US3577512A - Sustained release tablets - Google Patents

Sustained release tablets Download PDF

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US3577512A
US3577512A US766840A US3577512DA US3577512A US 3577512 A US3577512 A US 3577512A US 766840 A US766840 A US 766840A US 3577512D A US3577512D A US 3577512DA US 3577512 A US3577512 A US 3577512A
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methacrylate
polymer
ethylene glycol
acrylate
sustained release
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Thomas H Shepherd
Francis E Gould
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National Patent Development Corp
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National Patent Development Corp
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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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0092—Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/10—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of compressed tablets
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/0008—Organic ingredients according to more than one of the "one dot" groups of C08K5/01 - C08K5/59
    • C08K5/0058—Biocides

Definitions

  • Sustained release dosage forms e.g. tablets or pills, are prepared comprising a therapeutically active material and a hydrophilic acrylate or methacrylate polymer mixed therewith and/or as a coating therefor.
  • the polymer is cross-linked, most preferably by employing a diester of the acrylate or methacrylate in minor amounts.
  • This invention relates to sustained release tablets which are designed in a stabilized form to meet predetermined rates of release of a therapeutic substance contained there- 1n.
  • sustained release tablets have been used extensively in the treatment of various illnesses. Perhaps the most well known use is that of antihistamines in treating the common cold.
  • the main advantages of such tablets lie in the fact that they minimize the number of times a patient is required to take medication during a given day and, perhaps more importantly, ensure constant absorption of therapy over a given time period, thus avoiding peaks and valleys in the control of chronic and acute maladies.
  • One of the most commonly employed methods for obtaining a so-called prolonged therapeutic effect from a pharmaceutical formulation is to combine the active ingredients during the manufacturing process with one or more inert components in such a fashion that the release of the active drug from the totalpharmaceutical mass during its passage through the stomach and intestinal tract, is even and gradual.
  • inert components which are presently being used for such purposes are high molecular weight waxes, used singly or in various combinations, either evenly distributed among the active ingredients or first melted and then carefully coated over small particles of the active components.
  • alkaline earth metal salts of fatty acids in tablet manufacture is known. These substances have been used for many years as tablet lubricants. That is to say, they are incorporated in the final tablet granulation just prior to compression in relatively small quantities in order to facilitate compression of the granules without their adherence to the punches and dies in the tabletting machine.
  • saturated fatty acids themselves, their esters, ethers and alcohols can be pelletized with polyvinylpyrrolidone by converting the polymer, in the presence of the fatty acid or its derivative, into a molten mass, granulating the congealed mass, reheating, cooling, adding the therapeutic and pelletizing at a temperature near the set point.
  • a dosage unit combination of a hydrophilic polymeric material which is insoluble and non-assimilable in a biological system and a therapeutic substance which can be leached from the combination to provide an intended effect on the system.
  • the hydrophilic polymer can be admixed with the therapeutic and/or employed as a coating therefor. Preferably, it is employed as a coating, whether or not it is employed also admixed with the therapeutic.
  • the hydrophilic monomer employed is a hydroxy lower alkyl acrylate or methacrylate, or hydroxy lower alkoxy lower alkyl acrylate or methacrylate, e.g. Z-hydroxyethyl acrylate, Z-hydroxyethylene methacrylate, diethylene glycol monoacrylate, diethylene glycol rnonomethacrylate, 2- hydroxypropyl acrylate, 2hydroxypropyl methacrylate 3- hydroxypropyl acrylate, S-hydroxypropyl methacrylate and dipropylene glycol monomethacrylate.
  • the preferred monomers are the hydroxyalkyl acrylates and methacrylates, most preferably.2-hydroxyethyl methacrylates.
  • cross-linked copolymer is employed.
  • the cross-linking agent is present in an amount of 0.1 to 2.5%, most preferably not over 2.0%, although from 0.05 to or even 20%, of cross-linking agents can be used.
  • cross-linking agents include ethylene glycol diacrylate, ethylene glycol dimethacrylate, 1,2- butylene dimethacrylate, 1,3-butylene dimethacrylate, 1,4- butylene dimethacrylate, propylene glycol diacrylate, propylene glycol dimethacrylate, diethylene glycol dimethacrylate, dipropylene glycol dimethacrylate, diethylene glycol diacrylate, dipropylene glycol diacrylate, divinyl benzene, divinyl toluene, diallyl tartrate, allyl pyruvate, allyl malate, divinyl tartrate, triallyl melamine, N,N'methyl ene bis acrylamide, glycerine trimethacrylate, diallyl maleate, divnyl ether, diallyl monoethylene glycol citrate, ethylene glycol vinyl allyl citrate, allyl vinyl maleate, diallyl itaconate, ethylene glycol dicster
  • triallyl glucose polyallyl sucrose, e.g. pentaallyl sucrose, sucrose diacrylate, glucose dimethacrylate, pentaerythritol tetraacrylate, sorbitol dimethacrylate, diallyl aconitate, divnyl citraconate, diallyl fumarate.
  • polyallyl sucrose e.g. pentaallyl sucrose, sucrose diacrylate, glucose dimethacrylate, pentaerythritol tetraacrylate, sorbitol dimethacrylate, diallyl aconitate, divnyl citraconate, diallyl fumarate.
  • polymerization can be carried out by various procedures.
  • the polymer can be formed as a casting syrup and then cured.
  • the hydrophilic polymers are prepared by suspension polymerization of the hydrophilic monomer, including the cross-linking agent and stopping the polymerization when the polymer formed will precipitate in water but is still soluble in highly polar organic solvents such as alcohols, glycols and glycol ethers.
  • suitable solvents are ethyl alcohol, methyl alcohol, isopropyl alcohol, ethylene glycol, propylene gycol, diethylene glycol, dipropylene glycol, monomethyl ether of ethylene glycol, dimethyl formamide, dimethyl sulfoxide and tetrahydrofurane.
  • the suspension polymerization is carried out in a nonpolar medium such as silicone oil, mineral oil, xylene, etc.
  • the ⁇ polymer formed in the suspension polymerization or obtained from the casting syrup, either directly or after precipitation with water, is then dissolved in the appropriate solvent as indicated above and can be admixed with the pharmaceutical, the solvent removed and, if necessary, the polymerization completed.
  • the solvent containing polymer solution can be coated on a pharmaceutical entrapped in solvent insoluble hydrophilic polymer and the solvent removed to form a film or coating for the entrapped material.
  • the central portion of the casting is hollow and an entrance to the hollow portion is provided, either by the shape of the initial casting or simply by cutting a hole therein, the pharmaceutical inserted, and the aperture closed with more partially cured polymer followed by completion of the cure.
  • the casting syrup is cured to form products which exist in a solid state, e.g. rigid state, and can be swollen.
  • the polymer obtained from the cured liquids has reversible fluid absorption properties, the ability to retain its shape in a iluid absorption media and to elastically recover its shape after deformation.
  • catalysts for carrying out the polymerization there is employed a free radical catalyst in the range of 0.05 to 1% of the polymerizable hydroxyalkyl ester or the like.
  • the prefered amount of catalyst is 0.1 to 0.2% of the monomer.
  • Typical catalysts include t-butyl peroctoate, ben- 4 zoyl peroxide, isopropyl percarbonate, methyl ethyl ketone peroxide, cumene hydroperoxide, and dicumyl peroxide.
  • Irradiation e.g., by ultra violet light or gamma rays, also can be employed to catalyze the polymerization.
  • Polymerization can be done at 20 to 150 C., usually 40 to 90 C.
  • the resulting polymers can be prepared in the form of lms or rods suitable for grinding into line powders.
  • foaming agents such as sodium bicarbonate
  • the polymer may be obtained in the form of a foam which is easily disintegrated into a line powder by means of a shearing action.
  • Quantities of l to l0 grams foaming agent, e.g. 2 grams of sodium bicarbonate, per grams of reactants have been found to be sufficient.
  • Polymeric powders prepared by any of the above means are mixed with the desired therapeutic substances, dissolved in an appropriate solvent if necessary, and the mixture placed on a mechanical roller so that the solution becomes intimately mixed. The solution is then filtered and dried by air evaporation or forced heat. Upon evaporation of the solvent, the therapeutic substance is retained by the powder. Due to its extreme hydrophilicity and because the hydrophilic polymer of this invention has reversible uid adsorption properties, the powders can be reconstituted in a biological system so that the therapeuic subtstance is leached from the polymer to accomplish its intended elfect.
  • the therapeutically active material useful in the dosage units of the invention may include, for example, antibiotics, such as penicillin, tetracycline, Terramycin (hydroxytetracycline), Aureomycin (chlorotetracycline) and Chloromyeetin tchloramphenicol); sedatives and hypnotics such as pentabarbital sodium, phenobarbital, butabarbital, amobarbital, secobarbital sodium, codeine, Bromisovalum, cabromal and sodium phenobarbital; hypotensives and vasodilators such as pentaerythritol tetranitrate, erythrityl tetranitrate and nitroglycerin; amphetamines such as dl amphetamine sulfate and dextroamphetamine sulfate, hormones such as dienestrol, ethynyl estradiol, diethylstilbest
  • vitamin E vitamin E, vitamin K, ⁇ vitamin B1, vitamin B2 and vitamin C
  • tranquilizers such as reserpine, chlorpromazine hydrochloride and thipropazate hydrochloride, prednisolone, pentylene tetrazole, N-acetyl p-amino phenol, alkaloids of belladonna, atropine sulfate, hyoscine hydrobromide, hyoscyamine S04, chlorpheniramine maleate, phenylephedrine, quinidine salts, theophylline salts, ephedrine salts, pyrilamine maleate, quaiacol-glyoeryl-ether-theophyllinate, etc.
  • the therapeutic is normally present in finely divided form.
  • sustained release tablets of this invention may be taken orally or implanted subcutaneously.
  • the novel formulation of this invention comprises a dosage unit combination capable of releasing incorporated medication gradually over a controlled period of time.
  • the rate of release for the most part will be determined by the ratio of the hydrophilic polymer to the medicament, by the sequence or thickness of the coatings which are envisioned by the invention, or by the presence of a blocking layer between the active substances.
  • Blocking layers used in the invention may be any of those ingestible materials conventionally employed including waxes such as beeswax, carnauba wax, Japan wax, parafn, bayberry wax, higher fatty acids, such as oleic acid, palmitic acid and stearic acid, esters of such higher fatty acids such as glyceryl tristearate, cetyl palmitate, diglycol stearate, glyceryl myristate, triethylene glycol monostearate, higher fatty alcohols such as cetyl alcohol and stearyl alcohol, and high molecular weight polyethylene glycols such as the carbowaxes, polyethylene glycol mono-stearate, polyethylene glycol distearate, polyoxyethylene stearate, glyceryl monostearates and mixtures thereof.
  • waxes such as beeswax, carnauba wax, Japan wax, parafn, bayberry wax
  • higher fatty acids such as oleic acid, palmitic acid and
  • the blocking agent is made of the hydrophilic polymers of the present invention, the crosslinked polymers being most preferred,
  • the blocking layer or the coating layer can be 0.1 to mils thick to retard the diffusion of the inner therapeutic. The thickness can be chosen for any desired time delay.
  • FIGS. 1-5 which show various forms of tablets in cross-section:
  • the tablet is prepared in a concentrically layered form consisting of a central core 1, containing a unit dosage of medicament, e.g. penicillin.
  • the medicament may be admixed with a base which aids the solution or absorption of the medicament into the blood.
  • the core 1 is coated 2 with the hydrophilic polymer previously described, e.g. 2-hydroxyethyl methacrylate-ethylene glycol dimethacrylate (100:02).
  • the hydrophilic coating allows the medicament in the interior core to leach out at a predetermined rate. That coating can have a thickness of 1.0 mil.
  • FIG. 2 illustrates a further embodiment wherein the hydrophilic polymer is admixed with the medicament to form a core 3 which is then covered with a hydrophilic outer coating 4 as in FIG. l.
  • a tablet When two different medicaments are necessary for the treatment of an illness a tablet may be provided as will be described with reference to FIG. 3.
  • a core material 5 comprising a mixture of one medicament (A) and the hydrophilic polymer is coated 6 with a film, e.g. 0.5 mil, comprising the hydrophilic polymer and a second medicament (B).
  • a film e.g. 0.5 mil
  • medicament B in the outer layer will be leached out at a sustained rate and be assimilated into the blood leaving medicament A to be subsequently dissolved in the digestive tract.
  • FIG. 4 shows a sustained release tablet in which the presence of a blocking layer permits sustained release of medicament into a system at two separate intervals.
  • An inner core 7 comprising the hydrophilic polymer and a selected medicament is coated with a blocking layer 8 of 2 mils.
  • a third layer 9, of 2.5 mils, comprising the same mixture as presented in the core is applied over the blocking layer to complete the tablet.
  • An initial dose is liberated from the third layer 9 followed by ingestion of the blocking layer 8 and finally a second dose of the medicament derived from the core.
  • This embodiment will find particularly useful application in those cases where the rapid absorption of large amounts of certain drugs such as nicotinic acid, may result in unpleasant or even toxic effects.
  • such a tablet may be completed, if desired, with a conventional enteric or sugar coat 10, e.g. of l mil, and other enteric coatings can be used such as cellulose acetate, shellac, methyl cellulose, ethyl cellulose, carboxy methyl cellulose, polyethylene glycol 6000, lacquer, etc.
  • a conventional enteric or sugar coat 10 e.g. of l mil
  • other enteric coatings can be used such as cellulose acetate, shellac, methyl cellulose, ethyl cellulose, carboxy methyl cellulose, polyethylene glycol 6000, lacquer, etc.
  • EXAMPLE 1 Suitably purified 2hydroxy ethyl methacrylate (100 g.) is stirred with 0.15 g. isopropyl percarbonate in an anaerobic atmosphere at ambient temperature. Ethylene glycol dimethacrylate in the concentration of 0.1 g./100 g. 2- hydroxy ethyl methacrylate is added.
  • ⁇ Ihenoxymethyl penicillin an antibiotic
  • ethyl alcohol a solvent for ethyl alcohol
  • the resulting casting syrup is set aside as a stock solution for later casting or other use.
  • the casting syrup and the resulting cast product either in shaped or powdered form are ernployed as a pharmaceutical carrier for the antibiotic.
  • the use of the casting syrup or resulting shaped or powdered preparation has the advantage that it prevents deterioration and loss of potency to which the antibiotic is subject in conventional pharmaceutical carriers, thereby extending the shelf life or expiration date of the antibiotic preparation.
  • the hydrophilic polymer prepared in accordance with the present invention has the desirable characteristics, whether dry or solvent filled, of preventing the imbibition with microbial and fungal contaminants, such as gram negative and gram positive microorganisms, yeast, molds and viruses. This characteristic is af particular importance in the presence of contaminants, such as preventing contamination of penicillin with various yeast forms.
  • the polymerization of the casting syrup to a solid can then be completed, e.g. by adding 0.3 g. of further isopropyl percarbonate and heating to 40 C.
  • the product can serve as the core 3 in FIG. 2 and a similar casting syrup omtting the phenoxymethyl penicillin can serve as the outer coating 4.
  • EXAMPLE 2 In 3 oc. of 2-hydroxy ethyl methacrylate containing .2% of ethylene glycol dimethacrylate and 0.15% tertiary butyl peroctoate was dissolved milligrams of norethandrolone (Nilevar). The solution was cast in the form of a cylinder 1 cm. by 3 cm. and was polymerized at 80 C. for 3 hours in a nitrogen atmosphere. After removing from the mold, a cylinder suitable for in vivo implantation to provide prolonged release of the norethandrolone (Nilevar) was obtained for use in animal husbandry.
  • Nilevar norethandrolone
  • EXAMPLE 3 Distilled Z-hydroxy ethyl methacrylate (100 g.) is stirred with 0.1 g. tertiary butyl peroctoate in an anaerobic atmosphere at 25-70 C. for 15-40 minutes. The resultant mixture is cooled to 25 C. and tertiary butyl peroctoate added so as to make the total concentration of tertiary butyl peroctoate in the system 0.2/100 grams of Z-hydroxy ethyl methacrylate. Ethylene glycol dimethacrylate, in a concentration of 0.2 g./100 g. of 2hydroxy ethyl methacrylate is added at the same time as the catalyst concentration is brought up to the theoretical content.
  • Discs of hydrophilic polymer prepared as shaped articles from this solution, measuring 1A inch in diameter and 0.05 mrn. in thickness, were saturated with an antibiotic solution of lincomycin hydrochloride monohydrate (Lincocin) and tested against standard staphylococcic strains on agar plates. The zones of inhibition were compared with standardized 1 mg. discs obtained from the manufacturer. Multiple transfers of the hydrophilic polymer also were made on blood agar to determine how long the elution of the antibiotic from the gel would take place.
  • Lococin lincomycin hydrochloride monohydrate
  • EXAMPLE 4 Into a ask equipped with an agitator and a heating mantle was charged 1000 grams of silicone oil, 100 grams of 2-hydroxy ethyl methacrylate and 0.33 gram of isopropyl percarbonate. The flask was placed under a nitrogen atmosphere and the contents were rapidly agitated 7 and heated to 100 C. After 15 minutes at 100 C., the polymer slurry obtained was filtered hot to isolate the polymer. The polymer powder was reslurried in 300 ml. of xylene, filtered and dried.
  • EXAMPLE 5 A solution was made of 100 parts of 2-hydroxyethyl acrylate, 0.2 part of ethylene glycol dimethacrylate and 0.4 part of l-butyl peroctoate and then cast into a mold and polymerized.
  • EXAMPLE 6 A solution was made of 100 parts of an isomer mixture of hydroxyisopropyl methacrylates, 0.2 part propylene glycol dimethacrylate and 0.4 part of t-butyl peroctoate and then cast into a mold and polymerized.
  • EXAMPLE 7 100 parts of Z-hydroxyethyl methacrylate was stirred with 0.05 part of t-butyl peroctoate in a nitrogen atmosphere at a temperature of 40 C. for 30 minutes. The resultant mixture was cooled to 25 C. and t-butyl peroctoate added so as to make the total amount of t-butyl peroctoate added in the system 0.15 part. 0.1 part of ethylene glycol dimethacrylate was also added along with the second addition of the t-butyl peroctoate and cast.
  • EXAMPLE 8 The process of Example 7 was repeated, substituting 0.2 part of 1,3-butylene glycol dimethacrylate in place. of the ethylene glycol dimethacrylate as the cross-linking monomer.
  • EXAMPLE 9 100 parts of 2-hydroxyethyl methacrylate was stirred with 50 parts of distilled water and 0.1 part of t-butyl peroctoate in an anaerobic atmosphere at a temperature of 40 C. for 20 minutes. The water was removed, alcohol added as a solvent and the resultant mixture was cooled to 25 C. and 0.05 part of t-butyl peroctoate added and at the same time there was added 0.2 part of ethylene glycol dimethacrylate as a cross-linking monomer. The product was then polymerized to form a coating solution.
  • Example 10 The process of Example 9 was repeated in the absence of water or alcohol to give a casting syrup.
  • Example 11 The process of Example 10 was repeated but the initial catalyst consisted of a mixture of 0.05 part t-butyl peroctoate and 0.1 part of isopropyl percarbonate. The added catalyst ⁇ was 0.05 part of isopropyl percarbonate.
  • EXAMPLE 12 100 parts of distilled 2-hydroxyethyl methacrylate was stirred with 0.1 gram of t-butyl peroctoate in an anaerobic atmosphere at 70 C. for 40 minutes. The resultant mixture was cooled to 25 C. and t-butyl peroctoate added so as to make the total concentration of t-butyl peroctoate in the system 0.2 part per 100 parts of Z-hydroxyethyl methacrylate. Ethylene glycol dimethacrylate in the concentration of 0.2 part per 100 parts of 2hydroxyethyl methacrylate was added at the same time as the catalyst concentration was increased to give a casting liquid.
  • EXAMPLE 13 The process of Example 12 was followed, substituting hydroxypropyl methacrylate for the 2 hydroxyethyl methacrylate.
  • EXAMPLE 14 The process of Example 12 was followed using isopropyl percarbonate as the catalyst and substituting 1,3- butylene glycol dimethacrylate for the ethylene glycol dimethacrylate as the cross-linking monomer.
  • EXAMPLE 15 Suitably purified 2 hydroxyethyl methacrylate was stirred with 0.15 part of isopropyl percarbonate in an anaerobic atmosphere at ambient temperature. Ethylene glycol dimethacrylate in the concentration of 0.1 part per 100 parts of Z-hydroxyethyl methacrylate was added and the mixture heated to 40 C. for 20 minutes to form a casting syrup.
  • EXAMPLE 16 100 parts of 2 hydroxyethyl methacrylate was stirred with 0.05 part t-butyl peroctoate in a nitrogen atmosphere at a temperature of 30 C. for 30 minutes. The resultant mixture was cooled to 25 C. and additional peroctoate added to make up a total of 0.15 part, there being added at the same time 0.1 part of ethylene glycol dimethacrylate.
  • EXAMPLE 17 100 parts of 2-hydroxyethyl methacrylate was mixed with 0.20 part of t-butyl peroctoate in an inert atmosphere and 0.20 part of ethylene glycol dimethacrylate was added and the mixture heated at 50 C. for 15 minutes to form a casting syrup.
  • EXAMPLE 18 100 parts of 2-hydroxyethyl methacrylate was stirred with 0.1 part of t-butyl peroctoate and 0.15 part of ethylene glycol dimethacrylate was added and the mixture heated to 40 C. for 25 minutes to form a casting syrup.
  • EXAMPLE 19 100 parts of puried Z-hydroxyethyl methacrylate was mixed with l5 parts of ethylene glycol dimethacrylate and 0.3 part of t-butyl peroctoate and the mixture heated at 40 C. for 30 minutes to form a casting syrup.
  • EXAMPLE 20 In a 5 gallon resin kettle, there was placed 10 kilograms of 2-hydroxyethyl methacrylate, 150 grams of ethylene glycol dimethacrylate and 4.0 grams of t-butyl peroctoate. The kettle was heated to C. with stirring over a 50 minute period, whereupon the reaction mixture was rapidly cooled, yielding a syrup having a viscosity of 420 centipoises at 30 C. To the syrup was added 20 grams of ethylene glycol dimethacrylate and 20 grams of t-butyl peroctoate, and the syrup was stirred until a homogenous solution was obtained. This syrup was useful in casting coatings of the type shown in the drawings.
  • Example 21 The procedure of Example 20 was repeated replacing the ethylene glycol dimethacrylate by an equal weight of divinyl benzene. The resulting syrup was also useful in forming castings for use in forming coated pharmaceuticals.
  • tablet is intended to cover pills.
  • An oral sustained release dosage form which is a dry composition containing a nely divided therapeutically active material and a water insoluble hydrophilic acrylate or methacrylate polymer selected from the group consisting of polymers of hydroxy lower alkyl acrylates, and hydroxy lower alkoxy lower alkyl methacrylates, said composition being formed by casting or molding an anhydrous casting syrup or solution of the therapeutical material, the hydrophilic acrylate or methacrylate monomer and polymerizing the composition, the resulting cast or molded dosage form having the advantage of preventing deterioration or loss of potency and thereby extending the shelf life of the therapeutic.
  • hydrophilic polymer is a copolymer of said acrylate or methacrylate with a minor amount up to 20% of a cross-linking agent.
  • said therapeutically active material comprises a central core and said hydrophilic polymer is a solid outer layer surrounding said core.
  • hydrophilic polymer is a copolymer of said acrylate or methacrylate with a minor amount up to 20% of a crosslinking agent.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Engineering & Computer Science (AREA)
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  • Biodiversity & Conservation Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US766840A 1968-10-11 1968-10-11 Sustained release tablets Expired - Lifetime US3577512A (en)

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US (1) US3577512A (xx)
AT (2) AT298144B (xx)
BE (1) BE740070A (xx)
CH (1) CH570806A5 (xx)
DE (1) DE1949894C3 (xx)
DK (1) DK130627B (xx)
FR (1) FR2035811B1 (xx)
GB (1) GB1280711A (xx)
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NO (1) NO130668C (xx)

Cited By (61)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3710795A (en) * 1970-09-29 1973-01-16 Alza Corp Drug-delivery device with stretched, rate-controlling membrane
US3791927A (en) * 1971-07-14 1974-02-12 American Cyanamid Co Entrapped carrier bound enzymes
US3854480A (en) * 1969-04-01 1974-12-17 Alza Corp Drug-delivery system
US3857932A (en) * 1970-09-09 1974-12-31 F Gould Dry hydrophilic acrylate or methacrylate polymer prolonged release drug implants
US3859169A (en) * 1972-05-03 1975-01-07 Polymeric Enzymes Inc Enzymes entrapped in gels
US3860701A (en) * 1968-04-22 1975-01-14 Searle & Co Method for use and compositions of 11-lower alkyl steroids and drug delivery system for the controlled elution of 11-lower alkyl steroids
US3871964A (en) * 1972-03-30 1975-03-18 Bayer Ag Water-insoluble peptide materials
US3901966A (en) * 1973-09-10 1975-08-26 Union Corp Sustained release of methantheline
US3901967A (en) * 1973-09-10 1975-08-26 Union Corp Sustained release of atropine
US3901971A (en) * 1973-09-10 1975-08-26 Union Corp Sustained release of hydrochlorothiazide
US3901970A (en) * 1973-09-10 1975-08-26 Union Corp Sustained release of dexamethasone
US3901968A (en) * 1973-09-10 1975-08-26 Union Corp Sustained release of methantheline
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US4681755A (en) * 1984-07-26 1987-07-21 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Delivery device for zero-order release of an active principle into a dissolution fluid and process for its preparation
US4713237A (en) * 1984-06-18 1987-12-15 Schering Corporation Sustained release dosage form
US4749576A (en) * 1984-05-10 1988-06-07 Ciba-Geigy Corporation Active agent containing hydrogel devices wherein the active agent concentration profile contains a sigmoidal concentration gradient for improved constant release, their manufacture and use
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US4789548A (en) * 1986-04-24 1988-12-06 Tisdale John W Medication and method for treating heartworms in dogs
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US5011661A (en) * 1985-07-10 1991-04-30 Ciba-Geigy Corporation Contact lens care set
US5084278A (en) * 1989-06-02 1992-01-28 Nortec Development Associates, Inc. Taste-masked pharmaceutical compositions
US5093200A (en) * 1985-10-23 1992-03-03 Eisai Co., Ltd. Multilayer sustained release granule
US5433958A (en) * 1993-04-13 1995-07-18 Asta Medica Aktiengesellschaft Pharmaceutical dosage unit for rectal administration
US5553741A (en) * 1993-08-06 1996-09-10 River Medical, Inc. Liquid delivery device
US5571261A (en) * 1993-08-06 1996-11-05 River Medical, Inc Liquid delivery device
US5588556A (en) * 1993-08-06 1996-12-31 River Medical, Inc. Method for generating gas to deliver liquid from a container
US5662936A (en) * 1993-12-23 1997-09-02 Akzo Nobel, N.V. Sugar-coated pharmaceutical dosage unit
US5700245A (en) * 1995-07-13 1997-12-23 Winfield Medical Apparatus for the generation of gas pressure for controlled fluid delivery
US5730999A (en) * 1993-03-27 1998-03-24 Roehm Gmbh Chemische Fabrik Dermal therapeutic system made of a meltable poly (meth) acrylate
US20030059614A1 (en) * 1989-09-20 2003-03-27 Hani Sadek Enrobed core medicament
US6663893B2 (en) 2000-04-20 2003-12-16 Bristol-Myers Squibb Co. Taste masking coating composition
WO2006030260A1 (en) * 2004-09-17 2006-03-23 Bioprogress S.P.A. A controlled slow release formulation of thiamine and use thereof in the treatment of pathologies connected to defective process of learning and memorization
WO2006107593A2 (en) * 2005-04-06 2006-10-12 Mallinckrodt Inc. Matrix-based pulse release pharmaceutical formulation
US20080085248A1 (en) * 2005-01-03 2008-04-10 Yoram Sela Controlled Long Acting Release Pharmaceutical Preparation For Use In The Oral Cavity
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FR2565107B1 (fr) * 1984-05-30 1986-09-05 Ucb Laboratoires Nouveau medicament a base de charbon actif et son procede de preparation
AU5755986A (en) * 1985-05-20 1986-11-27 Autotrol Corporation Soluble polymeric material matrix + water treating material
JPS6261916A (ja) * 1985-09-12 1987-03-18 Fujisawa Pharmaceut Co Ltd 持続性製剤
DE3918801A1 (de) * 1989-06-06 1991-05-08 Schmidt Walter Praeparat zur geregelten wirkstoffabgabe und verfahren zu dessen herstellung
DE4029591C2 (de) * 1990-09-19 1995-01-26 Stockhausen Chem Fab Gmbh Verfahren zur Herstellung von Absorptionsmaterial auf Polymerbasis mit Zusatz von wasserlöslichen Substanzen und Verwendung dieses Absorptionsmaterials zur Aufnahme und/oder zur nachfolgenden Abgabe von Wasser oder wäßrigen Lösungen
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US3860701A (en) * 1968-04-22 1975-01-14 Searle & Co Method for use and compositions of 11-lower alkyl steroids and drug delivery system for the controlled elution of 11-lower alkyl steroids
US3854480A (en) * 1969-04-01 1974-12-17 Alza Corp Drug-delivery system
US3857932A (en) * 1970-09-09 1974-12-31 F Gould Dry hydrophilic acrylate or methacrylate polymer prolonged release drug implants
US3710795A (en) * 1970-09-29 1973-01-16 Alza Corp Drug-delivery device with stretched, rate-controlling membrane
US3791927A (en) * 1971-07-14 1974-02-12 American Cyanamid Co Entrapped carrier bound enzymes
US3910825A (en) * 1972-03-30 1975-10-07 Bayer Ag Water-insoluble peptide materials
US3871964A (en) * 1972-03-30 1975-03-18 Bayer Ag Water-insoluble peptide materials
US3859169A (en) * 1972-05-03 1975-01-07 Polymeric Enzymes Inc Enzymes entrapped in gels
US3954959A (en) * 1973-03-28 1976-05-04 A/S Alfred Benzon Oral drug preparations
US3995632A (en) * 1973-05-04 1976-12-07 Alza Corporation Osmotic dispenser
US3901967A (en) * 1973-09-10 1975-08-26 Union Corp Sustained release of atropine
US4178361A (en) * 1973-09-10 1979-12-11 Union Corporation Sustained release pharmaceutical composition
US3904745A (en) * 1973-09-10 1975-09-09 Union Corp Sustained release of chlorpheniramine maleate
US3906087A (en) * 1973-09-10 1975-09-16 Union Corp Sustained release of methantheline
US3901970A (en) * 1973-09-10 1975-08-26 Union Corp Sustained release of dexamethasone
US3911100A (en) * 1973-09-10 1975-10-07 Union Corp Sustained release of methantheline
US3901971A (en) * 1973-09-10 1975-08-26 Union Corp Sustained release of hydrochlorothiazide
US3901966A (en) * 1973-09-10 1975-08-26 Union Corp Sustained release of methantheline
US3901968A (en) * 1973-09-10 1975-08-26 Union Corp Sustained release of methantheline
US4649046A (en) * 1974-01-09 1987-03-10 Hydro Optics, Inc. Air freshener
US4194066A (en) * 1974-08-30 1980-03-18 Japan Atomic Energy Research Institute Immobilization of enzymes or bacteria cells
US4177107A (en) * 1976-01-31 1979-12-04 Japan Atomic Energy Research Institute Process for producing composition containing insolubilized enzyme and/or insolubilized bacterial cells
US4150110A (en) * 1976-05-14 1979-04-17 Nippon Kayaku Kabushiki Kaisha Coated granules of polyacrylic alkali metal salts and method of producing same
US4136250A (en) * 1977-07-20 1979-01-23 Ciba-Geigy Corporation Polysiloxane hydrogels
US4196187A (en) * 1977-09-02 1980-04-01 Eastman Kodak Company Rumen-stable pellets
US4181710A (en) * 1977-09-02 1980-01-01 Eastman Kodak Company Rumen-stable pellets
US4181709A (en) * 1977-09-02 1980-01-01 Eastman Kodak Company Rumen-stable pellets
US4321117A (en) * 1978-03-09 1982-03-23 Japan Atomic Energy Research Institute Process for preparing a polymer composition
US4411754A (en) * 1978-03-09 1983-10-25 Japan Atomic Energy Research Institute Process for preparing a polymer composition
US4351825A (en) * 1979-02-02 1982-09-28 Orion-Yhtyma Oy Process for the preparation of tablets with retarded liberation of the active agent is predetermined
US4310397A (en) * 1979-02-19 1982-01-12 Japan Atomic Energy Research Institute Polymer composition containing a physiologically active substance
US4587129A (en) * 1979-03-07 1986-05-06 National Patent Development Co. Hydrophilic gels containing high amounts of fragrance
US4298002A (en) * 1979-09-10 1981-11-03 National Patent Development Corporation Porous hydrophilic materials, chambers therefrom, and devices comprising such chambers and biologically active tissue and methods of preparation
US4379038A (en) * 1979-09-27 1983-04-05 Japan Atomic Energy Research Institute Process for preparing a physiologically active substance controlled release composite composition
US4370313A (en) * 1981-10-26 1983-01-25 Eaton Laboratories, Inc. Nitrofurantoin dosage form
US4576604A (en) * 1983-03-04 1986-03-18 Alza Corporation Osmotic system with instant drug availability
US4673405A (en) * 1983-03-04 1987-06-16 Alza Corporation Osmotic system with instant drug availability
US4624848A (en) * 1984-05-10 1986-11-25 Ciba-Geigy Corporation Active agent containing hydrogel devices wherein the active agent concentration profile contains a sigmoidal concentration gradient for improved constant release, their manufacture and use
US4749576A (en) * 1984-05-10 1988-06-07 Ciba-Geigy Corporation Active agent containing hydrogel devices wherein the active agent concentration profile contains a sigmoidal concentration gradient for improved constant release, their manufacture and use
US4713237A (en) * 1984-06-18 1987-12-15 Schering Corporation Sustained release dosage form
US4681755A (en) * 1984-07-26 1987-07-21 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Delivery device for zero-order release of an active principle into a dissolution fluid and process for its preparation
US4769027A (en) * 1984-08-15 1988-09-06 Burroughs Wellcome Co. Delivery system
US5011661A (en) * 1985-07-10 1991-04-30 Ciba-Geigy Corporation Contact lens care set
US5093200A (en) * 1985-10-23 1992-03-03 Eisai Co., Ltd. Multilayer sustained release granule
US4810500A (en) * 1986-04-24 1989-03-07 Tisdale John W Medication and method for treating heartworms in dogs
US4789548A (en) * 1986-04-24 1988-12-06 Tisdale John W Medication and method for treating heartworms in dogs
US4800087A (en) * 1986-11-24 1989-01-24 Mehta Atul M Taste-masked pharmaceutical compositions
US4994279A (en) * 1988-02-03 1991-02-19 Eisai Co., Ltd. Multi-layer granule
US5084278A (en) * 1989-06-02 1992-01-28 Nortec Development Associates, Inc. Taste-masked pharmaceutical compositions
US20030059614A1 (en) * 1989-09-20 2003-03-27 Hani Sadek Enrobed core medicament
US5730999A (en) * 1993-03-27 1998-03-24 Roehm Gmbh Chemische Fabrik Dermal therapeutic system made of a meltable poly (meth) acrylate
US5433958A (en) * 1993-04-13 1995-07-18 Asta Medica Aktiengesellschaft Pharmaceutical dosage unit for rectal administration
US5553741A (en) * 1993-08-06 1996-09-10 River Medical, Inc. Liquid delivery device
US5588556A (en) * 1993-08-06 1996-12-31 River Medical, Inc. Method for generating gas to deliver liquid from a container
US5571261A (en) * 1993-08-06 1996-11-05 River Medical, Inc Liquid delivery device
US5662936A (en) * 1993-12-23 1997-09-02 Akzo Nobel, N.V. Sugar-coated pharmaceutical dosage unit
US5700245A (en) * 1995-07-13 1997-12-23 Winfield Medical Apparatus for the generation of gas pressure for controlled fluid delivery
EP1267844B2 (en) † 2000-03-27 2016-04-13 Omega Pharma NV Sustained release vitamin composition
US6663893B2 (en) 2000-04-20 2003-12-16 Bristol-Myers Squibb Co. Taste masking coating composition
US20080311200A1 (en) * 2004-09-17 2008-12-18 Bioprogress S.P.A. Controlled Slow Release Formulation of Thiamine and Use Thereof in the Treatment of Pathologies Connected to Defective Process of Learning and Memorization
WO2006030260A1 (en) * 2004-09-17 2006-03-23 Bioprogress S.P.A. A controlled slow release formulation of thiamine and use thereof in the treatment of pathologies connected to defective process of learning and memorization
US20080085248A1 (en) * 2005-01-03 2008-04-10 Yoram Sela Controlled Long Acting Release Pharmaceutical Preparation For Use In The Oral Cavity
WO2006107593A3 (en) * 2005-04-06 2006-11-30 Mallinckrodt Inc Matrix-based pulse release pharmaceutical formulation
WO2006107593A2 (en) * 2005-04-06 2006-10-12 Mallinckrodt Inc. Matrix-based pulse release pharmaceutical formulation
US20100166864A1 (en) * 2005-04-06 2010-07-01 Mallinckrodt Inc. Matrix-based pulse release pharmaceutical formulation
US9713592B2 (en) 2005-04-06 2017-07-25 Mallinckrodt Llc Matrix-based pulse release pharmaceutical formulation

Also Published As

Publication number Publication date
BE740070A (xx) 1970-04-10
AT297224B (de) 1972-03-10
DE1949894B2 (de) 1973-03-08
DE1949894C3 (de) 1973-10-04
FR2035811A1 (xx) 1970-12-24
GB1280711A (en) 1972-07-05
DK130627B (da) 1975-03-17
CH570806A5 (xx) 1975-12-31
DK130627C (xx) 1975-08-04
NO130668B (xx) 1974-10-14
AT298144B (de) 1972-04-25
FR2035811B1 (xx) 1973-01-12
NO130668C (xx) 1975-01-22
DE1949894A1 (de) 1970-08-20
NL6915311A (xx) 1970-04-14

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