US3909444A - Microcapsule - Google Patents

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US3909444A
US3909444A US16923071A US3909444A US 3909444 A US3909444 A US 3909444A US 16923071 A US16923071 A US 16923071A US 3909444 A US3909444 A US 3909444A
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material
capsule
enteric
active
wall
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Jerrold L Anderson
Thomas C Powell
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Adare Pharmaceuticals Inc
NCR Corp
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NCR Corp
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5036Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1652Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02Making microcapsules or microballoons
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S436/00Chemistry: analytical and immunological testing
    • Y10S436/829Liposomes, e.g. encapsulation
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/29Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982Particulate matter [e.g., sphere, flake, etc.]
    • Y10T428/2989Microcapsule with solid core [includes liposome]
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/29Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982Particulate matter [e.g., sphere, flake, etc.]
    • Y10T428/2991Coated
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/29Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982Particulate matter [e.g., sphere, flake, etc.]
    • Y10T428/2991Coated
    • Y10T428/2998Coated including synthetic resin or polymer

Abstract

An enterically active, controlled release microcapsule is disclosed which includes: (a) an internal phase or capsule core of a continuous matrix of water-soluble polymeric material having finely-divided particles of an active contained material and finely-divided particles of an enteric contained material mixed throughout; and (b) a seamless external coating of capsule wall of a water-insoluble polymeric material which prevents disintegration of the internal phase in aqueous liquids but which is permeable to aqueous solutions.

Description

United States Patent Anderson et al.

1 Sept. 30, 1975 MICROCAPSULE Inventors: Jerrold L. Anderson, Dayton;

Thomas C. Powell, West Alexandria, both of Ohio Assignee: NCR Corporation, Dayton, Ohio Filed: Aug. 5, 1971 Appl. No.: 169,230

US. Cl. 252/316; 8/79; 252/184; 252/408; 252/426; 424/22; 424/32; 424/33; 424/35; 427/3; 427/212; 427/222; 428/403;

Int. Cl. B01J 13/02 Field of Search 252/316; 117/100 A;

References Cited UNITED STATES PATENTS 12/1945 Fox et al 424/37 X 6/1962 Goldman 424/35 X 9/1964 Gaunt 424/22 11- ACTIVE 3,415,758 12/1968 Powell et a1. l 1. 252/316 3,485,914 12/1969 Corn 424/22 3,577,514 5/1971 Robinson 424/22 Primary ExaminerRichard D. Lovering Attorney, Agent, or FirmRobert .l. Shafer; E. Frank McKinney [57] ABSTRACT An enterically active, controlled release microcapsule is disclosed which includes: (a) an internal phase or capsule core of a continuous matrix of water-soluble polymeric material having finely-divided particles of an active contained material and finely-divided particles of an enteric contained material mixed throughout; and (b) a seamless external coating of capsule wall of a water-insoluble polymeric material which prevents disintegration of the internal phase in aqueous liquids but which is permeable to aqueous solu' tions.

9 Claims, 2 Drawing Figures 12- POLYMERIC "CAPSULE WALL I 14- ENTERIC MATERIAL 13- MATRIX BINDER MATERIAL U.S. Patent Sept. 30,1975

MATERIAL m R E T N E M IZ-POLYMERIC CAPSULE WALL ll- ACTIVE MATERIAL BINDER MATERIAL D-CAPSULE OF THIS INVENTION CAPSULE WITH NO ENTERIC BARRIER MATERIAL C i. R H I R E wm mww E .N L C R I W A E Rwu N GE E B A PH L2 N m m 5 TIME MICROCAPSULE BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to an enterically active microcapsule which provides controlled release of a contained material in aqueous environments. It more particulary pertains to a microcapsule which exhibits rapid but controlled release of contained material in alkaline aqueous environments and which exhibits relatively slow release of contained material in acid aqueous environments. The slow release in acid environments is release as it would be expected from a microcapsule having a low internal phase content, but without enteric activity.

The microcapsule of this invention consists of an internal phase and a capsule wall encasing the internal phase;--the internal phase being a substantially homo geneous combination of water-soluble polymeric matrix material with finely-divided particles of an active material and of an enteric material mixed therethroughout. The enteric material is selected to be relatively insoluble in aqueous acid and relatively soluble in aqueous base. The capsule wall material is selected to be substantially insoluble in, but permeable to, all aqueous solutions thereby preventing disintegration of the internal phase in aqueous solutions. The matrix material, the enteric material and the capsule wall material operate in combination to produce the unexpected effect of providing rapid but sustained release of the ac tive material in alkaline environments and of providing relatively slow release of the active material in acid environments. The microcapsule of this invention finds particular utility in the pharmaceutical and medical fields where it may be desired or required that an active, capsule-contained, medicament material pass through the acid-condition of the stomach with a relatively low, but definite, amount of solution to then be released, relatively rapidly, but in a sustained manner, in the relatively basic environment of the intestinal tract. The rate controlling factor for release of active material in acid environments is the barrier of enteric particles coupled with diffusion of dissolved material through the capsule walls and the rate controlling factor for release of active material in alkaline environments is diffusion through the capsule walls. The microcapsule of this invention finds utility in fields other than the pharmaceutical and medical fields and the term enteric is used simply as a matter of convenience. For purposes of this invention, the meaning of the word enteric" is expanded to include progressively increased solubility with decreased acidity in aqueous environments, whether in a gastrointestinal tract or not. Also, for purposes of this invention, the active" capsule-contained material is the material to be released from the capsule. The active material is the material of the internal phase excluding the matrix material and the enteric material.

2. Description of the Prior Art In the past. several schemes have been developed for providing small particles of material with some degree of enteric activity or prolonged period of solution.

Examples representative of the prior art include: U.S. Pat. No. 2,553,544 issued May 22, 1951 on the application of Herman H. Bogin which discloses granular particles of a continuous, single-phase, matrix of gelatin, a plasticizer, and an enterically active material. The

matrix is disclosed to contain, distributed therethroughout, droplets of a liquid vitamin compound. The granules disclosed by Bogin comprise a relatively homogeneous mixture of an enterically active, continuous, matrix with vitamins dispersed therein and with no covering film to form capsules. The granular particles disclosed by Bogin disintegrate and release their vitamin contents very rapidly in an aqueous system of alkaline pH. The particles disclosed by Bogin contain 30 to 40 percent, by weight, vitamin material;

U.S. Pat. No. 2,656,298 issued Oct. 20, 1953 on the application of Leo Loewe which discloses an enterically active medicament composition for oral administration which can include solid particles of a medicament dispersed in a continuous matrix of formalized protein. The continuous matrix is coated, externally, by enteric anion exchange resin. In all embodiments, the anion exchange resin is disclosed to be utilized as an enclosing material for the medicament to be protected;

U.S. Pat. No. 2,809,916 issued Oct. 15, 1957 on the application of Victor M. Hermelin which simply discloses a sustained release medicament composition comprising granules of intermixed binder and medicament. The binder can be enteric in nature and the process for producing the product is repeated granulation and;

U.S. Pat. No. 3,115,441 issued Dec. 24, 1963 on the application of Victor M. Hermelin discloses a tabletted composition comprising particles of medicament covered by several individual layers of enteric coating material and included in a matrix of medicament and filler. Enteric activity is provided only at the surface of individual particles.

The present invention represents a substantial improvement over the prior art and provides a microcapsule construction with a combination of material properties not before recognized or utilized. The active contained material is included in a continuous matrix of water-soluble polymeric material and the matrix is encapsulated by a water-insoluble polymeric film permea ble to aqueous solution. The matrix also includes particles of an enteric material. Release of the active material is accomplished by solution and diffusion through the capsule wall and, very importantly, to the extent that the undissolved enteric material blocks solution or diffusion, release of the active material is slowed.

SUMMARY OF THE INVENTION At times, a method is desired or required for releasing a material into a liquid system in a controlled manner wherein the liquid system has certain predetermined characteristics. As an example, in the administration of medicines, it is sometimes advantageous to provide a medicament in a special form such that the medicament will be passed through the patients stomach with only a slight dosage there and then pass on into the intestine where the remainder is released in a relatively rapid but prolonged manner. This form of administration is especially advantageous when the medicament is in danger of being hydrolyzed or otherwise destroyed in an acid environment such as is usually found in a patients stomach or, when release of a large amount of the medicament into a patients stomach would cause unnecessary discomfort or irritation.

As further examples of the utility of selectively releasing active, capsule-contained materials, the rapid release of an encapsulated catalyst or reagent in a chemical reaction only during times when conditions in the system are correct for conducting the reaction may be mentioned, as can the release of anadditive, such as a dye, to indicate change of conditions or presence of a new condition in a system.

It is an object of this invention to provide a microcapsule which is partially enterically active to exhibit slow release of contained material in acid aqueous conditions, as though the material to be released were in a non-enteric binder, and to exhibit relatively more rapid, controlled, released in alkaline aqueous conditions.

It is a further object of this invention to provide a microcapsule having a construction comprising a capsule internal phase of a water-soluble, polymeric, matrix binder containing a multitude of particles of enteric material and a multitude of particles of active material enclosed by a capsule wall of water-insoluble but permeable polymeric material.

It is a further object of this invention to provide the above microcapsule wherein the insoluble but permeable polymeric material prevents disintegration of the microcapsule in aqueous solution and wherein the finely-divided active material is included in a matrix of water-soluble polymeric material along with finelydivided enteric material, which enteric material serves, in aqueous acid environment, as a partial barrier to solution and consequent diffusion of the active material.

The'inventors have not discovered and herein disclose and claim a microcapsule to accomplish the above'objects and other objects as will be made apparent to those skilled in the art.

The novel microcapsule has a capsule wall and contains an internal phase. The internal phase includes finely-divided particles of active material, finelydivided particles of enteric material and a continuous matrix of water-soluble polymeric material which also serves as a binder for the particles. Enteric material, as is referred to throughout this patent, means material which isrelatively water insoluble in acidic conditions and is relatively watersoluble in basic conditions. The capsule wall material is a Water-insoluble polymer and provides a film barrier which prevents disintegration of the internal phase on immersion of the capsules in water. Additionally, the capsule wall material permits release of water-dissolved capsule contents by transfer through the capsule wall film. All release of active material from the capsule of this invention occurs by transfer of a solution of the material through the capsule wall. Each entity of capsule internal phase includes a multitude of finely-divided particles of active material and a multitude of finely-divided particles of enteric material; all of the particles being bound together by the matrix of water-soluble polymeric material. The rate of release of the active material is controlled by the rate at which the active material is made available at the capsule wall and by the rate of transfer therethrough. An important feature of the present invention and what is considered to be patentable herein, is the capsule as above-described having four essential elements and providing'a release rate which is slow and controlled by a barrier of insoluble enteric particles at an acid pH and is more rapid and controlled by transfer rate through the capsule wall material at an alkaline pH. The four essential elements are particles of active material and particles of enteric material bound together as granules by water-soluble matrix material;

the granules being encapsulated by a Water-insoluble but permeable film of polymeric material. The novel capsule is individual and discrete alone or among others of its kind and is minute in size; individual capsules having a size range of from 200 microns to 1000 microns or perhaps slightly larger.

Enteric materials eligible for use in this invention as a contained material include any material soluble at certain selected environmental conditions and insoluble at others. The microcapsules of this invention are normally used in aqueous systems and the enteric materials are selected to be soluble in water at alkaline pH and insoluble in water at acid pH. Examples of such materials include partial esters and half-esters of maleic anhydride copolymers such as poly(methylvinyletherco-maleic anhydride) and poly(eth'ylene-comaleic anhydride) and specifically include methyl, ethyl, n-butyl, isobutyl, and Z-ethylhexyl half and partial esters of maleic anhydride copolymers. Further examples of such materials include polycarboxylic acid partial esters of cellulose esters of lower aliphatic monocarboxylic acids including esters derived from combination of an aromatic polycarboxylic acid such as phthalic acid and an aliphatic acid such as acetic, propionic, butyric, and the like, acids. Preferred ones of those mentioned above are partial esters and half-esters of cellulose acetate phthalate, cellulose propionate phthalate, and cellulose butyrate phthalate. The above materials derive their enteric properties from being partial esters, that is, from having free carboxyl groups in some positions on the molecules. Although it is not required that each repeating unit of the enteric material molecule contain a free carboxyl group, the material'as a whole should contain from about 5 to about 25 percent, by weight, free carboxyl groups. A free carboxyl group content from about 8 to about 15 percent, by, weight, has been found to be most preferable for use in "practicing this invention. It must be remembered, of course, that the enteric activity of the above materials is controlled by, among other things, the free carboxyl content; and that if desired or required for a particular use or effect, enteric materials can be used which have carboxyl contents outside the abovementioned ranges. Other materials eligible for use as the enteric material of this invention include: shellac, derivatives of shellac; certain fats, fatty acids, and waxes; esters of starch, methylcellulose, ethylcellulose, and ethyl(hydroxyethyl) cellulose; phthalates of sugars such as glucose, sucrose, sorbitol and dextrin; zein; and like materials.

Water-soluble polymeric matrix materials (also referred to, herein, as binder materials) eligible for use in this invention include: methyl cellulose; ethyl(hydroxyethyl) cellulose; poly(vinyl alcohol); gum arabic; gelatin, especially of low Bloom strength; poly(vinylpyrrolidone); completely hydrolyzed esters of maleic anhydride copolymers such as poly(methylvinylether-comaleic anhydride) and poly(ethylene-co-maleic anhydride), and the like. Although not specifically polymeric, sugars and similar organic materials such as glucose, sucrose, sorbitol, and dextran are eligible for use. In short, any water-soluble polymeric, or equivalent, material is eligible for'use as the matrix material of the present invention.

Polymeric materials eligible for use in this invention as capsule'wall material include any material which is both subst antially insoluble in the environmental condit'ions for use of 'thenovel capsules and permeable to aqueous solutions of the materials to be contained within the capsule walls. The microcapsules of this invention are normally used in aqueous systemsand the capsule wall material is, therefore, selected to be substantially insoluble in water. The selected capsule wall material, when used in a thin film such as found as capsule walls, must be permeable to aqueous solutions of the capsule-contained material. Examples of such eligible capsule wall materials include polymeric materials such as: poly(acrylics); poly(methacrylates), poly(acrylates), and the like; celluloses; -cellulose acetate propionate, cellulose acetate butyrate, ethylcellulose, cellulose acetate, cellulose nitrate, and the like; poly(- vinyls); poly(vinyl acetate), poly(vinyl butyrate), poly(vinylidene chloride) and the like; poly(olefins); polyethylene, polypropylene, and the like, including materials having the various forms of stem-regularity; poly(halocarbons); poly(tetrafluoroethylene), poly(- trifluorochloroethylcne), fluorinated poly(ethylene), fluorinated poly(propylene), and the like; poly(styrenes) and copolymers of poly(styrenes) with other materials such as acrylonitrile or butadiene; poly(a mides); poly(esters); poly(epoxides); and silicone resins. Preferred capsule wall materials are the cellulosic materials disclosed above and, in the present practice, most preferred of those is ethylcellulose.

Active material eligible to be contained by the microcapsule of this invention includes any material which can be included as a dispersion of fine particles in the matrix binder material without dissolving therein or reacting therewith. As has been previously disclosed, the capsule of this invention finds its normal utility in controlled release of the contained material in an aqueous environment. The preferred form of the invention is directed toward capsules containing water soluble mate' rials which water soluble materials can be released by permeation of aqueous solution through the capsule wall material. A most preferred form of the invention is directed toward containing water soluble medicaments.

Any acid-sensitive medicament substance, as a class, is eligible for use, such as, for example: penicillin salts, aureomycin, chloromycetin, streptomycin, bacitracin, subtilin, polymyxin, dihydrostreptomycin; and other acid-sensitive materials such as acetylsalicyclic insulin, adrenalin, heparin and the like. Other eligible materials include acetylsalicyclic acid, digitoxin, pyralimine, caffeine, phenobarbital, stilbesterol, methyl testosterone, scopolamine methylbromide, pentaerythritol tetranitrate, hexamethonium chloride, N-acetyl-paminopheno], and veratrum viride, d-amphetamine sulfate, pentobarbituric acid, mephobarbital, mannitol hexanitrate, pyralimine maleate, and the like. Of course, other materials physiologically active or not, acid sensitive or not, may be employed in the present invention as desired or required to a particular use. Such a use may be in controlled provision of a catalyst or coreactant in certain pH environments or in controlled release of a dye or indicator material under cer tain conditions,

The method for manufacturing microcapsules of this invention is not important and forms no part of the invention. Particles of internal phase can be manufac tured, for example, by granulating a paste of the matrix binder material mixed with finely-divided particles of the material to be contained and finely-divided particles of the enteric material. The paste if kneaded or otherwise mixed until homogeneous and then granules of the desired size are made and dried. Liquid to make the paste can be a solvent which dissolves the matrix material but does not dissolve the active material or the enteric material or it can be a solvent which dissolves the matrix material and the active material to the saturation of the active material.

The granules or particles, when manufactured, by whatever method, are coated by the polymeric film of capsule wall material. Any of several known methods can be used to apply the capsule wall material. Wellknown examples of eligible capsule wall coating methods include: pan-coating, wherein a solution of the capsule wall material is sprayed onto internal phase particles which are tumbling in a rotating bowl; impingement coating, wherein the internal phase particles are impinged onto and east through a liquid film of the capsule wall material and thereby become coated with the material; and encapsulation by liquiddiquid phase separation of the capsule wall material wherein the internal phase particles are distributed in a two-phase liquid capsule manufacturing system consisting of a phase of continuous suspending liquid and a phase of dispersed liquid droplets of the capsule wall material which droplets coat the internal phase particles to yield capsules. The phase separation method for coating the intended phase particles is preferred and will be used herein to teach practice of the invention.

BRIEF DESCRIPTION OF THE DRAWING FIG. 1 depicts a microcapsule of this invention in partial cross-section. The figure is a schematic representation and no attempt has been made to show relative dimensions or actual shapes of any components. A microcapsule of this invention may be more or less spherical than the representation of the figure.

FIG. 2 depicts a release comparison between active materials contained in capsules of this invention and active materials contained by prior art means.

Returning to FIG. 1, the novel capsule 10 comprises a homogeneous combination of active material It.

(hatching upward to the. left), enteric material 14 (hatching upward to the right) and matrix binder material 13, all encased in a polymeric capsule wall 12. The particle sizes of the active material 11 and the enteric material 14 can be larger or smaller, in relation to the capsule size as a whole, than the particle size in the figure; and the concentration of active material 11 and enteric material 14 in the matrix binder material 13 can be greater or less. The ratio of active material 1 l to enteric material 14 can be adjusted to any desired or required relation depending on the result to be achieved. Particle size for the active and enteric contained materials is usually less than 250 microns; a preferred size range being from a few microns to 150 microns. The contained materials are normally from about to about 98 percent, by weight, of the internal phase; about to about percent being preferred. The active material normally constitutes about 20 to 80 percent of the contained materialsabout 50 percent being preferred. The polymeric capsule wall 12 is a seamless film substantially conforming to the shape of the internal phase particle. The thickness of the poly meric capsule wall 12 can be varied over a considerable range. The thickness may even change as the capsule is produced or used by virtue of the capsule wall material either absorbing or losing liquid As used herein the 7 words internal phase" mean, allmaterial enclosed by a capsule wall and the words".contained material mean the active andentericniat erial granulated into the matrix binder to yield internal phase.

The graph of FIG. 2 is a schematic representation of the release of contained material in an aqueous environment. The ordinate represents percent, by weight, (on a logarithmic scale) of contained material remaining in a composition being tested. The abscissa represents passage of time and a secondary ordinate, designated as i, represents a time when the pH of the aqueous environment is changed from 1.2 to 7.5 as is customary in some in vitro laboratory tests. Curves and B depict the release expected for unencapsulated gran- "ules'of active material in a non-enteric, "insoluble,

binder material and in an enteric, insoluble, binder material, respectively. It should be noted that curves A and B are located in the pH 1.2 region of the graph and that, in that region, the preferred enteric materials exhibit solubility characteristics substantially identical with non-enteric materials.

Curve B depicts the release for granules with enteric binder in pH 7.5 aqueous medium. Time begins at the 1' axis for the curves A and B. What is intended to be represented by curve B is the slightly greater rate of release for granules having enteric binder when placed in alkaline media as compared to release in acid media. Curve A depicts a release relatively slower than that of curve B and represents the release to be expected from granules having non-enteric binder material immersed in analkaline medium. The release depicted by curve A and curve A is substantially equal. Note that release from granules is quite rapid.

Curve C depicts the release expected for encapsulated granules of active material in a non-enteric, water insoluble, binder I material with no enteric material added. It should be noted that the rate of release is substantially independent of pH and that the rate of release is substantialy slower than the unencapsulated granules of Curves A and B. The slope of curve C can vary considerably depending upon the type of non-enteric matrix, whether water soluble or not, the concentration of active contained material, and the like. Curve C evidences the fact that an insoluble capsule wall provided prolonged release of contained materials by virtue of the need for contained materials to be permeated through the capsule walls as liquid solution.

Curve D depicts the release expected for the capsule of this invention. It should be noted that a knee occurs in the release curve at the time of pH change ;the release rate in the alkaline medium being much greater than the release rate in the acid medium. Additionally,

i it is noted that release from the capsule of this invention is slower than release from the granules by reason of the rate controlling feature of transfer through the 7 capsule wall material.

1 DESCRIPTION OF PREFERREDEMBODIMENT In this example, gum arabicis used for the water soluble matrix binder material; cellulose acetate hydrogen iphthalate (CAP) is the enteric material; and N-acetylp-arniriophenol (APAP) is the active material. Two

00f acid, basicland varied pH. In an aqueous solution,

hundred grams of dryCAP, powdered to an average particle size of less than about 50rnicrons, is combined with 200 grams of dry'APAP having a similar average particle size. The powders are blended dry to achieve .a substantially homogeneous mixture and then a 10 grams usually sufficing. The mass is granulated by being force through a coarse (10 mesh) screen or by using a wet granulator which yields particles of about 1500 to 2500 microns in average diameter. The particles are dried, the dried particles are forced through a screen having openings of about 1200 microns, and the material retained on a screen having openings of about 500-600 microns is collected for use. The fines can be recycled through the granulating process to forestall waste of the materials. Internal phase particles could be used in the size range of from about 100 to more than about 1000 microns in average diameter.

The hydrophobic polymeric capsule wall material of this example is ethylcellulose. To accomplish encapsulation, 350 grams of cyclohexane, 105 grams of the granulated particles, 7 grams of ethylcellulose (as below specified) and 7 grams of polyethylene as below specified) are added to a vessel equipped for heating and agitation. The ethylcellulose has an ethoxyl content of 48.049.5 percent and exhibitsa viscosity of about -105 centipoises when tested at 20 centigrade as a 5 percent, by weight, solution in a 4/1, toluene/ethanol solvent. (An example of such material is sold by The Dow Chemical Co., Midland, Michigan as a commercially available, standard material, carrying the designation Grade 100.) The polyethylene of this example serves as a phase-separation-inducing polymer, has a molecular weight of about 7000 and a ring and ball softening point of about centigrade determined according to Specification D-36-26 of the American Society for Testing Materials, (An example of such material is sold under the trademark, Epolene C-10, by Eastman Chemical Products, Inc., New York, N. Y.)

Agitation is commenced to disperse all of the solid materials. Agitation is continued while the system is heated to about 80 centigrade and then slowly cooled to'about 25 centigrade. During the course of heating and cooling, capsules are formed wherein droplets of a liquid, separated phase, concentrated in ethylcellulose, wraps, as capsule wall material, about individual particles of the granulated material at the high temperature and wherein the liquid wall material solidifes as the temperature is lowered. The capsules are separated from the cyclohexane capsule manufacturing vehicle by filtration, are washed by two portions of cyclohexan'e,and the residual cyclohexane is removed by evapo ration. 1

As a test of capsules made in the example above, release of active material was measured in aqueous media buffered at pH 1.2, release of the active material was as follows:

Time (hours) Cumulative Release (percent) Time (hours) Cumulative Release (percent) The release is rapid due to solubility of the enteric material; --the active material being slowed only by solution transfer through the capsule wall.

Release was as follows in an aqueous solution wherein the pH was increased as the test progressed:

Time (hours) pH Cumulative Release (percent) The release is slow in the early portion of the test at low pH; the enteric material serving to block release of the active material. As the pH is increased, the release is more rapid; the active material being held only by the capsule wall.

These tests represent a significant exhibition of the invention described and claimed herein in that there is actual demonstration of the effect of the combination of hydrophobic capsule wall material and particulate enteric barrier material in release of active encapsulated material at a variety of pH levels.

The use of particulate enteric material in a water soluble binder is important to permit at least a partial release in acid aqueous environments. The hydrophobic polymeric capsule wall material is important to provide sustained release by diffusion and to prevent disintegration of the granules which would render release instantaneous.

What is claimed is:

l. A microcapsule consisting of an internal phase and a water soluble capsule wall permeable to aqueous solutions wherein the internal phase comprises an individual particle of a continuous matrix of water-soluble material and, distributed substantially evenly throughout the continuous matrix, a plurality of finely-divided particles of an active material and a plurality of finelydivided particles of enteric material and wherein the water insoluble capsule wall permeable to aqueous solutions comprises a thin coating of water-insoluble polymeric material substantially evenly covering the parti cle of continuous matrix material preventing disintegration of the internal phase.

2. A minute, enterically active, microcapsule having a capsule wall permeable to aqueous solutions and consisting essentially of hydrophobic polymeric filmforming material insoluble in aqueous systems and a solid core of finely-divided water-soluble active material and finely-divided enteric material intimately combined with a matrix of water-soluble binder material wherein the enteric material is relatively insoluble in acidic aqueous systems and is relatively more soluble in aqueous systems of decreased acidity and wherein the capsule wall prevents disintegration of the solid core.

3. The capsule of claim 2 wherein the hydrophobic polymeric film-forming capsule wall material is ethyl cellulose.

4. The capsule of claim 3 wherein the enteric material is cellulose acetate hydrogen phthalate.

5. A capsule consisting of:

a. a substantially water insoluble capsule wall permeable to aqueous solutions and b. an internal phase comprising i. a water-soluble, continuous, matrix binding ii. a multitude of particles of finely-divided active material and iii. a multitude of particles of finely-divided enteric material wherein the enteric material and the active material are substantially homogeneously dispersed in and bound by the matrix and the capsule wall prevents disintegration of the internal phase.

6. The capsule of claim 5 wherein the capsule wall consists essentially of a film of water insoluble, hydro phobic, polymeric material permeable to aqueous solutions and encasing the internal phase in conformance with the internal phase shape and preventing disinte gration of the internal phase.

7. The capsule of claim 6 wherein the particle of active material are Water soluble and of a size substantially the same as the particles of enteric material.

8. The capsule of claim 6 wherein the internal phase is substantially spherical and of a size more than about 100 microns and less than about 1000 microns.

9. The capsule of claim 8 wherein the internal phase constitutes to 98 percent, by weight, of the capsule;--the remainder being capsule wall material.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3, 909, 444 DATED September 30, 1975 INVENTOR(S) Jerrold L. Anderson and Thomas C. Powell It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Claim 1, line 2, "soluble" should be "insoluble-- Claim 7, line 1, "particle" should be -particles- Signed and Scaled this tenth D 8) Of February 1976 '[sEAL] Atlest:

RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner oj'Parenrs and Trademarks UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3, 909, 444

DATED September 30, 1975 INVENTOR(S) Jerrold L. Anderson and Thomas C. Powell It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Claim 1, line 2, "soluble" should be insolub1e Claim 7, line 1, "particle" should be partic1es q I I Signed and Scaled this tenth Day Of February 1976 '[SEAL] Arrest:

RUTH c. MASON C. MARSHALL DANN Arresting Officer (ommissiuner uj'latents and Trademarks

Claims (9)

1. A MICROCAPSULE CONSISTING OF AN INTERNAL PHASE AND A WATER SOLUBLE CAPSULE WALL PERMEABLE TO AQUEOUS SOLUTION WHEREIN THE INTERNAL PHASE COMPRISES AN INDIVIDUAL PARTICLE OF A CONTINUOUS MATRIX OF WATER-SOLUBLE MATERIAL AND, DISTRIBUTED SUBSTANTIALLY EVENLY THROUGHOUT THE CONTINUOUS MATRIX, A PLURALITY OF FINELY-DIVIDED PARTICLES OF AN ACTIVE MATERIAL AND A PLURALITY OF FINELY-DIVIDED PARTICLES OF ENTERIC MATERIAL AND WHEREIN THE WATER INSOLUBLE CAPSULE WALL PERMEABLE TO AQUEOUS SOLUTIONS COMPRISES A THIN COATING OF WATER-INSOLUBLE
2. A minute, enterically active, microcapsule having a capsule wall permeable to aqueous solutions and consisting essentially of hydrophobic polymeric film-forming material insoluble in aqueous systems and a solid core of finely-divided water-soluble active material and finely-divided enteric material intimately combined with a matrix of water-soluble binder material wherein the enteric material is relatively insoluble in acidic aqueous systems and is relatively more soluble in aqueous systems of decreased acidity and wherein the capsule wall prevents disintegration of the solid core.
3. The capsule of claim 2 wherein the hydrophobic polymeric film-forming capsule wall material is ethyl cellulose.
4. The capsule of claim 3 wherein the enteric material is cellulose acetate hydrogen phthalate.
5. A capsule consisting of: a. a substantially water insoluble capsule wall permeable to aqueous solutions and b. an internal phase comprising i. a water-soluble, continuous, matrix binding ii. a multitude of particles of finely-divided active material and iii. a multitude of particles of finely-divided enteric material wherein the enteric material and the active material are substantially homogeneously dispersed in and bound by the matrix and the capsule wall prevents disintegration of the internal phase.
6. The capsule of claim 5 wherein the capsule wall consists essentially of a film of water insoluble, hydrophobic, polymeric material permeable to aqueous solutions and encasing the internal phase in conformance with the internal phase shape and preventing disintegration of the internal phase.
7. The capsule of claim 6 wherein the particle of active material are water soluble and of a size substantially the same as the particles of enteric material.
8. The capsule of claim 6 wherein the internal phase is substantially spherical and of a size more than about 100 microns and less than about 1000 microns.
9. The capsule of claim 8 wherein the internal phase constitutes 85 to 98 percent, by weight, of the capsule;-the remainder being capsule wall material.
US3909444A 1971-08-05 1971-08-05 Microcapsule Expired - Lifetime US3909444A (en)

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US3909444A US3909444A (en) 1971-08-05 1971-08-05 Microcapsule
CA 143042 CA1013673A (en) 1971-08-05 1972-05-25 Enterically active microcapsule
GB3369772A GB1334658A (en) 1971-08-05 1972-07-19 Enterically active minute capsule
FR7227012A FR2148045B1 (en) 1971-08-05 1972-07-27
DE19722238162 DE2238162C3 (en) 1971-08-05 1972-08-03

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Cited By (74)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4153677A (en) * 1978-05-18 1979-05-08 Sterling Drug Inc. Controlled-release composition
US4154636A (en) * 1975-08-27 1979-05-15 Freund Industrial Co., Ltd. Method of film-coating medicines
US4205060A (en) * 1978-12-20 1980-05-27 Pennwalt Corporation Microcapsules containing medicament-polymer salt having a water-insoluble polymer sheath, their production and their use
US4223006A (en) * 1977-12-08 1980-09-16 Beecham Group Limited Coated particles
US4241048A (en) * 1979-05-01 1980-12-23 Bristol-Myers Company Suspension composition of benzocaine
US4261969A (en) * 1979-05-03 1981-04-14 World Health Organization Controlled drug release composition
US4341215A (en) * 1980-09-04 1982-07-27 Tampax Incorporated Absorbent device
US4343790A (en) * 1979-02-06 1982-08-10 American Cyanamid Company Controlled release acrylic polymer coated granular pesticidal compositions with attendant reduced dermal toxicity
US4367131A (en) * 1980-07-08 1983-01-04 Engelhard Corporation Photolytic production of hydrogen from water
US4462982A (en) * 1981-10-05 1984-07-31 Tanabe Seiyaku Co., Ltd. Microcapsules and method of preparing same
US4462839A (en) * 1983-06-16 1984-07-31 Fmc Corporation Enteric coating for pharmaceutical dosage forms
US4485103A (en) * 1980-08-04 1984-11-27 American Cyanamid Company Controlled release acrylic polymer coated granular pesticidal compositions with attendant reduced dermal toxicity
US4490436A (en) * 1981-10-30 1984-12-25 Japan Synthetic Rubber Co., Ltd. Polymer filler particles with filler free coating
US4507276A (en) * 1982-08-20 1985-03-26 Bristol-Myers Company Analgesic capsule
US4518478A (en) * 1984-05-23 1985-05-21 The United States Of America As Represented By The United States Department Of Energy Liquefaction with microencapsulated catalysts
US4568560A (en) * 1984-03-16 1986-02-04 Warner-Lambert Company Encapsulated fragrances and flavors and process therefor
US4572833A (en) * 1982-08-13 1986-02-25 A/S Alfred Benzon Method for preparing a pharmaceutical controlled release composition
US4574080A (en) * 1982-08-13 1986-03-04 A/S Alfred Benzon Combination formulation
US4600645A (en) * 1985-01-31 1986-07-15 Warner-Lambert Company Process for treating dosage forms
US4632843A (en) * 1983-02-23 1986-12-30 Basf Aktiengesellschaft Process for the preparation of solid pharmaceutical products
US4661162A (en) * 1983-04-18 1987-04-28 Sankyo Company, Limited Enteric-soluble preparations
US4671211A (en) * 1984-06-08 1987-06-09 Sundstrand Corporation Power source utilizing encapsulated lithium pellets and method of making such pellets
US4708834A (en) * 1986-05-01 1987-11-24 Pharmacaps, Inc. Preparation of gelatin-encapsulated controlled release composition
US4713237A (en) * 1984-06-18 1987-12-15 Schering Corporation Sustained release dosage form
US4746513A (en) * 1983-09-20 1988-05-24 The Dow Chemical Company Microcapsules and method for their production
US4748023A (en) * 1983-01-26 1988-05-31 Egyt Gyogyszervegyeszeti Gyar Process for the preparation of sustained release pharmaceutical compositions having a high active ingredient content
US4756844A (en) * 1986-12-29 1988-07-12 The Dow Chemical Company Controlled-release composition having a membrane comprising submicron particles
US4775536A (en) * 1986-02-24 1988-10-04 Bristol-Myers Company Enteric coated tablet and process for making
US4780318A (en) * 1984-01-10 1988-10-25 Lejus Medical Aktiebolag Oral pharmaceutical composition
US4795642A (en) * 1986-05-01 1989-01-03 Pharmacaps, Inc. Gelatin-encapsulated controlled-release composition
US4794682A (en) * 1985-05-13 1989-01-03 Sundstrand Corporation Making a power source utilizing encapsulated lithium pellets
US4800087A (en) * 1986-11-24 1989-01-24 Mehta Atul M Taste-masked pharmaceutical compositions
US4814184A (en) * 1987-02-28 1989-03-21 Dow Corning Ltd. Pharmaceutical delivery device having a siloxane polymer matrix
US4837032A (en) * 1986-02-04 1989-06-06 Farval Ag Theophylline sustained release tablet
US4842761A (en) * 1988-03-23 1989-06-27 International Flavors & Fragrances, Inc. Compositions and methods for controlled release of fragrance-bearing substances
WO1989007935A1 (en) * 1988-02-29 1989-09-08 Massachusetts Institute Of Technology Polymer composite for controlled release or membrane formation
US4912146A (en) * 1985-01-30 1990-03-27 Warner-Lambert Company Coated dosage forms
US4933182A (en) * 1986-03-25 1990-06-12 Rohto Pharmaceutical Co. Ltd. Pharmaceutical composition for treating periodontal
US4940588A (en) * 1984-10-30 1990-07-10 Elan Corporation Controlled release powder and process for its preparation
US5051305A (en) * 1988-12-30 1991-09-24 Arcade, Inc. Stabilized perfume-containing microcapsules and method of preparing the same
US5057323A (en) * 1988-10-18 1991-10-15 Showa Yakuhin Kako Co., Ltd. Hollow granular medicine and its preparation
US5064650A (en) * 1988-04-19 1991-11-12 Southwest Research Institute Controlled-release salt sensitive capsule for oral use and adhesive system
US5084278A (en) * 1989-06-02 1992-01-28 Nortec Development Associates, Inc. Taste-masked pharmaceutical compositions
US5153160A (en) * 1990-05-24 1992-10-06 Dow Corning Toray Silicone Company, Ltd. Method for preparing microparticles of a thermoplastic resin containing an encapsulated hydrosilylation reaction catalyst
US5187150A (en) * 1987-10-14 1993-02-16 Debiopharm S.A. Polyester-based composition for the controlled release of polypeptide medicinal substances
US5318798A (en) * 1991-09-05 1994-06-07 Tsumura & Co. Process for producing kampo medicine hard capsules
US5350741A (en) * 1988-07-30 1994-09-27 Kanji Takada Enteric formulations of physiologically active peptides and proteins
US5405416A (en) * 1989-02-23 1995-04-11 Commonwealth Of Australia Marine dye composition
US5591433A (en) * 1991-06-21 1997-01-07 University Of Cincinnati Oral administration of immunologically active biomolecules and other therapeutic proteins
US5597562A (en) * 1990-06-01 1997-01-28 Kirin-Amgen, Inc. Oral dosage form of biologically active proteins
US5651984A (en) * 1992-08-04 1997-07-29 Eurand America, Incorporated Controlled release potassium tablet
US5981719A (en) * 1993-03-09 1999-11-09 Epic Therapeutics, Inc. Macromolecular microparticles and methods of production and use
US6090925A (en) * 1993-03-09 2000-07-18 Epic Therapeutics, Inc. Macromolecular microparticles and methods of production and use
US6244265B1 (en) 1997-01-29 2001-06-12 Peter J. Cronk Adhesively applied external nasal strips and dilators containing medications and fragrances
US6276360B1 (en) 1997-01-29 2001-08-21 Peter J. Cronk Medicated nasal dilator
US6663893B2 (en) 2000-04-20 2003-12-16 Bristol-Myers Squibb Co. Taste masking coating composition
EP1421989A1 (en) * 2002-11-20 2004-05-26 Shin-Etsu Chemical Co., Ltd. Microcapsule and production method thereof
US20040127476A1 (en) * 2002-11-14 2004-07-01 Alvin Kershman Oral testosterone delivery system with improved sustained release
US6769428B2 (en) 1997-01-29 2004-08-03 Peter J. Cronk Adhesively applied external nasal strips and dilators containing medications and fragrances
US20050013860A1 (en) * 2003-07-15 2005-01-20 Gopi Venkatesh Controlled release potassium chloride tablets
US20050136096A1 (en) * 2003-08-22 2005-06-23 Davidson R. S. Edible films for administration of medicaments to animals, methods for their manufacture and methods for their use for the treatment of animals
US20060029653A1 (en) * 1997-01-29 2006-02-09 Cronk Peter J Therapeutic delivery system
US20060147526A1 (en) * 2002-11-29 2006-07-06 Cipla Limted Pharmaceutical formulations comprising ß-2 adrenoreceptor agonists and xanthines
US20060210610A1 (en) * 2002-11-14 2006-09-21 Davidson Robert S Methods for modulating dissolution, bioavailability, bioequivalence and drug delivery profile of thin film drug delivery systems, controlled-release thin film dosage formats, and methods for their manufacture and use
US20070036961A1 (en) * 2005-08-10 2007-02-15 Certainteed Corporation Loose fill insulation packaged with additive
US20070098148A1 (en) * 2005-10-14 2007-05-03 Sherman Kenneth N Aroma releasing patch on mobile telephones
US7431849B1 (en) * 2004-03-05 2008-10-07 Specialty Earth Sciences Llc Encapsulated reactant and process
US20090061082A1 (en) * 2004-03-05 2009-03-05 Jason Swearingen Process for Making Environmental Reactant(s)
US20120277323A1 (en) * 2009-11-07 2012-11-01 University Of Iowa Research Foundation Cellulose capsules and methods for making them
US20140039280A1 (en) * 2012-08-02 2014-02-06 Duke University Non-Invasive Diagnostic Device for Early Detection of Infection and Inflammation and Methods of Use
US8834514B2 (en) 2006-08-30 2014-09-16 Xennovate Medical Llc Resilient band medical device
US9155698B2 (en) 2003-03-28 2015-10-13 Cure Pharmaceutical Corporation Method and apparatus for minimizing heat, moisture, and shear damage to medicants and other compositions during incorporation of same with edible films
US9416050B2 (en) * 2011-12-16 2016-08-16 Construction Research & Technology Gmbh Shellac-coated particles of active ingredients with controlled release properties at high pH-values, process for their manufacture and use thereof
US9428419B2 (en) 2013-06-14 2016-08-30 Construction Research & Technology Gmbh Cementitious system comprising accelerator particles coated with crosslinked shellac

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4464434A (en) * 1978-03-13 1984-08-07 Celanese Corporation Microencapsulated alkaloidal material and method of producing same
DE3367324D1 (en) * 1982-04-15 1986-12-11 Prophin Lab Spa Pharmaceutical products in sustained-release form, and their preparation process
DE3367732D1 (en) * 1982-06-22 1987-01-08 Univ Glasgow Device for introducing nutrients and/or therapeutic materials into ruminant animals
FR2556965B1 (en) * 1983-12-21 1986-08-22 Rhone Poulenc Sante New dosage form of ketoprofen has controlled release
EP0177000A1 (en) * 1984-10-02 1986-04-09 EURAND ITALIA S.p.A. Process to obtain a sustained release formulation of water soluble components
CA1266235A (en) * 1985-03-25 1990-02-27 Wallace E. Becker Tablet composition for drug combinations
JPH03145418A (en) * 1989-10-27 1991-06-20 Sumitomo Pharmaceut Co Ltd Sustained release preparation of basic drug hydrochloride
WO1995019763A1 (en) * 1994-01-20 1995-07-27 New Zealand Pastorial Agriculture Research Institute Limited Device for administration of beneficial materials to ruminants

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2390088A (en) * 1942-09-24 1945-12-04 Gelatin Products Corp Enteric gelatin capsule shell or envelope
US3039933A (en) * 1957-10-07 1962-06-19 Premo Pharmaceutical Lab Inc Ethyl cellulose-polyethylene glycol tablet matrix
US3148124A (en) * 1962-06-12 1964-09-08 William E Gaunt Method of preparing sustained release pharmaceutical tablets
US3415758A (en) * 1960-03-09 1968-12-10 Ncr Co Process of forming minute capsules en masse
US3485914A (en) * 1966-07-05 1969-12-23 Chem & Pharm Patent Hold Ltd Process for the production of a pharmaceutical antibiotic preparation having delayed therapeutic action and the composition prepared according to such process
US3577514A (en) * 1968-06-10 1971-05-04 Pfizer Sustained release pharmaceutical tablets

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2390088A (en) * 1942-09-24 1945-12-04 Gelatin Products Corp Enteric gelatin capsule shell or envelope
US3039933A (en) * 1957-10-07 1962-06-19 Premo Pharmaceutical Lab Inc Ethyl cellulose-polyethylene glycol tablet matrix
US3415758A (en) * 1960-03-09 1968-12-10 Ncr Co Process of forming minute capsules en masse
US3148124A (en) * 1962-06-12 1964-09-08 William E Gaunt Method of preparing sustained release pharmaceutical tablets
US3485914A (en) * 1966-07-05 1969-12-23 Chem & Pharm Patent Hold Ltd Process for the production of a pharmaceutical antibiotic preparation having delayed therapeutic action and the composition prepared according to such process
US3577514A (en) * 1968-06-10 1971-05-04 Pfizer Sustained release pharmaceutical tablets

Cited By (94)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4154636A (en) * 1975-08-27 1979-05-15 Freund Industrial Co., Ltd. Method of film-coating medicines
US4223006A (en) * 1977-12-08 1980-09-16 Beecham Group Limited Coated particles
US4153677A (en) * 1978-05-18 1979-05-08 Sterling Drug Inc. Controlled-release composition
US4205060A (en) * 1978-12-20 1980-05-27 Pennwalt Corporation Microcapsules containing medicament-polymer salt having a water-insoluble polymer sheath, their production and their use
US4343790A (en) * 1979-02-06 1982-08-10 American Cyanamid Company Controlled release acrylic polymer coated granular pesticidal compositions with attendant reduced dermal toxicity
US4241048A (en) * 1979-05-01 1980-12-23 Bristol-Myers Company Suspension composition of benzocaine
US4261969A (en) * 1979-05-03 1981-04-14 World Health Organization Controlled drug release composition
US4367131A (en) * 1980-07-08 1983-01-04 Engelhard Corporation Photolytic production of hydrogen from water
US4485103A (en) * 1980-08-04 1984-11-27 American Cyanamid Company Controlled release acrylic polymer coated granular pesticidal compositions with attendant reduced dermal toxicity
US4341215A (en) * 1980-09-04 1982-07-27 Tampax Incorporated Absorbent device
US4462982A (en) * 1981-10-05 1984-07-31 Tanabe Seiyaku Co., Ltd. Microcapsules and method of preparing same
US4490436A (en) * 1981-10-30 1984-12-25 Japan Synthetic Rubber Co., Ltd. Polymer filler particles with filler free coating
US4572833A (en) * 1982-08-13 1986-02-25 A/S Alfred Benzon Method for preparing a pharmaceutical controlled release composition
US4574080A (en) * 1982-08-13 1986-03-04 A/S Alfred Benzon Combination formulation
US4507276A (en) * 1982-08-20 1985-03-26 Bristol-Myers Company Analgesic capsule
US4748023A (en) * 1983-01-26 1988-05-31 Egyt Gyogyszervegyeszeti Gyar Process for the preparation of sustained release pharmaceutical compositions having a high active ingredient content
US4632843A (en) * 1983-02-23 1986-12-30 Basf Aktiengesellschaft Process for the preparation of solid pharmaceutical products
US4661162A (en) * 1983-04-18 1987-04-28 Sankyo Company, Limited Enteric-soluble preparations
US4462839A (en) * 1983-06-16 1984-07-31 Fmc Corporation Enteric coating for pharmaceutical dosage forms
US4808206A (en) * 1983-09-20 1989-02-28 The Dow Chemical Company Microcapsules and methods for their preparation
US4746513A (en) * 1983-09-20 1988-05-24 The Dow Chemical Company Microcapsules and method for their production
US4780318A (en) * 1984-01-10 1988-10-25 Lejus Medical Aktiebolag Oral pharmaceutical composition
US4568560A (en) * 1984-03-16 1986-02-04 Warner-Lambert Company Encapsulated fragrances and flavors and process therefor
US4518478A (en) * 1984-05-23 1985-05-21 The United States Of America As Represented By The United States Department Of Energy Liquefaction with microencapsulated catalysts
US4671211A (en) * 1984-06-08 1987-06-09 Sundstrand Corporation Power source utilizing encapsulated lithium pellets and method of making such pellets
US4713237A (en) * 1984-06-18 1987-12-15 Schering Corporation Sustained release dosage form
US4940588A (en) * 1984-10-30 1990-07-10 Elan Corporation Controlled release powder and process for its preparation
US4952402A (en) * 1984-10-30 1990-08-28 Elan Corporation, P.L.C. Controlled release powder and process for its preparation
US4912146A (en) * 1985-01-30 1990-03-27 Warner-Lambert Company Coated dosage forms
US4600645A (en) * 1985-01-31 1986-07-15 Warner-Lambert Company Process for treating dosage forms
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US4837032A (en) * 1986-02-04 1989-06-06 Farval Ag Theophylline sustained release tablet
US4775536A (en) * 1986-02-24 1988-10-04 Bristol-Myers Company Enteric coated tablet and process for making
US4933182A (en) * 1986-03-25 1990-06-12 Rohto Pharmaceutical Co. Ltd. Pharmaceutical composition for treating periodontal
US4795642A (en) * 1986-05-01 1989-01-03 Pharmacaps, Inc. Gelatin-encapsulated controlled-release composition
US4708834A (en) * 1986-05-01 1987-11-24 Pharmacaps, Inc. Preparation of gelatin-encapsulated controlled release composition
US4800087A (en) * 1986-11-24 1989-01-24 Mehta Atul M Taste-masked pharmaceutical compositions
US4756844A (en) * 1986-12-29 1988-07-12 The Dow Chemical Company Controlled-release composition having a membrane comprising submicron particles
US4814184A (en) * 1987-02-28 1989-03-21 Dow Corning Ltd. Pharmaceutical delivery device having a siloxane polymer matrix
US5187150A (en) * 1987-10-14 1993-02-16 Debiopharm S.A. Polyester-based composition for the controlled release of polypeptide medicinal substances
WO1989007935A1 (en) * 1988-02-29 1989-09-08 Massachusetts Institute Of Technology Polymer composite for controlled release or membrane formation
US4842761A (en) * 1988-03-23 1989-06-27 International Flavors & Fragrances, Inc. Compositions and methods for controlled release of fragrance-bearing substances
EP0334490A3 (en) * 1988-03-23 1990-09-12 International Flavors & Fragrances Inc. Compositions and methods for controlled release of olfactory substances
EP0334490A2 (en) * 1988-03-23 1989-09-27 INTERNATIONAL FLAVORS & FRAGRANCES INC. Compositions and methods for controlled release of olfactory substances
US5064650A (en) * 1988-04-19 1991-11-12 Southwest Research Institute Controlled-release salt sensitive capsule for oral use and adhesive system
US5350741A (en) * 1988-07-30 1994-09-27 Kanji Takada Enteric formulations of physiologically active peptides and proteins
US5057323A (en) * 1988-10-18 1991-10-15 Showa Yakuhin Kako Co., Ltd. Hollow granular medicine and its preparation
US5087455A (en) * 1988-10-18 1992-02-11 Showa Yakuhin Kako Co. Ltd. Hollow granular medicine and its preparation
US5051305A (en) * 1988-12-30 1991-09-24 Arcade, Inc. Stabilized perfume-containing microcapsules and method of preparing the same
US5405416A (en) * 1989-02-23 1995-04-11 Commonwealth Of Australia Marine dye composition
US5084278A (en) * 1989-06-02 1992-01-28 Nortec Development Associates, Inc. Taste-masked pharmaceutical compositions
US5153160A (en) * 1990-05-24 1992-10-06 Dow Corning Toray Silicone Company, Ltd. Method for preparing microparticles of a thermoplastic resin containing an encapsulated hydrosilylation reaction catalyst
US5597562A (en) * 1990-06-01 1997-01-28 Kirin-Amgen, Inc. Oral dosage form of biologically active proteins
US5591433A (en) * 1991-06-21 1997-01-07 University Of Cincinnati Oral administration of immunologically active biomolecules and other therapeutic proteins
US5318798A (en) * 1991-09-05 1994-06-07 Tsumura & Co. Process for producing kampo medicine hard capsules
US5651984A (en) * 1992-08-04 1997-07-29 Eurand America, Incorporated Controlled release potassium tablet
US5981719A (en) * 1993-03-09 1999-11-09 Epic Therapeutics, Inc. Macromolecular microparticles and methods of production and use
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US20060029653A1 (en) * 1997-01-29 2006-02-09 Cronk Peter J Therapeutic delivery system
US20050066965A1 (en) * 1997-01-29 2005-03-31 Cronk Peter J. Adhesively applied external nasal strips and dilators containing medications and fragrances
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US7013889B2 (en) 1997-01-29 2006-03-21 Cronk Peter J Adhesively applied external nasal strips and dilators containing medications and fragrances
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US6663893B2 (en) 2000-04-20 2003-12-16 Bristol-Myers Squibb Co. Taste masking coating composition
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US8999372B2 (en) 2002-11-14 2015-04-07 Cure Pharmaceutical Corporation Methods for modulating dissolution, bioavailability, bioequivalence and drug delivery profile of thin film drug delivery systems, controlled-release thin film dosage formats, and methods for their manufacture and use
US20060210610A1 (en) * 2002-11-14 2006-09-21 Davidson Robert S Methods for modulating dissolution, bioavailability, bioequivalence and drug delivery profile of thin film drug delivery systems, controlled-release thin film dosage formats, and methods for their manufacture and use
EP1421989A1 (en) * 2002-11-20 2004-05-26 Shin-Etsu Chemical Co., Ltd. Microcapsule and production method thereof
US20040169298A1 (en) * 2002-11-20 2004-09-02 Shin-Etsu Chemical Co., Ltd. Microcapsule and production method thereof
US20060147526A1 (en) * 2002-11-29 2006-07-06 Cipla Limted Pharmaceutical formulations comprising ß-2 adrenoreceptor agonists and xanthines
US9155698B2 (en) 2003-03-28 2015-10-13 Cure Pharmaceutical Corporation Method and apparatus for minimizing heat, moisture, and shear damage to medicants and other compositions during incorporation of same with edible films
US7632521B2 (en) 2003-07-15 2009-12-15 Eurand, Inc. Controlled release potassium chloride tablets
US20050013860A1 (en) * 2003-07-15 2005-01-20 Gopi Venkatesh Controlled release potassium chloride tablets
US20080279937A2 (en) * 2003-07-15 2008-11-13 Eurand, Inc. Controlled release potassium chloride tablets
US20050136096A1 (en) * 2003-08-22 2005-06-23 Davidson R. S. Edible films for administration of medicaments to animals, methods for their manufacture and methods for their use for the treatment of animals
US9561182B2 (en) 2003-08-22 2017-02-07 Cure Pharmaceutical Corporation Edible films for administration of medicaments to animals, methods for their manufacture and methods for their use for the treatment of animals
US20080275288A1 (en) * 2004-03-05 2008-11-06 Jason Swearingen Encapsulated Reactant and Process
US7431849B1 (en) * 2004-03-05 2008-10-07 Specialty Earth Sciences Llc Encapsulated reactant and process
US20110195875A1 (en) * 2004-03-05 2011-08-11 Jason Swearingen Encapsulated reactant and process
US20090061082A1 (en) * 2004-03-05 2009-03-05 Jason Swearingen Process for Making Environmental Reactant(s)
US20070036961A1 (en) * 2005-08-10 2007-02-15 Certainteed Corporation Loose fill insulation packaged with additive
US7448494B2 (en) * 2005-08-10 2008-11-11 Certain Teed Corporation Loose fill insulation packaged with additive
US20100310798A1 (en) * 2005-08-10 2010-12-09 Saint-Gobain Isover Insulation packaged with additive
US20070098148A1 (en) * 2005-10-14 2007-05-03 Sherman Kenneth N Aroma releasing patch on mobile telephones
US8834514B2 (en) 2006-08-30 2014-09-16 Xennovate Medical Llc Resilient band medical device
US9050264B2 (en) * 2009-11-07 2015-06-09 University Of Iowa Research Foundation Cellulose capsules and methods for making them
US20120277323A1 (en) * 2009-11-07 2012-11-01 University Of Iowa Research Foundation Cellulose capsules and methods for making them
US9416050B2 (en) * 2011-12-16 2016-08-16 Construction Research & Technology Gmbh Shellac-coated particles of active ingredients with controlled release properties at high pH-values, process for their manufacture and use thereof
US20140039280A1 (en) * 2012-08-02 2014-02-06 Duke University Non-Invasive Diagnostic Device for Early Detection of Infection and Inflammation and Methods of Use
US9428419B2 (en) 2013-06-14 2016-08-30 Construction Research & Technology Gmbh Cementitious system comprising accelerator particles coated with crosslinked shellac

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CA1013673A1 (en) grant
FR2148045A1 (en) 1973-03-11 application
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DE2238162C3 (en) 1979-06-07 grant
GB1334658A (en) 1973-10-24 application
DE2238162A1 (en) 1973-02-15 application
CA1013673A (en) 1977-07-12 grant

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