US3247066A - Controlled release dosage form containing water-swellable beadlet - Google Patents

Controlled release dosage form containing water-swellable beadlet Download PDF

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US3247066A
US3247066A US223093A US22309362A US3247066A US 3247066 A US3247066 A US 3247066A US 223093 A US223093 A US 223093A US 22309362 A US22309362 A US 22309362A US 3247066 A US3247066 A US 3247066A
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coating
water
bead
beads
medicament
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Jr George Milosovich
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Parke Davis and Co LLC
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Parke Davis and Co LLC
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Priority to US223093A priority Critical patent/US3247066A/en
Priority to GB5113/66A priority patent/GB1085739A/en
Priority to BE676524D priority patent/BE676524A/xx
Priority to DE19661617724 priority patent/DE1617724A1/de
Priority to FR49726A priority patent/FR1594514A/fr
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    • 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
    • A61K9/50—Microcapsules 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1658—Proteins, e.g. albumin, gelatin
    • 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
    • A61K9/50—Microcapsules 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • 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
    • A61K9/50—Microcapsules 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
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Definitions

  • the present invention relates to novel forms and compositions of medicaments possessing advantages which are of value in the pharmaceutical field and other fields. More particularly, the invention relates to new controlled release dosage forms for the internal administration of medicaments.
  • a single dose can provide a nearly constant blood level of medicament over an eight to twelve hour period of time eliminating the peak and valley type blood level picture previously obtained with single doses administered at more frequent time intervals. It has been found that patients respond far better to certain medication with reduced incidence of side effects when given in this manner. I addition to possible reduction in cost, it is also more convenient for the patient, especially when blood levels must be maintained throughout the twenty-four hour day.
  • the medicament is either coated with or entrapped within a substance which is slowly digested or dispersed in the intestinal tract. As the digestive process progresses, the medicament is made availabie to the body fluids. The rate of availability is .a function of the rate of digestion of the slowly dispersible substance.
  • products utilizing this mechanism have been formulated as compressed, coated, or multilayer tablets, and as encapsulated granules or pellets, the variety of the size and shape of the dosage forms does not circumvent the physiological variability of the patients receiving the drugs. These variations may be in gastric mobility, enzymatic activity, and hydrogen ion concentration.
  • the leaching mechanism of release is obtained by coating the drug with a film, part of which is soluble and dissolves leaving pores through which the drug may diffuse, or by entrap-ping the drug in an insoluble matrix from which it diffuses. While the leaching mechanism is not dependent upon digestive processes, it still has an inherent disadvantage.
  • the rate of release is a function of the surface area exposed to the leaching fluid and the distance through which the medicament must diffuse in order to be available to the body fluids. As a result, the release of medicament is first order and the rate of release at any given time after ingestion will be dilferent 3,247,055 Patented Apr. 19, 1966 from the rate at any other time, and will be decreasing as time after ingestion increases.
  • Controlled release medicaments may also be classified by product types.
  • the two primary examples are controlled release tablets and capsules containing a multiplicity of small cores, pellets, or granules.
  • products prepared from small cores or pellets are preferred because of the uniformity of the release pattern from their larger surface area and ease of maintaining quality control.
  • a more uniform, reproducible movement of many small particles through the gastrointestinal tract can be attained than with a single large tablet.
  • the small particles likewise may be pictured as tWo distinct classes.
  • One class consists of molded, cast, or peiletized particles in which the drug is entrapped in the solid matrix. Although this procedure has the advantage that a multiplicity of particles can be administered, prodnets of this type utilize either the digestion or leaching release mechanism and are particularly noted for rapidly releasing the drug initially or not completely releasing the drug over the eight to twelve hour prescribed period.
  • the second class comprises coated particles.
  • they consist of nonpareil sugar seeds or cores coated first with the drug and subsequently coated with a partially water permeable film.
  • this technique has many other disadvantages.
  • the drug is coated on small seeds the basic technological limitations of this procedure invariably result in seeds coated with varying quantities of drug.
  • the coatings frequently are applied in layers alternating with the drug layers. Thus, because of dimensional restrictions, only small doses of drugs can be employed and, in addition, there is no positive release mechanism.
  • One object of the present invention is to provide a multiplicity of coated beads capable in dosage uni-t form of uniformly releasing medicament over an eight to twelve hour period of time at a rate sufficient to provide adequate blood levels for this period.
  • Another object of the invention is to provide a controlled release dosage form which operates independent of physiological variations encountered in individual patients.
  • Another object is to provide a dosage form affording complete release of medicament by means of internal pressure.
  • Still another object is to provide a medicament in dosage form which comprises a multiplicity of coated beads each containing a relatively high proportion of the medicarnent.
  • Yet another object is to provide coated beads containing medicament, each of which possesses the same ratio of drug content to bead weight thereby guaranteeing unexcelled uniformity.
  • a still further object is to provide a controlled release dosage form which can be adapted to medications having either relatively high or relatively low solubility in physiological fluids.
  • FIGURE 1 is an elevation of a coated medicament bead, cut away in part to show the interior of the bead;
  • FIGURE 2 is a perspective view of a ruptured coated medicament bead
  • FIGURE 3 is a plan view of a coated medicament bead following rupture.
  • the present invention in one of its embodiments includes a controlled release unit 1 which comprises a bead 2 speroidal in form, having a smooth surface, surrounded or enveloped by a contacting rupturable film coating 3 which is inert to body fluid (i.e. non-toxic, insoluble in body fluid and non-digestible) and permeable to diffusion of water.
  • the bead or core 2 in turn, comprises a water-swellable, medicated colloid, i.e., colloid material containing one or more medicaments which are compatible with the colloid material.
  • the medicament may be present in solution or, as shown in FIGURE 1, in the form of dispersed solid particles 4.
  • the unit 1 comes into contact with body fluid containing water which, with passage of time, diffuses gradually through the coating 3 into the central core 2.
  • the core contains a waterswellable colloid.
  • the colloid under influence of the water entering and coming into contact with the core, immediately begins to absorb the water and to swell. The process is a continuing one and the colloid progressively continues to swell as further amounts of water diffuse through the coating into the core.
  • FIGURE 2 represents a controlled release unit 1 after prolonged exposure to water as the result of which the coating 3 has undergone rupture, as described, to provide a gross opening defined in part by random edges 5 through which the bead 2 is visible.
  • the representation is typical of the case where the fluid surrounding the coating 3 is in motion.
  • FIGURE 3 is a representation of the rupture occurring when the fluid surrounding the coating is relatively static.
  • the bead 2 swells on the diffusion of water through the coating 3.
  • trace amounts of the medicament may possibly diffuse through the coating, but it is only with rupture accomplished by swelling that essentially the total content of the drug is released.
  • the release of the medicament is substantially immediate (i.e., within several minutes after rupture), it is accomplished at a time which is considerably subsequent to the time of administration.
  • the release of the medicament advantageously depends only on the presence of water and does not depend on enzyme action, pH, rate of digestion, mechanical attrition, etc. This feature is of great advantage since water is present in all individuals and its vapor pressure, a function of temperature, does not vary significantly among individuals.
  • colloid material for inclusion in the bead 2, in accordance with the invention, various colloid materials are satisfactory.
  • Gelatin is a particularly useful colloid for this purpose and although certain embodiments of the invention de scribed hereinafter are directed to dosage forms containing gelatin, it will be realized that other colloids or combinations of colloids can be used in place of or in addition to gelatin.
  • suitable colloids may be mentioned starch, starch phosphate, zein, gum arabic, agar, albumin, tragacanth and mixtures of colloids, such as gelatin-starch mixtures.
  • the quantity or relative proportion of the colloid material of the bead is subject to considerable variation.
  • colloid material should be present to provide, on uptake of water, a swelling pressure in excess of the cohesive strength of the film coating.
  • the choice of colloid is not critical, it being required merely that the colloid possess water absorption properties and undergo swelling with uptake of water.
  • the colloid material may optionally contain plasticizing agents such as sorbitol, glycerin, and the like.
  • the colloid material as used in the instant dosage forms is conveniently employed in dry form or in a form which has a substantial capacity for absorption of water.
  • gelatin for example, commercially available grades which ordinarily have a water content of about 11% are suitable for the present invention.
  • the water content of the gelatin should preferably be lower, i.e., less than 11% and downward to about 15%.
  • the colloid material contains, in accordance with the invention, one or more compatible medicaments.
  • the medicament may be present in the colloid material either in the liquid phase or solid phase, as desired.
  • the medicament is dissolved or dispersed in warm liquid gelatin and the liquid is extruded through an orifice into a non-turbulent stream of liquid coolant so as to cause the gelatin to form into smooth, discrete, solid spheroidal beads containing medicament uniformly dissolved or dispersed therethrough, following which the beads are dried to render them hygroscopic.
  • each head contains the same proportion of drug and in each the distribution of drug is homogeneous.
  • the beads may contain substantially more medicament on a Weight per dosage unit basis than conventional sustained release forms which comprise a multiplicity of individual delayed released granules or pellets.
  • the beads may contain as much as 50% or more by weight of medicament.
  • drying is accomplished at or below the tack point of the beads, i.e., the temperature at which the beads when subjected to cooling, cease to adhere to one another.
  • the tack point varies inversely with the drug concentration. In a case where the beads contain a relatively high concentration of medicament, the tack point is ordinarily low and therefore drying must be carried out at relatively low temperatures, e.g., temperatures approaching 10- 15 C. or lower.
  • a wide variety of medicaments may be included in the present dosage forms and the concentration thereof is also subject to wide variation, as desired.
  • non-digestible refers to film-forming or coating substances which are completely non-digestible or are resistant to digestion, i.e., undergo substantially little, if any, digestion prior to the desired rupture and release of the medicament from the coated beads.
  • Certain of the specific illustrative coating substances described hereinafter, although not completely non-digestible, are resistant to digestion and therefore when used as a coating substance should preferably be incorporated with at least one other more inert substance in a sufiicient quantity to provide controlled resistance to digestive attack.
  • the coating can be achieved with a substance that forms a relatively thin continuous rupturable cohesive film which is inert to leaching or digestion by body fluid.
  • plastic film formers any one of a wide variety of plastic film formers can be employed, among which are the following types of plastic bases; cellulose ethers such as ethyl cellulose and ethyl hydroxyethyl cellulose; cellulose esters such as cellulose acetate, cellulose acetate ph-thalate, celluose acetate butyrate and celulose nitrate; fluorocarbon resins, particularly fluoroethylene resins such as tetrafluoroethylene and chlorotrifiuoroethy-lene resins; polyamide-epoxy resins; synthetic rubbers such as polychloroprenes and butadienestyrene, isoprene-styrene, polysulfide, polyacrylic, polybutadiene and polyurethane rubbers; vinyl chloride resins, vinyl chloride-acetate resins, vinyl chloride-vinylidene chloride copolymers and vinyl
  • plastic bases are ethyl cellulose, chlorotrifluoroethylene (CTFE) resin such as Kel+F800g tetrafluoroethylene (TFE) resin such as Teflon 30 and vinyl chloridevinylidene chloride copolymers such as Saran resin F-220 and Saran latex F-122A15.
  • CTFE chlorotrifluoroethylene
  • TFE tetrafluoroethylene
  • Tedflon 30 vinyl chloridevinylidene chloride copolymers
  • Saran resin F-220 and Saran latex F-122A15 vinyl chloridevinylidene chloride copolymers
  • oils such as castor oil
  • glyceryl esters of such acids such as acetylated monoglycerides
  • the film coating material may be applied by any procedure which provides a continuous film of essentially uniform thickness.
  • One method of film coating involves rotating a bed of uncoated beads in a conventional tablet coating pan and applying a solution or dispersion of the coating agent in a suitable solvent by pouring or spraying onto the moving beads, care being taken to uniformly coat each bead and to avoid incomplete film coating such as is caused by bead agglomeration, etc. Drying of the coated beads is accomplished by exposure to Warm, dry air. The coating procedure conveniently is continued until the desired film thickness is obtained. The resulting film coated beads are then cured if necessary with heat (air drying, baking or force drying), polished and finished as desired. Other coating procedures such as fluid bed coating, vertical spray coating, etc., can also be employed.
  • a preferred procedure for coating is the vertical spray coating method described in US. Patents Nos. 2,648,669 and 2,799,241.
  • the beads to be coated are suspended in a column by means of a turbulent air stream, and an atomized solution or dispersion of the film coating agent is sprayed vertically upward into the column containing the suspended beads such that the beads become uniformly coated and dried. Curing of the coating where necessary can be accomplished in conjunction with the drying step or can be carried out subsequently.
  • Various solvents and mixtures of solvents can be used to provide the coating agent solutions or dispersions. One may use any solvent which dissolves or disperses the coating agent and yet can be readily removed by evaporation or other conventional means.
  • the solvent should be relatively volatile and have a low viscosity.
  • alcohols such as absolute alcohol, isopropanol and methanol
  • low molecular esters such as ethyl acetate and amyl acetate
  • ketones such as acetone, Z-butanone and the like.
  • K is the time for the uncoated colloid to release the medicament
  • d is the thickness of the coating film.
  • a preferred embodiment of the invention is a plurality of small coated beads of a single type (.i.e., uniform bead size, film coating, film thickness, etc.) or a blend of different types, either in bulk form or contained in a pharmaceutical carrier such as a hard or soft shell capsule, suppository, non-aqueous syrup,
  • each of such coated beads contains a partial dose and, as indicated, may be varied as desired with respect to one or more factors.
  • the principal factors are the following: (a) The identity of the film coating (b) The film thickness The identity of medicament (d) The identity of the colloid material, and
  • the dosage form includes a plurality of coated beads having individual variations with respect to medicament release, i.e., a plural dosage form
  • administration a controlled release dosage form there is provided on administration a controlled release dosage form.
  • a non-enteric gelatin capsule is administered orally containing a plurality of coated beads constituting a blend of beads having a uniformly graded variety of coatings or coating thicknesses, the capsule dissolves usually in about -30 minutes whereupon the individual coated beads become directly exposed to body fluid. In this condition, they each become separately ruptured in due course depending upon the film coating thickness and type of coating of each individual bead.
  • Such plural dosage forms can also include in admixture with the coated beads a number of uncoated beads which on administration operate to provide immediate medication.
  • the resulting colloid mixture has a viscosity of 1300 cps. at 70 C. as determined by a Brookfield viscosimeter using a No. 2 spindle at 30 rpm.
  • the mixture is then processed into solid beads by means of a bead-forming apparatus of an improved type.
  • this apparatus consists of a reservoir for the colloid material to be processed, conduit means connecting the reservoir with a manifold pipe having an integral bank of twenty parallel No. 22 gauge hypodermic needles for extrusion of the colloid, means for pumping the liquid colloid to the pipe at a desired rate, temperature and pressure, whereby the liquid colloid in the reservoir can be pumped to the manifold pipe and thence through the needles and out of the orifices thereof at a controlled rate.
  • the apparatus also includes an inclined trough over which is flowed, by pump and refrigeration means, at a controlled rate, depth and temperature, a coolant liquid which is immiscible with the liquid colloid.
  • the needles are arranged in a horizontal bank above and at right angles to the line of flow of the liquid coolant and are disposed vertically downward in a position such that the orifices thereof almost touch and are equidistant from the surface of the liquid coolant.
  • the needles receive the liquid colloid (maintained at a temperature of C.) and direct it in a plurality of flowing streams or filaments into the body of the flowing liquid coolant.
  • Petroleum ether maintained at a temperature of 10 C. is used as the liquid coolant; the flow thereof, as maintained, is laminar (i.e., non-turbulent) and the linear flow-rate is 50 cm. per second.
  • the depth of the liquid coolant stream is about one-half centimeter, the width of the trough is 20 cm., and the angle of inclination with the horizontal is 20.
  • the flow rate of the liquid colloid flowing from the needles is approximately 30 liters per hour.
  • the velocity of the liquid colloid as it first enters the flowing liquid coolant is essentially zero with respect thereto, but it is immediately diverted in the body thereof and carried along in a stream with the coolant and at increasing velocity until the coolant and the colloid stream are moving at approximately the same velocity. At this point, the colloid stream becomes dynamically unstable and breaks up into uniform spheroids or beads which on further movement with the flowing coolant congeal and become hardened.
  • the coolant containing the colloid beads is then collected in a receiver, and the beads are separated intact from the coolant and dried first at 10 C. to about 5% Water content and then at 45 C. to about 1% water content.
  • the procedure provides about 11 kg. of dried colloid beads in the size range 590 to 840 microns (i.e., #20 to #30 mesh, U.S. series) containing about 28% by weight of uniformly distributed diphenhydramine hydrochloride.
  • other methods of forming colloid beads can be employed in place of the foregoing procedure, such as dropping the liquid colloid into a vertical air column.
  • Example 1(a) For the preparation of similar colloid beads which differ only with respect to percentage of medicament content, the same procedure of Example 1( a) is followed except that the relative quantity of diphenyhdramine hydrochloride is varied as desired.
  • a sufficient amount of water is used to provide a solution of the diphenhydramine hydrochloride, the total amount of water used in the formulation of the colloid mixture being maintained substantially constant so as to insure the required viscosity of the mixture.
  • colloid beads containing 5% of diphenhydramine hydrochloride are provided by the procedure of Example 1(a) using the following starting materials:
  • the gelatin is hydrated in two liters of water, the third liter being used to dissolve the diphenhydramine.
  • the yield is 2.35 kg. of dry (1%) beads assaying 52.3% diphenhydramine.
  • the gelatin is prehydrated with 900 cc. of water at room temperature for three hours.
  • the hydrated mass is then heated to provide a melt and 1000 cc. of water containing the pyridazine in slurry form is added.
  • the melt is held at 70 C. and thoroughly mixed to assure complete dispersion.
  • the sorbitol is dissolved in 500 cc. of water and the solution blended into the melt suspension.
  • the resulting blend is then converted into small, dry, solid beads or spheroids by the bead-forming procedure described in Example 1(a).
  • Each bead contains approximately 29% by weight of the pyridazine.
  • This example illustrates the preparation of colloid beads which contain a water-insoluble medicament in the form of a suspension in the colloid.
  • water-insoluble medicaments or mixtures thereof particularly relatively highmelting medicaments (e.g., chloramphenicol, diphenhydramine salicylate, sulfaguanidine, dimenhydrinate, and the like) can be used in place of the above-mentioned pyridazine to provide similar suspensions.
  • relatively highmelting medicaments e.g., chloramphenicol, diphenhydramine salicylate, sulfaguanidine, dimenhydrinate, and the like
  • relatively highmelting medicaments e.g., chloramphenicol, diphenhydramine salicylate, sulfaguanidine, dimenhydrinate, and the like
  • the gelatin is prehydrated in 450 cc. of water at room temperature for three hours.
  • the hydrated mass is then heated to provide a melt and the succinimide is added.
  • the resulting mixture is vigorously agitated while hot (75 C.) to provide a finely divided emulsion of the molten succinimide.
  • a solution of the sor-bitol in 450 cc. of Water is mixed in and the resulting emulsion is converted into small, dry, solid beads or spheres by the bead-forming procedure described in Example 1(a).
  • Each bead contains approximately 45% by weight of the succinimide.
  • This example illustrates the preparation of colloid beads which contain a water-insoluble medicament in the form of an emulsion in the colloid.
  • water insoluble medicaments e.g., liquid medicaments or lowmelting medicaments such as phensuximide and ethsuximide
  • mixtures thereof can be used in place of the above-mentioned succinimide to provide similar emulsions.
  • the gelatin is prehydrated with 4 liters of water at room temperature for three hours. The hydrated gelatin is then heated to 70 C.
  • the Z-diethylamino-2-methylpropriophenone nitrate is dissolved in one liter of hot water and added to the above hot gelatin mixture with stirring.
  • the glycerin and an additional 3 liters of hot water are added While the temperature is maintained at about 70 C.
  • the resulting colloid mixture is converted into dry solid beads or spheres by the bead forming procedure described in Example 1(a)
  • the dried beads assey 27% by Weight of the nitrate salt This example illustrates the preparation of colloid beads which contain a water-soluble medicament.
  • water-soluble medicaments or mixtures thereof can be used in place of the above-mentioned nitrate salt to provide similar forms.
  • water soluble substances which may be used in place of the salt, there may be mentioned thiamine hydrochloride, chloroquin disphosphate, soluble acetylsalicylic acid compounds and the like.
  • Example 5 Gelatin kg 6.0 Methylene blue kg 0.1 Sorbitol, 70% in water kg 1 Water l 27
  • the gelatin is prehydrated overnight at room temperature in 15 liters of water.
  • the hydrated mass is heated to 70 C. and the methylene blue is added in the form of an aqueous solution (100 g. methylene blue in two liters of water).
  • the sorbitol solution and 10 liters of Water are added with stirring and heating to maintain the temperature at 70 C.
  • the resulting colloid solution is converted into small, dry, solid colloid beads by the beadforming procedure described in Example 1(a). Each of the resulting beads contains about 1.5% by weight of methylene blue.
  • a coating solution consisting of 500 grams of ethyl cellulose (10 cps.) dissolved in five liters of equal parts of chloroform and anhydrous ethanol.
  • the total volume of the solution is 5400 cc. and the viscosity l-2 cps. at 70 F.
  • the solution is added at a constant rate of about 33 cc. per minute.
  • the total time required for coating and drying is 2 hours and 45 minutes following which the finished coated beads (approximately 2950 grams) are recovered from the chamber.
  • Similar beads coated with a thinner coating of the same composition are prepared in the same manner.
  • a controlled release product designed to have an in vivo uniform release pattern of eight to twelve hours is provided by blending and encapsulating batches of such coated beads, each batch having a dilferent coating film thickness.
  • Example 7 Two kilograms of dried gelatin beads, 12-20 mesh containing 27.0% by weight of 2-diethylamino-2 methyl propiophenone nitrate, prepared in accordance with Example -4, are placed in the coating chamber of a Wurster air suspension apparatus of the type referred to above, and are fluidized in the chamber by turbulent air flowing at the rate of 60 cubic feet per minute. The air inlet temperature is maintained at 125 F. and the outlet temperature at 88 F. To the chamber is added, under an atomizing air pressure of 60 p.s.i., a coating solution consisting of 300 g. of ethyl cellulose (10 cps.), 60 g. of hydrogenated castor oil and 3 g.
  • Example 8 Two kilograms of dried gelatin beads, 16-20 mesh, containing 1.5% by weight of methylene blue, prepared in accordance with Example 5, are placed in the coating chamber of a Wurster coating apparatus of the type referred to above, and are fluidized in the chamber by turbulent air flow. The air flow and inlet and outlet temperatures are maintained at substantially the same values given in Example 6. To the chamber is added, in atomized form under a presure of 70 p.s.i., 6.4 liters of a solution of by weight of ethyl cellulose (10 cps.) in equal parts by volume of absolute ethanol and chloroform. The solution is added at a constant rate of about cc. per minute.
  • samples of the beads are periodically taken from the chamber as they are being coated, the first sample being taken when the first 2% weight increment of coating (relative to the weight of the uncoated bead) has been applied and successive samples being taken following application of succeeding 2% coating increments, specifically, 4% through 16% increments.
  • the coating procedure is continued until all of the coating solution has been applied and the coating has dried.
  • the coated beads are then recovered from the chamber; yield, exclusive of samples, about 2.2 kg. of free flowing, coated beads.
  • the film coating of the beads is, relatively speaking, extremely thin. For example, 20-mesh (i.e., 840-micron) beads, processed by the procedure to a 16% coating, have an average film thickness of about 28 microns.
  • Example 9 Employing the same primary bead formula and coating procedure referred to in Example 8, but utilizing a coating solution consisting of 300 g. of ethyl cellulose (10 cps.), 30 g. of hydrogenated castor oil and 3 g. of castor oil dissolved in four liters of equal parts of chloroform and alcohol, the following controlled release patterns are obtained:
  • Example 10 To provide a sustained release plural dosage form, in bulk, containing methylene blue as a medicament, equal weights (2 g.) of samples 4% through 16% of Example 8 are blended. The resulting blend can be administered orally, either in bulk form or other form. A No. 0 hard shell capsule contains about 0.4 gram of the blended beads.
  • a controlled release dosage form for internal administration comprising a solid bead and contacting and surrounding the bead a rupturable plastic, non-toxic, insoluble, non-digestible film coating which is inert to gastrointestinal fluid and permeable to diffusion of water, the bead consisting essentially of a uniform dispersion of medicament in a water-swellable colloid, the thickness of the coating and the swellability of the bead being such that on prolonged exposure to gastrointestinal fluid diffusion of water takes place through the coating into the bead causing the bead to swell and build up pressure exceeding the cohesive strength of the coating thereby resulting in outward rupture of the coating and substantially immediate and total release of the medicament from the head into the gastrointestinal fluid.
  • a controlled release dosage form for internal administration comprising a plurality of solid beads and a rupturable plastic, non-toxic, insoluble, non-digestible film coating for each of the beads which is inert to gastrointestinal fluid and permeable to diiiusion of Water, the beads each consisting essentially of a uniform dispersion of medicament in a Water-swellable colloid, the thickness of the individual coatings and the swellability of the individual beads being such that on prolonged eX- posure to gastrointestinal fluid diffusion of water takes place through the individual coatings into the respective beads causing each bead to swell and build up pressure exceeding the cohesive strength of its coating thereby resulting in outward rupture of the respective coatings and substantially immediate and total release of medicament from each bead into the gastrointestinal fluid.
  • a sustained release dosage form for internal administration comprising a plurality of solid beads and rupturable plastic, non-toxic, insoluble, non-digestible film coating for each of the beads, the beads each consisting essentially of Water-swellable colloid containing medicament uniformly distributed through the colloid, the individual coatings being inert to gastrointestinal fluid and Water-permeable, the water-permeability of said coatings being selected in a progressive series over a predetermined range, such that on prolonged exposure to gastrointestinal fluid diffusion of water takes place inward through the individual coatings at selected varying rates into the respective beads causing each bead to swell at a rate corresponding to the inward Water diffusion and to build up pressure exceeding the cohesive strength of its coating thereby resulting in serial outward rupture of the several coatings and substantially immediate and total release of medicament from each bead.
  • a sustained release dosage form in accordance with claim 8 in which the beads are contained in a pharmaceutical carrier adapted for internal administration.

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US223093A 1962-09-12 1962-09-12 Controlled release dosage form containing water-swellable beadlet Expired - Lifetime US3247066A (en)

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Application Number Priority Date Filing Date Title
US223093A US3247066A (en) 1962-09-12 1962-09-12 Controlled release dosage form containing water-swellable beadlet
GB5113/66A GB1085739A (en) 1962-09-12 1966-02-04 Controlled release medicaments (and process for producing the same)
BE676524D BE676524A (en:Method) 1962-09-12 1966-02-15
DE19661617724 DE1617724A1 (de) 1962-09-12 1966-02-15 Verfahren zur Herstellung von Arzneimitteln mit verzoegerter Wirkung
FR49726A FR1594514A (en:Method) 1962-09-12 1966-02-15

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GB (1) GB1085739A (en:Method)

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US3340152A (en) * 1963-12-06 1967-09-05 Ciba Geigy Corp Compressed oral drug tablet granulations containing admixed therein about 1% to 15% of polyfluorocarbon type polymer lubricant powders in about 1 to 150 micron particle size
US3361632A (en) * 1964-05-08 1968-01-02 Hoechst Ag Medicinal preparations having a protracted activity and method of making them
US3390050A (en) * 1964-06-19 1968-06-25 Ciba Geigy Corp Stable pharmaceutical beads conaining medicament incorporated in synthetic copolymerby bead polymerization
US3492397A (en) * 1967-04-07 1970-01-27 Warner Lambert Pharmaceutical Sustained release dosage in the pellet form and process thereof
US3538214A (en) * 1969-04-22 1970-11-03 Merck & Co Inc Controlled release medicinal tablets
DE2051580A1 (de) * 1969-10-23 1971-05-06 E I Du Pont de Nemours and Co, Wilmington, Del (V St A ) Polylactid Arzneimittel Mischungen
US3732865A (en) * 1971-01-13 1973-05-15 Alza Corp Osmotic dispenser
US3835221A (en) * 1970-03-05 1974-09-10 Hoechst Ag Orally administrable drug dosage form having delayed action
US3844285A (en) * 1969-08-28 1974-10-29 Commw Scient Ind Res Org Device for administration to ruminants
US3896806A (en) * 1971-01-08 1975-07-29 Ceskoslovenska Akademie Ved Implant for directed infusion of biologically active substances
US3906086A (en) * 1971-07-19 1975-09-16 Richard G Powers Timed-release aspirin
US3917813A (en) * 1973-03-28 1975-11-04 Benzon As Alfred Oral drug preparations
US3938515A (en) * 1971-12-20 1976-02-17 Alza Corporation Novel drug permeable wall
US3952741A (en) * 1975-01-09 1976-04-27 Bend Research Inc. Controlled release delivery system by an osmotic bursting mechanism
US3954959A (en) * 1973-03-28 1976-05-04 A/S Alfred Benzon Oral drug preparations
US4016880A (en) * 1976-03-04 1977-04-12 Alza Corporation Osmotically driven active agent dispenser
US4083949A (en) * 1973-07-17 1978-04-11 Byk Gulden Lomberg Chemische Fabrik Gmbh New oral form of medicament and a method for producing it
US4111203A (en) * 1976-11-22 1978-09-05 Alza Corporation Osmotic system with means for improving delivery kinetics of system
US4111202A (en) * 1976-11-22 1978-09-05 Alza Corporation Osmotic system for the controlled and delivery of agent over time
US4111201A (en) * 1976-11-22 1978-09-05 Alza Corporation Osmotic system for delivering selected beneficial agents having varying degrees of solubility
US4138475A (en) * 1977-06-01 1979-02-06 Imperial Chemical Industries Limited Sustained release pharmaceutical composition
US4153677A (en) * 1978-05-18 1979-05-08 Sterling Drug Inc. Controlled-release composition
US4155993A (en) * 1977-01-13 1979-05-22 Lipha, Lyonnaise Industrielle Pharmaceutique Prolonged-release pharmaceutical compositions for oral administration, their methods of making and use
FR2407720A1 (fr) * 1977-11-08 1979-06-01 Lipha Lyonnaise Indle Pharmace Preparations pharmaceutiques orales a activite therapeutique prolongee
US4173626A (en) * 1978-12-11 1979-11-06 Merck & Co., Inc. Sustained release indomethacin
US4190642A (en) * 1978-04-17 1980-02-26 Alza Corporation Ocular therapeutic system for dispensing a medication formulation
US4207890A (en) * 1977-01-04 1980-06-17 Mcneilab, Inc. Drug-dispensing device and method
US4229428A (en) * 1977-07-22 1980-10-21 Cherqui Jean S Galenical form of administration of betahistine and its derivatives
US4252786A (en) * 1979-11-16 1981-02-24 E. R. Squibb & Sons, Inc. Controlled release tablet
US4261971A (en) * 1978-12-05 1981-04-14 Aktiebolaget Hassle Pharmaceutically preparation comprising a cardiac glycoside in combination with a polymer
US4263273A (en) * 1978-12-22 1981-04-21 Aktiebolaget Astra Pharmaceutical preparation comprising a cardiac glycoside with a polymer coating
US4277364A (en) * 1975-12-22 1981-07-07 The United States Of America As Represented By The Secretary Of Agriculture Encapsulation by entrapment
US4344857A (en) * 1975-12-22 1982-08-17 The United States Of America As Represented By The Secretary Of Agriculture Encapsulation by entrapment
EP0052917A3 (en) * 1980-11-25 1982-10-06 Alza Corporation Osmotic device with hydrogel driving member
US4361546A (en) * 1978-07-15 1982-11-30 Boehringer Ingelheim Gmbh Retard form of pharmaceuticals with insoluble porous diffusion coatings
US4367217A (en) * 1980-01-12 1983-01-04 Boehringer Ingelheim Gmbh Dipyricamole sustained release forms comprising lacquer-coated particles and the preparation thereof
WO1983000284A1 (en) * 1981-07-15 1983-02-03 Key Pharma Sustained release theophylline
EP0077956A1 (en) * 1981-10-15 1983-05-04 Tanabe Seiyaku Co., Ltd. Enteric microcapsules and process for the preparation thereof
US4415547A (en) * 1982-06-14 1983-11-15 Sterling Drug Inc. Sustained-release pharmaceutical tablet and process for preparation thereof
WO1984000004A1 (en) * 1982-06-14 1984-01-05 Key Pharma Sustained release aspirin
WO1984000295A1 (en) * 1982-07-09 1984-02-02 Key Pharma Sustained release quinidine dosage form
US4438091A (en) 1981-07-07 1984-03-20 Dr. Karl Thomae Gmbh Bromhexine delayed-release pharmaceutical form
US4508702A (en) * 1982-06-14 1985-04-02 Key Pharmaceuticals, Inc. Sustained release aspirin
US4555399A (en) * 1983-11-18 1985-11-26 Key Pharmaceuticals, Inc. Aspirin tablet
US4557925A (en) * 1982-07-08 1985-12-10 Ab Ferrosan Membrane-coated sustained-release tablets and method
US4587118A (en) * 1981-07-15 1986-05-06 Key Pharmaceuticals, Inc. Dry sustained release theophylline oral formulation
US4629620A (en) * 1984-09-05 1986-12-16 Ab Ferrosan Membrane-coated sustained-release tablets and method
US4629619A (en) * 1984-09-05 1986-12-16 Ab Ferrosan Membrane-coated sustained-release tablets and method
US4634587A (en) * 1982-07-09 1987-01-06 Key Pharmaceuticals, Inc. Sustained release quinidine dosage form
EP0250374A1 (en) * 1986-06-17 1987-12-23 RECORDATI INDUSTRIA CHIMICA E FARMACEUTICA S.p.a. Therapeutic system for controlled release of drugs
US4752470A (en) * 1986-11-24 1988-06-21 Mehta Atul M Controlled release indomethacin
US4800084A (en) * 1984-02-01 1989-01-24 Horst Zerbe Pharmaceutical product in the form of a pellet with continuous, delayed medicament substance emission
US4820521A (en) * 1983-04-06 1989-04-11 Eland Corporation P.L.C. Sustained absorption pharmaceutical composition
US4871542A (en) * 1987-04-30 1989-10-03 Ferring Service Center, N.V. Method and apparatus useful for delivering medicinal compositions into the bladder and urinary tract
US5051262A (en) * 1979-12-07 1991-09-24 Elan Corp., P.L.C. Processes for the preparation of delayed action and programmed release pharmaceutical forms and medicaments obtained thereby
US5051305A (en) * 1988-12-30 1991-09-24 Arcade, Inc. Stabilized perfume-containing microcapsules and method of preparing the same
EP0467975A4 (en) * 1989-04-11 1992-03-11 Depomed Systems, Inc. Sustained-release oral drug dosage form
US5130171A (en) * 1988-12-22 1992-07-14 Rhone-Poulenc Sante Process for encapsulating particles with a silicone
US5219572A (en) * 1989-03-17 1993-06-15 Pitman-Moore, Inc. Controlled release delivery device for macromolecular proteins
US5275819A (en) * 1989-02-06 1994-01-04 Amer Particle Technologies Inc. Drug loaded pollen grains with an outer coating for pulsed delivery
US5358502A (en) * 1993-02-25 1994-10-25 Pfizer Inc PH-triggered osmotic bursting delivery devices
US5431921A (en) * 1990-09-28 1995-07-11 Pfizer Inc Dispensing device containing a hydrophobic medium
WO1996017598A1 (en) * 1994-12-06 1996-06-13 Bernard Charles Sherman Diltiazem hydrochloride formulation
EP0701437A4 (en) * 1992-05-04 1996-10-09 Chen Chih Ming PULSATORY RELEASE SYSTEM FOR PARTICULATE DRUGS
EP0670718A4 (en) * 1992-11-27 1996-10-09 Chen Chih Ming PULSATIL DELIVERY SYSTEM FOR PARTICLE DRUGS.
US5576022A (en) * 1993-07-22 1996-11-19 Warner Lambert Company Controlled release tacrine drug delivery systems and methods for preparing same
US5798119A (en) * 1995-06-13 1998-08-25 S. C. Johnson & Son, Inc. Osmotic-delivery devices having vapor-permeable coatings
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Cited By (95)

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US3340152A (en) * 1963-12-06 1967-09-05 Ciba Geigy Corp Compressed oral drug tablet granulations containing admixed therein about 1% to 15% of polyfluorocarbon type polymer lubricant powders in about 1 to 150 micron particle size
US3361632A (en) * 1964-05-08 1968-01-02 Hoechst Ag Medicinal preparations having a protracted activity and method of making them
US3390050A (en) * 1964-06-19 1968-06-25 Ciba Geigy Corp Stable pharmaceutical beads conaining medicament incorporated in synthetic copolymerby bead polymerization
US3492397A (en) * 1967-04-07 1970-01-27 Warner Lambert Pharmaceutical Sustained release dosage in the pellet form and process thereof
US3538214A (en) * 1969-04-22 1970-11-03 Merck & Co Inc Controlled release medicinal tablets
US3844285A (en) * 1969-08-28 1974-10-29 Commw Scient Ind Res Org Device for administration to ruminants
DE2051580A1 (de) * 1969-10-23 1971-05-06 E I Du Pont de Nemours and Co, Wilmington, Del (V St A ) Polylactid Arzneimittel Mischungen
US3835221A (en) * 1970-03-05 1974-09-10 Hoechst Ag Orally administrable drug dosage form having delayed action
US3896806A (en) * 1971-01-08 1975-07-29 Ceskoslovenska Akademie Ved Implant for directed infusion of biologically active substances
US3732865A (en) * 1971-01-13 1973-05-15 Alza Corp Osmotic dispenser
US3906086A (en) * 1971-07-19 1975-09-16 Richard G Powers Timed-release aspirin
US3938515A (en) * 1971-12-20 1976-02-17 Alza Corporation Novel drug permeable wall
US3917813A (en) * 1973-03-28 1975-11-04 Benzon As Alfred Oral drug preparations
US3954959A (en) * 1973-03-28 1976-05-04 A/S Alfred Benzon Oral drug preparations
US4083949A (en) * 1973-07-17 1978-04-11 Byk Gulden Lomberg Chemische Fabrik Gmbh New oral form of medicament and a method for producing it
US3952741A (en) * 1975-01-09 1976-04-27 Bend Research Inc. Controlled release delivery system by an osmotic bursting mechanism
US4344857A (en) * 1975-12-22 1982-08-17 The United States Of America As Represented By The Secretary Of Agriculture Encapsulation by entrapment
US4277364A (en) * 1975-12-22 1981-07-07 The United States Of America As Represented By The Secretary Of Agriculture Encapsulation by entrapment
US4016880A (en) * 1976-03-04 1977-04-12 Alza Corporation Osmotically driven active agent dispenser
US4111203A (en) * 1976-11-22 1978-09-05 Alza Corporation Osmotic system with means for improving delivery kinetics of system
US4111202A (en) * 1976-11-22 1978-09-05 Alza Corporation Osmotic system for the controlled and delivery of agent over time
US4111201A (en) * 1976-11-22 1978-09-05 Alza Corporation Osmotic system for delivering selected beneficial agents having varying degrees of solubility
US4207890A (en) * 1977-01-04 1980-06-17 Mcneilab, Inc. Drug-dispensing device and method
US4155993A (en) * 1977-01-13 1979-05-22 Lipha, Lyonnaise Industrielle Pharmaceutique Prolonged-release pharmaceutical compositions for oral administration, their methods of making and use
US4138475A (en) * 1977-06-01 1979-02-06 Imperial Chemical Industries Limited Sustained release pharmaceutical composition
US4229428A (en) * 1977-07-22 1980-10-21 Cherqui Jean S Galenical form of administration of betahistine and its derivatives
FR2407720A1 (fr) * 1977-11-08 1979-06-01 Lipha Lyonnaise Indle Pharmace Preparations pharmaceutiques orales a activite therapeutique prolongee
US4190642A (en) * 1978-04-17 1980-02-26 Alza Corporation Ocular therapeutic system for dispensing a medication formulation
US4153677A (en) * 1978-05-18 1979-05-08 Sterling Drug Inc. Controlled-release composition
US4459279A (en) * 1978-07-15 1984-07-10 Boehringer Ingelheim Gmbh Retard form of pharmaceuticals with insoluble porous diffusion coatings
US4361546A (en) * 1978-07-15 1982-11-30 Boehringer Ingelheim Gmbh Retard form of pharmaceuticals with insoluble porous diffusion coatings
US4261971A (en) * 1978-12-05 1981-04-14 Aktiebolaget Hassle Pharmaceutically preparation comprising a cardiac glycoside in combination with a polymer
US4173626A (en) * 1978-12-11 1979-11-06 Merck & Co., Inc. Sustained release indomethacin
US4263273A (en) * 1978-12-22 1981-04-21 Aktiebolaget Astra Pharmaceutical preparation comprising a cardiac glycoside with a polymer coating
US4252786A (en) * 1979-11-16 1981-02-24 E. R. Squibb & Sons, Inc. Controlled release tablet
US5051262A (en) * 1979-12-07 1991-09-24 Elan Corp., P.L.C. Processes for the preparation of delayed action and programmed release pharmaceutical forms and medicaments obtained thereby
US4367217A (en) * 1980-01-12 1983-01-04 Boehringer Ingelheim Gmbh Dipyricamole sustained release forms comprising lacquer-coated particles and the preparation thereof
EP0052917A3 (en) * 1980-11-25 1982-10-06 Alza Corporation Osmotic device with hydrogel driving member
US4438091A (en) 1981-07-07 1984-03-20 Dr. Karl Thomae Gmbh Bromhexine delayed-release pharmaceutical form
WO1983000284A1 (en) * 1981-07-15 1983-02-03 Key Pharma Sustained release theophylline
US4587118A (en) * 1981-07-15 1986-05-06 Key Pharmaceuticals, Inc. Dry sustained release theophylline oral formulation
EP0077956A1 (en) * 1981-10-15 1983-05-04 Tanabe Seiyaku Co., Ltd. Enteric microcapsules and process for the preparation thereof
WO1984000004A1 (en) * 1982-06-14 1984-01-05 Key Pharma Sustained release aspirin
US4415547A (en) * 1982-06-14 1983-11-15 Sterling Drug Inc. Sustained-release pharmaceutical tablet and process for preparation thereof
US4508702A (en) * 1982-06-14 1985-04-02 Key Pharmaceuticals, Inc. Sustained release aspirin
US4557925A (en) * 1982-07-08 1985-12-10 Ab Ferrosan Membrane-coated sustained-release tablets and method
US4634587A (en) * 1982-07-09 1987-01-06 Key Pharmaceuticals, Inc. Sustained release quinidine dosage form
WO1984000295A1 (en) * 1982-07-09 1984-02-02 Key Pharma Sustained release quinidine dosage form
US4820521A (en) * 1983-04-06 1989-04-11 Eland Corporation P.L.C. Sustained absorption pharmaceutical composition
US4555399A (en) * 1983-11-18 1985-11-26 Key Pharmaceuticals, Inc. Aspirin tablet
US4800084A (en) * 1984-02-01 1989-01-24 Horst Zerbe Pharmaceutical product in the form of a pellet with continuous, delayed medicament substance emission
US4629620A (en) * 1984-09-05 1986-12-16 Ab Ferrosan Membrane-coated sustained-release tablets and method
US4629619A (en) * 1984-09-05 1986-12-16 Ab Ferrosan Membrane-coated sustained-release tablets and method
EP0250374A1 (en) * 1986-06-17 1987-12-23 RECORDATI INDUSTRIA CHIMICA E FARMACEUTICA S.p.a. Therapeutic system for controlled release of drugs
US4752470A (en) * 1986-11-24 1988-06-21 Mehta Atul M Controlled release indomethacin
US4871542A (en) * 1987-04-30 1989-10-03 Ferring Service Center, N.V. Method and apparatus useful for delivering medicinal compositions into the bladder and urinary tract
US5130171A (en) * 1988-12-22 1992-07-14 Rhone-Poulenc Sante Process for encapsulating particles with a silicone
US5051305A (en) * 1988-12-30 1991-09-24 Arcade, Inc. Stabilized perfume-containing microcapsules and method of preparing the same
US5275819A (en) * 1989-02-06 1994-01-04 Amer Particle Technologies Inc. Drug loaded pollen grains with an outer coating for pulsed delivery
US5219572A (en) * 1989-03-17 1993-06-15 Pitman-Moore, Inc. Controlled release delivery device for macromolecular proteins
EP0467975A4 (en) * 1989-04-11 1992-03-11 Depomed Systems, Inc. Sustained-release oral drug dosage form
US5431921A (en) * 1990-09-28 1995-07-11 Pfizer Inc Dispensing device containing a hydrophobic medium
EP0701437A4 (en) * 1992-05-04 1996-10-09 Chen Chih Ming PULSATORY RELEASE SYSTEM FOR PARTICULATE DRUGS
EP0670718A4 (en) * 1992-11-27 1996-10-09 Chen Chih Ming PULSATIL DELIVERY SYSTEM FOR PARTICLE DRUGS.
US5358502A (en) * 1993-02-25 1994-10-25 Pfizer Inc PH-triggered osmotic bursting delivery devices
US5609590A (en) * 1993-02-25 1997-03-11 Pfizer Inc. PH-triggered osmotic bursting delivery devices
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BE676524A (en:Method) 1966-07-18
DE1617724A1 (de) 1972-03-30
GB1085739A (en) 1967-10-04
FR1594514A (en:Method) 1970-06-08

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