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US3071513A - Process for sealing capsules - Google Patents

Process for sealing capsules Download PDF

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Publication number
US3071513A
US3071513A US854566A US85456659A US3071513A US 3071513 A US3071513 A US 3071513A US 854566 A US854566 A US 854566A US 85456659 A US85456659 A US 85456659A US 3071513 A US3071513 A US 3071513A
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Prior art keywords
capsule
capsules
sealing fluid
sealing
percent
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US854566A
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Boer Herman R De
Thurlow E King
Edwin L Knoechel
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Pharmacia and Upjohn Co
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Upjohn Co
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/07—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use
    • A61J3/071—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use into the form of telescopically engaged two-piece capsules
    • A61J3/072—Sealing capsules, e.g. rendering them tamper-proof
    • 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
    • A61K9/4883—Capsule finishing, e.g. dyeing, aromatising, polishing

Definitions

  • This invention relates to a method of sealing filled hard gelatin capsules.
  • a hard gelatin capsule consists of two cylinders of gelatin each of which is open at one end and closed at the other end by a domeshaped seal.
  • One of the cylinders is slightly longer but smaller in diameter than the other and is termed the base or body.
  • This member is filled with the drug mixture or medicament or other substances and is then forced into the other cylinder which is termed the cap.
  • the cap generally fits fairly tightly over the base, but even though the cap and base are made with the greatest possible precision the assembled capsule is usually not entirely spill-proof.
  • the filled capsules will on rough handling, for example, when passed through a high-speed machine for branding or filling into bottles or other containers, show evidence of spillage of the contentssometimes because of leakage between the surfaces of the cap and the base, bht often because the cap and base come apart. Accordingly, it is desirable that the hard gelatin capsule after filling be sealed so as to reduce leakage, to prevent the cap and base from falling apart, and to reduce contamination of the contents by air, moisture, etc.
  • sealing as employed in the specification and claims includes not only treatments in which the gap between the cap and base of a capsule is completely closed but also treatments in which said gap is only partially closed. Sealing within the context of the present invention has been eiiected when the cap and base cannot be separated or can be separated only with difficulty by hand.
  • Another method which has been employed to seal hard capsules comprises the dipping of the filled and assembled capsule in a solution of aqueous formaldehyde.
  • This process has a denaturing effect upon the gelatin which becomes more difficult to digest in the gastrointestinal tract.
  • the method cannot be used to encapsulate medicaments which are required to be released in the gastro-intestinal tract within a relatively short period of time.
  • the method results in small amounts of formaldehyde solution entering the capsules, particularly where the cap does not fit tightly over the base.
  • a method of sealing which is commonly employed consists in placing a band of gelatin in a slightly molten state around the joint between the cap and the base.
  • the use of this method requires expensive machinery, since each capsule must be banded individually. Further, the method requires rigorous inspection of all banded capsules to reject any which have not been sealed satisfactorily. Accordingly, the use of the method increases considerably the cost and the production time involved in the sealing of the capsules.
  • Another method proposed for the sealing of hard gelatin capsules involves heat treatment as set forth in US. Patent 2,738,827. This method produces distortion of the capsule and application of heat to the capsule cannot be carried out in the case of capsules containing heat-labile material.
  • the process of the invention consists in contacting a hard gelatin capsule, which has been filled with medicament or other material and then fully assembled, with a sealing fluid comprising a dispersion of an airdrying, hydrophilic, film-forming polymer in an organic solvent.
  • the organic solvents which can be employed in the process of the invention include lower alkanols such as methanol, ethanol, propanol, isopropyl alcohol, and the like, lower alkanones such as acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone and the like, and lower aliphatic chlorinated hydrocarbons such as trichloroethylene, carbon tetrachloride, dichlorethane, tetrachloroethane and the like, and mixtures of any of the above-named solvents.
  • lower alkanol is employed as solvent it is advantageous that said alkanol should contain a small amount of water. However the amount of water present in said alkanol should not be substantially greater than about 5 percent by volume otherwise distortion of the capsules may occur.
  • Air-drying, hydrophilic, film-forming polymers which can be used in the process of the invention include polycarboxylic acid polymers, i.e., polymers which contain free carboxylic acid groups in the units forming the polymer, and polyhydroxylated polymers, i.e., polymers which contain free hydroxyl groups in the units forming the polymer.
  • the hydrolyzed styrene-maleic anhydride copolymers which canbe used in the process of the invention comprise styrene-maleic anhydride copolymers which are more than 50 percent hydrolyzed.
  • the copolymer can be modified to a minor extent by the presence of some other homopolymer-izable ethylenic unit, such as that of acrylonitrile, acrylic acid, methacrylic acid, itaconic acid, vinyl chloride, vinylidene chloride, dipentene, and the like.
  • hydrolyzed styrene-maleic anhydride copolymer includes such modifications as well as modifications in the structure and method of preparation which do not alter the essential resinous nature, toxicity and acid properties of the copolymer.
  • styrene-maleic anhydride copolymers which can be employed in the process of the present invention can be represented by the following formula:
  • RX YD wherein R represents homopolymerizable ethylenic units of which more than 70 percent are styrene units (the other ethylenic units being those of acrylonitrile, acrylic acid, methacrylic acid, itaoonic acid, vinyl chloride, vinylidene chloride, dipentene, and the like), X represents ethylenic units of maleic acid and maleic anhydride of which more than 50 percent are maleic acid units (preferably more than 70 percent), and x/y equals from 1 to about 4 (preferably from 1 to about 1.2).
  • the average molecular weight of the copolymer ranges from about 20,000 to about 200,000.
  • the present invention relates to hydrolyzed styrene-maleic anhydride copolymers which are more than 50 percent hydrolyzed. It includes the material described no matter how it is produced or how it is modified so long as the structure of the copolymer is primarily that of hydrolyzed styrene-maleic anhydride copolymer of the indicated properties and structure.
  • Styrene-maleic anhydride copolymer is a commercially available compound which can be obtained in modified or unmodified form.
  • Resin SC-2 is available from the Monsanto Chemical Company and is a modified styrenemaleic anhydride copolymer. These copolymers are hydrolyzed to obtain a styrene-maleic acid copolymer which is useful in the process of the present invention.
  • the hydrolysis can be partial or it can be complete and involves a conversion of the acid anhydride linkages to Oc-dlCfllbDXYiiC acid units. It is preferred that the hydrolysis be substantially complete i.e., more than about 50 percent complete.
  • Polyvinyl ether-maleic anhydride copolymers which can be used in the process of the invention, after hydrolysis or alcoholysis as hereinafter described, are the linear copolymers of alternating methyl vinyl ether and maleic anhydride units.
  • Examples of such copolymers are those which are available commercially from the General Aniline and Film Corporation under the designation PVM/MA. These copolymers can be obtained with different viscosity ranges varying from 0.2 to 6 18p) (1 g./ 100 ml. of 2-butanone at 25 C.) according to the chain length.
  • copolymers do not themselves contain hydrophilic groups but when dissolved in water or in alkanols are hydrolyzed or alcoholyzed with the formation of free carboxylic acid groups. Thus when dissolved in water the anhydride groups are hydrolyzed to m'aleic acid residues. When dissolved in alkanols the anhydride groups break down with the formation of half esters leaving one free carboxylic group in each maleic acid residue. Accordingly these copolymers are employed in the process of the invention in the form of a solution thereof preferably in a lower alkanol such as ethanol which solution may contain up to about percent water as hereinbefore described.
  • copolymers can be dissolved directly in the alkanol but the rate of solution is slow and solutions are prepared more conveniently by first dissolving the copolymer in a small amount of a ketone such as acetone, methyl ethyl ketone, and the like, and then diluting the resulting solution with the lower alkanol.
  • a ketone such as acetone, methyl ethyl ketone, and the like
  • the polyacrylic acids which can be used in the process of the invention include polyacrylic acid, polymethacrylic acid and partially or completely hydrolyzed polyacrylonitrile, polymethacrylonitrile, polyacrylamide, polymethacrylamide, polyacrylic acid esters, polymethacrylic acid esters and copolymers of acrylic acid or methacrylic acid with acrylonitrile, acrylamide or acrylic acid esters.
  • the hydrolysis of the said nitriles, amides and esters and copolymers thereof is more than 50 percent complete and preferably the hydrolysis is substantially 100 percent complete. It is to be understood that the term polyacrylic acids as used in the specification and claims includes both polyacrylic acid and all the above-mentioned derivatives thereof.
  • polyhydroxylated polymers examples include polyvinylalcohols, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers, and partially etherified cellulose.
  • polyvinylalcohols includes all polymers produced by the hydrolysis of polyvinyl esters, usually the acetate.
  • the properties of these polymers vary according to the molecular weight of the parent polyvinylacetate and the extent of hydrolysis. The degree of hydrolysis is generally indicated by the percent acetate content and for the purposes of the present invention it is preferred to use polyvinyl alcohols wherein the acetate content is within the range of about percent to about 50 percent.
  • the molecular Weight of polyvinyl alcohol varies from about 10,000 to about 400,000 but, for the purposes of the present invention we prefer to use material having a molecular weight within the range of about 25,000 to about 50,000.
  • Typical of products which are commercially available is Elvanol 72-60 Polyvinyl alcohol which is marketed by E. I. du Pont de Nemours and Company.
  • partially etherified celluloses includes the methyl, ethyl and higher alkyl ethers of cellulose in which 1 name Ethocel is typical.
  • the preferred alkyl cellulose is ethyl cellulose in which the ethoxyl content ranges from about 43 to about 50 percent, of which the product available commercially under the
  • the partially etherified celluloses are employed in the process of the invention in the form of solutions in chlorinated hydrocarbon solvents such as those hereinbefore described.
  • the concentration of air-drying, hydrophilic, filmforming polymer, hereinafter referred to as filler material, present in the sealing fluid employed in the process of the invention is advantageously within the range of about 1 percent to about 20 percent.
  • concentrations higher than 20 percent leads to practical difliculties due to the high viscosity of the sealing fluid and to excessive deposit of filler material on the treated capsules.
  • concentration of filler material in the sealing fluid is within the range of about 2.5 to about 5.0 percent.
  • the process of contacting the filled capsules with the sealing fluid can be carried out in a number of ways.
  • the capsules can be dipped into the sealing fluid using apparatus which is conventional for such purposes.
  • the capsules can be sprayed with the sealing fluid using conventional apparatus.
  • the actual time during which the sealing fluid is in contact with the capsule is not critical, the essential requirement being that the area of the capsule around the region of the joint between the cap and base be thoroughly wetted with the sealing fluid.
  • unduly prolonged contact between the sealing fluid and the capsules is to be avoided to minimize the possibility of contamination of the contents of the capsule.
  • a contact time of the order of about seconds or less is sufficient to effect excellent sealing of the capsules.
  • the concentration of filler material in the sealing fluid is within the preferred range of about 2.5 to about 5 percent the amount of filler material which remains on the external surface of the capsules, after the latter have been contacted with the sealing fluid and allowed to drain, is very small and no washing or other treatment of the capsules is necessary before these are dried.
  • higher concentrations of filler material it is desirable to Wash the capsules after contacting the latter with sealing fluid to avoid the presence of excessive deposits of filler material on the capsules.
  • the Washing can be effected using the same solvent employed in the sealing fluid or using any of the other solvents listed above.
  • the capsules are dried.
  • the drying step can be accomplished using methods well known in the art, for example by exposing the treated capsules to a current of dry air.
  • the amount of filler material which remains on the surface of the capsule after sealing according to the process of the invention is very small and is usually of the order of about 20 milligrams to about 100 milligrams.
  • the actual amount deposited on the capsule naturally varies with the size of the capsule.
  • the capsule of size 0, which is that most frequently used in dispensing pharmaceutical preparations, has been found to have about 30 to about 40 milligrams of filler material deposited on its surface (including the gap between the apposite sides of the cap and base) after sealing according to the process of the invention.
  • the capsules which are sealed according to the process of the invention, are intended to be used for pharmaceutical purposes it is necessary to employ a filler material which is pharmaceutically acceptable.
  • the preferred filler materials for this purpose are polyvinylpyrrolidone and hydrolyzed styrene-maleic anhydride copolymers. Where the sealed capsules are to be employed for non-pharmaceutical purposes, such considerations of purity of the filler material do not apply.
  • a particularly convenient method of carrying out the steps of sealing and, if desired, washing the capsules consists in supporting the filled capsules, for example on a wire mesh screen, whilst moving the capsules successively through an area in which they are sprayed with sealing fluid, then, if desired, through an area in which they are sprayed with washing solvent, and finally through an area in which they are dried.
  • the surfactants employed in the sealing fluid are nonionic surfactants such as ethylene oxide-polypropylene glycol condensates (Pluronic F68), sorbitan higher aliphatic acid esters (Span 80, Span 85), polyoxyethylene sorbitan higher aliphatic esters (Tween 20), nonylphenoxy polyoxyethylene ethanol (Igepal (IO-430), and the like.
  • nonionic surfactants such as ethylene oxide-polypropylene glycol condensates (Pluronic F68), sorbitan higher aliphatic acid esters (Span 80, Span 85), polyoxyethylene sorbitan higher aliphatic esters (Tween 20), nonylphenoxy polyoxyethylene ethanol (Igepal (IO-430), and the like.
  • capsules which have been sealed according to the process of the invention show excellent handling and storage properties. Thus the capsules do not leak when subjected to the vigorous handling involved in packaging and shipping.
  • the contents of the capsules are not contaminated in any Way during the sealing process and the process of the invention can be applied to the sealing of capsules containing a Wide variety of materials.
  • capsules containing the following medicaments can be sealed efliciently and permanently by the process of the invention: Panalba (a mixture of tetracycline phosphate with novobiocin), novobiocin, Comycin (a mixture of tetracycline phosphate with nystatin), Alba-Penicillin (a mixture of novobiocin and penicillin). a mixture of methoxyphenamine and aminophylline, Polykol (an oxyethylene oxypropylene polymer) and Casakol (a mixture of Polykol and casanthranol).
  • the process of the invention is a significant step forward in the art of hard capsule sealing.
  • the process provides a method of sealing capsules which is simple, effective, and economical to use on the large scale.
  • the process does not require individual handling of capsules, and can be employed on a large scale without the use of expensive machinery.
  • EXAMPLE 1 A batch of 100,000 hard filled gelatin capsules (size 0) containing lactose was sealed using the following procedure.
  • the sealing fluid employed in the process had the following composition.
  • the capsules were fed continuously on to a stainless steel wire mesh conveyor traveling at about 15 feet per minute.
  • the capsules were carried by the conveyor through an area in which they were sprayed with the above sealing fluid.
  • the spraying device was equipped with means for collecting and recirculating the sealing fluid. After spraying with sealing fluid the capsules were fed into a rotating tube in which they were tumbled and subjected to a blast of dry air. The time taken to pass through this tube was 30 to 60 seconds.
  • the capsules were allowed to air-dry for about 12 to 24 bonus.
  • the dry, sealed capsules so produced were then packaged using conventional procedures.
  • EXAMPLE 2 A batch of 100,000 hard filled gelatin capsules (size 0) containing lactose was sealed using the procedure described in Example 1 but employing a sealing fluid having the following composition.
  • EXAMPLE 4 Hard filled capsules containing lactose were sealed by suspending the capsules in a Wire mesh basket and dipping said basket for a period of approximately seconds in a sealing fluid having the following composition.
  • Ethyl cellulose (Ethocel; centipoises) 2.5 Trichloroethylene 97.5
  • the capsules After being dipped the capsules were allowed to drain and were then dried in a current of dry air.
  • the sealing fluid was prepared by dissolving the PVM/ MA in the methyl ethyl ketone and diluting the resulting solution with the alcohol.
  • Table said capsule but insuflicient to deposit a significant amount of coating on the exposed surfaces of said capsule.
  • sealing fluid also contains a nonionic surfactant.
  • a process for sealing a filled hard gelatin capsule which comprises contacting said filled and fully assembled capsule with a sealing fluid comprising a dispersion of an air-drying, hydrophilic, film-forming polymer selected from the class consisting of polyvinylpyrrolidone and hydrolyzed styrene-maleic anhydride copolymer, in an organic solvent selected from the class consisting of lower-allanols, lower-alkanones, and lower-aliphatic chlorinated hydrocarbons, said capsule being contacted with said sealing fluid for a time sufficient to wet thoroughly with sealing fluid the joint between the cap and the base of said capsule but insuflicient to deposit a significant amount of coating on the exposed surfaces of said capsule.
  • a sealing fluid comprising a dispersion of an air-drying, hydrophilic, film-forming polymer selected from the class consisting of polyvinylpyrrolidone and hydrolyzed styrene-maleic anhydride copolymer, in an organic solvent selected from
  • sealing fluid also contains a nonionic surfactant.
  • a process for sealing a filled hard gelatin capsule which comprises contacting said filled and fully assembled capsule with a sealing fluid comprising a solution of polyvinylpyrrolidone in ethanol containing from O to about 5 percent by volume of water said capsule being contacted with said sealing fluid for a time sufficient to wet thoroughly with sealing fluid the joint between the cap and the base of said capsule but insuflicient to deposit a significant amount of coating on the exposed surfaces of said capsule.
  • a process for sealing a filled hard gelatin capsule which comprises contacting said filled and fully assembled capsule with a sealing fluid comprising a solution of a hydrolyzed styrene-maleic anhydride copolymer in ethanol containing from 0 to about 5 percent by volume of water said capsule being contacted with said sealing fluid for a time suflicient to wet thoroughly with sealing STABILITY DATA ON HARD FILLED CAPSULES SEALED W ITI I POLYVINYLPYRROLIDONE All assays expressed in mg. unless otherwise indicated Initial 1 Month 47 C. 3 Months 40 0.
  • a process for sealing a filled hard gelatin capsule which comprises contacting said filled and fully assembled capsule with a sealing fluid comprising a dispersion of an air-drying, hydrophilic, film-formiug polymer in an organic solvent selected from the class consisting of loweralkanols, lower-alkanones, and lower-aliphatic chlorinated hydrocarbons, said capsule being contacted with said sealing fluid for a time sufficient to wet thoroughly with sealing fluid the joint between the cap and the base of fluid the joint between the cap and the base of said capsule but insuflicient to deposit a significant amount of coating on the exposed surfaces of said capsule.
  • a sealing fluid comprising a dispersion of an air-drying, hydrophilic, film-formiug polymer in an organic solvent selected from the class consisting of loweralkanols, lower-alkanones, and lower-aliphatic chlorinated hydrocarbons
  • sealing fluid also contains a nonionic surfactant.
  • a hard gelatin capsule having deposited thereon between the apposite surfaces of the cap and the base a film formed from an air-drying, hydrophilic, homogeneous film-forming polymer.
  • a hard gelatin capsule having deposited thereon between the apposite surfaces of the cap and the base a homogeneous film formed from polyvinylpyrrolidone.
  • a hard gelatin capsule having deposited thereon between the apposite surfaces of the cap and the base a homogeneous film formed from a hydrolyzed styrenemaleic anhydride copolymer.
  • a hard gelatin capsule having deposited on the outer surface thereof, including the apposite surfaces of the cap and the base, from about 20 milligrams to about 100 milligrams of a homogeneous film formed from an air-drying, hydrophilic, film-forming polymer.
  • a process for sealing a filled hard gelatin capsule which consists in the steps or contacting said filled and fully assembled unsealed capsule with a sealing fluid comprising a dispersion of an air-drying, hydrophilic, film-forming polymer in an organic solvent selected from the class consisting of lower alkanols, lower alkanones, and lower-aliphatic chlorinated hydrocarbons, removing comprises the steps of contacting said filled and fully assembled unsealed capsule with a sealing fluid comprising a solution of said polymer in an organic solvent selected from the class consisting of lower alkanols, loweralkanones, and lower-aliphatic chlorinated hydrocarbons, removing said capsule from contact with said sealing fluid, and air-drying said capsule to form a non-sticky homogeneous film of said polymer between the cap and the base of said capsule.

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Description

Sta
Patented Jan. 1, 1963 iifice 3,071,513 PROCESS FOR SEALING CAPSULES Herman R. De Boer, Comstock Township, Kalamazoo County, Thurlow E. King, Pavilion Township, Kalamazoo County, and Edwin L. Knoechel, Kalamazoo Township, Kalamazoo County, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed Nov. 23, 1959, Ser, No. 854,566
17 Claims. (Cl. 167-83) This invention relates to a method of sealing filled hard gelatin capsules.
A hard gelatin capsule consists of two cylinders of gelatin each of which is open at one end and closed at the other end by a domeshaped seal. One of the cylinders is slightly longer but smaller in diameter than the other and is termed the base or body. This member is filled with the drug mixture or medicament or other substances and is then forced into the other cylinder which is termed the cap. The cap generally fits fairly tightly over the base, but even though the cap and base are made with the greatest possible precision the assembled capsule is usually not entirely spill-proof. The filled capsules will on rough handling, for example, when passed through a high-speed machine for branding or filling into bottles or other containers, show evidence of spillage of the contentssometimes because of leakage between the surfaces of the cap and the base, bht often because the cap and base come apart. Accordingly, it is desirable that the hard gelatin capsule after filling be sealed so as to reduce leakage, to prevent the cap and base from falling apart, and to reduce contamination of the contents by air, moisture, etc.
It is to be understood that the term sealing as employed in the specification and claims includes not only treatments in which the gap between the cap and base of a capsule is completely closed but also treatments in which said gap is only partially closed. Sealing within the context of the present invention has been eiiected when the cap and base cannot be separated or can be separated only with difficulty by hand.
A number of methods have been adopted in the past to eifect such sealing. One such method consists in treating the cap, before application to the base, with hot water or aqueous alcohol on the inside surface, and then placing the cap over the base. A weld-type of seal is thus effected between the outer surface of the base and the inner surface of the cap. However, this method is subject to a number of disadvantages. The capsules must be handled and treated individually when applying this method and further the water or other solvent employed will come into contact with the contents of the base and in many instances will have a deleterious effect thereon. The method therefore is of limited application where the contents of the capsule are of an unstable nature, and is also not useful in the large-scale production and mechanical handling of capsules. Furthermore, distortion and disfigurement of the capsules have also resulted from application of the above method.
Another method which has been employed to seal hard capsules comprises the dipping of the filled and assembled capsule in a solution of aqueous formaldehyde. This process, however, has a denaturing effect upon the gelatin which becomes more difficult to digest in the gastrointestinal tract. Hence, the method cannot be used to encapsulate medicaments which are required to be released in the gastro-intestinal tract within a relatively short period of time. Further, the method results in small amounts of formaldehyde solution entering the capsules, particularly where the cap does not fit tightly over the base. In the case of many proteinaceous medicaments or other susceptible substances, it is undesirable to introduce formaldehyde to the contents of the capsule in this way because of the possibility of adverse interactions and the method has not been used with any great success.
A method of sealing which is commonly employed consists in placing a band of gelatin in a slightly molten state around the joint between the cap and the base. The use of this method, however, requires expensive machinery, since each capsule must be banded individually. Further, the method requires rigorous inspection of all banded capsules to reject any which have not been sealed satisfactorily. Accordingly, the use of the method increases considerably the cost and the production time involved in the sealing of the capsules. Another method proposed for the sealing of hard gelatin capsules involves heat treatment as set forth in US. Patent 2,738,827. This method produces distortion of the capsule and application of heat to the capsule cannot be carried out in the case of capsules containing heat-labile material.
We have now found that filled hard gelatin capsules can be sealed after assembly in a simple and convenient manner which lends itself readily to large-scale operation at low cost. The process of the invention consists in contacting a hard gelatin capsule, which has been filled with medicament or other material and then fully assembled, with a sealing fluid comprising a dispersion of an airdrying, hydrophilic, film-forming polymer in an organic solvent.
The organic solvents which can be employed in the process of the invention include lower alkanols such as methanol, ethanol, propanol, isopropyl alcohol, and the like, lower alkanones such as acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone and the like, and lower aliphatic chlorinated hydrocarbons such as trichloroethylene, carbon tetrachloride, dichlorethane, tetrachloroethane and the like, and mixtures of any of the above-named solvents. Where a lower alkanol is employed as solvent it is advantageous that said alkanol should contain a small amount of water. However the amount of water present in said alkanol should not be substantially greater than about 5 percent by volume otherwise distortion of the capsules may occur.
Air-drying, hydrophilic, film-forming polymers which can be used in the process of the invention include polycarboxylic acid polymers, i.e., polymers which contain free carboxylic acid groups in the units forming the polymer, and polyhydroxylated polymers, i.e., polymers which contain free hydroxyl groups in the units forming the polymer.
Examples of polycarboxylic acid polymers are hydrolyzed styrene-maleic anhydride copolymers, polyvinyl ether-maleic anhydride copolymers which have been hydrolyzed or alcoholized, and polyacrylic acids.
The hydrolyzed styrene-maleic anhydride copolymers which canbe used in the process of the invention comprise styrene-maleic anhydride copolymers which are more than 50 percent hydrolyzed. The copolymer can be modified to a minor extent by the presence of some other homopolymer-izable ethylenic unit, such as that of acrylonitrile, acrylic acid, methacrylic acid, itaconic acid, vinyl chloride, vinylidene chloride, dipentene, and the like. As used in the present specification the term hydrolyzed styrene-maleic anhydride copolymer includes such modifications as well as modifications in the structure and method of preparation which do not alter the essential resinous nature, toxicity and acid properties of the copolymer.
Essentially the styrene-maleic anhydride copolymers which can be employed in the process of the present invention can be represented by the following formula:
RX YD wherein R represents homopolymerizable ethylenic units of which more than 70 percent are styrene units (the other ethylenic units being those of acrylonitrile, acrylic acid, methacrylic acid, itaoonic acid, vinyl chloride, vinylidene chloride, dipentene, and the like), X represents ethylenic units of maleic acid and maleic anhydride of which more than 50 percent are maleic acid units (preferably more than 70 percent), and x/y equals from 1 to about 4 (preferably from 1 to about 1.2). The average molecular weight of the copolymer ranges from about 20,000 to about 200,000.
it is to be understood that, in its broader aspects, the present invention relates to hydrolyzed styrene-maleic anhydride copolymers which are more than 50 percent hydrolyzed. It includes the material described no matter how it is produced or how it is modified so long as the structure of the copolymer is primarily that of hydrolyzed styrene-maleic anhydride copolymer of the indicated properties and structure.
Styrene-maleic anhydride copolymer is a commercially available compound which can be obtained in modified or unmodified form. Resin SC-2 is available from the Monsanto Chemical Company and is a modified styrenemaleic anhydride copolymer. These copolymers are hydrolyzed to obtain a styrene-maleic acid copolymer which is useful in the process of the present invention. The hydrolysis can be partial or it can be complete and involves a conversion of the acid anhydride linkages to Oc-dlCfllbDXYiiC acid units. It is preferred that the hydrolysis be substantially complete i.e., more than about 50 percent complete.
Polyvinyl ether-maleic anhydride copolymers which can be used in the process of the invention, after hydrolysis or alcoholysis as hereinafter described, are the linear copolymers of alternating methyl vinyl ether and maleic anhydride units. Examples of such copolymers are those which are available commercially from the General Aniline and Film Corporation under the designation PVM/MA. These copolymers can be obtained with different viscosity ranges varying from 0.2 to 6 18p) (1 g./ 100 ml. of 2-butanone at 25 C.) according to the chain length. These commercially available copolymers do not themselves contain hydrophilic groups but when dissolved in water or in alkanols are hydrolyzed or alcoholyzed with the formation of free carboxylic acid groups. Thus when dissolved in water the anhydride groups are hydrolyzed to m'aleic acid residues. When dissolved in alkanols the anhydride groups break down with the formation of half esters leaving one free carboxylic group in each maleic acid residue. Accordingly these copolymers are employed in the process of the invention in the form of a solution thereof preferably in a lower alkanol such as ethanol which solution may contain up to about percent water as hereinbefore described. The copolymers can be dissolved directly in the alkanol but the rate of solution is slow and solutions are prepared more conveniently by first dissolving the copolymer in a small amount of a ketone such as acetone, methyl ethyl ketone, and the like, and then diluting the resulting solution with the lower alkanol.
The polyacrylic acids which can be used in the process of the invention include polyacrylic acid, polymethacrylic acid and partially or completely hydrolyzed polyacrylonitrile, polymethacrylonitrile, polyacrylamide, polymethacrylamide, polyacrylic acid esters, polymethacrylic acid esters and copolymers of acrylic acid or methacrylic acid with acrylonitrile, acrylamide or acrylic acid esters. Advantageously the hydrolysis of the said nitriles, amides and esters and copolymers thereof is more than 50 percent complete and preferably the hydrolysis is substantially 100 percent complete. It is to be understood that the term polyacrylic acids as used in the specification and claims includes both polyacrylic acid and all the above-mentioned derivatives thereof. Typical polyacrylic acids are Acrysol A1 and Acrysol A-3, marketed by the Rohm and Haas Company. Typical of commercially available polyacrylamides is PAM 10 which is marketed by American Cyanamid Company. This product has a molecular weight in the range of 38,000 to 48,500 and can be hydrolyzed by heating with the appropriate quantity of aqueous caustic soda to give polyacrylic acids, containing from to 90 percent amide groups, which can be used in the process of the invention.
Examples of polyhydroxylated polymers are polyvinylalcohols, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers, and partially etherified cellulose.
The term polyvinylalcohols includes all polymers produced by the hydrolysis of polyvinyl esters, usually the acetate. The properties of these polymers vary according to the molecular weight of the parent polyvinylacetate and the extent of hydrolysis. The degree of hydrolysis is generally indicated by the percent acetate content and for the purposes of the present invention it is preferred to use polyvinyl alcohols wherein the acetate content is within the range of about percent to about 50 percent. The molecular Weight of polyvinyl alcohol varies from about 10,000 to about 400,000 but, for the purposes of the present invention we prefer to use material having a molecular weight within the range of about 25,000 to about 50,000. Typical of products which are commercially available is Elvanol 72-60 Polyvinyl alcohol which is marketed by E. I. du Pont de Nemours and Company.
The term partially etherified celluloses includes the methyl, ethyl and higher alkyl ethers of cellulose in which 1 name Ethocel is typical.
. N-vinylpyrrolidone.
not all the hydroxy groups are etherified. The preferred alkyl cellulose is ethyl cellulose in which the ethoxyl content ranges from about 43 to about 50 percent, of which the product available commercially under the Advantageously, the partially etherified celluloses are employed in the process of the invention in the form of solutions in chlorinated hydrocarbon solvents such as those hereinbefore described.
Polyvinylpyrrolidone is a macromolecular polymer of It is available commercially in a variety of forms having molecular weights ranging from 1 and PVP/VA E-535, in which the ratio of N-vinylpyrrolidone to vinylacetate is 70:30, 60:40, and 50:50, respectively, are marketed by Antara Chemicals as 50 percent solutions of the copolymers in anhydrous ethanol.
The concentration of air-drying, hydrophilic, filmforming polymer, hereinafter referred to as filler material, present in the sealing fluid employed in the process of the invention is advantageously within the range of about 1 percent to about 20 percent. The use of concentrations higher than 20 percent leads to practical difliculties due to the high viscosity of the sealing fluid and to excessive deposit of filler material on the treated capsules. Preferably the concentration of filler material in the sealing fluid is within the range of about 2.5 to about 5.0 percent.
The process of contacting the filled capsules with the sealing fluid can be carried out in a number of ways. Thus the capsules can be dipped into the sealing fluid using apparatus which is conventional for such purposes. Alternatively and preferably the capsules can be sprayed with the sealing fluid using conventional apparatus. The actual time during which the sealing fluid is in contact with the capsule is not critical, the essential requirement being that the area of the capsule around the region of the joint between the cap and base be thoroughly wetted with the sealing fluid. However, unduly prolonged contact between the sealing fluid and the capsules is to be avoided to minimize the possibility of contamination of the contents of the capsule. In general a contact time of the order of about seconds or less is sufficient to effect excellent sealing of the capsules.
When the concentration of filler material in the sealing fluid is within the preferred range of about 2.5 to about 5 percent the amount of filler material which remains on the external surface of the capsules, after the latter have been contacted with the sealing fluid and allowed to drain, is very small and no washing or other treatment of the capsules is necessary before these are dried. However, when higher concentrations of filler material are employed it is desirable to Wash the capsules after contacting the latter with sealing fluid to avoid the presence of excessive deposits of filler material on the capsules. The Washing can be effected using the same solvent employed in the sealing fluid or using any of the other solvents listed above. After washing, the capsules are dried. The drying step can be accomplished using methods well known in the art, for example by exposing the treated capsules to a current of dry air.
Generally speaking the amount of filler material which remains on the surface of the capsule after sealing according to the process of the invention is very small and is usually of the order of about 20 milligrams to about 100 milligrams. The actual amount deposited on the capsule naturally varies with the size of the capsule. The capsule of size 0, which is that most frequently used in dispensing pharmaceutical preparations, has been found to have about 30 to about 40 milligrams of filler material deposited on its surface (including the gap between the apposite sides of the cap and base) after sealing according to the process of the invention.
When the capsules, which are sealed according to the process of the invention, are intended to be used for pharmaceutical purposes it is necessary to employ a filler material which is pharmaceutically acceptable. The preferred filler materials for this purpose are polyvinylpyrrolidone and hydrolyzed styrene-maleic anhydride copolymers. Where the sealed capsules are to be employed for non-pharmaceutical purposes, such considerations of purity of the filler material do not apply.
A particularly convenient method of carrying out the steps of sealing and, if desired, washing the capsules consists in supporting the filled capsules, for example on a wire mesh screen, whilst moving the capsules successively through an area in which they are sprayed with sealing fluid, then, if desired, through an area in which they are sprayed with washing solvent, and finally through an area in which they are dried.
We have found that in certain instances capsules which have been sealed by the process of the invention do not pass smoothly through a high-speed filling machine used in packaging the sealed capsule in bottles and the like containers. We have found that this problem can be overcome readily by incorporating a surfactant into the sealing fluid. Only a small amount of surfactant is necessary in order to accomplish the desired result. Advantageously, the amount of surfactant present in the sealing fluid is of the order of about 0.05 to 0.5 percent and preferably of the order of 0.1 percent.
Generally speaking any surfactant, which is soluble at the concentrations given above in the organic solvents employed in the process of the invention, can be employed for the above purpose. Advantageously the surfactants employed in the sealing fluid are nonionic surfactants such as ethylene oxide-polypropylene glycol condensates (Pluronic F68), sorbitan higher aliphatic acid esters (Span 80, Span 85), polyoxyethylene sorbitan higher aliphatic esters (Tween 20), nonylphenoxy polyoxyethylene ethanol (Igepal (IO-430), and the like.
We have found that capsules which have been sealed according to the process of the invention show excellent handling and storage properties. Thus the capsules do not leak when subjected to the vigorous handling involved in packaging and shipping. The contents of the capsules are not contaminated in any Way during the sealing process and the process of the invention can be applied to the sealing of capsules containing a Wide variety of materials. For example, capsules containing the following medicaments can be sealed efliciently and permanently by the process of the invention: Panalba (a mixture of tetracycline phosphate with novobiocin), novobiocin, Comycin (a mixture of tetracycline phosphate with nystatin), Alba-Penicillin (a mixture of novobiocin and penicillin). a mixture of methoxyphenamine and aminophylline, Polykol (an oxyethylene oxypropylene polymer) and Casakol (a mixture of Polykol and casanthranol).
Accordingly, the process of the invention is a significant step forward in the art of hard capsule sealing. The process provides a method of sealing capsules which is simple, effective, and economical to use on the large scale. The process does not require individual handling of capsules, and can be employed on a large scale without the use of expensive machinery.
The following examples are illustrative of the process and products of the present invention but are not to be construed as l'nniting:
EXAMPLE 1 A batch of 100,000 hard filled gelatin capsules (size 0) containing lactose was sealed using the following procedure. The sealing fluid employed in the process had the following composition.
Percent by weight Polyvinylpyrrolidone (Plasdone) (molecular weight=ca. 40,000) 2.5 Pluronic P68 0.1 Ethanol (S.D. 3A) 97.4
The capsules were fed continuously on to a stainless steel wire mesh conveyor traveling at about 15 feet per minute. The capsules were carried by the conveyor through an area in which they were sprayed with the above sealing fluid. The spraying device was equipped with means for collecting and recirculating the sealing fluid. After spraying with sealing fluid the capsules were fed into a rotating tube in which they were tumbled and subjected to a blast of dry air. The time taken to pass through this tube was 30 to 60 seconds. The capsules were allowed to air-dry for about 12 to 24 bonus. The dry, sealed capsules so produced were then packaged using conventional procedures.
EXAMPLE 2 A batch of 100,000 hard filled gelatin capsules (size 0) containing lactose was sealed using the procedure described in Example 1 but employing a sealing fluid having the following composition.
Percent by weight Hydrolyzed styrene-maleic anhydride copolymer (prepared as described in U.S. Patent 2,897,121, Table VI, Preparation H) 2.5 Ethanol (SD. 3A) 97.5
EXAMPLE 3 Hard filled capsules containing aspirin 'were sealed using the procedure described in Example 1 but employ ing a sealing fluid having the following composition.
Percent by weight Polyvinylpyrrolidone (Plasdone) (molecular weight ca. 40 ,000) 2.5 Pluronic F68 0.1 Absolute ethanol 97.4
EXAMPLE 4 Hard filled capsules containing lactose were sealed by suspending the capsules in a Wire mesh basket and dipping said basket for a period of approximately seconds in a sealing fluid having the following composition.
Percent by weight Ethyl cellulose (Ethocel; centipoises) 2.5 Trichloroethylene 97.5
After being dipped the capsules were allowed to drain and were then dried in a current of dry air.
EXAMPLE 5 The sealing fluid was prepared by dissolving the PVM/ MA in the methyl ethyl ketone and diluting the resulting solution with the alcohol.
EXAMPLE 6 Using the procedure and the sealing fluid described in Example 1, hard filled capsules containing the following medicaments were sealed:
Panalba (tetracycline+novobiocin) Albamycin (novobiocin) Comycin (tetracycline-l-nystatin) Alba-Penicillin (novobiocin-l-potassium penicillin G) Orthoxine (methoxyphenarnine+aminophylline) Some of the sealed capsules were maintained at 47 C. for 1 month and others were maintained at 40 C. for 3 months. At the end of the storage period the contents of the capsules were assayed and the assays were compared with those of unsealed capsules maintained under the same storage conditions. The assay results are recorded in the following table from which it will be seen that the sealed capsules exhibited the same storage characteristics as the unsealed capsules.
Table said capsule but insuflicient to deposit a significant amount of coating on the exposed surfaces of said capsule.
2. The process of claim 1 wherein the sealing fluid also contains a nonionic surfactant.
3. A process for sealing a filled hard gelatin capsule which comprises contacting said filled and fully assembled capsule with a sealing fluid comprising a dispersion of an air-drying, hydrophilic, film-forming polymer selected from the class consisting of polyvinylpyrrolidone and hydrolyzed styrene-maleic anhydride copolymer, in an organic solvent selected from the class consisting of lower-allanols, lower-alkanones, and lower-aliphatic chlorinated hydrocarbons, said capsule being contacted with said sealing fluid for a time sufficient to wet thoroughly with sealing fluid the joint between the cap and the base of said capsule but insuflicient to deposit a significant amount of coating on the exposed surfaces of said capsule.
4. The process of claim 3 wherein the sealing fluid also contains a nonionic surfactant.
5. A process for sealing a filled hard gelatin capsule which comprises contacting said filled and fully assembled capsule with a sealing fluid comprising a solution of polyvinylpyrrolidone in ethanol containing from O to about 5 percent by volume of water said capsule being contacted with said sealing fluid for a time sufficient to wet thoroughly with sealing fluid the joint between the cap and the base of said capsule but insuflicient to deposit a significant amount of coating on the exposed surfaces of said capsule.
6. The process of claim 5 in which the sealing fluid also contains a nonionic surfactant.
7. The process of claim 5 in which the concentration of polyvinylpyrrolidone in the sealing fluid is from about 2.5 to about 5 percent by weight.
3. A process for sealing a filled hard gelatin capsule which comprises contacting said filled and fully assembled capsule with a sealing fluid comprising a solution of a hydrolyzed styrene-maleic anhydride copolymer in ethanol containing from 0 to about 5 percent by volume of water said capsule being contacted with said sealing fluid for a time suflicient to wet thoroughly with sealing STABILITY DATA ON HARD FILLED CAPSULES SEALED W ITI I POLYVINYLPYRROLIDONE All assays expressed in mg. unless otherwise indicated Initial 1 Month 47 C. 3 Months 40 0.
Control PVP Sealed Control PVP Sealed Control PVP Sealed II. I 0. Panalba: F
Tetracycline Hydrochloride 263 263 258 203 259 2n Novobiocin 127. 5 128. 129 132. 5 12:) 12a Moisture, percent..- 4, 05 4.16 H. F. C. Albamycin, 250
N ovobiocin 250 253 255 250 242. 5 240 Moisture, percent. 3. 44. 3. 73 11 F. 0. Com cin: n
Tetracycline Hydrochloride 275 272. 5 2 253 JO Nystatln, units 303, 000 300, 000 261, 250 200, 250 247, 500 250, 000
Moisture, percent. 4. 6s 5. 27 H. F. O. Alba-Pcnicill Novobiocin 283. 8 261. 3 262. 5 260 "5 256 Penicillin G Potassium, units 266, 000 270, 000 269, 000 267, 000 266, 000 206, 000 H. F. C. Orthoxine and Aminophylli Aminophylliiie 103. 1 111. 2 99 100 101 102. 2
Orthoxine Hydrochloride 49. 7 49. 7 49. 9 50. 2 49. 1 i9. 7
We claim:
1. A process for sealing a filled hard gelatin capsule which comprises contacting said filled and fully assembled capsule with a sealing fluid comprising a dispersion of an air-drying, hydrophilic, film-formiug polymer in an organic solvent selected from the class consisting of loweralkanols, lower-alkanones, and lower-aliphatic chlorinated hydrocarbons, said capsule being contacted with said sealing fluid for a time sufficient to wet thoroughly with sealing fluid the joint between the cap and the base of fluid the joint between the cap and the base of said capsule but insuflicient to deposit a significant amount of coating on the exposed surfaces of said capsule.
9. The process of claim 8 in which the concentration 70 of hydrolyzed styreiie-maleic anhydride copolymer in the Sealing fluid is from about 2.5 to about 5 percent by weight.
10. A process for sealing a filled hard gelatin capsule which comprises the steps of contacting said filled and 5 fully assembled capsule with a sealing fluid comprising 9 a dispersion of an air-drying, hydrophilic, film-forming polymer selected from the class consisting of polyvinylpyrrolidone and hydrolyzed styrene-maleic anhydride copolymer in an organic solvent, washing the sealed capsule with an organic solvent, and drying the washed, sealed capsule.
11. The process of claim 10 in which the sealing fluid also contains a nonionic surfactant.
12. A hard gelatin capsule having deposited thereon between the apposite surfaces of the cap and the base a film formed from an air-drying, hydrophilic, homogeneous film-forming polymer.
13. A hard gelatin capsule having deposited thereon between the apposite surfaces of the cap and the base a homogeneous film formed from polyvinylpyrrolidone.
14. A hard gelatin capsule having deposited thereon between the apposite surfaces of the cap and the base a homogeneous film formed from a hydrolyzed styrenemaleic anhydride copolymer.
15. A hard gelatin capsule having deposited on the outer surface thereof, including the apposite surfaces of the cap and the base, from about 20 milligrams to about 100 milligrams of a homogeneous film formed from an air-drying, hydrophilic, film-forming polymer.
16. A process for sealing a filled hard gelatin capsule which consists in the steps or contacting said filled and fully assembled unsealed capsule with a sealing fluid comprising a dispersion of an air-drying, hydrophilic, film-forming polymer in an organic solvent selected from the class consisting of lower alkanols, lower alkanones, and lower-aliphatic chlorinated hydrocarbons, removing comprises the steps of contacting said filled and fully assembled unsealed capsule with a sealing fluid comprising a solution of said polymer in an organic solvent selected from the class consisting of lower alkanols, loweralkanones, and lower-aliphatic chlorinated hydrocarbons, removing said capsule from contact with said sealing fluid, and air-drying said capsule to form a non-sticky homogeneous film of said polymer between the cap and the base of said capsule.
References Cited in the file of this patent UNITED STATES PATENTS 2,897,121 Wagner l uly 28, 1959 2,924,920 Margolis Feb. 16, 1960 FOREIGN PATENTS 536,875 Canada Feb. 5, 1957 OTHER REFERENCES Drug & Cosmetic, July 1954, p. 36. The Art of Compounding, Ninth Edition, McGraw- Hill, New York, 1957, pp. 61, 77-79. (Copy in Div. 43.)
UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent N0a 3,071,513 January 1, 1963 Herman R, De Boer et all,
It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.
Column 9, line 10, after "a" insert homogeneous line 11, strike out "homogeneous",
Signed and sealed this 16th day of July 1963 (SEAL) Attest:
ERNEST w. SWIDER DAVID LADD Attesting Officer 3 Commissioner of Patents

Claims (1)

1. A PROCESS FOR SEALING A FILLED HARD GELATIN CAPSULE WHICH COMPRISES CONTACTING SAID FILLED AND FULLY ASSEMBLED CAPSULE WITH A SEALING FLUID COMPRISING A DISPERSION OF AN AIR-DRYING, HYDROPHILIC, FILM-FORMING POLYMER IN AN ORGANIC SOLVENT SELECTED FROM THE CLASS CONSISTING OF LOWERALKANOLS, LOWER-ALKANONES, AND LOWER-ALIPHATIC CHLORINATED HYDROCARBONS, SAID CAPSULE BEING CONTACTED WITH SAID SEALING FLUID FOR TIME SUFFICIENT TO WET THROUGHLY WITH SEALING FLUID THE JOINT BETWEEN THE CAP AND THE BASE OF SAID CAPSULE BUT INSUFFICIENT TO DEPOSIT A SIGNIFICANT AMOUNT OF COATING ON THE EXPOSED SURFACES OF SAID CAPSULE.
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Cited By (22)

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Publication number Priority date Publication date Assignee Title
US3159546A (en) * 1962-10-12 1964-12-01 F G Okie Inc Capsule sealing composition
US3186910A (en) * 1962-03-08 1965-06-01 Jacob A Glassman Method for producing peroral capsules
US3200556A (en) * 1962-10-12 1965-08-17 Hartnett Co R W Capsule sealing method and apparatus
US3996183A (en) * 1972-02-21 1976-12-07 Ogawa Chemical Industries, Ltd. Solid paste and method of making same
DE3239955A1 (en) * 1982-10-28 1984-05-03 Gunther Meinhardt 8918 Dießen Voss Manipulation-secured medicament capsule and process for its production
EP0116743A1 (en) * 1983-02-18 1984-08-29 Warner-Lambert Company Apparatus for and method of sealing capsules
EP0116744A1 (en) * 1982-12-20 1984-08-29 Warner-Lambert Company Apparatus for and method of sealing capsules
EP0127105A3 (en) * 1983-05-23 1985-05-15 Capsulbond Incorporated Method for sealing capsules
EP0152517A1 (en) * 1984-02-22 1985-08-28 Warner-Lambert Company Apparatus and method for sealing capsules
FR2599251A1 (en) * 1986-06-02 1987-12-04 Warner Lambert Co METHOD FOR SEALING PHARMACEUTICAL GELATINE GELATINE CARDS.
USRE33251E (en) * 1983-02-18 1990-07-03 Warner-Lambert Company Apparatus and method of sealing capsules
US5188688A (en) * 1990-07-20 1993-02-23 Minnesota Mining And Manufacturing Company Method of sealing a gelatin capsule
US5460824A (en) * 1990-06-27 1995-10-24 Warner-Lambert Company Method for the preparation of an encapsulated medicament
US5464631A (en) * 1990-06-27 1995-11-07 Warner-Lambert Company Encapsulated dosage forms
US20060159745A1 (en) * 2002-09-26 2006-07-20 Vita-Herb Nutraceuticals, Inc. Probiotic and preservative uses of oil-emulsified probiotic encapsulations
EP1752140A1 (en) * 2005-08-12 2007-02-14 Warner-Lambert Company LLC Method for banding hard capsules using hydroxypropylmethyl cellulose (HPMC) as a base
WO2007030431A3 (en) * 2005-09-08 2007-09-07 Cadbury Adams Usa Llc Gelatin capsules containing actives
WO2013150331A1 (en) 2011-11-09 2013-10-10 Capsugel Belgium Nv Acid resistant banding solution for acid resistant two piece hard capsules
EP3167867A1 (en) 2015-11-16 2017-05-17 Capsugel Belgium NV Tamperproof dosage form
EP3167868A1 (en) 2015-11-16 2017-05-17 Capsugel Belgium NV Tamperproof dosage form
EP3167880A1 (en) 2015-11-10 2017-05-17 Capsugel Belgium NV Acid resistant banding or sealing solution for acid resistant two piece hard capsules
US12383504B2 (en) 2012-05-21 2025-08-12 Capsugel Belgium Nv Acid resistant banding solution for two piece hard capsules

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US2924920A (en) * 1958-09-02 1960-02-16 Elly T Margolis Sealing hard-shell gelatin capsules

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3186910A (en) * 1962-03-08 1965-06-01 Jacob A Glassman Method for producing peroral capsules
US3159546A (en) * 1962-10-12 1964-12-01 F G Okie Inc Capsule sealing composition
US3200556A (en) * 1962-10-12 1965-08-17 Hartnett Co R W Capsule sealing method and apparatus
US3996183A (en) * 1972-02-21 1976-12-07 Ogawa Chemical Industries, Ltd. Solid paste and method of making same
DE3239955A1 (en) * 1982-10-28 1984-05-03 Gunther Meinhardt 8918 Dießen Voss Manipulation-secured medicament capsule and process for its production
EP0116744A1 (en) * 1982-12-20 1984-08-29 Warner-Lambert Company Apparatus for and method of sealing capsules
EP0116743A1 (en) * 1983-02-18 1984-08-29 Warner-Lambert Company Apparatus for and method of sealing capsules
US4539060A (en) * 1983-02-18 1985-09-03 Warner-Lambert Company Apparatus and method of sealing capsules
USRE33251E (en) * 1983-02-18 1990-07-03 Warner-Lambert Company Apparatus and method of sealing capsules
EP0127105A3 (en) * 1983-05-23 1985-05-15 Capsulbond Incorporated Method for sealing capsules
US4820364A (en) * 1983-05-23 1989-04-11 Capsulbond Incorporated Method for sealing capsules
EP0152517A1 (en) * 1984-02-22 1985-08-28 Warner-Lambert Company Apparatus and method for sealing capsules
FR2599251A1 (en) * 1986-06-02 1987-12-04 Warner Lambert Co METHOD FOR SEALING PHARMACEUTICAL GELATINE GELATINE CARDS.
BE1001317A4 (en) * 1986-06-02 1989-09-26 Warner Lambert Co Process for sealing capsules in hard gelatin.
US5464631A (en) * 1990-06-27 1995-11-07 Warner-Lambert Company Encapsulated dosage forms
US5460824A (en) * 1990-06-27 1995-10-24 Warner-Lambert Company Method for the preparation of an encapsulated medicament
US5188688A (en) * 1990-07-20 1993-02-23 Minnesota Mining And Manufacturing Company Method of sealing a gelatin capsule
US20060159745A1 (en) * 2002-09-26 2006-07-20 Vita-Herb Nutraceuticals, Inc. Probiotic and preservative uses of oil-emulsified probiotic encapsulations
US8846082B2 (en) * 2002-09-26 2014-09-30 Vita-Herb Nutriceuticals, Inc. Probiotic and preservative uses of oil-emulsified probiotic encapsulations
US9579290B2 (en) * 2005-08-12 2017-02-28 Capsugel Belgium Nv Method for banding hard capsules using hydroxypropylmethyl cellulose (HPMC) as a base
EP1752140A1 (en) * 2005-08-12 2007-02-14 Warner-Lambert Company LLC Method for banding hard capsules using hydroxypropylmethyl cellulose (HPMC) as a base
US20070065501A1 (en) * 2005-08-12 2007-03-22 Xiongwei He Method for banding hard capsules using hydroxypropylmethyl cellulose (HPMC) as a base
WO2007020529A3 (en) * 2005-08-12 2007-04-26 Warner Lambert Co Method for banding hard capsules using hydroxypropylmethyl cellulose (hpmc) as a base
WO2007030431A3 (en) * 2005-09-08 2007-09-07 Cadbury Adams Usa Llc Gelatin capsules containing actives
US9980918B2 (en) 2011-11-09 2018-05-29 Capsugel Belgium Nv Acid resistant banding solution for acid resistant two piece hard capsules
WO2013150331A1 (en) 2011-11-09 2013-10-10 Capsugel Belgium Nv Acid resistant banding solution for acid resistant two piece hard capsules
EP3566698A1 (en) 2011-11-09 2019-11-13 Capsugel Belgium NV Acid resistant banding solution for acid resistant two piece hard capsules
US12383504B2 (en) 2012-05-21 2025-08-12 Capsugel Belgium Nv Acid resistant banding solution for two piece hard capsules
EP3167880A1 (en) 2015-11-10 2017-05-17 Capsugel Belgium NV Acid resistant banding or sealing solution for acid resistant two piece hard capsules
EP3566699A1 (en) 2015-11-10 2019-11-13 Capsugel Belgium NV Acid resistant banding or sealing solution for acid resistant two piece hard capsules
US11246837B2 (en) 2015-11-10 2022-02-15 Capsugel Belgium, NV Acid resistant banding or sealing solution for acid resistant two piece hard capsules
EP3167867A1 (en) 2015-11-16 2017-05-17 Capsugel Belgium NV Tamperproof dosage form
EP3167868A1 (en) 2015-11-16 2017-05-17 Capsugel Belgium NV Tamperproof dosage form
WO2017084775A1 (en) 2015-11-16 2017-05-26 Capsugel Belgium N.V. Tamperproof dosage form
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