`[11]
`4,365,060
`Onda et a1.
`[45]
`* Dec. 21, 1932
`
`
`[19]
`
`_
`[73] Assignee;
`
`[ * ] Notice:
`
`[58] Field of Search ........
`
`[54] ENTEROSOLUBLE CAPSULES
`_
`_
`.
`_
`1“V‘’J“°rs= vY°sh“'° 011435 Himakl Mum;
`175]
`*
`1
`Kazumasa Maruyama, all of Joetsu,
`Japan
`‘
`‘
`shin.Etsu Chemical Co_ Ltd.’ Tokyo, 6
`Japan
`1
`t
`_
`The portion of the term of this patent
`. subsequent to Oct 7, 1997’ has been
`disC1aiiii¢d-
`[21] APP1-N0-3 140,473
`[22] Filed;
`Am-_ 15’ 1930
`7
`6
`I301
`Foieieii Avviicaiien Priority Data
`Apr. 28, 1979 [JP]
`Japan ................................ .. 54-52914
`Aug. 27, 1979 [JP]
`Japan .............................. .. 54408888
`[51]
`Int. Cl.3 ....................... .. cosn 3/16; cosn 13/oo
`[52] U.S. Cl. ........................................ 536/65; 536/66;
`.
`424/35
`........ .. 106/169; 536/65, 66;
`424/35_'
`
`[56]
`
`,
`References Clted
`U.S. PATENT DOCUMENTS
`2,794,799
`6/1957 Hiatt et al.
`........................ .. 260/225
`2,856,399 10/1958 Mench et al. ................. .. 260/224
`
`2/1970 ’Greminger ........................ .. 106/189
`
`3,493,407
`
`
`4,017,647 2/1977 Ohno ......... ..
`427/3
`4,138,013
`2/1979 Ok "
`..
`4,226,981 1o/1930 On:-l2:n.l.E.1................................fgggjgg
`,
`FOREIGN PATENT DOCUMENTS
`46-29743
`8/1971 Japan ..................................... 424/35
`Primary EJtaminer—A1lan Lieberman
`A55i‘t“”’ Ex“mi"9’—_P3t Short
`Attorney, Agent, or Fzrm—-Toren, McGeady & Stanger
`[57]
`6
`'
`ABSTRACT
`The invention provides a novel enterosoluble capsule
`for containing a medicament, which is shaped with a
`h. h
`.
`.
`.
`_
`_
`1$§e°§2?13§£3§§3§‘§,§iZ§eii?i?S§fdaZ“L“£§;Yf Sfiiffifli-
`kyl- or hydroxyalkyl alkylcellulose esterified with suc-
`‘ cinyl anhydride and an aliphatic monocarboxylic acid
`a"hYd’ids-. The s“*si9s°1“b1s capsules hi_We sis°i=1_1siii
`eiitsiosslubiliiy bi—‘haVi9r as Well as siifficieiit pliability
`even without the addition of a plasticizer which is al-
`H105‘ "1d1SPe“S3b1e 111 the P110? art materials The 061111-
`lplse derivative can be shaped into capsules not only by
`t e conventional dipping method but also by the plastic
`deformation at an elevated temperature under pressure
`such as compression molding, vacuum forming, match-
`39111019 “mung and the like-
`'
`
`3 Claims, N0 Drawings
`
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`
`l
`
`ENTEROSOLUBLE CAPSULES
`
`BACKGROUND OF THE INVENTION
`
`4,365,060
`
`2
`succinic acid resulting in gradual decrease of the solu-
`bility in the intestinal juice.
`SUMMARY OF THE INVENTION
`
`The present invention relates to a novel enterosoluble
`capsule for containing a medicament or, more particu-
`larly, to an enterosoluble capsule for containing a medi-
`cament shaped with a novel enterosoluble cellulose
`derivative as the base material.
`An enterosoluble capsule used for oral administration
`of a medicament contained therein is required to be
`stable and undissolved in the stomach but readily dis-
`solved when it arrives at the intestinal canals to release
`the medicament contained therein. In other words, the
`solubility of the capsule material depends on the condi-
`tion of acidity or alkalinity, being insoluble in the acidic ’
`condition in the stomach but soluble in the neutral or
`alkaline condition in the intestinal canals. Enterosoluble
`capsules having such a solubility performance are con-
`ventionally ‘ made of gelatine ‘followed by treatment
`with formalin to modify the solublility or followed by
`coating with an enterosoluble polymeric material.
`One of the problems in such a gelatine-based en-
`terosoluble capsule is the complicacy of the manufac-
`turing process since shaping of a capsule with gelatine
`must be followed by the formalin treatment or by the
`coating procedure. Moreover, very delicate control of
`the process conditions is required in the formalin treat-
`ment to impart adequate enterosolubility since a gela-
`tine capsule insufficiently treated with formalin is partly
`dissolved in the stomach while a gelatine capsule exces-
`sively formalin-treated becomes insoluble even in the
`intestinal canal. .
`"
`
`5
`
`l0
`
`15
`
`20
`
`25
`
`30
`
`Coating with an enterosoluble polymeric material is
`also not free from problems of incomplete adhesive
`bonding between the gelatine surface and the coating
`film or denaturation of the coating film by the influence
`of the moisture contained in the gelatine resulting in
`inferior enterosolubility performance.
`On the other hand, there have been proposed en-
`terosoluble capsules shaped with an inherently en-
`terosoluble polymeric material as the base, i.e. a poly-
`meric material which itself isinsoluble in the gastric '
`juice but soluble in the intestinal juice. Known examples
`of such an enterosoluble polymeric material
`include
`copolymers of aliphatically unsaturated carboxylic
`acids such as copolymers of methacrylic acid and
`methyl methacrylate and certain kinds of cellulose de-
`rivatives such as cellulose acetate phthalate, hydroxy-
`propyl methylcellulose
`phthalate, methylcellulose 50
`phthalate, cellulose acetate succinate and the like.
`In the shaped articles, e.g. capsules, made of the
`above mentioned copolymers of aliphatically unsatu-
`» rated carboxylic acids, hydroxypropyl methylcellulose
`and the other is an aliphatic monovalent acyl group
`phthalate or methylcellulose phthalate, it is necessary to 55 represented by the general formufla
`formulate a considerable amount_ of a plasticizer in
`order to improve the hardness and brittleness of the
`articles so that disadvantages are sometimes unavoida-
`ble by the bleeding of the plasticizer on to the surface of
`the shaped article which may adversely influence the
`effective ingredient of the medicament contained in the
`capsule.
`i
`‘
`Further, cellulose acetate phthalate, cellulose acetate
`succinate and the like shaped into a capsule are subject
`to a very undesirable phenomenon that they are hydro-
`lyzed by the influence of the atmospheric moisture in
`the lapse of time during storage to liberate acid decom-
`position products such as acetic acid, phthalic acid and
`
`It is therefore an object of the present invention to
`provide a novel and improved enterosoluble capsule for
`medicament free from the above described problems in
`the prior art enterosoluble capsules.-
`Thus, the enterosoluble capsules of the invention are
`shaped with an enterosoluble cellulose derivative of a
`specific type as the base material which exhibits excel-
`lent enterosolubility performance,
`is intoxic to the
`human body, is stable in storage conditions not produc-
`ing any noxious substances in the lapse of time capable
`of giving a physically and chemically stable enterosolu-
`ble capsule having excellent pliability even without the
`addition of a plasticizer.
`,
`,
`' The enterosoluble capsule of the invention for con-
`taining a medicament is shaped with a mixed ester of a
`cellulose ether substituted with alkyl groups and/or
`hydroxyalkyl groups esterified with acidic succinyl
`groups and aliphatic monovalent acyl groups.
`The invention further relates to a method for the
`preparation of the enterosoluble capsule for medica-
`ment with the above defined cellulose derivative as the
`base material.‘
`‘
`
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENTS
`
`The cellulose derivative above defined to be used for
`shaping the enterosoluble capsules of the invention is a
`novel substance newly developed by the inventors (see
`Japanese Patent Disclosure No. 54-61282); This mate-
`rial has advantages in several respects. Firstly, a very
`pliant film can be formed with the material with addi-
`tion'of no or a very small amount of plasticizers. Se-
`condly, the films formed of the material exhibit no stick-
`iness and never adhere to each other. Thirdly, the mate-
`rial is chemically and physically stable so that no dena-
`turation takes place in the lapse of time by the influence
`of moisture during storage. Lastly, the purification pro-
`cedure of the cellulose derivative after completion of
`the esterification reaction can be carried out without
`any difficulties so that a cellulose derivative of high
`purity is readily obtained.
`‘
`.
`'
`The above mentioned cellulose derivative used in the
`invention has two kinds of ester groups. One is an acidic
`succinyl group expressed by the formula
`
`_
`
`‘"3
`fl’
`HoccH2cH2c—
`
`'
`
`'0 .
`‘
`H
`«
`, RC-.
`
`V
`
`*
`
`35
`
`40
`
`45
`
`60
`
`where R is a monovalent aliphatic hydrocarbon group.
`The mixed ester of a cellulose ether with the above two
`kinds of ester groups is readily obtained by the esterifi-
`cation reaction of a cellulose ether with succinyl anhy-
`dride and an anhydride of an aliphatic monocarboxylic
`acid.
`.
`.
`_
`V
`,
`-
`.
`' The cellulose ether as the starting material in the
`’ above mentioned esterification reaction is necessarily
`
`65_
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`4,365,060
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`4
`numbers of substitution with acidic succinyl groups and
`the aliphatic monovalent acyl groups are at least 0.1 and
`0.05, respectively, per glucose unit. A mixed ester prod-
`uct having the average numbers of substitution smaller
`than above is undesirable due to its inferior pliability
`and enterosolubility performance.
`In the following, methods for fabricating capsules
`with the mixed ester of cellulose ether are described.
`
`3
`substituted or etherified with alkyl groups and/or hy-
`droxyalkyl groups. Examples of the alkylcelluloses in-
`clude methylcellulose, ethylcellulose and propylcel-
`lulose and examples of the hydroxyalkylcelluloses in-
`clude hydroxyethylcellulose, hydroxypropylcellulose
`andhydroxybutyl cellulose. Cellulose ethers substituted
`with both alkyl groups and hydroxyalkyl groups are
`exemplified by hydroxyethyl methylcellulose, hydroxy-
`ethyl ethylcellulose, hydroxypropyl methylcellulose,
`hydroxypropyl ethylcellulose, hydroxybutyl methyl-
`cellulose and hydroxybutyl ethylcellulose. Further,
`cellulose ethers substituted with two kinds or more of
`hydroxyalkyl groups are also suitable such as hydroxy-
`ethyl hydroxypropylcellulose, hydroxyethyl hydrox-
`ybutylcellulose and hydroxyethyl hydroxypropyl meth-
`ylcellulose. Among the above named cellulose ethers,
`most preferred are the hydroxyalkyalkylcelluloses hav-
`ing hydroxypropyl or hydroxybutyl groups as the hy-
`droxyalkyl groups and methyl or ethyl groups as the
`alkyl groups due to their relatively high plasticity.
`These cellulose ethers are not particularly limitative
`, with respect to their molecular weight and the degree
`of molar substitution with the substituent groups al-
`though it is recommendable in the case of alkylcel-
`luloses and hydroxyalkyl alkylcelluloses that the num-
`ber of the alkyl groups as the substituent groups is 2.5 or
`smaller per glucose unit of the cellulose since larger
`molar substitution with alkyl groups increases difficul-
`ties in the esterification reaction with the above men-
`tioned acid anhydrides. It is further recommendable
`that the molecular weight of the cellulose ether is in the
`range from. about 5000 to 200,000 to obtain adequate
`plasticity and that the total number of the substituent
`groups is at least 1.5 per glucose unit since a cellulose
`‘ ether with a degree of substitution smaller than above
`no longer exhibits desirable properties as a cellulose
`ether. These cellulose ethers are commercially available
`and can be used without further purification.
`As the succinic anhydride and the aliphatic monocar-
`boxylic acid anhydride to be reacted with the cellulose
`ether in the esterification reaction, commercially avail-
`able technical grade products can be used as such. The
`aliphatic monocarboxylic‘ acid anhydride suitable for
`the reaction is exemplified by the anhydrides of acetic
`acid, propionic acid, butyric acid, valeric acid, lauric
`acid and the like but the former four are preferred in
`view of their reactivity with the cellulose ether and
`their inexpensiveness.
`_
`The esterification reaction is undertaken by the
`method in which the cellulose ether is subjected to the
`esterification reaction with succinic anhydride and the
`aliphatic monocarboxylic acid anhydride in an aliphatic
`carboxylic acid as the reaction medium such as acetic
`acid, propionic acid, butyric acid and the like in the
`presence of an alkali metal salt of a carboxylic acid as
`the catalyst such as sodium acetate, potassium acetate
`and the like. Alternatively, the esterification reaction of
`the cellulose ether with succinic anhydride and the
`aliphatic monocarboxylic acid anhydride is carried out
`in a suitable organic solvent such as acetone and di-
`methylformamide in the presence of a basic catalyst
`such as pyridine and a-picoline.
`The average numbers of substitution with the ester
`groups,
`i.e. acidic succinyl groups and the aliphatic
`_ monovalent acyl groups, per glucose unit are dependent
`on the properties required in the mixed ester product or
`on the type of the cellulose ether as the starting mate-
`rial. Generally speaking, it is desirable that the average
`
`‘
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`One of the most conventional methods for fabricating
`a capsule is the so-called dipping method or pin-mold
`method. In this method, the polymeric material is dis-
`solved in a suitable solvent in an appropriate concentra-
`tion to give a dipping solution, in which a pin-like male
`mold is clipped and pulled up gradually to form a vis-
`cous coating layer of the clipping solution therearound
`followed by drying with evaporation of the solvent and
`taking the dried polymer crust off the pin-mold to give
`a shaped article of the form of desired dimensions, if
`necessary, with finishing, e.g. trimming of the periph-
`ery, into a finished product.
`The organic solvents suitable for the preparation of
`the dipping solution with the mixed ester of the cellu-
`« lose ether in the invention are exemplified by methyl
`alcohol, ethyl alcohol, acetone, ethyl acetate, ethylene-
`glycol monomethyl ether, ethyleneglycol monoethyl
`ether and the like. These solvents may be used either
`singly or as a mixed solvent of two kinds or more ac-
`cording to need.
`The concentration of the dipping solvent is not par-
`ticularly limitative and should be determined with con-
`sideration'of the viscosity of the solution and the desired
`wall thickness of the capsule products. It may be too
`much to say that a solution of lower concentration
`should be used when capsules of thin wall thickness are
`desired while thick-walled capsules are obtained with a
`viscous dipping solution of high concentration.
`It is optional that the clipping solution is admixed with
`conventional additive ingredients such as coloring
`agents, flavor and taste improvers, flavorings, plasticiz-
`ers and the like in limited amounts not to influence the
`advantages properties of the mixed ester of the cellulose
`ether. In particular, the addition of a plasticizer can be
`entirely omitted when a capsule of hard-type is desired
`different from conventional capsule-forming polymeric
`materials since‘ the capsules formed of the mixed ester of
`the cellulose ether as such according to the invention
`have adequate pliability even without the addition of a
`plasticizer.
`-
`An alternative method for the fabrication of the cap-
`sules according to the invention is molding by plastic
`deformation of the material at an elevated temperature
`under pressure. This principle of molding is widely
`utilized in the technology of shaping of plastic articles
`but rarely utilized in manufacturing capsules. The mold-
`ing of thermoplastic material according to this principle
`is carried out by compression molding, injection mold-
`ing and extrusion molding of the polymeric material in
`the form of powder, granules, pellets and the like as
`’ well as by vacuum forming, pressure forming and
`matched-mold forming of a sheet prepared in advance
`with the polymeric material.
`Advantages in the plastic deformation molding over
`the above described dipping method are obtained,
`chiefly by the unnecessity of an organic solvent since
`the use of an organic solvent is undesirable from the
`standpoints of workers’ health and atmospheric pollu-
`tion as well as the danger of fire or explosion. Further-
`more,
`the method of plastic deformation molding is
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`4,365,060
`
`5
`advantageous owing to the much better productivity
`than in the dipping method so that the method is recom-
`mendable, especially, when the plastic material has a
`sufficient heat stability to withstand the temperature of
`molding.
`The temperature of molding for shaping capsules
`with the mixed ester of the cellulose ether is in the range
`from 60° to 250° C. or, preferably, from 80° to 200° C.
`since plastic flow of the cellulose derivative is insuffi-
`cient at a temperature below 60° C. leading to inhomo-
`geneity of the products while thermal decomposition of
`the material takes place at a temperature higher than
`250° C.
`~
`
`The molding pressure in compression molding or
`injection molding is at least 5 kg/cm? or, preferably, in
`the range from 10 to 2000 kg/cml.
`It is optional that various kinds of additive ingredients
`are admixed to the mixed ester of the cellulose ether
`prior to molding including plasticizers, lubricants, anti-
`oxidants, coloring agents, flavor and taste improvers
`and the like.
`1
`
`Plasticizers_ are added when higher pliability is de-
`sired in the shaped articles, e. g. capsules. Suitable plasti-
`cizers are, for example, ethyleneglycol, diethylenegly-
`col, polyethyleneglycol, propyleneglycol, di- and tri-
`propyleneglycols, polypropyleneglycol, glycerine and
`esters thereof such as mono-, di- and triacetins, esters of
`phthalic acid such as dimethyl phthalate and diethyl
`phthalate, tri-n-butyl citrate and the like.
`Addition of lubricants is effective in improving the
`workability in molding and suitable lubricants are exem-
`plified by stearic acid and salts and esters thereof such
`as magnesium stearate, calcium, stearate, n-butyl stea-
`rate and the like, ester waxes such as beeswax, carnauba
`wax, montanic acid’ esters and the like, polyethylene
`wax’ and rice wax.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`In addition to the manufacturing of capsules per se by
`the plastic deformation method apart from the medica-
`ment to be contained therein, a method of encapsulation 40
`of a pre-shaped tablet is also applicable with a sheet of
`the inventive cellulose derivative prepared in advance.
`Thus, a tablet is sandwiched between two pieces of the
`film of the cellulose derivative and heat-sealed with
`pressure by pressing the films at the portions just out-
`side the tablet on to the side surface of the tablet to give
`an enterosoluble encapsulated tablet.
`Following are the examples to illustrate the proce-
`dure for the preparation of mixed esters of cellulose
`ethers and shaping of capsules with these mixed esters.
`In the examples, parts are all given by parts by weight.
`EXAMPLE 1
`
`50
`
`45
`
`Into a reaction vessel equipped with a stirrer were
`introduced 100 parts of glacial acetic acid, 20 parts of
`sodium acetate, 20 parts of a cellulose ether of the kind
`indicated in Table 1 below, indicated amount of succi-
`nyl anhydride and indicated kind and amount of an
`aliphatic monocarboxylic acid anhydride and the reac-
`tion mixture was heated at 85° C. for 3 hours to effect
`the esteriiication reaction.
`After the end of the above reaction time, water was
`added to the reaction mixture to precipitate the reaction
`product which was washed with water and dried to
`give the mixed esters containing the acidic succinyl
`groups and the aliphatic monovalent acyl groups as
`shown in Table 1. The cellulose ethers used as the start-
`ing material appearing in Table l were as follows.
`
`55
`
`60
`
`65
`
`6
`in which the average
`HPC: hydroxypropylcellulose,
`number of substitution with hydroxypropoxyl groups
`was 3.0 per glucose unit.
`HPMC: hydroxypropyl methyl.cellu1ose, in which the
`average numbers of substitution with hydroxy-
`propoxyl groups and methoxyl groups were 0.27 and
`1.82, respectively, per glucose unit.
`in
`HEHPC: hydroxyethyl hydroxypropylcellulose,
`which the average number of substitution with hy-
`droxyethoxyl groups and hydroxypropoxyl groups
`were 2.5 and 0.32, respectively, per glucose unit.
`HBMC: hydroxybutyl methylcellulose,
`in which the
`average_ numbers of
`substitution with hydrox-
`ybutoxyl groups and methoxyl groups were 0.10 and
`1.80, respectively, per glucose unit.
`In the next place, the above obtained Samples No. 1
`to No. 6 shown in Table 1 as well as comparative Sam-
`ples No. ‘77 and No. 8 below were examined for the
`stability against hydrolysis and elongation of the films
`formed therewith in the testing procedures given below
`to give the results shown in Table 2. Sample No. 7:
`cellulose acetate phthalate, in which the average num-
`bers of substitution with acetyl groups and phthaloyl
`groups were 1.84 and 0.76, respectively, per glucose
`unit. Sample No. 8: hydroxypropyl methylcellulose
`phthalate, in which the average numbers of substitution
`with hydroxypropoxyl groups, methoxyl groups and
`phthaloyl groups were, 0.22 1.80 and 0.68, respectively,
`per glucose unit.
`
`Testing Method for the Stability Against Hydrolysis
`(a) Determination of free aliphatic carboxylic acid:
`the sample kept at 60° C. in an atmosphere of 100%
`relative humidity for 6 days or 12 days was extracted
`with diethyl ether for 5 hours in a Soxhlet’s extractor
`and the amount of the aliphatic monocarboxylic acid in
`the ether extract was determined by gas chromatogra-
`phy-
`(b) Determination of free acid other than aliphatic
`monocarboxylic acid: the sample kept at 60° C. in an
`atmosphere of 100% relative humidity for 6 days or 12
`days was dried at 105° C. for 2 hours and 1.5 g of
`weighed amount of the sample was dissolved in 50 ml of
`a 1:1 by volume mixed solvent of methylene chloride
`and methyl alcohol. The solution was admixed with 100
`ml of water and then 100 ml of n-hexane as a phase
`separation aid and shaken vigorously. After standing
`and separation into layers, the aqueous layer was taken
`and combined with the washing water of the organic
`layer with 100 ml of water and the thus obtained water
`extract was titrated with 0.1 N aqueous solution of
`sodium hydroxide to determine total amount of free
`acids. The amount of free acid other than aliphatic
`monocarboxylic acid, viz. succinic acid or phthalic
`acid, was obtained as the difference between here ob-
`tained value and the value obtained in (a) above.
`TABLE 1
`Product
`Reactants
`Aliphatic
`Acidic
`Succinic Aliphatic
`succinyl monovalent
`an-
`monocarb-
`Sam-
`ple Cellulose
`hydride,
`oxylic acid,
`groups,
`acyl
`
`No.
`ether
`parts
`parts
`DS
`groups, DS
`1
`HPC,
`4
`Acetic am
`0.20
`0.86
`hydride, 20
`Acetic an-
`hydride, 20
`Acetic an-
`hydride, 32
`
`2
`
`3
`
`HPC
`
`HPMC
`
`6
`
`6
`
`‘
`
`-
`
`0.35
`
`0.25
`
`0.76
`.
`0.57
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`8
`TABLE 3-continued
`
`Sam. .
`ple - C°u“l°s°
`No‘
`ether
`4
`1-1pMc
`
`7
`TABLE l-continued
`Reactants
`Succiiiic Aliphatic
`an.
`monoca,-b.
`hydride’
`°xyll° acid’
`Parts
`parts
`7
`Acetic an.
`hydride, 15
`0.30
`Propionic an-
`6
`5 HEHPC
`h d ‘d ,4o
`0.30
`Pl-logiofiie an-
`6
`6
`HBMC
`hydride. 20
`DS: degree of substitution with the substituent groups per glucose unit
`A
`
`0.85
`0.60
`
`Product
`Aliphatic
`Acidic
`succinyl monovment
`3"°“P5'
`acyl
`DS
`groups’ DS
`0.42
`040
`
`TABLE 2
`Smbim 8 aim h dml Sis
`— —jl'—-g—L—y--———
`After 12 days
`After 6 days
`Sample
`
`,
`‘ Elongation
`
`pH of
`lesllllg
`H
`_
`
`solution
`Solubility behavior of capsule
`6.0
`Content was released within 8 to 10 minutes
`out of the dissolved capsule.
`7.5
`Content was released within 6 to 9 minutes
`
`out of the dissolved capsule.
`
`5
`
`’
`10
`
`EXAMPLE 3
`Experimental procedure was substantially the same as
`in Example 2 except that the dipping solution was pre-
`15 gated liy 1clissc;l(yingf20 sgzoli Samlple No. ldobtziined
`xamp e
`in
`g o a .
`y vo ume mixe
`so vent o
`. ethyl alcohol and water. The capsules were also trans-
`.
`.
`.
`.
`.
`.
`.
`parent and excellent in pliability. The solubility test
`undertaken in the same manner as in Example 2 indi
`20 cated that the capsule was undissolved in the first solu-
`tion of pH 1.2 for at least 2 hours while dissolved within
`15 to 20 minutes in the second solution of pH 7.5 to
`release the content into the solution.
`
`EXAMPLE 4
`
`25
`
`‘I
`#2
`‘I
`No"
`‘ 3:?
`g:
`3::
`4 5
`0_7
`0.4
`0.5
`3
`_ 0.3
`0.2»
`0.1
`4
`0-5
`0-4
`0-7
`5
`0.6
`0.4
`0.4
`6
`11.0
`9.3
`7.0
`7
`—-
`3.1
`—
`8
`.1: nee aliphatic monmnmync acid’ % by weight
`-2: free succinic acid or phthalic acid, % by weight
`
`.2
`3%
`05
`0.4
`0-4
`0.7
`13.2
`3.5
`
`of mm’ %
`gig
`10
`10'
`l0
`10
`4
`3
`
`_
`_
`_ Experimental procedure was substantially the same as
`in Example 2 except that the dipping solution was pre-
`pared by dissolving 25 g of Sample No. 5 obtained in
`:::‘::.'e:.:.“ :f.5.::;:.:;::.Y.t.‘:3::*.:.':::;‘rd.:.?::“i.?:‘
`or or
`The sample was dissolved in a 1:1 by volume mixed 30 capsules were also transparent and excellent in pliabil-
`solvent of methylene chloride and methyl alcohol and
`ity; The solubility test undertaken in the same manner as
`films of 0.1 mm thickness wereprepared by the casting
`in Example 2 indicated that the capsule was undissolved
`method with the thus prepared solution. Measurement
`in the first solution of pH 1.2 for at least 2 hours while
`of elongation Was Carried Out at 25° C-
`35 dissolved within 15 to 25 minutes in the second solution
`EXAMPLE 2
`of pH 7.5 to release the content into the solution.
`A homogeneous, viscous solution wasprepared by
`EXAMPLE 5
`dissolving 90 g Of Sample N0. 3 obtained in Example l
`Sample No,’ 4 obtained in Example 1 was admixed
`in 210 g of a 6:4 by volume mixed solvent of acetone and 40- with 5% by weight of polyethyleneglycol having an
`ell1Yl 3lC0l10l f0ll0WeCl 0}’ d0f0aml1'1g 0}’ Slandlng at
`average molecular weight of about 400 and 0.5% by
`T0010 lemP01'3l01'0-
`weight of rice wax in Henschel mixer and the blend was
`Plll'm0ld_5 l0T Cap and 0003’ 0f 3 Capsule. llfeaffid in
`kneaded in a two-roller mill at 130° C. for about 10
`adVaI!C€ Wlth 8 lubricant. Were dipped lll lllls S0_ll1ll0I1
`minutes and shaped into a sheet of 0.5 mm thickness.
`3nd'l?l1lle(l “P gradllalll’ t0 f0fm 3 lllm Of tlle V1S0:3l15 45 This sheet was transparent and excellent in pliability.
`solution l2heI;l(E:I'Oll1I1ld folbloweddby dTY1l(118:l:0 ‘f0 42 C-
`The sheet was sandwiched between a male and fe-
`lllto °Tll5t5-
`0 t 115 0 t-31110 Cap 311
`0 Y 0 3 00D‘
`male metal molds of dimensions and form correspond— V
`sule, taken off from the pin-molds with necessary finish-
`ing to the can or body of #0 capsule and compression.
`108: Were transparent and excellent lll Pll3bllllY-
`molded at 120° C. for 3 minutes under a pressure of 40
`Tl1‘?0aPS“l0 W35 lllled Wllll P0W<l0f-0flaCt055 300 Elle 50 kg/cmz. The thus obtained cap and body of capsule had
`°}‘1’“Pll“g P‘_”tl°“ ofllh‘? Cal’ and 0°03’ W35 Sealefl Wllll
`about 0.2 mm of wall thickness with necessary finishing
`t e ‘same viscous so ution as above. The solubility be-
`and was transparent and excellent In nhab,1ny_
`havlol‘ 0f l5ll.e_ thus _PT§Paled °0P5“le5 W33 examllled l0
`The capsule was filled with powder of lactose and the
`llle firs} S°l“ll°ll Wlih 3 PH °t_‘ 1'2 and the .5600“ 591"’
`coupling portion of the cap and body was sealed with a
`“on Wlth 3 PH °f 75 ?°°°rd",‘g '50 lfhe Nlnth Re‘_’l5_ed 55 15% acetone solution of the same cellulose derivative.
`'laP_a"eSe_ Ph“_"Tla°°p°ela a_s 3 slmulatmn °f _ga5t“° -l“l‘_’e
`The solubility behavior of the thus prepared capsules
`or intestinal _]11lCe,_ respectively, as well as in Mcllvain
`was examined in the Same manner as in Example 2
`buffer solutions with pH values of 4.5, 5.0, 5.5 and 5-0 *0
`above with the first and the second solutions according
`gwe results shown "‘-Table 3 bel°W'
`to the Ninth Revised Japanese Pharmacopoeia as well
`
`TABLE 3
`60 as with Mcllvain buffer solutions of pH values 5.0, 5.5
`and 6.0 to give the results set out in Table 4 below.
`
`PH of
`testing
`
`solution
`Solubility behavior of capsule
`1.2
`Not dissolved for more than 2 hours.
`4.5
`Not dissolved for more than 2 hours.
`5.0
`Content was released within 20 to 25 minutes
`out of the dissolved capsule.
`Content was released within 12 to 15 minutes
`out of the dissolved capsule. .
`
`5.5
`
`TABLE 4
`
`65
`
`tpliof
`815 gig
`so u lo“
`1.2
`- 5.0
`5.5
`
`I
`f
`.
`I b.1.t b h
`0 u I I y
`C awor 0 Caps“ 6
`Not dissolved for more than 2 hours.
`Not dissolved for more than 2 hours.
`Content was released within 20 to 25 minutes
`
`Mylan V. Qualicaps, |PR2017—OO203 '
`QUALICAPS EX. 2025 — 5/6
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2025 - 5/6
`
`
`
`9
`TABLE 4-continued
`_______..._.._._....___._..__...._._...._
`
`4,365,060
`
`
`
`10
`
`EXAMPLE 6
`
`10
`weighing 280 mg was sandwiched between two pieces
`of the above prepared film heated at 120° C. and heat-
`sealed by pressing the films at the portions just outside
`a
`gig;
`
`
`
`Solubility behavior of capsule ‘ 5solution . the tablet on to the side surface of the tablet to give an ‘
`enterosoluble encapsulated tablet.
`V
`out of the dissolved capsule.
`The solubility behavior of the encapsulated tablets
`6.0
`Content was released within 10 to 15 minutes
`_
`_
`g
`_
`6
`.
`was examined in the same manner as in Example with
`out of the dissolved capsule.
`‘
`Content was released within 6 to 9 minutes
`7.5
`the first and the second solution having pH values of 1.2
`*___.:...
`out of the dissolved capsule.
`'.
`- and 7.5, respectively, tofind that the tablet remained
`undissolved for more than 2 hours in the first solution
`while the tablet was dissolved and disintegrated within
`8 to 13 minutes in the second solution. The disintegra-
`tion time of the simulation tablet per se in the second
`solution was 2.5 to 3.5 minutes.
`
`15
`
`Sample No. 4 obtained in Example 1 was admixed
`with 5% by weight of propyleneglycol and 2% by
`weight of stearic acid in a Henschel mixer and the blend
`' was extruded using a single screw extruder of 25 mm L
`diameter at 150° C. with a discharging pressure of 200
`kg/cm? into rods of 2 mm diameter. These rods were
`chopped in a pelletizing machine into pellets of 5 mm -
`20‘
`length and the pellets were extruded through a T-die
`with a 0.2 mm spacer mounted on the same single screw
`extruder as used above to give films of 0.20 to 0.22 mm
`thickness having transparency and excellent pliability.
`The thus prepared films were shaped into caps and
`bodies of #0 capsules by the techniques of vacuum
`forming at 110° C. using respective female metal molds.
`The wall thickness of the caps and bodies was about 0.1
`mm.
`
`_
`_
`EXAMPLE 8
`A film of 0.1 mm thickness was prepared with Sample
`, No. 2 obtained in Example 1 by the casting method with
`a 10% solution in a» 8:2 by volume mixed solvent of
`ethyl alcohol and water. An encapsulated tablet was
`prepared in the same manner as in Example 7 by heat-
`sealing at 100° C. with the above prepared film. The
`. encapsulated tablet remained undissolved for more than
`2 hours in the first solution of pH 1.2 while it was dis-
`solved and disintegrated within 10 to 15 minutes in the
`second solution of pH 7.5.
`What is claimed is:
`
`25
`
`The solubility behavior of the capsules was examined
`in the same manner as in the preceding example to find
`that the capsule remained undissolved in the first solu-
`tion of pH 1.2 for more than 2 hours while rapidly
`dissolved in the second solution of pH 7.5 within 15 to
`20 minutes.
`
`' EXAMPLE 7
`
`30
`
`35
`
`A solution prepared by dissolving 50 g of Sample No.
`6 obtained in Example 1 in 450 g of a 1:] by volume
`mixed solvent by methylene chloride and methyl alco-
`hol with addition of 5 g of propyleneglycol was spread
`on a glass plate and dried up to give a film of 0.1 mm
`thickness.
`
`A simulation tablet prepared. with a mixture com- ‘
`posed of 59.5% of lactose, 35% of corn starch, 5% of a
`low-substitution hydroxypropylcellulose and 0.5% of
`magnesium stearate and having a diameter of 9 mm and
`
`45
`
`1. An enterosoluble capsule for containing a medica-
`ment shaped with a mixed ester of’ a cellulose ether
`substituted with substituent groups selected from the
`class containing of alkyl groups, and hydroxyalkyl
`groups esterified with acidic succinyl groups and ali-
`phatic monovalent acyl groups wherein the average
`numbers of substitution of the acidic succinyl groups
`and the aliphatic monovalent acyl groups bonded to the
`cellulose ether are at least 0.1 and 0.05, respectively, per
`glucose unit.
`a
`0
`2. The enterosoluble capsule as claimed in claim 1
`wherein the average number of substitution of the cellu-
`lose ether with alkyl groups is not exceeding 2.5 per
`glucose unit,
`3. The enterosoluble capsule alsclaimed in claim 1
`wherein the aliphatic monovalent acyl group is selected
`from the class consisting of acetyl, propionyl and bu_tyr-
`oyl.
`'
`'
`»
`r‘=r.*=u:i=
`
`50
`
`55
`
`60
`
`65"
`
`|\'/Iyia