`
`2,526,683
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`UNITED. STATES PATENT OFFICE
`
`2,526,683
`METHYL CELLULOSE ‘CAPSULES AND I
`PROCESS OF MANUFACTURE
`V
`
`Hubert W. Murphy, Indianapolis, Ind., assignor
`to Eli Lilly and Company, Indianapolis, Ind., a
`corporation of Indiana.
`No Drawing. Application April 13, 1946,
`Serial No. 662,102
`6 Claims.
`(Cl. 167-83)
`
`1
`This invention relates to medicinal capsules
`and more particularly to capsules of etherified
`cellulosic material such as methyl cellulose, and
`to methods of manufacturing the same.
`For over a century capsules have been made
`almost universally from gelatin despite the fact
`that the manufactureand use of such capsules
`are attended with difiiculties. While alternative
`materials, such as cellulose acetate, have been
`proposed for use in capsule manufacture, and
`while such proposed materials may not be sub-
`ject to certain of the deficiencies and defects pos-
`sessed by gelatin capsules, other difficulties, prin-
`— cipally in the manufacture of the capsules, are
`encountered. -
`Objects of this invention are to provide medici-
`nal capsules which have substantial advantages
`over prior capsules, both in general utility and
`in manufacture, and to provide a convenient and
`rapid process for their manufacture.
`Medicinal capsules provided in accordance
`with this invention are prepared from a readily
`available and inexpensive material. They are
`non-toxic.
`In contrast to capsules made “from
`cellulose acetate or gelatin, they do not become
`soft or sticky or acquire an unpleasant taste or’
`odor when exposed to relatively high humidity.
`Furthermore they do not become dry and brittle
`when filled with materials having hygroscopic
`properties or when exposed to air of low humid-
`ity. They retain their strength and form even
`when containing compositions of relatively high
`or low pH. They are not attacked by micro-
`organisms such as molds, as frequently happens
`with gelatin capsules, especially when exposed to
`_ warm and humid atmosphere. They are sturdy
`and withstand, without fracturing, the mechani-
`cal shocks encountered in ordinary handling, and
`-in filling’ and packaging operations. They are
`readily disintegrated when taken internally, thus
`making available their medicinal contents. Fur-
`ther, the time required for disintegration may be
`controlled within limits. They may be made in
`a wide variety of colors and may be made opaque
`or clear as desired.
`.
`The medicinal capsules provided by this in-
`vention are prepared from methyl -cellulose which
`is soluble in cold water, insoluble in hot water,
`and possesses peculiar gelling characteristics.
`Water solutions of such methyl cellulose vary in
`viscosity. with temperature changes in a way
`quite different from gelatin "solutions. Whereas v
`the viscosity of gelatin solutions continuously de-
`creases with rising temperatures through a rela-
`tively wide range, with the gelation point-at the
`
`2
`lower end of the temperature curve, the viscosity
`of these cellulose derivatives decreases with a rise
`in temperature through a. relatively narrow range
`of low temperatures, and then increases rapidly
`through an exceedingly narrow range of rising
`temperature with gel formation a few degrees
`above the temperature at which minimal vis-
`cosity is displayed.
`The methyl cellulose I employ in making my
`‘novel medicinal capsules is of a type having an
`unusually low intrinsic viscosity, advantageously
`in the range of about 7 to 15 cps. (centipoises) in-
`trinsic viscosity.
`(By intrinsic viscosity is meant
`the viscosity displayed under certain standard
`conditions, arbitrarily chosen as 2 per cent con-
`centration in distilled water solution at 20° C.)
`In this range I prefer to use -methyl cellulose
`types of about 8 to 10 cps. intrinsic viscosity.
`'
`As exemplified, there is employed in the mak-
`ing of my capsules, methyl cellulose with a
`methoxyl content of about 30 percent and which
`when dissolved in distilled water at a concentra-
`tion of 2 percent yields a solution which displays
`an intrinsic viscosity of about 9 cps. at 20° C.
`The intrinsic. viscosity characteristic of
`the
`methyl‘ cellulose is a very important factor in
`determining the rate of mass production of cap-
`sules. For example, it requires about 10 times
`as long for the formation of capsules from a
`coating composition prepared from a. methyl
`cellulose of the 15 cps. intrinsic viscosity type as
`it does from a coating composition prepared from
`the 9 centipoise type. Moreover,
`it has been
`found that whenever the intrinsic viscosity char-
`acteristic is decreased much beyond that of the
`'7 centipoise type, the quality of the capsular wall,
`particularly with regard to tensile strength, elas-
`ticity, and yield point, is excessively reduced and
`otherwise seriously affected-
`'
`In the production of methyl cellulose capsules,
`I prepare a clear, substantially bubble-free coat-
`ing composition desirably containing from 15 to
`20 percentof a low viscosity type methyl cellu-
`lose. This is accomplished,
`for example, by T
`treating 5.2 kg. of low viscosity methyl cellulose,
`designated as 9 -centipoise type, with 2'? liters of
`boiling water to facilitate wetting of the cellu-
`lose particles. This mixture is then cooled and
`maintained at a temperature of about 5° C- for
`12 to 24 hours during which time complete solu-
`tion of the methyl cellulose takes place.
`If; air
`bubbles persist, they can be removed by subject-
`ing the solution to vacuum, but in most instances
`this will not be necessary. This coating compo-
`. sition is very stable and can be stored at about
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`10° C. for months without being attacked by
`microorganisms or apparent change in viscosity.
`At 15 percent concentration, such a solution of
`methyl cellulose has viscosity of about 8000 cps.
`at 2° C. and 4500 cps. -at 18° C.
`This composition is used to coat ca;Jsu1e-form-
`ing members, such as round-ended, highly pol-
`ished, stainless steel pins, by dipping them into
`the composition for a few seconds.
`It is desirable to maintain the coating composi-
`tion at a temperature a few degrees below the
`temperature at which it displays minimum vis-
`cosity because there is a Very rapid rise in vis-
`cosity and subsequent gel formation if the tem-
`perature is raised only a few degrees beyond thi
`point of minimal value.
`In general, ternperatures
`within t.‘
`range of about 5° to 29° C. will be em-
`ployed. T. e clear, bubble-{rec coating composi-
`tion described above desirably is maintained at a
`temperature of about 18° C. during the coating
`operations.
`Before being imrncrscd in the cold methyl cel-
`lulose solution, the capsule-forming pins are suit-
`ably heate to a temperature substantially above
`the gelation point of the solution employed.
`'\7‘Jith .
`the specific co-m1:-osition descrii
`cl above,
`pin
`temp,el‘a.ture of about 65° C. desn ably is employed,
`and this temperature causes rapid gelling of the
`composition in contact v
`the pins. It has been
`found that by operating under these conditions,
`a very uniform capsular wall is obtained, largely
`because that portion of the coating composition
`which iminediately surrounds that portion gelat-
`ing on the capsule-fo
`ng pin is heated suin-
`ciently (as will be he‘ nafter described) to bring
`it to the temperature at which the lowest vis-
`cosity is displayed. Among other
`things,
`this
`causes free draining of excess coating material
`from the pins wheri. they are withdrawn, and con-
`tributes to the uniform clistribution of the coal:— =
`ing on the pins.
`A plurality of co,psule-forming pins can be
`coated in one clip
`operation and C011?!‘
`iently
`the entire metal portion, including the pins and
`the bar on which they are mounted, is heated to
`such a degree that enough latent heat is 1'3-tainetl
`by the metal therein to gel-ate substantially all the
`coating composition adherent
`to the capsule-
`forming pins within an interval of about 35 sec-
`onds after they have been removed from the coat-
`ing composition. While the temperature to which
`the metallic portion including the capsule-form-
`ing pins must be preheated will vary, as for dif-
`ferent sizes of capsules, generally it will fall with-
`in the teniperature range of about 46° to about
`80° C. Moreover, it is also possible to control, to
`a limited extent, the thickness of the capsule wall
`by varying the temperature to which the metal-
`lic portion is preheated.
`The surfaces of the capsule-forming pins de-
`sirably are Very smooth and highly polished
`although a lubricant for them is not essential, it
`has been found advantageous in order to facili-
`tate removal of the capsular elements therehom,
`to precoat the capsule-forming bins with a very
`thin uniform film of lubri.,ant before they are im-
`mersed in the coating composition.
`Ia. suitable
`lubricant comprises a mixture of equal parts of
`soft soap U. S. P. and anhydrous lanolin with 0.1
`percent chromium trioxide.
`The heated and lubricated capsule-forming
`pins are dipped to the required extent
`in the
`cold methyl cellulose coating composition to form
`a coating thereon, and are then withdrawn. The
`time required in the clipping operation varies with
`
`4
`the size Of the capsules being formed and is some-
`what longer for the larger capsules. With meth-
`yl cellulose of the 15 cps. intrinsic viscosity type
`there is required about '75 seconds to dip and coat
`the pins for the standard No. 0 capsule. With
`coating compositions prepared from methyl cel-
`lulose of 9 cps. intrinsic viscosity type, the vis-
`cosity of the coating composition is such that the
`time of dipping and coating is about '7 or 8 sec-
`onds. The coated pins are then transferred to a
`drying kiln, while being at first rapidly and then
`more slowly turned on a median horizontal axis
`of their supporting member thus evenly distrib-
`uting the relatively small fiowable portion of the
`coating.
`‘A period of about 35 seconds usually
`serves to obtain. substantially complete gelation.
`Desirably the drying kiln is so constructed that
`a method of zone drying is obtained while a cur-
`rent of warm dry air is slowly passed over the
`coated pins, Thus for about the first 30 minutes
`in their passage through the kiln, the coated pins
`are subjected to a temperature of about 40° C.
`and after this period they advance in the dry-
`ing kiln into successively warmer regions or zones
`until a temperature of about 60° C.
`is obtained
`about 45 minutes after they have entered the
`kiln. The movement of air through the kiln is
`directed from the lower temperature region to
`the higher temperature region.
`Infra-red radia-
`tion may also be used in drying the capsular ele-
`ments on the pins. With the aid of infra-red
`lamps, the time of drying the capsules is only
`about 50 minutes, this time being dependent to
`some extent upon the concentration,
`intrinsic
`viscosity and thickness of the methyl cellulose.
`After drying, the capsule-forming pins bear-
`ing the methyl cellulose capsular elements are
`desirably allowed to cool to about room tempera-
`ture which effects slight contraction of the cap-
`sule-forming pins and thereby promotes easier
`removal of the methyl cellulose capsular ele-
`ments. These capsular elements are stripped
`from the capsule-forming pins, cut to appropri-
`ate size, and the bodies and caps assembled as
`capsules. These operations may be performed
`manually, or mechanically on appropriately de-
`signed machines.
`The capsules obtained by this process consist
`essentially of methyl cellulose and when in equili-
`brium with air of 40‘ per cent relative humidity
`at 20° C., contain about 2.5 percent of water by
`weight. At higher relative humidities, the cap-
`sule will gradually absorb more water and if
`maintained at a relative humidity of 90 percent,
`for 48 hours or more, as much as 20‘ percent of
`water may be absorbed.
`Although these capsules are satisfactory for
`many purposes, I have found that they can be
`improved by the additionof an essentially non-
`toxicplasticizer to the capsule-forming composi-
`tion, designed to impart to the',capsules made
`therefrom greater flexibility and to prevent ex-
`cessive hardness and loss of flexibility whenever
`hygroscopic medicaments are enclosed therein,
`and to aid in obtaining more rapiddisintegration
`of the capsule in the digestive tract of a patient.
`There are a very large number of plasticizers
`which can be used for this purpose among which
`may be mentioned: sucrose, invert sugar, dextose,
`glycerol,
`lower alkyl fatty acid monoesters of
`glycerol such as monacetin, monoethers of glyc-
`erol such as glycerol .2-methyl ether, a- and e-
`gluco heptonic acidand/or their lactones, and
`their lower alkyl and glycol esters, g1ucono-A-
`lactone, ry-valerolactone, a—amino acids such as
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`5
`glycine, ethyl glycinate, amines such as mono-
`ethanolamine and triethanolamine, glycols such
`as propylene glycol, triethylene glycol, -2-ethyl-
`1,3-hexanediol, 1,3-butylene glycol, glycosides
`such as a-methyl glucoside, acetopropanol, am-
`ides such as acetamide and propionamide, sorbi-
`tol, mannitol, lactose, and lower alkyl phosphates
`such as triethyl phosphate. V
`.
`The selection of an appropriate plasticizer or
`combination of plasticizers and the determina-
`tion of the amount to. be used will be governed
`by certain prime considerations: that the amount
`present will be essentially non-toxic; that it be
`not appreciably volatile; that it does not impart
`a disagreeable odor or taste to the capsule: and
`that it be inexpensive and readily available. The
`choice of plasticizer is further governed to some
`extent by the following factors: its freedom from
`attack by microorganisms;
`its influence on the
`amount of water absorbed by the capsular film
`at high relative humidities;
`the nature of the
`medicament to be dispensed within the capsule;
`the eflfect desired on the hardness, flexibility,
`and toughness of the capsular wall; and the
`rapidity of disintegration desired after adminis-~~
`tration of the capsule.
`.
`In general, for semi-rigid capsules, I prefer
`to use not more than 5 percent of a plasticizer
`(based on the weight of the dried capsule) and
`have found invert sugar, manitol, monacetin, tri-
`ethyl phosphate, and sorbitol
`to be the most
`generally useful. Whenever the capsules are to
`be exposed to an atmosphere of high relative
`humidity, mannitol, monacetin and triethyl phos-
`phate are superior to invert sugar or sorbitol be-
`cause the former promote minimal absorption of
`water in the capsular wall.
`Invert sugar and
`sorbitol, on the other hand, promote more rapid
`disintegration of
`the capsule in the digestive
`tract.
`More rapid disintegration may also be 40
`effected by incorporating in the coating composi-
`tion small quantities of electrolytes, for exam-
`ple, salts of organic acids such as benzene sul-
`ionic acid, toluene sulfonic
`acid. citric acid, and
`the like.
`'
`,
`. The process for the preparation of plasticized
`methyl cellulose capsules is essentially the same
`as that used for methyl cellulose alone although‘
`when the amount of plasticizer is relatively large,
`it is desirable to performthe coating and gela-
`tion operations at slightly higher temperatures.
`The plasticizer can be incorporated in the meth-
`yl cellulose solution in a number of convenient
`ways, such as by adding it to the methyl cellu-
`lose and then treating the mixture with boiling .
`Water, by dissolving the plasticizer in the water
`first and then heating the solution to boiling be-
`fore treating the methyl cellulose, or the plas-
`ticizer may be dissolved in a small amount of a
`compatible organic solvent, such as ethanol, and
`then intimately mixed with the methyl cellulose
`solution to obtain a clear, substantially bubble-
`free coating composition,
`'
`The preparation of plasticized methyl cellu-
`lose capsules is illustrated by the following ex-
`amples:
`‘
`
`Example 1
`A mixture of 5.2 kg. of low-viscosity methyl
`cellulose, designated as 9 centipoise type, and 50
`g. of monacetin is treated with 27 liters of boiling
`water and the mixture allowed to cool, Where-
`upon there is obtained a clear, bubble-free solu-
`tion. Capsules prepared from this composition,
`by coating steel pins in accordance with the de-
`scribed process, were found to possess greater
`
`7
`
`6.
`flexibility" than ‘those made from methyl cellu-*~
`lose‘ alone- The approximate composition’ of
`these capsules when at equilibrium with air of
`40 percent relative humidity at 20° C. was: meth- ~
`yl cellulose 97 percent, monacetin 1.2 percent, and
`water 2.1 percent.
`
`Example 2
`
`5.2 kg. of Spcentipoise type ‘methyl cellulose
`are treated with a hot solution of 150 g. of sorbi-
`tol in 27 liters of water, and the resulting mix-
`-ture is then cooled. Capsules prepared from this
`composition possessed greater flexibility and dis-
`solved much more readily in artificial gastric
`juice than those prepared ‘from methyl cellulose
`alone. For example, capsules prepared from
`methyl cellulose alone ruptured and liberated
`the medicaments contained therein when ex-
`posed to the action of artificial gastric juice at
`37° C.
`in approximately 10‘ minutes, but cap-
`sules prepared from the same lot of methyl cel-
`lulose with the addition of sorbitol, as described
`above, ruptured and liberated their medicaments
`in approximately 5» minutes. These capsules
`when in equilibrium with air of 40 percent rela-
`tive humidity at 20° C. had approximately the
`following composition: methyl cellulose 94.3 per-
`cent, sorbitol 3.3 percent, and water 3 percent.
`At high relative humidities these capsules dis-
`played a greater tendency to absorb water than
`those plasticized with monacetin.
`It is frequently desirable to prepare colored
`and/or opaque capsules in order to serve as a
`means of identification, to protect the ingredients
`thereof from the destructive action of light, or
`merely for aesthetic purposes. Methyl cellulose
`is very satisfactory for the preparationof cap-
`sules of this type and in many instances is supe-
`rior to gelatin. Generally, the gelatin used for
`the manufacture of capsules is treated with sul-
`fur dioxide to improve its clarity; However, the
`sulfur dioxide remaining in the gelatin (or by-
`7 products resulting from this treatment) .’fre-
`quently effect a deleterious action on certain
`colorants such as ponceau SX. Methyl cellulose
`on the other hand requires no corresponding
`clarifying treatment, and appears to have no
`deleterious efiects on colorants. Furthermore,
`since methyl cellulose can generally be utilized
`with substances within the pH range of 3 to 10,
`in contrast to the narrow range which must be
`maintained with gelatin, one is permitted greater
`freedom in the choice of colorants and is able
`to obtain different hues from the same colorant
`by taking advantage of the effect of pH changes
`in producing such hues.
`The colorant used for the preparation of col-
`ored methyl cellulose capsules may be an edible
`dye of plant or animal origin, such as carmine,
`cudbear, or caramel; or a synthetic certified dye
`' such as amaranth, brilliant blue F. C. F., eosin,
`erythrosine, guinea green certified, orange I,
`ponceau 3R, ponceau SX, sunset yellow F. C, F.
`and tartrazine. Combinations of these or other
`permissible colorants can be used to obtain meth-
`yl cellulose capsules of any desired color.
`‘
`Example 3
`‘l50 g. of sorbitol, 9 g. of ponceau SK, and 1.6
`g. of brilliant blue F. C. F. are dissolved in 25
`liters of_ hot water and the resultant solution is
`added to 5.2 kg. of 9 centipoise type methyl cel-
`lulose. This mixture is then stored at about 5°
`C. for 24 hours to allow the methyl cellulose to
`dissolve and atthe end of this period sufficient,
`5 water is added to bring the volume to 27 liters,
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`The solution is well mixed and allowed to stand
`for a few hours to permit separation of air bub-
`bles. This coating composition is then used to
`prepare brown capsules in the manner described
`above.
`Capsules made in accordance with this exam-
`ple, when in equilibrium with air of 40 percent
`relative humidity at 20° C., had approximately
`the following composition: methyl cellulose 93
`percent, sorbitol 3.3 percent, brilliant blue F. C. F.
`0.03 percent, ponceau SX 0.2 percent, and water
`3.5 percent.
`
`E..’L’£7o??'l113'l0 4
`
`Substantially 150 g. of sorbitol and 4.4 g. of
`brilliant blue F. C. F. are dissolved in 27 liters
`of water and the solution is poured over 5.2 kg.
`of methyl cellulose, 15 centipoise type, and the
`mixture is then stored at about 5“ C. for 24 hours.
`It is then thoroughly mixed to obtain a clear
`uniformly colored solution and allowed to stand
`an additional 12 hours at about 5° C. to allow
`the air bubbles to separate. The cold bubble-free
`solution is then used to prepare blue methyl
`cellulose capsules according to the described
`procedure. These capsules when in equilibrium
`with the air of 40 percent relative humidity at
`20° C. had approximately the following composi-
`tion: methyl cellulose 93.75 percent, sorbitol 2.7
`percent, brilliant blue F. C. F. 0.08 percent, and
`water 3.47 percent.
`Opaque capsules prepared from methyl cellu-
`lose made by incorporating small amounts of
`i.nsoluble and inert materials of very small par-
`ticle size in the capsule-forming composition are
`much more satisfactory than those prepared
`from gelatin because the former retain their.
`flexibility where as opaque gelatin capsules dis-
`play amarked tendencyto become brittle and
`shatter.
`Moreover, for some unknown reason, _
`the small amount of opacity-producing material
`expedites the thermogelation of
`the cellulose
`ether on the capsule-forming pins and thus per-
`mits an increased rate of capsule production.
`Two of the most frequently used inert materials ,
`for the preparation of opaque capsules are char-
`coal and titanium dioxide.
`It is necessary that
`the particle size of the material added to pro-
`duce opacity be rather small, preferably so that
`all
`the material will pass through a No. 200.
`standard mesh sieve. Uniform distribution of
`these insoluble materials in methyl cellulose
`solutions
`is
`facilitated by the use of small
`amounts of natural gums or surface tension de-
`pressants, such as “Aerosol OT" (3. sodium salt .
`oi dioctyl sulfosuccinate). The preparation of
`opaque capsules is illustrated by the following
`examples.
`
`Example 5
`
`About 150 g. of sorbitol are dissolved in 2'7 liters I‘
`of water and the solution is heated to boiling.
`70 g. of titanium dioxide are then slowly added
`while the mixture is stirred and the hot mixture
`thus obtained is added to 5.2 kg. of methyl cellu-
`The latter mixture is’
`lose, 9 centipoise type.
`allowed to stand for 24 hours at about 5° C., very
`thoroughly mixed, and then allowed to stand an-
`other 24 hours at about 5° C. to promote separa-
`tion of air bubbles. The white opaque methyl
`cellulose capsules prepared from the bubble-free
`coating composition in the manner described
`above were flexible and did not become brittle.
`When in equilibrium with air of 40 percent rela-
`tive humidity at 20° C. these capsules had the
`éwproximate composition: methyl cellulose 93
`
`8
`percent, sorbitol 2.69 percent, titanium dioxide
`1.25 percent, and water 3 percent.
`
`Example 6
`Substantially 150. g. of, acacia (a natural gum),
`150' g. of sorbitol, and 5 g- of caramel are dis-
`solved in 27 liters of .water.and the solution is
`heated to boiling. To the hot solution 70 g. of
`titanium dioxide are added slowly while the mix-
`ture is stirred and when the addition is complete,
`the mixture is added to 5 kg. of methyl cellulose,
`9 centipoise type. The latter mixture is allowed
`to stand at about 5“ C‘. for 24 hours, mixed very
`thoroughly to obtain a uniform distribution of
`the titanium dioxide, and then stored an addi-
`tional 24 hours at about.5° C. to promote the
`separation of air bubbles. The separation of the
`air bubbles can be facilitated by the addition
`of a few drops of an antifcam agent such as pine
`oil or by the use of reduced pressure as previ-
`ously mentioned. Buff-colored opaque capsules,
`prepared from this bubble-free coating composi-
`tion in'the manner described above, retained
`their flexibility even when dried in a vacuum
`desiccator. When in equilibrium with air of 40
`percent relative humidity at 20° C. these cap--
`sules had the approximate composition: methyl
`cellulose 89.75 percent, acacia 2.69 percent, sor-
`bitol 2.69 percent, caramel 0.089 percent, titani-
`um dioxide 1.25 percent and water 3.5 percent.
`Example 7
`A mixture of 5.2 kg. of methyl cellulose, 9 cen-
`tipoise type, and 50 g. of monacetin is treated
`with 27 liters of boiling water and the mixture
`is allowed to stand at about_5° C. for 24 hours.
`A mixture of 50 g.,of charcoal and 0.5- g. of
`“Aerosol OT” (100 percent)
`is triturated in a
`cold mortar with -about a liter of cold water to
`form a suspension. This suspension is added
`to the cold methyl cellulose solution, mixed thor-
`oughly and the whole maintained at about 5° C.
`The mixing is continued until a uniform distri-
`bution of the charcoal is obtained. This mixture
`is then allowed to stand an additional 24 hours
`to obtain a substantially bubble-free coating
`composition. From this, dark opaque capsules
`are prepared in the manner described above.
`Such capsules, when in equilibrium with air of
`40 percent relative humidity at 20° C., had ap-
`proximately the following composition; methyl
`cellulose 96.2 percent, monacetin 0.92 percent,
`charcoal 0.92 percent, “Aerosol OT” 0.0092 per-
`cent, and water 2 percent.
`By utilizing the unique gel-forming property
`of methyl cellulose it has been found possible to
`prepare capsules containing methyl cellulose as
`the principal component with the admixture of
`small amounts of compatible cellulose derivatives
`such as water-soluble hydroxyethyl cellulose, nat-
`ural gums, and synthetic water-soluble polymers
`such as “Carbowax 4000” (a polyethylene glycol
`with an average molecular weight of about 4000).
`The admixture of
`these materials to methyl
`cellulose solutions has the effect of raising the
`temperature required to induce gel formation
`and therefore it will in most instances be advis-
`able to use not more than 20 percent of such
`material (based on the weight of the dried cap-
`sule). The preparation of capsules containing
`such admixed materials is illustrated in the fol-
`lowing examples.
`’
`Example 8
`580 g. of “Carbowax 4000” are dissolved in 27
`liters of boiling water and the solution thus ob-
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`tained is poured over a mixture of 58 g. of mon-
`acetin and 5.2 kg. of methyl cellulose, 15 centi-
`poise type. The latter mixture is allowed to
`stand at about 5° C. for 24 hours to obtain a sub-
`stantially bubble-free solution’ suitable for coat-
`ing. Capsules are prepared from this composi- _
`tion in the manner described above and by per-
`forming the dipping and gelation operations at
`about the upper temperature limits there stated.
`Capsules so made when in equilibrium with air
`of 40 percent relative humidity at 20° C. had the
`approximate composition 1‘ methyl cellulose 87.25
`percent, “Carbowax 4.000" 9.78 percent, menace-
`tin 0.97 percent, and water 2 percent.
`'
`Example 9
`
`10
`sules was less than 1 percent, whereaswith gela-
`tin capsules of the “run of the mill” the loss
`was 15 percent, and sometimes as high as 20
`percent.
`'
`Since many medicinal preparations must be
`prepared to contain considerably less than 8.per.-
`cent moisture (the approximate lower limit of
`satisfactory utility of the gelatin capsule), the
`advantage of the methyl cellulose capsule is ob-
`vious. Thus, methyl cellulose capsules can, if
`desired, be dried before filling them with essen-
`tially dry medicaments by exposing them to a
`dry atmosphere or by vacuum drying. A similar
`procedure is not practical with gelatin capsules
`since, as mentioned before, gelatin capsules con-
`taining much less than 7 percent moisture are
`too fragile for filling and handling operations.
`If desired, methyl cellulose capsules containing
`, medicaments can be stored in a container in con-
`junction with eifective drying agents, such as
`{anhydrous calcium chloride,
`to maintain the
`medicament
`in a substantially’ dry state and
`preventdeterioration due to theabsorption’ of
`moisture.
`Having described my invention, what I .claim
`and desire to secure by Letters Patent is:
`1. A telescoping medicinal capsule,
`the sub-
`stance of which comprises a thermo-gelled film
`of a water-soluble methyl cellulose having a
`methoxyl content of about 25 to about 35 percent
`and an intrinsic viscosity of about 7 to about 15
`centipoises.
`2. A telescoping medicinal capsule, the sub-
`stance of which comprises a thermo-gelled film
`of a water-soluble methyl cellulose having a
`methoxyl content of about 30 percent and an
`intrinsic viscosity of about 9 centipoises.
`3. A telescoping medicinal capsule, the sub-
`stance of which comprises a thermo-gelled film
`of a water-soluble methyl cellulose having a
`methoxyl content of about 25 to about 35 percent
`and an intrinsic viscosity of about 7 to about
`15 centipoises, and a compatible plasticizer there-
`for.
`=
`4. In the process of making a telescoping
`medicinal capsule, the steps which comprise ap-
`plying a film of an aqueous solution of a methyl
`cellulose ether having a methoxyl content of
`about 25 to about 35 percent and an intrinsic
`viscosity of about 7 to about 15 centipoises, to
`a capsule-forming member heated above the gel
`point of said solution to cause thermo-gelation
`of a film of methyl cellulose on said member, and
`maintaining said film and said member continu-
`ously in heated condition from the moment of
`commencement of said thermo-gelation until the
`film is rendered self-sustaining in form.
`5. The method of manufacturing a telescoping
`medicinal capsule from a water-soluble, thermo-
`gellable methyl cellulose having a methoxyl con-
`tent of about 25 to about 35 percent and an
`intrinsic viscosity of about '7 to about 15 centi-
`- poises, which comprises dipping into an aqueous
`solution of said methyl cellulose capsule-form-
`ing members heated above the gel point of said-
`methyl cellulose to form thereon a film of said
`methyl cellulose and supplying heat to said cap-
`sule-forming member and film thereby maintain-
`ing said film in thermo-gelled state, and remov-
`ing substantially all water from said thermo-
`gelled film to render said film self-sustaining.
`6. The method of manufacturing a telescoping
`medicinal capsule from a water-soluble methyl
`cellulose having a methoxyl content of about 25
`to about 35 percent and an intrinsic viscosity of
`
`A mixture of 4.7 kg. of methyl cellulose, ‘9 cen-
`tipose type, 540 g. of water-soluble hydroxyethyl
`cellulose, and 160? g. of sorbitol is treated with
`27 liters of boiling water to obtain a coating
`composition. Capsules prepared from this coat-
`ing composition by the process described above
`when in equilibrium with air of 40‘ percent rela-
`tive humidity at 20° C‘. had the approximate
`composition: methyl cellulose 83.5 percent, wa-
`ter-soluble hydroxyethyl cellulose 9.6 percent,
`sorbitol 2.85 ‘percent and water 4 percent.
`After methyl cellulose capsules have been filled
`with a medicinal agent they can be sealed by
`applying a band of methyl cellulose to the region
`where the telescoping end of the capsule cap en-
`circles the capsule body. This is conveniently
`accomplished by extruding a cold 15 percent
`aqueous solution of the 9 centipoise type onto
`this region in a thin band and subsequently re-
`volving the capsule until the band has substan-
`tially dried. The band applied may be of the
`same color or a distinctive color from that of the
`body of the capsule. Other water-soluble cellu-
`lose derivatives which can be utilized in aqueous
`solution as capsule-sealing material are water-
`soluble salts, such as sodium and ammonium
`salts, of carboxymethyl cellulose and cellulose
`acetate-phthalate, and hydroxyethyl cellulose.
`Gelatin capsules when in equilibrium with air
`of 50 percent relative humidity at 201° C. contain
`about 25 percent of moisture, which causes exces-
`sive swelling and renders them unsuitable for
`mechanical filling operations.
`,Methyl cellulose
`capsules, plasticized with 3 percent sorbitol, un- r
`der the same conditions contain 7 percent of
`moisture and remain wholly suitable for filling
`operations.
`If both capsules are stored at 25°
`C. in an atmosphere dried with silica gel, the
`moisture content of the gelatin capsule is re-
`duced to 7.5 percent and that of the methyl cel-
`lulose capsule to 1.3 percent. The gelatin cap-
`sule, however, is now very brittle and is easily
`shattered or broken upon handling or being
`otherwise manipulated in filling operations,
`whereas the methyl cellulose capsule still retains
`substantially its original flexibility and