in a fluitized-bed granulator with a solution of 5.0 weight percent of hytroxypropylmethylcelluloso until the a~ount of hydroxypropyl~ethylcellu~
lose coatod had reached 4 parts, followed by drying in situ to obtain L-~, ascorbic acid-containing granules.
b) To 520 parts of the granules prepared as abo~e there were added 5 parts of magnesiu~ stearate and 15 parts of co~n starch, and after mixing, the composition w~5 co~pressed into a 540 mg. tablet.
L-Ascorbic acit content: 92.6 weight percent Hardness: 15.5 kg.
. .
:' -, .
Tensile strength: 23.6 kg/cm2 Example 4 a) 97 parts of finely ground L-ascorbic acid, 100 weight percent of which was minus 200-mesh, 4.5 weight percent of which was plus 250-mesh but 82.8 weight percent of which was minus 325-mesh, were sprayed under constant agitation in a fluidized-bed granulator with a solution of 4.0 weight percent of ethylcellulose until the amount of ethylcellulose coated had reached 3 parts, followed by drying m situ to obtain L-ascorbic acid-containing gra-nules.
Exa~ple 5 a) L-Ascorbic acid granules were obtained by the same manner as ~x-ample 4 ~a), but using hydroxypropylmethylcellulose instead of ethyl cellulose.
b) 515 parts of the granules prepared as above (a) were co~pressed as in Exa~ple 1, b)-l into a 535 mg. tablet.
L-Ascorbic acid content: 93.5 weight percent Hardness: 12.2 kg.
Tensile strength: 18.6 kg/cm2 Exa~ple 6 a) 97 parts of finely ground L-ascorbic acid, 100 weight percent of which was ~inus 200-mesh, 4.5 weight percent of which was plus 250-mesh but 82.8 weight percent of which was minus 325-mesh, were sprayed under constant agitation in a fluidized-bed granulator with a paste had be0n prepared by ge-latinizing a 3.0 weight percent aqueous suspension of hydroxypropyl starch, which is tescribet in Code of Feteral Regulation 121,1031, at 70C and cooling to 50C, until the amount of hydroxypropyl starch coated llad reached
potato starch), pregelatinized modified starch (see Code of Federal Regulation tU.S,A,) 5 121,1031, a,b,c,d,e,f,g and h), water soluble cellulose derivatives ~e.g. hydroxypropyl-cellulose, hydroxymethyl-cellulose hydroxypropylmethyl-cellulose, carboxymethyl-cellulose), polyvinylpyrrolidone, polyvinyl alcohol, dextrin, gum arabic and gelatin; and organic solvent-soluble binders, such as cellulose derivatives (e.g. cellulose acetate phthalate, hydroxypropylmethyl-cellulose phthalate, ethyl-cellulose).
As the solvent for preparing the solution for spray-coating, there may be ~entioned, for exa~ple, water, alcohols (e.g. methyl slcohol, ethyl alcohol, isopropyl alcohol), and acetone.
The concentration of the binder in the solution ~or spray-coating is not particularly critical but practically ranges from about 1 to about 10 weight pcrcent, ~nd preferably about 2 to about 8 weight percent.
The n uidizet-bed granulating zone ay be provided by a fluitized-bed trying tevice fitted with spray means to inject a ~ist of a binder solution in such a ~anner that the granulating ant drying sperations are accomplishet in a 5~ single s~age. By way of exa~ple, Glatt (made by Glatt AG, West Germany), Aero-matic (mate by Aero~atic AG, Switzerlant), Cal~ic (~ade by Calmic Engineering Co., Englant), Growmax ~mate by Fuji Powtal Co., Japan) or Plo~coater (Dade by Freund Industrios Co., Japan) aro mentioned as suitable types of apparatus.
The granulating process co~tinues until ~he amount of the binder has roached about 2 to about 4 woight percent relative to the weight of the L-ascorbic acid.
As an optional second step of the process of tho present invention, tho thus-coated L-ascorbic acid granules are mixed with a phar~aceutically acceptable tabletting lubric3nt and compresset into tabIets.
As the lubricant use may be made, $or instance, of stearates (e.g.
magnesium stearate, calciu~ stearate, stearic acid), corn starch and so on, the amouDt of lubricant used i5 ~ore or less conventional, but as a~ounts about 1 to about 7 woight percent relative to ~he ~eight of L- ascorbic acid TrAI~ ~arl~5 _ 3 _ ", . . . . . . . ..
are preferred, the stearates offer the best pcrformance at this level.
In ~he process of this invention minus 200-mesh L-ascorbic acid pow-der is homogeneouslr coated with only 2 to 4 perccnt of binder, a rather small amount of binder compared to conventional practice, ant the thus coated L-ascorbic acid granules are substantially free from fine dust and possess excel-lent fluidity, being easy to mix with other components. Besides, the L-ascor-bic acid component in the granules are more stable since whereas moisture is highly teterimental to L-ascorbic acid, the granules preparet by the present process are coated with only a small a~ount of moisture-absorbing binder.
The granules obtained by the present process are distinguishable from granules obtained by wet-granulating methods in electron microsopic photographs.
Tho atvantages of the granules of the in~ention combino to contri-bute to the impro~e~ent in the final L-ascorbic acid tablets. Thus, the tab-lets prepared fro~ the coatet L-ascorbic acid granules excel in ter~s of L-ascorbic acit content and mechanical strength. Shus, the tablets can contain as high as about 90 to about 97,1 weight percent of L-ascorbic acid while aintaining a tensile strength not lower than 12.5 kg/cm2. In terms of L-ascorbic acit content per tablet the range is from about 100 to about 2000 mg., preferably about 400 to about 600 mg. Hardness is generally 8.5 kg. or grea-ter.
In terms of disintegsation, the tablets are satisfactory in that the disintcgration time of the tablets falls within the require~ent of the standard in the Japanese Phar~acopoeia, 8th dition.
The following exa~ples and tests~are further illustrative of this invention. In the examples ant tests, "partts)" and "percent(s)" are based on weight, unless otherwise speci~ied.
The relationship between hartness and tensile strength of a tablet is shown by the following equation;
2P t~g/cm2) ~DT
~ .
wherein a stands for tensile strength, P for hardness, D for diameter, T for thickness and ~ for circular constant, respecti~ely. For the practical use tablets having not lower than 12.5 kg/cm2 of tensile strength is satisfactory.
Example 1 a) 97 parts of finely ground L-ascorbic acid, 100 weight percent of which was minus 200-mesh, 4.5 weight percent of which was plus 250-mesh but 82.8 weight percent of which was minus 325-mesh, were sprayed under constant agitation in a fluidized-bed granulator with a paste which had been prepared by gelatinizing a 5.0 weight percent aqueous suspension of corn starch at 85C
and cooling to 50C, until the amount of starch coating had reached 3 parts, followed by drying in situ. The product was then comminuted in a Fitz-mill equipped with a 1.0 mm-screen to obtain L-ascorbic acid granules.
b)-l To 515 parts of the granules prepared as above there were added S
parts of magnesium stearate and 15 parts of corn starch, and after mixing, the composition was co~pressed into a 535 mg. tablet.
L-Ascorbic acid content: 93.5 weight percent Hardnoss: 12.1 kg.
Tensilo strength: 18.4 kg/cm2 b)-2 To 515 parts of the granules prepared as above (a) there were added 5 parts of magnesium stearate, and after mixing, the composition was conpres-set into a 520 mg. tablet.
L-Ascorbic acid content: 96.2 weight percent Hardness: 11.5 kg.
Tensile strength: 17.5 kg/cm2 b)_3 To 515 parts of the granules prepared as above (a) ~here were added 5 parts of magnesium stearate and 30 parts of corn s~arch, and after mixing, the composition was compressed into a 550 mg. tablet.
L-Ascorbic acid content: 90.9 weight percent Hardness: 11.8 kg.
Tensile strength: 18.0 kg/cm2 .
: .
lOS45ZO
Example 2 a) 98 parts of finely ground L-ascorbic acid 100 weigh~ percent of which was minus ~00-mesh, 4.5 weight percent of which was plus 250-mesh but 82.8 weight percent of which was minus 325-mesh, were sprayed under constant agitation in a fluidized-bed granulator with a paste which had been prepared by gelatinizing a 2.5 weight percent aqueous suspension of white potato starch at 85C and cooling to 50C, until the amount of white potato starch coated on the L-ascorbic acid hat reached 2 parts, followed by drying in situ. The product was then comminutet in a Fitz-nill equipped with a 1.5 mm-screen to obtain L-ascorbic acid granules.
b) To 510 parts of the granules prepared as above there were added 5 parts of magnesium stearate and 15 parts of corn s~arch, and after mixing, the composition was compressed into a 530 mg. tablet.
L-Ascorbic acid content: 94.3 weight percent Hardness: 10.0 kg.
Tensile strength: 15.2 kg/c~2 Example 3 a) 96 parts of fin~ly ground L-ascorbic acid, 100 ~eight percent of which was minus 200-mesh, 4.5 weight percent of which was plus 250-mesh but 82.8 woight percent of which was minus 325-mesh, were sprayed under constant ; agitation in a fluitized-bed granulator with a solution of 5.0 weight percent of hytroxypropylmethylcelluloso until the a~ount of hydroxypropyl~ethylcellu~
lose coatod had reached 4 parts, followed by drying in situ to obtain L-~, ascorbic acid-containing granules.
b) To 520 parts of the granules prepared as abo~e there were added 5 parts of magnesiu~ stearate and 15 parts of co~n starch, and after mixing, the composition w~5 co~pressed into a 540 mg. tablet.
L-Ascorbic acit content: 92.6 weight percent Hardness: 15.5 kg.
. .
:' -, .
Tensile strength: 23.6 kg/cm2 Example 4 a) 97 parts of finely ground L-ascorbic acid, 100 weight percent of which was minus 200-mesh, 4.5 weight percent of which was plus 250-mesh but 82.8 weight percent of which was minus 325-mesh, were sprayed under constant agitation in a fluidized-bed granulator with a solution of 4.0 weight percent of ethylcellulose until the amount of ethylcellulose coated had reached 3 parts, followed by drying m situ to obtain L-ascorbic acid-containing gra-nules.
Exa~ple 5 a) L-Ascorbic acid granules were obtained by the same manner as ~x-ample 4 ~a), but using hydroxypropylmethylcellulose instead of ethyl cellulose.
b) 515 parts of the granules prepared as above (a) were co~pressed as in Exa~ple 1, b)-l into a 535 mg. tablet.
L-Ascorbic acid content: 93.5 weight percent Hardness: 12.2 kg.
Tensile strength: 18.6 kg/cm2 Exa~ple 6 a) 97 parts of finely ground L-ascorbic acid, 100 weight percent of which was ~inus 200-mesh, 4.5 weight percent of which was plus 250-mesh but 82.8 weight percent of which was minus 325-mesh, were sprayed under constant agitation in a fluidized-bed granulator with a paste had be0n prepared by ge-latinizing a 3.0 weight percent aqueous suspension of hydroxypropyl starch, which is tescribet in Code of Feteral Regulation 121,1031, at 70C and cooling to 50C, until the amount of hydroxypropyl starch coated llad reached
3 parts, followed by drying in situ. The product was then co~inuted in a Fitz- ill provided with a l,S mm-screen to obtain L-ascorbic acid granules.
b) To 515 parts of the granules prepared as above there were added 5 parts of agnesium stearate and 15 parts of corn starch, and after mixing, the composition was compressed into a 535 mg. tablet.
.
.
_ 7 _ lOS4520 L-Ascorbic acid content: 93.5 weight percent Hardness: 12.3 kg.
Tensile strength: 18 7 kg/cm2 Example 7 a) 96 parts of finely ground L-ascorbic acid, 100 weight percent of which was minus 200-mesh, 4.5 weight percent which was plus 250-mesh but 82.8 weight percent of which was minus 325-mesh, were sprayed under contant agi^
tation in a fluidized-bed granulator with a paste which had been prepared by ; gelatinizing a 5,0 weight percent aqueous suspension of corn starch at 85C
and cooling to 50C, until the amount of starch coated had reached 4 parts, followed by drying in situ. The product was then comminuted in a Fitz-mill equipped with a 1.5 mm-screen to obtain L-ascorbic acid granules.
b) To 520 parts of the granules prepared as above there were added 5 parts of calcium stearate and 15 parts of corn starch, and after mixing, the composition was compressed into a 545 mg. tablet.
L-Ascorbic acid content: 92.6 weight percent ` Hardness: 15.7 kg.
Tensile strength; 23.9 kg/cm Example 8 a) 96 parts of finely ground L-ascorbic acid, 100 weight percent of .~ .
which was minus 200-~esh, 4.5 weight percent of which was plus 250-mesh but 82,8 weight percen~ of which was minus 325-mesh, were sprayed under constant agitation in a fluitizet-bet granulator with a paste which had been prepared by gelatinizing a 8 weight percent aqueous suspension of pregelatinized modi-S ~ fied starch, STA-RX 1500 (A.~. Staley Mfg. Co., U.S.A.) at 85C and cooling 1 to 50C until the amount of the starch coated had reached 4 parts followed by `~ trying in situ. The product was then comn m uted in a Fitz-mill equippet with ` a 1.5 mm-screen to obtain L-ascorbic acid granules.
b) To 520 parts of tho granules preparet as above there were added 5 parts of calciu~ stearato and 1.5 parts of corn starch, ant after mixing, the . ' ' - , . . .
:, , . . , ,. ,:, : ~ ; . .,.:
., - ~ . .. . . -. -. ~ .. :
10545;~(~
composition was compressed into a 540 mg. t:ablet.
L-Ascorbic acid content: 92.6 weight percent Hardness: 13.6 kg.
Tensile strength: 20.7 kg/cm2 Exampl_ 9 a) 98 parts of finely ground L-ascorbic acid, 100 weight percent of which was minus 200-mesh, 4.5 weight percent of which was plus 250-mesh but 82.8 weight percent of which was minus 325-mesh, were sprayed under constant agitation in a fluidized-bed granulator with a paste which had been prepared by gelatinizing a 5.0 weight percent aqueous suspension of corn starch at 85C and cooling to 50C until the amount of starch coated had reached 2 parts, followet by drying in situ. The product was then comminuted in a Fitz-mill equipped with a 1.0 m~-screen to obtain L-ascorbic acid granules.
b) To 510 parts of the granules preparet as above there were added 5 parts of magnesium stearate, ant after mixing, the composition was co~pres-sed into a 515 mg. tablet.
L-Ascorbic acid content: 97.1 weight persent Hardness: 8.9 kg.
Tensile strength: 13.6 kglc~2 Test (A) Method (i)-l Preparation of granules a) Granules obtained by the present invention ; (grount powder was e~ployed) Granulo 1) - granules obtained by Example 3 (a) (granules containing about 96 % of L-ascorbic acid).
Granule 2) - granules obtained by Example 1 (a) (granules con~aining abou~ 97 % of L-ascorbic acid), Granule 3) - granules obtained by Example 9 (a) ~granules containing about 98 % of L-ascorbic acid).
_ g _ - : . . , . .` ~ . . . : : . . :
b) Granules obtained by the wet-granulation method tground powder was employed) Powtered L-ascorbic acid, 100 weight percent of which was minus 200-mesh, 4.5 percent of which was plus 250-mesh and 82.8 percent of which was minus 325-mesh, and pregelatinizet starch, Amicol* C (mate b~ Nippon Starch Refining Co., Japan), were charged into a Pony Mixer, mixed well and 10 percent of wa~er was added, followed by massing. The resulting moistened powter was forced through a 3.0 mm-screen, and dried overnight at 40C, and then comminuted in a Fitz-mill equipped with a 1.5 mm-screen.
Granule 4) - granules which contain about 90 percent of L-ascorbic acid.
Granule 5) - granules which contain about 95 percent of L-ascorbic acid.
Granule 6) - granules which contain about 97 percent of L-ascorbic acid.
(i)-2 Preparation of tablets.
The following tabletting granules were co~pressed in a rotary `~ tablet machine (RTM-S36-2S, made by ~ikusui Seisakusho Co., Japan) to obtain 600 sgs. tablets with 11.5 ~m flat faced, beveled edged punch and die.
Tablets Granules Calcium Silicon Corn used stearate dioxide starch (1) Granule t2) 1.0 % - 5.0 ~
(2) Granule (1) 1.0 % - 3.0 %
(3) Granule (2) 1.0 % - 3.0 %
` (4) Granule (3) 1.0 % _ 3.0 %
y (5) Granule (3) 1.0 %
(6) Granule (4) 1.0 % 1.0 % 3.0 %
(7) Granule (4) 1.0 ~ - 3.0 (8) Granule (5) 1.0 % 1.0 ~ 3.0 (9) Granule (5) 1.0 t - 3.0 %
(10) Granule (6) 1.0 % 1.0 % 3.0 %
(ii) Tests of strength of tablets ~
; 30 Tablets (1) to (10) were compressed diametrically in a physical ~ -Trademark :, . . . .. . .
testing instrument (Autograph IS-5000, made by Shimazo Seisakusho Co., Japan) to measure their crushing strength. (See page 124 of Y. Yamaguchi and Y.
Nishimatsu; Introduction of Rock Mechanics, University Press of Tokyo (1967)).
(iii) Disintegration test This was done according to the general test 31 disintegration test of the Japanese Pharmacopoeia, 8th Edition, with exception that in the pre-sent test the attached disk was not used and water was used as a solvent.
The requirement of the Japanese Pharmacopoeia is that the disinteg-ration time of a tablet be not longer than 30 minutes.
(B) Results Tablet L-Ascorbic TroublesHardness Tensile Disinteg-number acid in (kg) strength ration content tabletting 2 (minutes) % (kg/cm ) (1) about 90.9 No 12.2 16.9 5.1 (2) about 92.3 No 16.0 22.2 28.0 (3) about 93.2 No 12.5 17.3 9.7
b) To 515 parts of the granules prepared as above there were added 5 parts of agnesium stearate and 15 parts of corn starch, and after mixing, the composition was compressed into a 535 mg. tablet.
.
.
_ 7 _ lOS4520 L-Ascorbic acid content: 93.5 weight percent Hardness: 12.3 kg.
Tensile strength: 18 7 kg/cm2 Example 7 a) 96 parts of finely ground L-ascorbic acid, 100 weight percent of which was minus 200-mesh, 4.5 weight percent which was plus 250-mesh but 82.8 weight percent of which was minus 325-mesh, were sprayed under contant agi^
tation in a fluidized-bed granulator with a paste which had been prepared by ; gelatinizing a 5,0 weight percent aqueous suspension of corn starch at 85C
and cooling to 50C, until the amount of starch coated had reached 4 parts, followed by drying in situ. The product was then comminuted in a Fitz-mill equipped with a 1.5 mm-screen to obtain L-ascorbic acid granules.
b) To 520 parts of the granules prepared as above there were added 5 parts of calcium stearate and 15 parts of corn starch, and after mixing, the composition was compressed into a 545 mg. tablet.
L-Ascorbic acid content: 92.6 weight percent ` Hardness: 15.7 kg.
Tensile strength; 23.9 kg/cm Example 8 a) 96 parts of finely ground L-ascorbic acid, 100 weight percent of .~ .
which was minus 200-~esh, 4.5 weight percent of which was plus 250-mesh but 82,8 weight percen~ of which was minus 325-mesh, were sprayed under constant agitation in a fluitizet-bet granulator with a paste which had been prepared by gelatinizing a 8 weight percent aqueous suspension of pregelatinized modi-S ~ fied starch, STA-RX 1500 (A.~. Staley Mfg. Co., U.S.A.) at 85C and cooling 1 to 50C until the amount of the starch coated had reached 4 parts followed by `~ trying in situ. The product was then comn m uted in a Fitz-mill equippet with ` a 1.5 mm-screen to obtain L-ascorbic acid granules.
b) To 520 parts of tho granules preparet as above there were added 5 parts of calciu~ stearato and 1.5 parts of corn starch, ant after mixing, the . ' ' - , . . .
:, , . . , ,. ,:, : ~ ; . .,.:
., - ~ . .. . . -. -. ~ .. :
10545;~(~
composition was compressed into a 540 mg. t:ablet.
L-Ascorbic acid content: 92.6 weight percent Hardness: 13.6 kg.
Tensile strength: 20.7 kg/cm2 Exampl_ 9 a) 98 parts of finely ground L-ascorbic acid, 100 weight percent of which was minus 200-mesh, 4.5 weight percent of which was plus 250-mesh but 82.8 weight percent of which was minus 325-mesh, were sprayed under constant agitation in a fluidized-bed granulator with a paste which had been prepared by gelatinizing a 5.0 weight percent aqueous suspension of corn starch at 85C and cooling to 50C until the amount of starch coated had reached 2 parts, followet by drying in situ. The product was then comminuted in a Fitz-mill equipped with a 1.0 m~-screen to obtain L-ascorbic acid granules.
b) To 510 parts of the granules preparet as above there were added 5 parts of magnesium stearate, ant after mixing, the composition was co~pres-sed into a 515 mg. tablet.
L-Ascorbic acid content: 97.1 weight persent Hardness: 8.9 kg.
Tensile strength: 13.6 kglc~2 Test (A) Method (i)-l Preparation of granules a) Granules obtained by the present invention ; (grount powder was e~ployed) Granulo 1) - granules obtained by Example 3 (a) (granules containing about 96 % of L-ascorbic acid).
Granule 2) - granules obtained by Example 1 (a) (granules con~aining abou~ 97 % of L-ascorbic acid), Granule 3) - granules obtained by Example 9 (a) ~granules containing about 98 % of L-ascorbic acid).
_ g _ - : . . , . .` ~ . . . : : . . :
b) Granules obtained by the wet-granulation method tground powder was employed) Powtered L-ascorbic acid, 100 weight percent of which was minus 200-mesh, 4.5 percent of which was plus 250-mesh and 82.8 percent of which was minus 325-mesh, and pregelatinizet starch, Amicol* C (mate b~ Nippon Starch Refining Co., Japan), were charged into a Pony Mixer, mixed well and 10 percent of wa~er was added, followed by massing. The resulting moistened powter was forced through a 3.0 mm-screen, and dried overnight at 40C, and then comminuted in a Fitz-mill equipped with a 1.5 mm-screen.
Granule 4) - granules which contain about 90 percent of L-ascorbic acid.
Granule 5) - granules which contain about 95 percent of L-ascorbic acid.
Granule 6) - granules which contain about 97 percent of L-ascorbic acid.
(i)-2 Preparation of tablets.
The following tabletting granules were co~pressed in a rotary `~ tablet machine (RTM-S36-2S, made by ~ikusui Seisakusho Co., Japan) to obtain 600 sgs. tablets with 11.5 ~m flat faced, beveled edged punch and die.
Tablets Granules Calcium Silicon Corn used stearate dioxide starch (1) Granule t2) 1.0 % - 5.0 ~
(2) Granule (1) 1.0 % - 3.0 %
(3) Granule (2) 1.0 % - 3.0 %
` (4) Granule (3) 1.0 % _ 3.0 %
y (5) Granule (3) 1.0 %
(6) Granule (4) 1.0 % 1.0 % 3.0 %
(7) Granule (4) 1.0 ~ - 3.0 (8) Granule (5) 1.0 % 1.0 ~ 3.0 (9) Granule (5) 1.0 t - 3.0 %
(10) Granule (6) 1.0 % 1.0 % 3.0 %
(ii) Tests of strength of tablets ~
; 30 Tablets (1) to (10) were compressed diametrically in a physical ~ -Trademark :, . . . .. . .
testing instrument (Autograph IS-5000, made by Shimazo Seisakusho Co., Japan) to measure their crushing strength. (See page 124 of Y. Yamaguchi and Y.
Nishimatsu; Introduction of Rock Mechanics, University Press of Tokyo (1967)).
(iii) Disintegration test This was done according to the general test 31 disintegration test of the Japanese Pharmacopoeia, 8th Edition, with exception that in the pre-sent test the attached disk was not used and water was used as a solvent.
The requirement of the Japanese Pharmacopoeia is that the disinteg-ration time of a tablet be not longer than 30 minutes.
(B) Results Tablet L-Ascorbic TroublesHardness Tensile Disinteg-number acid in (kg) strength ration content tabletting 2 (minutes) % (kg/cm ) (1) about 90.9 No 12.2 16.9 5.1 (2) about 92.3 No 16.0 22.2 28.0 (3) about 93.2 No 12.5 17.3 9.7
(4) about 94.1 No 9.6 13.3 4.1
(5) about 97.1 No 9.1 12.6 4.3 not free
(6) about 86.4 following,6.0 8.3 26.0 Sticking
(7) about 87.3 Sticking 5.7 7.9 26.1
(8) about 91.4 Sticking 4.9 6.8 3.3
(9) about 90.5 Sticking, 4.1 5.7 3.5 Lamination
(10) about 93.2 Sticking, 2.8 3.9 0.6 Lamination - From the tests the tablets (1) to (5) in accordance with the inven-tion show for excellent properties in terms of ease of tabletting high tensile strength and hardness, ant can be made to possess satisfactory disintegration times.
. .
. .
Claims (8)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS;
1. A process for producing L-ascorbic acid granules, which comprises spray-coating minus 200-mesh (Tyler) L-ascorbic acid powder with a solution of a pharmaceutically acceptable binder under constant agitation in fluid-ized-bed granulating zone until the the amount of binder coating the powder has reached about 2 to about 4 weight percent relative to the weight of the L-ascorbic acid, and recovering dry, coated L-ascorbic acid granules from said zone.
2. A process according to claim 1, wherein not less than 50 weight per-cent of the L-ascorbic acid is of minus 325-mesh.
3. A process according to claim 1 or 2, wherein the concentration of the binder in the solution is about 1 to about 10 weight percent.
4. A process according to claim 1 or 2, which includes the step of admixing a pharmaceutically acceptable tabletting lubricant with said coated granules, and tabletting the mixture.
5. L-Ascorbic acid granules produced by spray-coating minus 200-mesh L-ascorbic acid powder with a solution of a pharmaceutically acceptable binder under constant agitation in a fluidized-bed granulating zone until the amount of the binder has reached about 2 to about 4 weight percent relative to the weight of the L-ascorbic acid.
6. An L-ascorbic acid tablet prepared essentially from granulated L-ascorbic acid, a pharmaceutically acceptable binder and a tabletting lubri-cant, and having the following characteristics: a) L-ascorbic acid content:
about 100 to about 2000 mg. per tablet and forming about 90 to about 97.1 percent by weight of the tablet; b) binder content: about 2 to about 4 weight percent relative to the weight of the L-ascorbic acid; c) lubricant content: about 1 to about 7 weight percent relative to the weight of the L-ascorbic acid, d) tensile strength: not lower than 12.5 kg/cm2.
about 100 to about 2000 mg. per tablet and forming about 90 to about 97.1 percent by weight of the tablet; b) binder content: about 2 to about 4 weight percent relative to the weight of the L-ascorbic acid; c) lubricant content: about 1 to about 7 weight percent relative to the weight of the L-ascorbic acid, d) tensile strength: not lower than 12.5 kg/cm2.
7. L-Ascorbic acid tablet according to claim 6, wherein the lubricant is a stearate.
8. L-Ascorbic acid tablet according to claim 7, wherein the stearate is magnesium stearate, calcium stearate or stearic acid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP50090742A JPS58403B2 (en) | 1975-07-24 | 1975-07-24 | L- Ascorbine Sanseizaino Seizouhou |
| US05/610,003 US4036948A (en) | 1975-07-24 | 1975-09-03 | L-ascorbic acid tablets |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1054520A true CA1054520A (en) | 1979-05-15 |
Family
ID=26432181
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA249,080A Expired CA1054520A (en) | 1975-07-24 | 1976-03-29 | L-ascorbic acid tablets |
Country Status (8)
| Country | Link |
|---|---|
| CA (1) | CA1054520A (en) |
| DE (1) | DE2616078C2 (en) |
| ES (1) | ES446464A1 (en) |
| FR (1) | FR2318621A1 (en) |
| GB (1) | GB1534066A (en) |
| HK (1) | HK2182A (en) |
| MX (1) | MX3239E (en) |
| NL (1) | NL184308C (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5759803A (en) * | 1980-09-30 | 1982-04-10 | Takeda Chem Ind Ltd | Granule of l-sodium ascorbate, its preparation, and tablet comprising it |
| DE3891219T1 (en) * | 1988-01-22 | 1990-02-01 | Kh Nii Endokrinologii I Chimii | P-CHLORPHENOXYSOBUTTERIC ACID AND DEZYLES AND MEDICINAL PRODUCTS BASED ON THE TREATMENT OF HYPERLIPIDAEMIA |
| US5837292A (en) * | 1996-07-03 | 1998-11-17 | Yamanouchi Europe B.V. | Granulate for the preparation of fast-disintegrating and fast-dissolving compositions containing a high amount of drug |
| JP4098376B2 (en) * | 1996-09-05 | 2008-06-11 | ビーエーエスエフ ソシエタス・ヨーロピア | Water-soluble vitamin composition having excellent tablet characteristics and method for producing the same |
| DE19733094A1 (en) * | 1997-07-31 | 1999-02-04 | Merck Patent Gmbh | Formulation based on ascorbic acid with improved color stability |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3453368A (en) * | 1966-01-13 | 1969-07-01 | Hoffmann La Roche | Smaller high potency compressed tablets of ascorbic acid |
-
1976
- 1976-03-12 NL NL7602657A patent/NL184308C/en not_active IP Right Cessation
- 1976-03-26 GB GB1221176A patent/GB1534066A/en not_active Expired
- 1976-03-29 CA CA249,080A patent/CA1054520A/en not_active Expired
- 1976-03-29 ES ES446464A patent/ES446464A1/en not_active Expired
- 1976-03-29 FR FR7609066A patent/FR2318621A1/en active Granted
- 1976-03-30 MX MX12876U patent/MX3239E/en unknown
- 1976-04-13 DE DE19762616078 patent/DE2616078C2/en not_active Expired
-
1982
- 1982-01-14 HK HK2182A patent/HK2182A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE2616078A1 (en) | 1977-02-10 |
| HK2182A (en) | 1982-01-22 |
| MX3239E (en) | 1980-08-06 |
| ES446464A1 (en) | 1977-10-16 |
| FR2318621B1 (en) | 1979-03-30 |
| NL184308C (en) | 1989-06-16 |
| GB1534066A (en) | 1978-11-29 |
| FR2318621A1 (en) | 1977-02-18 |
| DE2616078C2 (en) | 1985-05-15 |
| NL7602657A (en) | 1977-01-26 |
| NL184308B (en) | 1989-01-16 |
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