EP0169236A1 - Controlled release liquid dosage formulations for pharmaceuticals - Google Patents

Controlled release liquid dosage formulations for pharmaceuticals

Info

Publication number
EP0169236A1
EP0169236A1 EP85900864A EP85900864A EP0169236A1 EP 0169236 A1 EP0169236 A1 EP 0169236A1 EP 85900864 A EP85900864 A EP 85900864A EP 85900864 A EP85900864 A EP 85900864A EP 0169236 A1 EP0169236 A1 EP 0169236A1
Authority
EP
European Patent Office
Prior art keywords
coating
dosage forms
liquid
controlled release
cellulose acetate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP85900864A
Other languages
German (de)
English (en)
French (fr)
Inventor
Ben Franklin Benton
David Lee Gardner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Battelle Development Corp
Original Assignee
Battelle Development Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Battelle Development Corp filed Critical Battelle Development Corp
Publication of EP0169236A1 publication Critical patent/EP0169236A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings

Definitions

  • This invention relates to controlled release pharmaceuticals, specifically dual-coated controlled re ⁇ lease pharmaceuticals as a liquid dosage formulation which have substantial shelf life. More particularly, this invention relates to and discloses liquid suspens- ions of dual coated controlled release dosage forms that retain their controlled release characteristics even though dispersed in a liquid medium for a significant period of time prior to use.
  • Controlled release forms of medication are well known in the art. Some such medications are prepared as tablets in the form of a therapeutically active core coated with various thicknesses of ingestible materials. Other time release medications take the form of an in- nocuous core coated with alternating layers of thera ⁇ Terminally active materials and inactive ingestible ma ⁇ terials. More recently microcapsules or microspheres, with selected proportions of the microcapsules having coatings of differing solubilities, have been placed in conventional gelatin capsules to yield controlled release dosage forms.
  • Dosage form is defined as referring to the solid carrier or housing vehicle for a therapeutically active compound exhibiting controlled release.
  • a dosage form would include any type of common prill, and would also include, for example, tab ⁇ lets, capsules, matrix materials, microcapsules, reser- voir type tablets, and microspheres.
  • Controlled release is understood to mean re ⁇ lease, preferably uniform release, of the active compound over a span of time, thus would encompass such terms as time-release, delayed release, and sustained release.
  • Dosage formulation is defined as referring to the combination of dosage forms and liquid carrier in which the dosage forms are dispersed.
  • the present invention relates to and discloses compositions for making liquid suspensions of controlled release dosage forms of therapeutically active compounds that retain their controlled release characteristics even though dispersed in a liquid medium for a significant period of time prior to use.
  • the present invention can be applied to and suc ⁇ cessfully used with any known solid controlled release pharmaceutical to convert it into a liquid dosage formu ⁇ lation having significant shelf life while still re ⁇ taining an acceptable controlled release profile upon ingestion.
  • the present invention can be applied to and used with tablets, capsules, matrix materials, micro- capsules, reservoir-type tablets, microspheres and any other type of controlled release dosage form capable of being coated.
  • the present invention discloses use of a unique combination dual coating of fats overcoated with cel- lulose derivatives or prolamins and a liquid carrier for achieving a versatile liquid controlled release dosage formulation having substantial shelf life prior to in ⁇ proof.
  • the present invention is a controlled release liquid dosage formulation for pharmaceuticals.
  • the pres ⁇ ent invention discloses use of a unique combination of dual coatings of controlled release type dosage forms in combination with a suitable liquid carrier.
  • Suitable con ⁇ trolled release type dosage forms useful in the practice of the present invention include tablets, capsules, con- trolled-release matrix beads, microcapsules, reservoir- type tablets, and microspheres, all by way of example and not limitation.
  • suitable controlled release type dosage forms are coated with at least two different materials.
  • the first coating is with a hydrophobic, digestible or degradable material preferably having a melting point of approximately 120°F or lower such that the coating would be almost liquid or rendered permeable following ingestion.
  • the first coat ⁇ ing over said dosage forms can be a lipid including a fat, a fatty acid, fatty alcohol, wax, ester or mixtures thereof, having a melting point of less than 120°F.
  • the first coating preferably is one or more fats, i.e., glycerides composed of fatty acids of from 3 to 22 carbons, with said glycerides or blends of glycerides having a melting point of 120°F or less.
  • the fats or glycerides include minor percentages of sterols, hydrocarbons, to- copherols and other nonglyceride constituents.
  • the fats or glycerides can include mono-, di-, or triglycerides or glyceryl esters, phosphatides, phosphoglycerides, or mix ⁇ tures thereof.
  • the first coating is, preferably, a hard butter such as cocoa butter, or partially hydrogenated cottonseed and/or soybean vegetable oil such as Kaomel* (Durkee) which has a Wileymelting point of 97-101°F.
  • Also useful for the first coatings are: animal fats, tallow; shortening; lard including modified lard; vegetable oils including partially hydrogenated vegetable oils; beeswax; lecithin; butterfat; oleic acid; elaidic acid; margarine; or blends of any of the foregoing.
  • melting point is an approximate term when applied to fats, waxes, fatty acids and esters since these materials melt over a range of temperature.
  • the first coating can be a fat, fatty acid, fatty alcohol, wax, ester, or mixture thereof having a melting point of less than approximately 120°F or capable of being rendered permeable following ingestion.
  • Substances useful as the first coating include mono-, di-, and triglycerides composed of fatty acids of from 3 to 32 carbons; wax esters composed of fatty acids of from 3 to 36 carbons and composed of alcohols of from 8 to 46 carbons; fatty alcohols of from 8 to 54 carbons; hydrocarbons of from 18 to 54 carbons; olefins of from 18 to 54 carbons, and free fatty acids of 8 to 36 carbons, all additionally having a melting point below approximately 120°F or capable of being rendered permeable following ingestion.
  • the waxes making up the first coating can in ⁇ clude, by way of illustration and not limitation; wax hydrocarbons - such as n - alkanes and branched alkanes, olefins, cyclic alkanes and isoprenoid hydrocarbons; ketones such as monoketones, 8- diketones, wax alcohols - such as secondary alcohols and alkane diols, wax acids - such as alkanoic and alkenoic acids, - or ⁇ - hydroxy acids, and wax esters - such as primary alcohol esters, secondary alcohol esters, diester waxes, alkane diol di- esters, diesters of hydroxy acids, triesters, trigly- cerides, triesters of alkane -1,2 -diol, ⁇ - hydroxy acid and fatty acid; esters of hydroxy malonic acid,,fatty acid and alcohol; triesters of hydroxy acids, fatty acid and fatty alcohol; triesters
  • an overcoat or second coating is provided which is: 1) amenable to being render ⁇ ed permeable in early portions of the gastrointestinal tract, preferably within approximately the first hour of entering the gastrointestinal tract; and 2) able to pre ⁇ vent agglomeration or clumping of the coated microcap ⁇ sules or microspheres.
  • Compounds useful for the second coating or overcoating include: the prolamins, such as zein, glia- din, or hordein; also carotin; also starch and its deriva ⁇ tives; also cellulose derivatives, such as the dibasic acid monoester derivatives of cellulose including cellu ⁇ lose acetate phthalate and cellulose acetate succinate, also cellulose derivatives such as carboxymethyl cellu- lose acetate, carboxymethyl ethyl cellulose, carboxy ⁇ methyl hydroxypropyl cellulose acetate, carboxymethyl cellulose stearic acid, also cellulose ethers such as ethyl cellulose. Compatible blends of any of the fore ⁇ going can also be used.
  • the prolamins such as zein, glia- din, or hordein
  • carotin also starch and its deriva ⁇ tives
  • cellulose derivatives such as the dibasic acid monoester derivatives of cellulose including cellu ⁇ lose a
  • the second coating should be selected so as to be generally nonsoluble in the carrier liquid, however, rendered permeable in the gastrointestinal tract.
  • Vari ⁇ ous means of rendering the second coating permeable can be employed.
  • the second coating can be pH sensitive, meaning soluble in only a limited range of pH i.e., alkaline soluble in the GI tract; or the second coating can be broken down by enzymes such as Upases, proteases, or a alases, i.e., the second coating, can be a protein which is broken down by any of various proteases in the gastrointestinal tract; or the second coating can be a starch broken down by enzymes such as amalase within the GI tract.
  • the preferred materials for the second coating or overcoating are zein or cellulose acetate phthalate.
  • plasticizer such as diethyl ptha- late, tributyl citrate, tributyrin; triacetin, castor oil, partially or fully acetylated monoglycerides or butyl phthalyl butyl glycolate can be employed in either or both coatings to impart desired or what is deemed suitable flexibility, workability or resiliency to the coating.
  • the plasticizer can also be used to modify the permeability of the respective coating.
  • the dual coated microspheres or dual coated controlled release dosage form can be dispersed in the carrier or delivery liquid medium.
  • water may be used as the carrier liquid it is preferred to add thickeners to assure uniform dispersion.
  • liquid carriers which diminish the amount of available water such as aqueous solutions of colloidal carbohy ⁇ drates or sugar syrups.
  • suitable carrier liquids can be employed, such as, by way of illustration and not limitation, high fructose corn syrup, honey, sugar syrup, an aqueous solution of carboxymethyl cellulose, glycerin, gum arabic, agar, or gelatin. Miscible combinations of the foregoing are also possible.
  • the delivery medium is chosen so as to reduce the proportion of water available to leach the active drug from the dual coated dosage form, but also to-be palat ⁇ able to the recipient of the liquid dosage formulation.
  • Slightly acid carrier liquids are preferred since they also tend to retard microbial growth.
  • High fructose corn syrup was found to be a particularly suitable delivery medium as such syrup has only approximately 30% water and is naturally acidic.
  • the liquid carrier is best selected so as to be a poor solvent of the particular pharmaceutic.
  • Sugar solutions and sugar syrups are useful as the carrier liquid from the aspect of limiting the avail- able water but also as a preservative.
  • any of the foregoing liquids can be used as the carrier liquid inwhich the dual coated dosage forms are dispersed, it is advantageous where possible to select a carrier liquid such that the active drug held in the dual coated dosage form is not soluble or only minimally solu- ble in the carrier liquid.
  • the present in ⁇ vention provides an improved delivery vehicle for con ⁇ trolled release dosage forms, which dosage forms are understood to include controlled-release matrix beads, microspheres, microcapsules, or reservoir type capsules or devices, by enabling preparing of liquid formulations of such dosage forms having a substantial shelf life.
  • dosage forms are understood to include controlled-release matrix beads, microspheres, microcapsules, or reservoir type capsules or devices, by enabling preparing of liquid formulations of such dosage forms having a substantial shelf life.
  • Microspheres, microcapsules, and matrix beads are pre ⁇ ferred dosage forms, especially in the size range of 15 microns to 7000 microns.
  • microspheres and controlled release dosage forms useful for the purposes of being dual coated accord ⁇ ing to the invention can be prepared by any of several known microencapsulation processes or microsphere or ma- trix bead production processes including pan coating, prilling, granulation fluidization processes, pressing through fine mesh screens and other processes.
  • controlled release microspheres packageable and administrable in a liquid formulation intended for young children or the elderly can also be practiced with any of the earlier-mentioned controlled release type dosage forms.
  • controlled- release tablets, capsules, devices, spheres or matrix beads coated according to the present invention can pro ⁇ vide dosage forms suitable for preparation in a liquid formulation, for example, in veterinary applications, where micro sizes become relative to the size of the recipient.
  • the liquid suspension of dual coated controlled release dosage forms according to this invention can be prepared in advance in many cases as early as 35 days or sooner before the intended day of administration of the liquid formulation.
  • the controlled release characteristics of the dual coated microspheres are expressed with active drug release commencing in the upper gastrointestinal tract and active drug release continuing at a uniform rate thereafter for at least 8-12 or 24 hours.
  • the controlled release liquid dosage formu ⁇ lations of the present invention are particularly suit ⁇ able for such drugs as theophylline, dimethylxanthine, antihistamines, cold formulations, analgesics, amino acid supplements, geriatric drugs such as sleeping aids and blood pressure regulators, antidepressants such as lith ⁇ ium chloride, also potassium salts, and alkaloids such as caffeine and codeine.
  • Theophylline was selected to illustrate the dual coated dosage form and liquid dosage formulation of the present invention.
  • Theophylline was selected to illustrate the scope of the invention since a suitable liquid dosage formulation, especially one in which the ⁇ ophylline is the therapeutically active compound, must satisfy a particularly rigid controlled-release profile.
  • Theophylline is a representative alkaloid drug. lt is isomeric with dimethylxanthine and the common alka ⁇ loid, caffeine, differs from theophylline by one less methyl group.
  • Theophylline, typical of alkaloids, is bitter.
  • Theophylline is used as an antiasthmatic but it has an unpleasant taste and requires careful dose mea ⁇ surement and administration to maintain therapeutic serum concentrations. Especially with young children, the now required every 4-6 hour round-the-clock dosing levels of theophylline are difficult to administer and maintain. c hildren often dislike the taste.
  • theophyl ⁇ line is a tissue irritant and thus is preferred to be administered in an enteric release form.
  • the preferred controlled release liquid dosage formulation containing theophylline according to this invention should satisfy the rigid criteria of:
  • liquid dosage formu- lation of the present invention is particularly advan- tageous for the administering of theophylline.
  • a liquid dosage formulation sustaining theophylline release up to 12 or 24 hours according to this invention would_.be parti ⁇ cularly beneficial to asthmatic children, would be easy to administer because of the liquid carrier and its masking of the unpleasant taste, and would require less frequent administration.
  • the premixed liquid dosage formulation would be practical for dispensing by pharmacies.
  • Examples of five commercially available con ⁇ trolled release type dosage forms are illustrated below.
  • the active drug is theophylline in these preparations.
  • Aerolate*, 1, 2 and 4 grain capsules (Flem- ming and Company, St. Louis, Missouri) .
  • Sustaire* tablet (Roerig, Division of Pfi ⁇ zer, Inc., New York, New York). Based upon the release profile of these sus ⁇ tained release type products, the Theo-Dur* scored tab ⁇ lets and Slo-Phylline Gyrocaps* when placed into apple ⁇ sauce exemplify the typical "liquid dosage formulation" available today. Tested for release of theophylline via serum levels it was found that after 1 hour, the Theo-dur ⁇ scored tablets had released 10% of their theophylline and the Slo-Phylline Gyrocaps* had released 80% of their theo ⁇ phylline.
  • the typical controlled release dosage form available today does not have any significant shelf life in an aqueous based carrier fluid since appreciable re- lease proceeds from the initial time of dispersion in the carrier liquid.
  • Typical sustained release dosage forms in the 5 form of spherical beads or microspheres are readily ob ⁇ tained from commercial sources.
  • the micro ⁇ spheres were obtained from Central Pharmaceuticals, Inc. ,
  • a plas ⁇ ticizer was included to enhance the coating properties of the zein and CAP.
  • the plasticizer used was 05 Myvacet* (Eastman Kodak) a distilled acetylated mono- glyceride.
  • cellulose acetate pthalate a butyl ptha- lyl-butyl glycolate liquid sold as Sanitizer* (Pfizer) was used as a plasticizer.
  • coated dosage forms were 10 prepared for testing (all percents given are by weight) .
  • the (D) in vitro release study was similar to the (B) and (C) _in vitro release studies with the exception of duration, temperature and test solution. All (D) jln vitro release studies were conducted at 37 C by placing the test tubes on the Lab Quake rotator in a thermostatistic- ally-controlled oven. The test solution for this in vitro release study was a simulated gastric fluid during the first hour followed by a simulated intestinal fluid.
  • the simulated gastric fluid was prepared as follows:
  • the simulated intestinal fluid was prepared as follows: 6.8 g of monobasic potassium phosphate was dis ⁇ solved in 250 ml of water. With stirring, 190 ml of 0.2 N sodium hydroxide was added along with 400 ml of water. 10 g of pancreatin was then added with stirring. The pH of the resulting solution was adjusted to apH of 7.5 + 0.1 by the addition of 0.2 N sodium hydroxide, then the so ⁇ lution was diluted with water to 1000 ml.
  • Theophylline release in the simulated gastric fluid test solution followed by simulated intestinal fluid test solution was determined at the end of 1, 2, 3, 4, 5, 6 and 8 hours.
  • Table 3 ⁇ show that when the dosage form is placed in high fructose corn syrup, HFCS, an acidic environment, several dosage forms show extremely low levels of theophylline release.
  • type #4 dosage form released only 0.2 percent of the available theophylline over a 14-day period.
  • the uncoated dosage form under these same condi ⁇ tions and duration released 14.8% of the available the ⁇ ophylline.
  • Another four types #'s 5, 7, 8 and 10 exhibited less than 1 percent release after 7 days.
  • the reduced amount of theophylline released is due primarily to the coatings placed over the controlled release dosage forms.
  • the low percentage of water in the HFCS i.e., 29 percent, tends to further minimize the amount of theophylline which 5 is released.
  • Theophylline solubility in water 8.3 mg/ml.
  • the results of the (B) and (C) in vitro release studies verify the importance of the liquid carrier pH in which the dosage form will be eventually formulated. For instance, in Table 4, the lowest per- Q centage of theophylline release from the #4 type dosage form was 47.1%. However, in Table 5, when this same type #4 dosage form was placed in an acidic environment (pH 4.5) , the theophylline release had dropped to 1.8%. Addi ⁇ tionally, the dosage form overcoated with Kaomel®-CAP produced the least amount of theophylline release. The importance of these two coatings, i.e., Kaomel* and CAP, is clearly established if compared with dosage form types #8 and #9 (See Table 5) . Table 3 Results of In Vitro Release Study (A)

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP85900864A 1984-01-13 1985-01-09 Controlled release liquid dosage formulations for pharmaceuticals Withdrawn EP0169236A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US57046984A 1984-01-13 1984-01-13
US570469 2000-05-12

Publications (1)

Publication Number Publication Date
EP0169236A1 true EP0169236A1 (en) 1986-01-29

Family

ID=24279767

Family Applications (1)

Application Number Title Priority Date Filing Date
EP85900864A Withdrawn EP0169236A1 (en) 1984-01-13 1985-01-09 Controlled release liquid dosage formulations for pharmaceuticals

Country Status (11)

Country Link
EP (1) EP0169236A1 (enrdf_load_stackoverflow)
JP (1) JPS61500910A (enrdf_load_stackoverflow)
AU (1) AU3835885A (enrdf_load_stackoverflow)
CA (1) CA1239347A (enrdf_load_stackoverflow)
ES (1) ES8605975A1 (enrdf_load_stackoverflow)
GR (1) GR850069B (enrdf_load_stackoverflow)
IL (1) IL74049A0 (enrdf_load_stackoverflow)
IT (1) IT1184309B (enrdf_load_stackoverflow)
NZ (1) NZ210785A (enrdf_load_stackoverflow)
WO (1) WO1985003000A1 (enrdf_load_stackoverflow)
ZA (1) ZA85239B (enrdf_load_stackoverflow)

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0302065B1 (en) * 1986-03-21 1994-08-10 Eurasiam Laboratories, Inc. Pharmaceutical compositions
SE8605515D0 (sv) * 1986-12-22 1986-12-22 Astra Laekemedel Ab A liquid dosage form for oral administration of a pharmaceutically active substance
FI77573C (fi) * 1987-05-08 1989-04-10 Orion Yhtymae Oy Ny konsistens.
US5030454A (en) * 1987-10-26 1991-07-09 Alza Corporation Method for delivering drug in tiny pills in liquid carrier
US4853229A (en) * 1987-10-26 1989-08-01 Alza Corporation Method for adminstering tiny pills
IT1226940B (it) * 1988-09-16 1991-02-22 Recordati Chem Pharm Sistema terapeutico a rilascio controllato per formulazioni farmaceutiche liquide
US5296236A (en) * 1988-09-16 1994-03-22 Recordati S.A., Chemical And Pharmaceutical Company Controlled release therapeutic system for a liquid pharmaceutical formulations
US5202128A (en) * 1989-01-06 1993-04-13 F. H. Faulding & Co. Limited Sustained release pharmaceutical composition
EP0535937B2 (en) * 1991-10-01 2008-05-21 Takeda Chemical Industries, Ltd. Prolonged release microparticle preparation and production of the same
US5160742A (en) * 1991-12-31 1992-11-03 Abbott Laboratories System for delivering an active substance for sustained release
IL104093A (en) * 1991-12-31 1999-06-20 Abbott Lab Prolamine is expected to mask the taste of drugs given orally
AU4198793A (en) † 1992-07-24 1994-01-27 Takeda Chemical Industries Ltd. Microparticle preparation and production thereof
US5744164A (en) * 1994-12-16 1998-04-28 Nestec S.A. Sustained release microparticulate caffeine formulation
FR2791888B1 (fr) * 1999-04-06 2004-10-08 Ethypharm Lab Prod Ethiques Suspension pharmaceutique buvable
PT1165042E (pt) 1999-04-06 2005-06-30 Ethypharm Sa Suspensao farmaceutica bebivel de ibuprofeno
FR2821745B1 (fr) * 2001-03-09 2004-07-02 Ethypharm Lab Prod Ethiques Granules et granules enrobes au gout masque
WO2004096175A2 (en) * 2003-04-30 2004-11-11 Ranbaxy Laboratories Limited Taste masked microcapsules and processes for their preparation
CA2959414C (en) 2014-09-05 2023-03-14 Symbiomix Therapeutics, Llc Secnidazole for use in the treatment of bacterial vaginosis
US12280037B2 (en) 2020-09-22 2025-04-22 Evofem Biosciences, Inc. Method and pharmaceutical composition for treating or preventing trichomoniasis and uses thereof

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Publication number Priority date Publication date Assignee Title
US2805977A (en) * 1955-01-04 1957-09-10 Smith Kline French Lab Sustained release pharmaceutical preparation
US3265629A (en) * 1958-12-22 1966-08-09 Ncr Co Coating by phase separation
US3432593A (en) * 1963-09-18 1969-03-11 Key Pharm Inc Delayed and sustained release type pharmaceutical preparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8503000A1 *

Also Published As

Publication number Publication date
IL74049A0 (en) 1985-04-30
ZA85239B (en) 1985-08-28
AU3835885A (en) 1985-07-30
IT8519086A0 (it) 1985-01-11
GR850069B (enrdf_load_stackoverflow) 1985-05-03
ES8605975A1 (es) 1986-04-01
CA1239347A (en) 1988-07-19
JPS61500910A (ja) 1986-05-08
ES539500A0 (es) 1986-04-01
IT1184309B (it) 1987-10-28
NZ210785A (en) 1987-11-27
WO1985003000A1 (en) 1985-07-18

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