US 2155445 A
Description (OCR text may contain errors)
April 25, 1939. P. s. PITTENGER ET AL 2,155,445
MANUFACTURE OF HEXYLRESORCINOL CAPSULES Original Filed May 10, 1935 2 Sheets-Sheet l ISnventor: Paul J Pz'iicz ycr' @7727 W Jesigsr attorney- Patented Apr. 25, 1939 MANUFACTURE or HEXYLRESORCINOL CAPSULES Paul s. Pittenger and John w. Jester, Philadel- Pa., assignors to Sharp & Dohme, Incorporated, Philadelphia,- Pa., a corporation of Maryland rlginal application Mario, 1935, Serial No.
20,859. 'Dividcd and this application August 20, 1935, Serial No. 37,695
This invention relates to the production of hexyl resorcinol capsules. More particularly the invention relates to a new method of making the new capsules described and claimed in our parent application Serial No. 20,859,'-filed May 10, 1935, of which this application is a division.
The new capsules, produced by the new method of the present invention, contain solid hexyl resorcinol in the form of a pill or tablet coated with a tough, tenacious, or soluble coating of soluble elastic sheet gelatin or similar material in which the hexyl resorcinol is hermetically sealed.
The improved process of the invention is one in which soluble elastic sheet gelatin has depressions or cavities preformed therein by the action of a l vacuum, which cavities receive the solid hexyl resorcinol pills or centers, and in which the preformed sheets of gelatin, with the pills contained in the depressions or cavities, are subjected to pressure between suitable dies to cut the gelatin 0 sheets and hermetically seal the layers of gelatin together around the hexyl resorcinol center.
Hexyl resorcinol in solid or crystalline form has valuable properties as an anthelmintic but it is difiicult to administer without injury to the mucous membranes of the mouth and throat. Pure hexyl resorcinol crystals, because of their phenol-like properties, have a local coagulating effect on the mucous membranes of the mouth and throat, so that it is important that the hexyl resorcinol crystals be kept from coming into direct contact with themouth when administered. I1 hexyl resorcinol is placed in the ordinary hard gelatin capsules it affects the gelatin in a deleterious manner with the result that after a certain time'the gelatin of the capsules becomes full of pinholes. If the hexyl resorcinol pill is coated with gelatin by the ordinary coating and dipping process, in which a solution of the gelatin is used for coating the pills, with drying of the moisture o from the coating, the gelatin is similarly affected in a deleterious way by the hexyl resorcinol. Attempts have been made to coat the hexyl resorcinol pills with sugar but the sugar coating does not adhere satisfactorily, owing to the greasy nature of the hexyl resorcinol, with the result that the coating tends to crack off of the pill with the slightest pressure between the teeth. A sugar coating also readily dissolves in the mouth and causes the hexyl resorcinol to come into contact with the membranes of the mouth. A chocolate v coating on the hexyl resorcinol pills is similarly objectionable.
There is a natural tendency on the part of those taking the capsule, or several capsules, to hold them in the mouth and to chew them, particularly in the case of children, and with coatings which are soluble in the mouth and are removed, or with coatings which are easily broken or crushed between the teeth, there is danger of tively thick sheet of such tough, soluble, plastic,
elastic sheet gelatin and hermetically sealing the gelatin around the hexyl resorcinol a satisfactory capsule can be produced with a tough, tenacious coating which is difiicult to chew so that the eapsules can be administered with a minimum of danger of injury to the mouth by releasing of the hexyl resorcinol before it reaches the digestive tract. The objectionable burning eiiect which hexyl resorcinol causes when it comes into direct contact with the mucous membranes of the mouth and throat is not shown when the capsules reach the stomach and the hexyl resorcinol is released from the capsules and admixes withthe contents of the stomach and passes therewith through the intestines, even though large amounts of hexyl resorcinol are thus administered for anthelmintic purposes.
It has been customary, in the production of liquid-containing capsules, to use soluble sheet gelatin, to place a sheet of the gelatin in a female mold member having raised edges and having spaced openings therein, to pour the desired amount of liquid to be incapsulated on the sheet,
then to place a second sheet of gelatin over this liquid in a manner which eliminates all air bubbles, and with the edge of the top sheet overlapping the raised edges of the lower sheet, and
then to place a male mold member, having openings opposite those in the female member, on top of the top sheet, and place the mold members in a hydraulic press, where the pressure is applied. As the mold members are forced together, the liquid, not being able to escape, pushes the elastic gelatin in both directions into the openings, thus forming the upper and lower halves of the capsule, and the action of the mold members finally cuts the gelatin. and forces the edges together, thus hermetically sealing the capsules.
This method of forming gelatin coated cap:
sules, whil satisfactory for the incapsulation of liquids, cannot be applied to the coating of solid pills or tablets.
We have found, however, that if the sheet galatin is subjected to a preforming-treatment by the application of a vacuum in a suitable mold having openings therein, depressions or recesses can be made in the sheet; in which the pills or tablets can be placed, and by suitable preforming depressions in the top sheet of gelatin, these pills or tablets can be enclosed, and the sheets can then be forced together and hermetically sealed by the application of pressure to give a continuous tough, elastic gelatin coating which resists the action of the teeth and which protects the hexyl resorcinol when the capsule is administered. The preforming of the depressions or recesses in the gelatin sheets, by the application of vacuum, is important, since it insures a practically uniform thickness of the gelatin coating without tearing of the gelatin sheet and without variations in the thickness of the coating at diflerent parts such as would be caused by the action of the mold members if the depressions or recesses had not been preformed in the sheets before the pressing andcutting operation was applied.
The hexyl resorcinol pills or centers which are coated with sheet gelatin, in making the new capany suitable way, for expulverous pills of suitable sules, may be made in ample, in the form of size, e. g., containing 0.2 gr. may themselves contain some moisture, and the soluble elastic gelatin may also contain some moisture as well as glycerin. In order to protect the hexyl resorcinol and the gelatin coating from coming into contact with each other, and to prevent or minimize any action of the hexyl resorcinol upon the gelatin coating, the hexyl resor-. cinol pills are advantageously coated with a thin layer of an inert material, such as starch, which will form an insulating layer between the hexyl resorcinol and the gelatin coating.
In making the new capsules it is possible to use -molds such as have heretofore been commonly used for making liquid-containing capsules of sheet gelatin, but these molds are modified to permit the application of a vacuum to draw the sheet gelatin down into the openings in the lower or female mold member, thereby forming depressions or recesses in which the hexyl resorcinol pills can be placed, and provision is also made for applying a vacuum to the upper sheet of gelatin to form corresponding recesses or depressions in it, corresponding to the openings in the upper or male mold member, so that, when the upper or male member is placed on top of the lower mold member, the depressions in both sheets of gelatin will have been preformed, and the mold members can then be placed in a hydraulic press and the two sheets forced together to cut the capsules from the sheets andto cause the edges of the two sheets to come together to form a seal, thus giv-.
ing hermetically sealed capsules.
The invention will be further described in connection with the accompanying drawings, which illustrate, more or less diagrammatically, an apparatus adapted for the practice of the process of the invention.
In the accompanying drawings,
Fig. 1 is a transverse vertical section of part of the apparatus showing the lower mold member and part of the vacuum producing equipment;
Fig. 2 is a similar view showing the gelatin sheet with depressions formed in it by means of the vacuum;
are depressed portions These pills or centers Fig. 3 is a similar view showing the pills inserted in the depressions and covered with another gelatin sheet;
Fig. 4 is a similar view showing the preforming of depressions in the upper gelatin sheet by the application of a vacuum;
Fig. 5 is a similar view with the upper mold member applied;
Fig. 6 is a view showing the mold members and capsules after pressure has been applied;
13g. 7 is a plan view of the apparatus of Fig. 1; an
Fig. 8 shows the finished capsule.
The lower or female mold member I is shown as supported by the rubber gasket 2 above a vacuum chamber 3 having pipe connections 4 and 5 leading to a vacuum producing means (not shown), and valve 6 for connecting or disconnecting the vacuum chamber with the vacuum producing means.
The mold member I has a raised edge portion I and a series of openings 8 having a diameter and/or shape corresponding to that of the capsule to be produced, these openings being surrounded by raised cutting edge portions 9, between which guide lugs I I for centering the upper mold member, or mold member frame, when applied.
On one side the mold member I has a groove I2 adapted to receive a pipe I3 connected through the flexible pipe connection Iltand the pipe IS with the vacuum producing means. A valve I8 ID. The mold member has is provided for connectingand disconnecting this a pipe with the vacuum producing means.-
The gelatin sheet I1 is shown in Fig. 1 as it is first applied to the lower mold member, and in Figs. 2, 3 and i as having depressions or recesses I8 formed by the application of a vacuum to the lower side of the gelatin sheet. The pills I9 are shown in Figs. 3 and 4 as located in the depressions III. The top sheet of gelatin is shown in Fig. 3 as first applied, and in'Fig. 4 as it exists after the vacuum has been applied between the two sheets, and with preformed recesses 22 simi-,
lar to the recesses I8 of the lower gelatin sheet.
The upper mold member 25 is shown in Figs. 5 and 6, this. mold member being enclosed in 'a frame 23 having openings or recesses aligning with the lugs I I of the lower mold member. The upper mold member has openings 28, cutting edges 21 and depressions 28 corresponding tothe similar elements of the lower mold member;
The finished capsules 29 are shown'ih Figs. 6 and 8, these capsules having the central solid pill I9 surrounded with a thin layer of inert material such as starch, indicated at 33, and with a continuous gelatin coating made up of the upper ducing means to cause the gelatin to be drawn into the openings 8', thus 'preforming the depressions I8 in the gelatin sheet as shown in Fig. 2. The pills to be coated are then placed in the depressions thus formed, as shown in Fig. 3.
The pipe I3 is then inserted in the groove I2 above the lower gelatin sheet, and the upper gelatin sheet 20 is then laid over'the pills as shown in Fig. 3. As thus applied, the sheet contacts only with the pills at their highest points, and the edges of the upper sheet extend over the edges or the lower sheet and form av tight seal, with the pipe I1 extending betwee the edges or the two sheets. v
A vacuum is now applied through the pipe i3 and between the two sheets is withdrawn and the upper sheet is forced down around thepills and against the lower sheet, thus preforming recesses or depressions 22 in the upper sheet corresponding to the recesses or'depressions I. in the lower sheet. The action oi! atmospheric pressure above the top sheet, together with the 5 application of a vacuum between the two sheets,
while maintaining a vacuum below the lower sheet, results in uniformly stretching the gelatin of the upper sheet around the upper portions of the pills. A somewhat higher degree 01 vacuum can be applied between the sheet than that maintained below the lower sheet, so that the depressions or recesses in the upper and lower sheets will be of approximately the same depth, and so that approximately half of each pill will be ;5 covered by eachof the gelatin sheets.
Before releasing the vacuum the upper or male mold member and its surrounding frame are placed upon the upper sheet, as shown in Fig. 5. The vacuum is then released, the pipe I! m removed, and the upper and lower mold members are then placed in a hydraulic press (not shown) or other suitable press or means of applying a high pressure to force the upper and lower mold members together and cut the two sheets of gelatinand to force the edges of the cut sheets together to form a seal and complete the capsule-as shown in Figs. 6 and 8.
The pills I! may be. made in an ordinary pill or tablet machine, and these may have only suiiicient strength to withstand handling and such pressure as is applied during the applying I of the gelatin sheets thereto. These pills may, as
previously stated, advantageously be coated with a layer of inert material, such as starch, before the gelatin coating is applied. The finished capsules, shown in Fig. 8, have the central pill IS with the layer of starch or other inert material 33 surrounding them, and with'the outer gelatin coating which is made up of the upper and lower 0 parts 30 and 3i, of generally semi-spherical shape, united at 32 where the cut edges of the gelatin sheets are forced together under the high pressure and efiectively sealed to give, in eifect, a continuous gelatin coating which is,
5 however, made up of two parts of sheet gelatin integrally united together.
The result of the preforming .oi' the depressions or recesses in the upper and lower gelatin sheets is to stretch the gelatin more or less uniformly so that the coating as a whole is of approximately uniform thickness. B'ecause gelatin is elastic, it is important to hold the vacuum on the sheet after the depressions are preformed therein, and until the mold members are brought together, and the application of a vacuum between the sheets has the added advantage of removing air so that, when the capsules are sealed, they are free or substantially s'o from air.
The pills are thus retained in an evacuated and tin, as the mold, used in this way, simply serves to press the cutting i'aces together, thus hermetically sealing and dieing out the coated pills.
The new hexyl resorcinol capsules, produced as above described, contain the solid crystalline hexyl resorcinol protected by the layer of starch from direct contact with the gelatin coating, and they have a soluble plastic elastic gelatin coating hermetically sea-ling them, which coating, because it is tough, elastic and tenacious, is dimcult to chew, and is not readily removed to permit the hexyl resorcinol to escape and come into contact with the mouth when the capsules are administered.
The new hexyl resorcinol capsuleshave been subjected to extensive clinical tests, and the results have proven these capsules to be highly satisfactory for oral administration for anthelmintic purposes. Crystalline hexyl. resorcinol, properly administered, is remarkably eflfective in the treatment of Ascaris, hook worms and pinv worms, and the new capsules oi the present invention are particularly advantageous for oral administration for that purpose. The tough elastic nature of "the sheet gelatin coating reduces to a minimum the danger of breaking or cracking of the coating by chewing, particularly when administered to children, while the nature and method oi application of the coating protects the hexyl resorcinol both prior to and during the time 01' administration but nevertheless enablesit to be readily made effective when the capsules are swallowed and the soluble gelatin coating is removed. 1
While we have described the use oi. soluble elastic sheet gelatin for forming the coating around the capsules, other suitable tough, elastic, soluble material can be used provided it has a suflicient degree of toughness, elasticity, etc., to permit it to be preformed and sealed in a similar way, and a suflicient degree of solubility to enable it to serve as a soluble coating which will release the hexyl resorcinol after swallowing 01' the capsules, but protect the hexyl resorcinol prior to and during administration.
We claim: 1. The process of producing coated pills of solid hexyl resorcinol which comprises coating solid hexyl resorcinol pills with a coating of an 1 the application of a vacuum thereto, inserting solid hexyl resorcinol pills in said depressions, applying another'sheet 0! such material to enclose the pills, applying a vacuum between the two sheets to form depressions in the second sheet corresponding to and opposite to those formedin the first sheet, applying a mold member to mold the sheets together while the vacuum is still maintained, releasing the vacuum and sub- Jecting the mold members topres'sure to cut the two sheets of material to cause the edges 01' the cut portions to adhere together to form hermetically sealed coated pills.
. resorcinol pills applying a vacuum between 3. The process of producing coated pills of solid hexyl resorcinol which comprises applying -a sheet of soluble elastic, material to a mold member, applying a vacuum to form recesses or depressions in in said depressions, applying another similar sheet of material over said pills, the two sheets to produce recesses or depressions in the top sheet and remove the air from between the sheets, ap-
plying another mold member above the top sheet atin with corresponding and opposite recesses or depressions to enclose the pills oi hexyl resorcinol and cutting the two sheets of gelatin and applying pressure thereto to cause the edges of the cut portions to adhere together to form hermetically sealed coated pills.
5. The process of producing coated pills of solid hexyl resorcinol which comprises preforming recesses or depressions in a sheet of soluble elastic gelatin, inserting solid hexyl resorcinol pills in said depressions, applying another similar sheet of gelatin and forming recesses or depressions therein by applying a vacuum between the two sheets, and cutting the two sheets of gelatin and applying pressure thereto to cause the edges of the cut portion to adhere together to form hermetically sealed coated pills.
6. The process of producing coated pills of" solid hexyl resorcinol which comprises coating solid hexyl resorcinol pills with an inert coating said sheet, inserting solid hexyl of starch or similar material, inserting the coated hexyl resorcinol pills inpreiormed recesses in a sheet of soluble elastic gelatin, applying another similar sheet of gelatin with corresponding and opposite recesses or depressions to enclose the pills, and cutting the two sheets of gelatin and applying pressure thereto to cause the edges oi! the cut portions to adhere together to form hermetically sealed coated pills.
'7. The process of producing coated pills oi solid hexyl resorcinol which comprises preforming depressions in a sheet of soluble elastic gelatin, supported by a mold member, by the application or a vacuum thereto, inserting solid hexyl resorcinol pills in said depressions, applying another sheet of gelatin to enclose the pills, applying a vacuum between the sheets of gelatin to form depressions in the second sheet corresponding to and opposite to those formed inthe first sheet, applying a mold member to hold the sheets together while the vacuum is still maintained,
releasing the vacuum and subjecting the mold members to pressure to cut the two sheets of gelatin and cause the edges of the cut portions to adhere together to form hermetically sealed coated pills. v
8. The process of producing coated pills of solid hexyl resorcinol which comprises preforming recesses or depressions in a sheet of soluble elastic coating material, coating solid hexyl resorcinol pills with an inner coating of inert material, inserting the coated hexyl resorcinol pills in the preformed depressions or recesses, applying another similar sheet of soluble elastic coating material with corresponding and opposite recesses or depressions to enclose the pills of hexyl resorcinol and cutting the two sheets of material and applying pressure thereto to cause the edges of the two portions to adhere together to form hermetically sealed coated pills.
' PAUL S. PITTENGER.
JOHN W. JESTER.