CA1150148A - Enterosoluble hard-capsulated medicaments - Google Patents
Enterosoluble hard-capsulated medicamentsInfo
- Publication number
- CA1150148A CA1150148A CA000356189A CA356189A CA1150148A CA 1150148 A CA1150148 A CA 1150148A CA 000356189 A CA000356189 A CA 000356189A CA 356189 A CA356189 A CA 356189A CA 1150148 A CA1150148 A CA 1150148A
- Authority
- CA
- Canada
- Prior art keywords
- enterosoluble
- medicament
- capsule
- weighted
- hard
- 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.)
- Expired
Links
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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/485—Inorganic compounds
Abstract
ABSTRACT OF THE DISCLOSURE
A weighted enterosoluble hard-capsulated medicament having an overall specific gravity of at least 1.05. These medicaments overcome the problems of delay and irregular release of a medicine subsequent to oral administration.
A weighted enterosoluble hard-capsulated medicament having an overall specific gravity of at least 1.05. These medicaments overcome the problems of delay and irregular release of a medicine subsequent to oral administration.
Description
13:1~B
The present invention relates to an improved entero-soluble hard capsule containing a medicament.
As ls generally known an enkerosoluble hard capsule containing a medicament is a capsulated drug form orally administered with the object of releasing the active medicinal ingredient only in the intestinal canal. These enterosoluble capsules and enterosoluble tablets as a class have the advantage of: preventing inactivation of the active ingredient . . .
by the gastric juices; preventing problems of digestion in the stomach; increasing the effective concentration of the active ingredient in the intestinal canal; and extending the ...~, ; effective working time of the active ingredient.
Enterosoluble hard capsules are usually prepared by providing an enterosoluble coating ilm on the surface o~ a hard capsule made of gelatine or the like which hds been sealed after filling with a desired active inqredien-t. The film-forming enterosoluble substances used in the above coating include copolymers of unsaturated carboxylic acids such as copolymers of methacrylic acid, methyl methacrylate, phthalic acid or succinic acid and esters of certain cellulose derivatives such ~ as cellulose acetate phthalate, hydroxypropylmethylcellulose -; phthalate, methylcellulose phthalate, cellulose acetate succinate and the like.
An alternative way for rendering a gela-tine hard capsule enterosoluble is a method in which the outer surface of the gelatine capsule is treated with formalin in order to reduce the solubility of the capsule in the gastric juices.
Both of the above described methods utilize the principle of imparting enteric solubility to the outer surface of an inherently gastrosoluble gelatine hard capsule by a ~ ' secondary trea~lent~ These methods have, accordinyly, several deficiencies no-t only in the complicated process oE the secondary treatn~ent but also in tAe somewhat doubtful effective-ness of the enterosolubility imparted by the trea~ment. For example, an enterosoluble coating Eilm formed on the surface of a gelatine capsule suffers from incomple-te adhesion to the -~ gelatine surface; as well as gradual loss of its enterosolubility with the lapse of time, probably, due to the hydrolysis or other undesirable reaction which the enterosoluble substance ; 10 undergoes with the moisture contained in th gelatine.
... , :
Further, the method of decreasing the solubi:Lity of gelatine by the formalin treatment is a delicate proce~ss so that a desired degree of enterosolubility is obtained with ex-treme difficulty even with a most careful process control.
It has recently been proposed that a hard capsule be formed from a substance which is itself enterosoluble as .
exemplified by the above named copolymers or cellulose deriva-tives for enterosoluble coating films. These capsules, made from an enterosoluble~substance, are promising from a practical standpoint since enterosoluble capsulated medicaments can be prepared by merely filling a capsule with the desired active ingredient without the necessity of the above-identified secondary treatments. However, there are several remaining problems with capsules of this type with respect to the fragility and inflexibility of their shells and the toxicity of additives such as plasticizers usually incorporated in the capsule - forming materials. ~`
Despite the very wide prevalence of administering to patients enterosoluble capswlated medicaments for a therapeu-tic purpose, clinical experience has shown that often ;~
The present invention relates to an improved entero-soluble hard capsule containing a medicament.
As ls generally known an enkerosoluble hard capsule containing a medicament is a capsulated drug form orally administered with the object of releasing the active medicinal ingredient only in the intestinal canal. These enterosoluble capsules and enterosoluble tablets as a class have the advantage of: preventing inactivation of the active ingredient . . .
by the gastric juices; preventing problems of digestion in the stomach; increasing the effective concentration of the active ingredient in the intestinal canal; and extending the ...~, ; effective working time of the active ingredient.
Enterosoluble hard capsules are usually prepared by providing an enterosoluble coating ilm on the surface o~ a hard capsule made of gelatine or the like which hds been sealed after filling with a desired active inqredien-t. The film-forming enterosoluble substances used in the above coating include copolymers of unsaturated carboxylic acids such as copolymers of methacrylic acid, methyl methacrylate, phthalic acid or succinic acid and esters of certain cellulose derivatives such ~ as cellulose acetate phthalate, hydroxypropylmethylcellulose -; phthalate, methylcellulose phthalate, cellulose acetate succinate and the like.
An alternative way for rendering a gela-tine hard capsule enterosoluble is a method in which the outer surface of the gelatine capsule is treated with formalin in order to reduce the solubility of the capsule in the gastric juices.
Both of the above described methods utilize the principle of imparting enteric solubility to the outer surface of an inherently gastrosoluble gelatine hard capsule by a ~ ' secondary trea~lent~ These methods have, accordinyly, several deficiencies no-t only in the complicated process oE the secondary treatn~ent but also in tAe somewhat doubtful effective-ness of the enterosolubility imparted by the trea~ment. For example, an enterosoluble coating Eilm formed on the surface of a gelatine capsule suffers from incomple-te adhesion to the -~ gelatine surface; as well as gradual loss of its enterosolubility with the lapse of time, probably, due to the hydrolysis or other undesirable reaction which the enterosoluble substance ; 10 undergoes with the moisture contained in th gelatine.
... , :
Further, the method of decreasing the solubi:Lity of gelatine by the formalin treatment is a delicate proce~ss so that a desired degree of enterosolubility is obtained with ex-treme difficulty even with a most careful process control.
It has recently been proposed that a hard capsule be formed from a substance which is itself enterosoluble as .
exemplified by the above named copolymers or cellulose deriva-tives for enterosoluble coating films. These capsules, made from an enterosoluble~substance, are promising from a practical standpoint since enterosoluble capsulated medicaments can be prepared by merely filling a capsule with the desired active ingredient without the necessity of the above-identified secondary treatments. However, there are several remaining problems with capsules of this type with respect to the fragility and inflexibility of their shells and the toxicity of additives such as plasticizers usually incorporated in the capsule - forming materials. ~`
Despite the very wide prevalence of administering to patients enterosoluble capswlated medicaments for a therapeu-tic purpose, clinical experience has shown that often ;~
- 2 -: ~, the effectiveness of the active ingredient contained in an enterosoluble hard capsule is unduly or irregularly delayed for an unknown reason so that the expected effect of the medicine for therapy or protection is obtained insufficiently or only with grea-t variation in effectiveness. This undesirable phenomenon of delayed effect appears not only in the case of administration after meal but also in the case of administra-tion before meal.
Accordingly, an object of the invention is to provide ; 10 enterosoluble medicaments which obviate or mitigate the above identified disadvantages of the prior art.
Accordinq to an aspect of the invention there is provided a weighted enterosoluble hard-capsulated medicament having an overall specific gravity of a-t least 1.05.
Embodiments of ~he invention will now be described by way oE example with reference to the accompanying drawings in which:
Figures 1 to 5 are schematic representations of X-ray examinations of the present and prior art enterosoluble capsules in the digestive tract at intervals after administration.
It has been commonly accepted that an enterosoluble hard capsule would be relatively rapidly transferred from the stomach to the intestinal canal. When taken before meal the capsule was expected to be pushed smoothly to the pyloric region and to the intestinal canal by the mass of food taken after administration of the capsule~ When taken after meal the capsule was expected to intermingle with the ingested food and by the digestive process of the stomach be transferred with the food into the intestinal canal. Ilowever, X-ray studies of capsules by means of a contrast medium in the digestive tract have shown :J ` `i, .
that the capsules remain in -the stornach for several hours af-ter administration floating on the mass of ingested food. llhis behaviour is seen whether the capsules are adminis~ered before o:r after meal.
: The above described unexpected behavior of an : enterosoluble capsule in the stomach is s~en regardless of the , materials of the capsule shell prepared by any one of the above-described methods for impar~ing enterosolubility to the capsule.
It has been concluded from the above X-ray studies that the overall specific gravity of the capsulated medicament is the key parameter to ensure rapid and smooth transfer of the capsule from the stomach to ~he intestinal canal. Conventional capsulated medicaments having an overall specific ~ravity not exceeding 0.7-0.8 were always subject to the undesirable phenomenon of floating on the ~ood while test capsules prepared by incorporating a weighting agent, e.g. barium sulfate, were rapidly and smoothly transferred ~.rom the stomach to the intestinal canal~
1'he overall spec1fic gravity of an enterosoluble capsulated medicament should be at least l.05 or, preferably, at least l.l0 in order that the rapid and smooth transfer of the capsule Erom the stomach to the intestinal canal is ensured.
When the administered enterosoluble capsule has an overall specific gravity less than 1.05, floatation of the capsule on the contents of the stomach is unavoidable regardless of whether the administration is before or after meal resulting in a marked delay of transfer to the intestinal canal. On the other hand, the behavior of an enterosoluble capsule having an overall specific gravity of at least 1.05 or, in particular, at least :`~
l.lO is hardly influenced by the contents of the stomach. Such a weighted capsule rapidly sinks to -the boktom of the stomach from where it is smoothly transferred to the intestinal canal through the pyloric region witholl-t being disturbed by the contents o~ the stomach. When the overall specific gravity of an enterosoluble capsule is increased over l~lO, no particular further improvement is obtained in the behavior of the capsule in the stomach and the order of transfer of capsules having various overall specific gravities no longer depends on the overall specific gravity. The time taken ~or the transfer of the ;~ weighted enterosoluble capsules is about the same as conven-tional enterosoluble tablets and several of the capsules have been transferred to the intestinal canal after abou~ 5 hours from administration.
The above-mentioned increased overall specific gravity of an enterosoluble capsulated medicament is readily ohtained by use of a weighting agent. Suitable weighting agents include barium sulfate, calcium dihydrogerlphosphate; iron oxide, titanium dioxide, calcium sulfate, pIatinum and the lilce which 2Q not only provide sufficient weight but are also physiologically inert and non~reactive with the active ingredient contained in the capsule. It is, of course, optional to use two or more types of these weighting agents in combination. Among the above named weigh-ting agents, the most preferred weighting agent is barium sulfate. These weighting agents are most conveniently incorporated into the capsule together with the active ingredient and other additives but it is optional that they are admixed in advance with the gelatine or other capsule materials before shaping into capsule shells, provided that the admixture of the weighting agents has no adverse effect on the moldability of the capsule material.
.
; .
~:~5~4~
When the weighting agent is incorporated into -the capsule together with the other inyredients, the blend can be in the form of a powder or in the form of a suspension or paste by use of a suitable suspension medium or an oily base. Oily bases suitable for this purpose are exemplified by liquid oils such as sesame oil, olive oil, soybean oil, rapeseed oil, cottonseed oil, ~inseed oil, castor oilt rice-bran oil, camellia oil, coconut oil, peanut oil, corn oil, poppy oil and the like as well as those fats which are solid at room temperature but melt at 37C or higher such as cacao butter, cinnamon butter, laurin, beef tallow, hog fat, wool fat and the like. Further, the produc~s obtalned from the above oils and fats by hydrogena-tion, carboxylic acid exchange or acetylation splitting are also suitable and esters of glycerine with a carboxylic acid having from 6 to 30 carbon atoms per molecuie such as glycerine palmitate, glyceîine stearate, glycerine myristate and the like may be used. In addition to these oily bases, glycerine and sugar syrup can be used as the base according to the nature of the active ingredient.
It is further optional that the capsules contain, according to need, various~other conventional addltives such as water-soluble additives. e.g. hydroxypropylcellulose of a low degree of substitution, carboxymethylcellulose, carboxymethyl-starch, lecithine, polyethyleneglycol, Po]ysolvate 80 and the like: thickeners or thioxotropy-imparting agents, e.g. colloidal silica, aluminum stearate and the like; and surface active agents. Approximate ratios of the oily base and the weighting agent to the active ingredient are 1.5 to lS times by weight and up to 15 times by weight, respectively.
~; 30 The amount of the weighting agent, e.g., barium sulfate, to be incorporate~ in-to a capsule is readily calculated from the volume of -the capsule, weight of the capsule, amount of ingredients contained in the capsule other than the weightiny agent and the desired overall specific gravity. ~ssuming that a ~0 ca~sule haviny a weight of 120 mg ancl a volume of 1.0 ml or 1,000 ~1 is used to contain 250 mg of an active ingredient,e.g.
aspirin, and the desired overall specific gravity of the weighted capsule is 1.10, then the amount of barium sulfate to be incorporated into the capsule is (1,000 x 1.10) - (120 + 250) -= 730 mg.
When the effective volume of a #0 capsule, ~hich has ordinarily a volume of 1.0 ml, can be reduced by some means, the amount of the weighting ~gent can accordingly be reduced.
For example, the normally hemispherical cap ends of a capsule shell are flattened so that the effective volume of the capsule is reduced to 0.8 ml, then the necessary amount o F the weightlng agent would be, the other parameters being the same as above, (800 x 1.10) - (120 ~ 250) = 510 rng. Tabulation of the necessary amounts of the weighting agent with varying parameters as shown in Tables 1 and 2 can be obtained by similar calculations.
Further calculations were undertaken to obtain results for ternary suspensions composed of aspirin, sesame oil and barium sulfate -to just fill the effective volume of a capsule from the true densities of these components. The calculated results of the amounts of sesame oil and ba~ium sulfate in mg are shown in Tables 3 to 6, of which Table 3 is for a #0 capsule containing 250 mg of aspirin with varying effective volumes, Table 4 is for a #0 capsule containing 50 mg of aspirin with varying effective volumes, Table 5 is for #1 and #2 . ,. ~.,,'~, ~, capsules containing 250 mg o~ aspirin and Table 6 is for #l and : #2 capsules containinq 50 mg of aspirin.
TABLE
.~ Amount of weighting agent, mq, wi-th 250 mg of the base ingredient.
. ~_ _ . ... .A .... ., ..
Size of capsule #0 #1 #2 : _eiqht, mg) (] 20) (92)(78) : Effective volume, (ml) 1.0 0.9 0.8 0.72 0.60 0.44 __ _ __ __ _ ____ 0.90 530 440350 278 117 23 1.00 630 530430 350 168 62 Overall 1.10 730620 510 422 219 101 specific 1l20 _ 710 590 494 270 140 ;: gravity 1.30 _ 800 670 566 321 179 1.~0 _ _ 750 63~ 372 218 _ .1.50 _ _ _ 710 ~ 423 _ :
.';
Amount of weighting agent, mg, with 50 mg of the base ingredient~
~' -: -- ...
..Size of capsule #0 #1 #2 :
20(weiqht, mq) (120) (92)(78) _ _ _ _ _ ; Effective volume, (ml) 1.00.9 0.8 0.72 0.6 _0.44 ;: 0.90 730640 550 478 317 223 ; 1.00 830730 630 550 367 262 : Overall 1.10930820 710 6~2 419 301 Specific 1.201030910 790 694 470 340 Gravity 1.3011301000 870 766 521 379 1.40 _1090 950 838 572 418 _ 1.50 - _ 1030 910 623 _ .~
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Accordingly, an object of the invention is to provide ; 10 enterosoluble medicaments which obviate or mitigate the above identified disadvantages of the prior art.
Accordinq to an aspect of the invention there is provided a weighted enterosoluble hard-capsulated medicament having an overall specific gravity of a-t least 1.05.
Embodiments of ~he invention will now be described by way oE example with reference to the accompanying drawings in which:
Figures 1 to 5 are schematic representations of X-ray examinations of the present and prior art enterosoluble capsules in the digestive tract at intervals after administration.
It has been commonly accepted that an enterosoluble hard capsule would be relatively rapidly transferred from the stomach to the intestinal canal. When taken before meal the capsule was expected to be pushed smoothly to the pyloric region and to the intestinal canal by the mass of food taken after administration of the capsule~ When taken after meal the capsule was expected to intermingle with the ingested food and by the digestive process of the stomach be transferred with the food into the intestinal canal. Ilowever, X-ray studies of capsules by means of a contrast medium in the digestive tract have shown :J ` `i, .
that the capsules remain in -the stornach for several hours af-ter administration floating on the mass of ingested food. llhis behaviour is seen whether the capsules are adminis~ered before o:r after meal.
: The above described unexpected behavior of an : enterosoluble capsule in the stomach is s~en regardless of the , materials of the capsule shell prepared by any one of the above-described methods for impar~ing enterosolubility to the capsule.
It has been concluded from the above X-ray studies that the overall specific gravity of the capsulated medicament is the key parameter to ensure rapid and smooth transfer of the capsule from the stomach to ~he intestinal canal. Conventional capsulated medicaments having an overall specific ~ravity not exceeding 0.7-0.8 were always subject to the undesirable phenomenon of floating on the ~ood while test capsules prepared by incorporating a weighting agent, e.g. barium sulfate, were rapidly and smoothly transferred ~.rom the stomach to the intestinal canal~
1'he overall spec1fic gravity of an enterosoluble capsulated medicament should be at least l.05 or, preferably, at least l.l0 in order that the rapid and smooth transfer of the capsule Erom the stomach to the intestinal canal is ensured.
When the administered enterosoluble capsule has an overall specific gravity less than 1.05, floatation of the capsule on the contents of the stomach is unavoidable regardless of whether the administration is before or after meal resulting in a marked delay of transfer to the intestinal canal. On the other hand, the behavior of an enterosoluble capsule having an overall specific gravity of at least 1.05 or, in particular, at least :`~
l.lO is hardly influenced by the contents of the stomach. Such a weighted capsule rapidly sinks to -the boktom of the stomach from where it is smoothly transferred to the intestinal canal through the pyloric region witholl-t being disturbed by the contents o~ the stomach. When the overall specific gravity of an enterosoluble capsule is increased over l~lO, no particular further improvement is obtained in the behavior of the capsule in the stomach and the order of transfer of capsules having various overall specific gravities no longer depends on the overall specific gravity. The time taken ~or the transfer of the ;~ weighted enterosoluble capsules is about the same as conven-tional enterosoluble tablets and several of the capsules have been transferred to the intestinal canal after abou~ 5 hours from administration.
The above-mentioned increased overall specific gravity of an enterosoluble capsulated medicament is readily ohtained by use of a weighting agent. Suitable weighting agents include barium sulfate, calcium dihydrogerlphosphate; iron oxide, titanium dioxide, calcium sulfate, pIatinum and the lilce which 2Q not only provide sufficient weight but are also physiologically inert and non~reactive with the active ingredient contained in the capsule. It is, of course, optional to use two or more types of these weighting agents in combination. Among the above named weigh-ting agents, the most preferred weighting agent is barium sulfate. These weighting agents are most conveniently incorporated into the capsule together with the active ingredient and other additives but it is optional that they are admixed in advance with the gelatine or other capsule materials before shaping into capsule shells, provided that the admixture of the weighting agents has no adverse effect on the moldability of the capsule material.
.
; .
~:~5~4~
When the weighting agent is incorporated into -the capsule together with the other inyredients, the blend can be in the form of a powder or in the form of a suspension or paste by use of a suitable suspension medium or an oily base. Oily bases suitable for this purpose are exemplified by liquid oils such as sesame oil, olive oil, soybean oil, rapeseed oil, cottonseed oil, ~inseed oil, castor oilt rice-bran oil, camellia oil, coconut oil, peanut oil, corn oil, poppy oil and the like as well as those fats which are solid at room temperature but melt at 37C or higher such as cacao butter, cinnamon butter, laurin, beef tallow, hog fat, wool fat and the like. Further, the produc~s obtalned from the above oils and fats by hydrogena-tion, carboxylic acid exchange or acetylation splitting are also suitable and esters of glycerine with a carboxylic acid having from 6 to 30 carbon atoms per molecuie such as glycerine palmitate, glyceîine stearate, glycerine myristate and the like may be used. In addition to these oily bases, glycerine and sugar syrup can be used as the base according to the nature of the active ingredient.
It is further optional that the capsules contain, according to need, various~other conventional addltives such as water-soluble additives. e.g. hydroxypropylcellulose of a low degree of substitution, carboxymethylcellulose, carboxymethyl-starch, lecithine, polyethyleneglycol, Po]ysolvate 80 and the like: thickeners or thioxotropy-imparting agents, e.g. colloidal silica, aluminum stearate and the like; and surface active agents. Approximate ratios of the oily base and the weighting agent to the active ingredient are 1.5 to lS times by weight and up to 15 times by weight, respectively.
~; 30 The amount of the weighting agent, e.g., barium sulfate, to be incorporate~ in-to a capsule is readily calculated from the volume of -the capsule, weight of the capsule, amount of ingredients contained in the capsule other than the weightiny agent and the desired overall specific gravity. ~ssuming that a ~0 ca~sule haviny a weight of 120 mg ancl a volume of 1.0 ml or 1,000 ~1 is used to contain 250 mg of an active ingredient,e.g.
aspirin, and the desired overall specific gravity of the weighted capsule is 1.10, then the amount of barium sulfate to be incorporated into the capsule is (1,000 x 1.10) - (120 + 250) -= 730 mg.
When the effective volume of a #0 capsule, ~hich has ordinarily a volume of 1.0 ml, can be reduced by some means, the amount of the weighting ~gent can accordingly be reduced.
For example, the normally hemispherical cap ends of a capsule shell are flattened so that the effective volume of the capsule is reduced to 0.8 ml, then the necessary amount o F the weightlng agent would be, the other parameters being the same as above, (800 x 1.10) - (120 ~ 250) = 510 rng. Tabulation of the necessary amounts of the weighting agent with varying parameters as shown in Tables 1 and 2 can be obtained by similar calculations.
Further calculations were undertaken to obtain results for ternary suspensions composed of aspirin, sesame oil and barium sulfate -to just fill the effective volume of a capsule from the true densities of these components. The calculated results of the amounts of sesame oil and ba~ium sulfate in mg are shown in Tables 3 to 6, of which Table 3 is for a #0 capsule containing 250 mg of aspirin with varying effective volumes, Table 4 is for a #0 capsule containing 50 mg of aspirin with varying effective volumes, Table 5 is for #1 and #2 . ,. ~.,,'~, ~, capsules containing 250 mg o~ aspirin and Table 6 is for #l and : #2 capsules containinq 50 mg of aspirin.
TABLE
.~ Amount of weighting agent, mq, wi-th 250 mg of the base ingredient.
. ~_ _ . ... .A .... ., ..
Size of capsule #0 #1 #2 : _eiqht, mg) (] 20) (92)(78) : Effective volume, (ml) 1.0 0.9 0.8 0.72 0.60 0.44 __ _ __ __ _ ____ 0.90 530 440350 278 117 23 1.00 630 530430 350 168 62 Overall 1.10 730620 510 422 219 101 specific 1l20 _ 710 590 494 270 140 ;: gravity 1.30 _ 800 670 566 321 179 1.~0 _ _ 750 63~ 372 218 _ .1.50 _ _ _ 710 ~ 423 _ :
.';
Amount of weighting agent, mg, with 50 mg of the base ingredient~
~' -: -- ...
..Size of capsule #0 #1 #2 :
20(weiqht, mq) (120) (92)(78) _ _ _ _ _ ; Effective volume, (ml) 1.00.9 0.8 0.72 0.6 _0.44 ;: 0.90 730640 550 478 317 223 ; 1.00 830730 630 550 367 262 : Overall 1.10930820 710 6~2 419 301 Specific 1.201030910 790 694 470 340 Gravity 1.3011301000 870 766 521 379 1.40 _1090 950 838 572 418 _ 1.50 - _ 1030 910 623 _ .~
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:, O ~ ,~ Ln ~D
"~ Ln m ~. ~ ~ ~ a~ . _ .
a) O ~ 1- Ln ~ a~
U~ ~I L~ r ~ o r~
uo ~ O ~o Ln Ln Ln Ln Ln~r ', : a) ~ _ .
v O O 0~ ~ o ~ a~
U~ rr~ g oo ~d ~ tY ~ Ln ~ co Q Pq .~ . .
,_i _,, _ -;~ 3 ~
ao U~-rl al o Ln Ln Ln Ln _ _ _ . ,, o o o o o o o ; ~ o~ o ,~ ~ ~ ~ Ln ~ o ,~.
o .
'~, .~ ~
v ~ a) u ~
: ~, .~ ~ .
:- ~
, -- 10 --~,
4~3 TAsLE 5 ~nounts of sesame oil and barium sulfate, mg, in capsules with 250 nlg of aspirin.
_ ___~ . ......
Size ~f Capsule #1 ~2 . .~ ..... ~ , .. _ rngredient SesameBaSO4 8esame BaSO4 1.10 290 28 __ _ _ _ .
~verall 1.20 275 103 183 17 Specific 1.30 260 17S 172 72 ;.ravity 1.40 244 255 161 126 1.50 229 330 150 181 :~ _ _ . .. , .. , : ~ TABLE 6 ~mounts of sesame oil and barium sulfate, my, in capsules with 50 mg of aspirin.
~ . .
Size of capsule #1 ~2 _ . __ , . . . , .. ~ . _ ~ngredient Sesame BaSO4 Sesame BaSO,l nr~ _ _ _ _ _ ~_ _ ~ - ~ A.__. .. _ ._ _.. _ _ . 1.00 424 34 _ ~~
Overall 1.10 409 109 312 44 Speci~ic 1.20 393 184 301 99 Gravity 1.30 378 260 290 154 . 1.40 362 33a 279 209 1.50 3~7 413 _ 268 263 : .
~3~8 Bas~d on the above calcula-tions~ several enterosoluble capsules were prepared and their overall specific gravities were de-termined as described below.
Preparation of weighted en-terosoluble capsules:
. ~P~
The overall specific gravity of an enterosoluble capsule, #0 size~ filled with a uniform mixture of 250 mg of aspirin and 730 mg of barium was 1.10.
Preparation 2 A dispersion was prepared by dispersing 50 g of aspirin and 38.8 g of barium sulfate in 54.2 g oE sesame oil and an enterosoluble capsule, #0 size, was filled with 980 mg of the suspension. The overall specific gravity of the capsule was 1 ~ 10 .
;
-" Preparation 3 ~ A suspension was prepared by dispersing 5 ~ of , ;~ aspirin and 11 g of barium sulfate in 41 g o~ sesame oil and an enterosoluble capsule, #1 size, was filled with 750 mg of the suspension containing S0 mg of aspirin. The overall specific gravity of the capsule was about 1.10.
Preparation 4 A paste was prepared by kneading 25 g of aspirin and 56 g of barium sulfate with 37 g of sesame oil and an enterosoluble capsule, #0 size, was filled with 1,180 mg of the ; paste containing 250 mg of aspirin. The overall specific gravity of the capsule was about 1.30.
Preparation 5 suspension was prepared by dispersing 12.5 g of aspirin, 2.7 g of aluminum stearate and 21.8 g of barium sulfate .
, ~,` 1 ~iD~ 8 in 17 g of ses~me oil and an enterosoluble capsule, ~0 size, was filled with 1,080 mg of the suspension containing 250 mg of aspirin. The overall specific gravity of the capsulP was about 1.20O
Preparation 6 A suspension was prepar~d by dispersing 12.5 g of aspirin and 2.0 g of aluminum stearate in 5.8 g of sesame oil and an enterosoluble capsule, #2 size, was filled with 405 mg of the suspension containing 250 mg of aspirin. The overall specific gravity of the capsule was about 1.10.
The following examples illustrate the behavior of ; weighted enterosoluhle capsules in the digestive tract as -traced by X-ray examination. The results of the tests including ~ several comparative tests are shown schematically in Figs. 1 to .~
_ ___~ . ......
Size ~f Capsule #1 ~2 . .~ ..... ~ , .. _ rngredient SesameBaSO4 8esame BaSO4 1.10 290 28 __ _ _ _ .
~verall 1.20 275 103 183 17 Specific 1.30 260 17S 172 72 ;.ravity 1.40 244 255 161 126 1.50 229 330 150 181 :~ _ _ . .. , .. , : ~ TABLE 6 ~mounts of sesame oil and barium sulfate, my, in capsules with 50 mg of aspirin.
~ . .
Size of capsule #1 ~2 _ . __ , . . . , .. ~ . _ ~ngredient Sesame BaSO4 Sesame BaSO,l nr~ _ _ _ _ _ ~_ _ ~ - ~ A.__. .. _ ._ _.. _ _ . 1.00 424 34 _ ~~
Overall 1.10 409 109 312 44 Speci~ic 1.20 393 184 301 99 Gravity 1.30 378 260 290 154 . 1.40 362 33a 279 209 1.50 3~7 413 _ 268 263 : .
~3~8 Bas~d on the above calcula-tions~ several enterosoluble capsules were prepared and their overall specific gravities were de-termined as described below.
Preparation of weighted en-terosoluble capsules:
. ~P~
The overall specific gravity of an enterosoluble capsule, #0 size~ filled with a uniform mixture of 250 mg of aspirin and 730 mg of barium was 1.10.
Preparation 2 A dispersion was prepared by dispersing 50 g of aspirin and 38.8 g of barium sulfate in 54.2 g oE sesame oil and an enterosoluble capsule, #0 size, was filled with 980 mg of the suspension. The overall specific gravity of the capsule was 1 ~ 10 .
;
-" Preparation 3 ~ A suspension was prepared by dispersing 5 ~ of , ;~ aspirin and 11 g of barium sulfate in 41 g o~ sesame oil and an enterosoluble capsule, #1 size, was filled with 750 mg of the suspension containing S0 mg of aspirin. The overall specific gravity of the capsule was about 1.10.
Preparation 4 A paste was prepared by kneading 25 g of aspirin and 56 g of barium sulfate with 37 g of sesame oil and an enterosoluble capsule, #0 size, was filled with 1,180 mg of the ; paste containing 250 mg of aspirin. The overall specific gravity of the capsule was about 1.30.
Preparation 5 suspension was prepared by dispersing 12.5 g of aspirin, 2.7 g of aluminum stearate and 21.8 g of barium sulfate .
, ~,` 1 ~iD~ 8 in 17 g of ses~me oil and an enterosoluble capsule, ~0 size, was filled with 1,080 mg of the suspension containing 250 mg of aspirin. The overall specific gravity of the capsulP was about 1.20O
Preparation 6 A suspension was prepar~d by dispersing 12.5 g of aspirin and 2.0 g of aluminum stearate in 5.8 g of sesame oil and an enterosoluble capsule, #2 size, was filled with 405 mg of the suspension containing 250 mg of aspirin. The overall specific gravity of the capsule was about 1.10.
The following examples illustrate the behavior of ; weighted enterosoluhle capsules in the digestive tract as -traced by X-ray examination. The results of the tests including ~ several comparative tests are shown schematically in Figs. 1 to .~
5.
.:
EXA~LE 1 .: -~- Enterosoluble hard capsules, #0 size, were prepared from an enterosoluble cellulose derivative which was a mixed ~ .
acidic succinyl and aliphatic monoacyl ester of an alkyl- and hydroxyaLkyl-substituted cellulose ether and the overall :
specific gravity o the sealed capsules were adjusted to 0~75 ; by incorporating a su1table amount of barium sulfate thereinto.
Four healthy subjects, all male and adult, with empty stomachs were each administered 4 of the above capsules together with 70 ml of water and the behavior of the caysules was recorded by means of X-ray examination to give results as illustrated in Fig 1. As is clear from the Figure, all of the capsules had been transferred to the intestinal canal within 1 hour in all of the subjects.
~' .,~ .~ i , .
Enterosoluble capsules having overall specific gravities of 0.75 and 1.25, respectively, were prepared in the same manner as in Example 1 and a subject was administered two ;~ each of these capsules with 70 ml of water 30 minutes after an ordinary meal.
As is illustrated in Fig. 2, the capsules having an overall specific gravity of 0.75 floated on the mass of ingested food and remained there for at least 5 hours after administra-tlon. On the other hand, the heavier capsules had passedthrough the ingested food within 1 hour after admlnistration and had sunk to the bottom of the stomach from where they reached the intestinal canal within 3 to 4 hours where they disintegrated.
. ~ --~ hree subjects with empty stomachs were admini~tered four capsules as used in Example ~ with 70 ml of water lO
rninutes before an ordinary meal.
Despite administration before meal, the lighter capsules having an overall specific gravity of 0.75 passed upwardly through the ingested food and were floating, by 30 minutes after administration, in the upper part of the stomach where they still remained after S hours from administration as is shown in Fig~ 3. On the other hand, the heavier capsules having an overall specific gravity of 1.25 rapidly san}c to the bottom of the stomach from where they were smoothly transferred to the intestinal canal within 5 hours after administration in all of the subjects as also illustrated in Fig. 3.
:: .
~ - 14 -I~o subjects were each administered three weighted capsules wi~h 70 ml of water 30 minutes after an ordinary meal.
The capsules wi-th which the subject ~I.Y. was administered had ~ overall specific graviti,es of 1.00, 1.10 and 1.20, respectively, '~ while the capsules with which the subject Y.D. was adminis-tered had overall specific gravities of 1.00, 1.05 and 1.20, .' ~ respectively.
As is illustrated in Fig. 4, the lightest capsule 10 administered to the subject H.Y. floated in the upper part of :
the stomach where it still remained 3 hours after administration while the two heavier capsules rapidly reached the bottom of the stomach from where they were smoothly transferred to the ~ intestinal canal.
,.-, In the subject Y.D. r the l.i~htest capsule still remained in the uppe~ part of the stomach 3 hours after administration while the two heavier capsules duly reached the bottom oE the stomach.
.
Two subjects were each administered three entero-soluble capsules having overall specific gravities of 1.10, 1~20 and 1.30, respectively, and two enterosoluble tablets having a specific gravity oE 1.42 together with 70 ml of water 30 minutes after an ordinary meal. As is illustrated in Fig. 5, all of the capsules, having overall specific gravities of at least 1.10, rapidly reached the bottom of the stomach and several of them had been transferred to the intestinal canal 5 hours after administration. No. correlation between the order of transfer and the specific gravities was noted. Further, the 30 behavior of the capsules was almost identical to that of the enterosoluble tablets administered at the same time.
.:
EXA~LE 1 .: -~- Enterosoluble hard capsules, #0 size, were prepared from an enterosoluble cellulose derivative which was a mixed ~ .
acidic succinyl and aliphatic monoacyl ester of an alkyl- and hydroxyaLkyl-substituted cellulose ether and the overall :
specific gravity o the sealed capsules were adjusted to 0~75 ; by incorporating a su1table amount of barium sulfate thereinto.
Four healthy subjects, all male and adult, with empty stomachs were each administered 4 of the above capsules together with 70 ml of water and the behavior of the caysules was recorded by means of X-ray examination to give results as illustrated in Fig 1. As is clear from the Figure, all of the capsules had been transferred to the intestinal canal within 1 hour in all of the subjects.
~' .,~ .~ i , .
Enterosoluble capsules having overall specific gravities of 0.75 and 1.25, respectively, were prepared in the same manner as in Example 1 and a subject was administered two ;~ each of these capsules with 70 ml of water 30 minutes after an ordinary meal.
As is illustrated in Fig. 2, the capsules having an overall specific gravity of 0.75 floated on the mass of ingested food and remained there for at least 5 hours after administra-tlon. On the other hand, the heavier capsules had passedthrough the ingested food within 1 hour after admlnistration and had sunk to the bottom of the stomach from where they reached the intestinal canal within 3 to 4 hours where they disintegrated.
. ~ --~ hree subjects with empty stomachs were admini~tered four capsules as used in Example ~ with 70 ml of water lO
rninutes before an ordinary meal.
Despite administration before meal, the lighter capsules having an overall specific gravity of 0.75 passed upwardly through the ingested food and were floating, by 30 minutes after administration, in the upper part of the stomach where they still remained after S hours from administration as is shown in Fig~ 3. On the other hand, the heavier capsules having an overall specific gravity of 1.25 rapidly san}c to the bottom of the stomach from where they were smoothly transferred to the intestinal canal within 5 hours after administration in all of the subjects as also illustrated in Fig. 3.
:: .
~ - 14 -I~o subjects were each administered three weighted capsules wi~h 70 ml of water 30 minutes after an ordinary meal.
The capsules wi-th which the subject ~I.Y. was administered had ~ overall specific graviti,es of 1.00, 1.10 and 1.20, respectively, '~ while the capsules with which the subject Y.D. was adminis-tered had overall specific gravities of 1.00, 1.05 and 1.20, .' ~ respectively.
As is illustrated in Fig. 4, the lightest capsule 10 administered to the subject H.Y. floated in the upper part of :
the stomach where it still remained 3 hours after administration while the two heavier capsules rapidly reached the bottom of the stomach from where they were smoothly transferred to the ~ intestinal canal.
,.-, In the subject Y.D. r the l.i~htest capsule still remained in the uppe~ part of the stomach 3 hours after administration while the two heavier capsules duly reached the bottom oE the stomach.
.
Two subjects were each administered three entero-soluble capsules having overall specific gravities of 1.10, 1~20 and 1.30, respectively, and two enterosoluble tablets having a specific gravity oE 1.42 together with 70 ml of water 30 minutes after an ordinary meal. As is illustrated in Fig. 5, all of the capsules, having overall specific gravities of at least 1.10, rapidly reached the bottom of the stomach and several of them had been transferred to the intestinal canal 5 hours after administration. No. correlation between the order of transfer and the specific gravities was noted. Further, the 30 behavior of the capsules was almost identical to that of the enterosoluble tablets administered at the same time.
Claims (9)
1. A weighted enterosoluble hard-capsulated medicament having an overall specific gravity of at least 1.05.
2. A weighted enterosoluble hard-capsulated medicament as defined in claim 1 having an overall specific gravity of at least 1.10.
3. A weighted enterosoluble hard-capsulated medicament as defined in claim 1, wherein the weighting agent is barium sulfate.
4. A weighted enterosoluble hard-capsulated medicament as defined in claim 1, wherein the weighting agent is selected from the group consisting of: barium sulfate, calcium dihydrogen-phosphate, iron oxide, titanium dioxide calcium sulfate, platinum and mixtures thereof.
5. A weighted enterosoluble hard-capsulated medicament as defined in claim 3 or 4, wherein said weighting agent is blended with the active ingredient of said medicament.
6. A weighted enterosoluble hard-capsulated medicament as defined in claim 3 or 4, wherein said weighting agent is contained in the capsule of said medicament.
7. An enterosoluble hard-encapsulated medicament which is weighted with a weighting agent so that the entire encapsulated medicament possesses an overall specific gravity of at least 1.05 and wherein the medicament is a suspension of the effective ingredient in an oily base.
8. The medicament of claim 7 wherein the oily base is sesame oil.
9. A barium sulfate weighted enterosoluble mixed acidic succinyl and aliphatic monoacyl ester of an alkyl and hydroxyalkyl substituted cellulose ether coated and sealed hard gelatin telescoping two-piece capsule shell-encapsulated medicament suspended in sesame oil and having the usual semi-spherical cap ends of the capsule shells flattened so that the effective volume of the capsule is reduced, and being weighted with barium sulfate either in the capsule shell or in the capsule fill and having an overall specific gravity of at least 1.05.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP54-108447 | 1979-08-24 | ||
| JP54108447A JPS6024767B2 (en) | 1979-08-24 | 1979-08-24 | enteric-coated hard capsules |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1150148A true CA1150148A (en) | 1983-07-19 |
Family
ID=14485005
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000356189A Expired CA1150148A (en) | 1979-08-24 | 1980-07-15 | Enterosoluble hard-capsulated medicaments |
Country Status (5)
| Country | Link |
|---|---|
| US (2) | US4339463A (en) |
| JP (1) | JPS6024767B2 (en) |
| AU (1) | AU533394B2 (en) |
| CA (1) | CA1150148A (en) |
| IT (1) | IT1132195B (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6024767B2 (en) * | 1979-08-24 | 1985-06-14 | 塩野義製薬株式会社 | enteric-coated hard capsules |
| JPS57140710A (en) * | 1981-02-24 | 1982-08-31 | Shionogi & Co Ltd | Capsule agent for rectal administration |
| DE3431861A1 (en) * | 1984-08-30 | 1986-03-13 | Troponwerke GmbH & Co KG, 5000 Köln | PELLET PREPARATION |
| GB8507779D0 (en) * | 1985-03-26 | 1985-05-01 | Fujisawa Pharmaceutical Co | Drug carrier |
| EP0198769A3 (en) * | 1985-04-12 | 1987-09-02 | Forest Laboratories, Inc. | Floating sustained release therapeutic compositions |
| ES2038669T3 (en) * | 1986-09-18 | 1993-08-01 | London School Of Pharmacy Innovations Ltd | PHARMACEUTICAL FORMULATION. |
| US11548940B2 (en) | 2014-05-15 | 2023-01-10 | Rani Therapeutics, Llc | Anti-interleukin antibody preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
| JP6588193B2 (en) * | 2014-07-31 | 2019-10-09 | カプスゲル・ベルギウム・ナムローゼ・フェンノートシャップＣａｐｓｕｇｅｌ Ｂｅｌｇｉｕｍ ＮＶ | Capsule formulation |
| EP3181125A4 (en) * | 2014-07-31 | 2018-01-17 | Capsugel Belgium NV | Capsule formulation |
| AU2016261599B2 (en) * | 2015-05-08 | 2021-08-26 | Rani Therapeutics, Llc | Anti-interleukin antibody preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
| CN113398087B (en) * | 2021-06-17 | 2022-06-14 | 北京斯利安药业有限公司 | Iron protein succinate enteric-coated capsule and preparation method thereof |
Family Cites Families (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2349430A (en) * | 1941-05-15 | 1944-05-23 | Eastman Kodak Co | Medical capsule |
| US2491475A (en) * | 1946-03-25 | 1949-12-20 | Parke Davis & Co | Enteric capsule |
| US2801203A (en) * | 1951-03-22 | 1957-07-30 | Byk Gulden Lomberg Chem Fab | X-ray method of digestive enzyme diagnosis using protected core of contrast agent |
| US2718667A (en) * | 1952-05-01 | 1955-09-27 | Eastman Kodak Co | Method of preparing enteric capsules |
| BE562124A (en) * | 1956-11-05 | |||
| US3017329A (en) * | 1957-08-15 | 1962-01-16 | Dow Chemical Co | Method of locating enteric constrictions with a plurality of pills containing an x-ray contrast agent |
| GB1093286A (en) * | 1965-02-15 | 1967-11-29 | Biorex Laboratories Ltd | Improvements in or relating to dosage unit forms for the administration of medicaments and diagnostic agents |
| US3341417A (en) * | 1965-07-14 | 1967-09-12 | Edwin S Sinaiko | Method of and means for diagnosis of ingested drugs with radio-opaque and other indicators |
| US3535419A (en) * | 1965-12-15 | 1970-10-20 | Syntex Corp | Veterinary compositions and methods |
| US3574820A (en) * | 1968-01-08 | 1971-04-13 | Upjohn Co | Medicinal dosage forms of unpolymerized thiolated gelatin with a cross-linking accelerating agent providing slowly released medication from a swollen matrix |
| US3507952A (en) * | 1968-12-20 | 1970-04-21 | Smithkline Corp | Sustained release bolus for animal husbandry |
| YU36434B (en) * | 1969-05-14 | 1984-02-29 | Sanol Arznei Schwarz Gmbh | Process for obtaining gelation capsules filled with the active substance resistant to gastric juice and dissolvable in the small intestine |
| US3823228A (en) * | 1971-09-29 | 1974-07-09 | Univ Illinois | Tge virus vaccine |
| US3927195A (en) * | 1974-01-31 | 1975-12-16 | Lilly Industries Ltd | Production of capsules |
| JPS5512411B2 (en) * | 1974-03-12 | 1980-04-02 | ||
| US4126672A (en) * | 1976-02-04 | 1978-11-21 | Hoffmann-La Roche Inc. | Sustained release pharmaceutical capsules |
| US4138013A (en) * | 1976-08-27 | 1979-02-06 | Parke, Davis & Company | Enteric capsules |
| GB1576376A (en) * | 1977-03-30 | 1980-10-08 | Benzon As Alfred | Multiple-unit drug dose |
| US4365060A (en) * | 1979-04-28 | 1982-12-21 | Shin-Etsu Chemical Co. Ltd. | Enterosoluble capsules |
| JPS6024767B2 (en) * | 1979-08-24 | 1985-06-14 | 塩野義製薬株式会社 | enteric-coated hard capsules |
-
1979
- 1979-08-24 JP JP54108447A patent/JPS6024767B2/en not_active Expired
-
1980
- 1980-07-15 IT IT23445/80A patent/IT1132195B/en active
- 1980-07-15 CA CA000356189A patent/CA1150148A/en not_active Expired
- 1980-07-16 US US06/169,395 patent/US4339463A/en not_active Expired - Lifetime
- 1980-07-18 AU AU60612/80A patent/AU533394B2/en not_active Ceased
-
1982
- 1982-04-28 US US06/372,791 patent/US4397835A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| IT8023445A0 (en) | 1980-07-15 |
| IT1132195B (en) | 1986-06-25 |
| JPS5632413A (en) | 1981-04-01 |
| JPS6024767B2 (en) | 1985-06-14 |
| US4339463A (en) | 1982-07-13 |
| US4397835A (en) | 1983-08-09 |
| AU533394B2 (en) | 1983-11-24 |
| AU6061280A (en) | 1981-02-26 |
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| MKEX | Expiry |