EP0837675A2 - Methods and compositions for preparing soft gelatin capsules having shells resistant to permeation by fill materials - Google Patents

Methods and compositions for preparing soft gelatin capsules having shells resistant to permeation by fill materials

Info

Publication number
EP0837675A2
EP0837675A2 EP96919128A EP96919128A EP0837675A2 EP 0837675 A2 EP0837675 A2 EP 0837675A2 EP 96919128 A EP96919128 A EP 96919128A EP 96919128 A EP96919128 A EP 96919128A EP 0837675 A2 EP0837675 A2 EP 0837675A2
Authority
EP
European Patent Office
Prior art keywords
gelatin
layer
barrier layer
fill material
shell
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Withdrawn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
EP96919128A
Other languages
German (de)
English (en)
French (fr)
Inventor
Mani R. Sundararajan
Elizabeth Youngblood
Gilbert T. Rodrigues
David J. Walker
Peter Beke
Norman S. Stroud
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.)
Catalent Pharma Solutions Inc
Original Assignee
Catalent Pharma Solutions Inc
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 Catalent Pharma Solutions Inc filed Critical Catalent Pharma Solutions Inc
Publication of EP0837675A2 publication Critical patent/EP0837675A2/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Withdrawn legal-status Critical Current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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • 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

Definitions

  • This invention relates to the field of gelatin capsules containing a fill material comprising a liquid phase. More specifically, this invention relates to gelatin capsules compris ⁇ ing a gelatin shell rendered impervious to migration of the fill material into the gelatin shell. Description of the Related Art
  • Soft gelatin capsules or softgels are predominantly used to contain liquids wherein the active ingredients are present in the dissolved or suspended state.
  • the liquids employed as a portion of the fill materials commonly include vegetable oils, animals oils, mineral oils, liquid hydrocarbons, etheral oils, polyethyl ⁇ ene glycol . Fats and waxes are also commonly used or added to the fill to modify its consistency.
  • the soft gelatin capsule fill material may contain at most about 8% water by weight.
  • liquid materials migrate into and/or interact with the gelatin forming the shell of the capsule. This migration or interaction has a harmful effect on the stability and structure of the gelatin capsule.
  • water a solvent for the proteinaceous material forming gelatin, dissolves gelatin.
  • fill materials for gelatin capsules may only be prepared to include a liquid phase comprising at most about 8% water by weight.
  • Similar problems are encountered using other liquids in fill materials for gelatin capsules. Polyethylene glycol, ethanol, propylene glycol and similar low molecular weight, polar solvents also adversely interact with the gelatin shell. These problems are described in U.S. Patent Nos. 4,888,239 and 4,780,316.
  • the invention encompasses gelatin capsules having a barrier that effectively isolates the gelatin shell and its components from the fill material.
  • the invention provides gelatin capsules comprising a multilayer shell having an outer layer and at least one inner layer acting as a barrier.
  • the fill material which comprises a hydrophilic or a hydrophobic component.
  • the outer layer of the gelatin capsule typically comprises gelatin while the barrier (in certain cases the layer in contact with the fill) is formed from a material resistant to migration of hydrophilic or hydrophobic components from the fill material into the outer layer.
  • the barrier in certain cases the layer in contact with the fill
  • a variety of combinations of the outer gelatin layer adhered to other layers including the barrier are encompassed within the scope of the invention.
  • the invention thus provides gelatin capsules capable of containing a fill material comprising in excess of 8% by weight water.
  • the resulting gelatin capsules comprising water have excellent long-term stability and are capable of encapsulating a variety of liquid fill materials.
  • the invention further encom ⁇ passes gelatin capsules capable of containing a fill material having a tendency to absorb water or other shell materials without any of the shell components from being absorbed by the fill.
  • the resulting gelatin capsules can be prepared to include a variety of solutions, lotions, emulsions, creams, gels or suspen ⁇ sions.
  • the invention further provides gelatin capsules capable of encapsulating within the fill material a variety of components that may adversely affect the physical or chemical stability of the gelatin capsule shell.
  • the fill material may include pharmaceuticals such as synthetic drugs and proteins, various antibodies and enzymes, and vitamins and minerals, fine chemicals, industrial chemicals, solvents, insecticides, etc.
  • the invention further provides a method for manufacturing gelatin capsules where the gelatin capsules are capable of containing a liquid fill material that is also capable of interacting adversely with the gelatin shell .
  • the method comprises forming a gelatin ribbon, the gelatin ribbon having an outer layer comprising gelatin and an inner layer resistant to migration of hydrophilic and hydrophobic materials; preparing a fill material to comprise a system comprising a liquid that may adversely interact with gelatin; and encapsulating the fill
  • the invention also provides composite films comprising a gelatin layer and a barrier layer where the barrier layer is resistant or impervious to migration of hydrophilic and hydrophobic materials across the barrier.
  • the composite films i.e., the multilayer gelatin ribbons, prepared according to the invention to have a gelatin layer and at least one barrier layer can also be used as sheets to wrap a package or a variety of articles.
  • FIGURE 1 is a cross-sectional diagram of a die having a single slot coat-hanger cavity configuration showing port 2 and die lip 1;
  • FIGURE 2 is a cross-sectional diagram of a coextrusion feedblock die showing ports 4, 4a and 4b, and exit port 3;
  • FIGURE 3 is a cross-sectional diagram of a multi-slot multiexit die showing ports 5, 5a and 5b, and die lip 6;
  • FIGURES 4 and 5 are cross-sectional diagrams of multi- manifold single exit dies showing ports 7, 7a and 7b, and die lip 8.
  • the gelatin capsules of the invention comprise a shell and a fill material disposed within the shell.
  • the shell comprises at least one outer layer and at least one inner layer functioning as a barrier layer.
  • the outer layer typically comprises gelatin while the barrier layer is formed from a material that is resistant to permeation by the materials forming the fill material.
  • the shell includes a barrier layer as an inner layer that prevents migration of the liquid material from the fill into the outer gelatin layer.
  • the barrier layer may be adjacent to the fill material and in contact with the fill material or may be isolated from the fill material by an interposed layer of gelatin or other material. Further, the barrier layer may comprise a plurality of layers of material impervious or resistant to permeation by the fill material.
  • the fill material comprises any of a variety of liquid components in addition to various solid materials.
  • the liquid may be a hydrophilic liquid or may be a hydrophobic, i.e., lipophilic, liquid.
  • Representative hydrophilic components include water, C ⁇ -C 3 alcohols, polyethylene glycols, glycerol, propylene glycol, C ⁇ C j acids, saturated polyglycolyzed C 8 -C 10 glycerides, glycofural, diethylene glycol monoethyl ether, high fructose corn syrup, maltose syrup, maltitol syrup, glucose syrup, sugar syrup, honey, and sorbitol .
  • hydrophobic or lipophilic components include hydrocarbons such as, for example, mineral oils, petrolatum, polyethylene waxes, and microcrystalline waxes, synthetic esters such as, for example, isopropyl myristate; natural esters such as, for example, vegetable oils, animal fats and lanolin; natural long-chain alcohols; synthetic chain alcohols; natural long-chain fatty acids; synthetic long-chain fatty acids; ethers such as, for example polyoxypropylenes; silicones such as, for example, substituted or unsubstituted silicones; mixed plant waxes such as candelilla; mixed animal waxes such as bees wax; or mixtures of any of these components.
  • hydrocarbons such as, for example, mineral oils, petrolatum, polyethylene waxes, and microcrystalline waxes
  • synthetic esters such as, for example, isopropyl myristate
  • natural esters such as, for example, vegetable oils, animal fats and lanolin
  • natural long-chain alcohols such as
  • the shell comprises an outer layer and at least one barrier layer that may be the inner layer in contact with the capsule fill material. These layers are discrete layers that preferably are blended at their interface to improve adherence between layers.
  • the invention encompasses a variety of combinations of an outer gelatin layer and inner layers where at least one inner layer is a barrier layer.
  • the other inner layers may be formed from gelatin or other suitable material, such as, for example, agar, pectin, alginate, starch, carrageenan, cellulose or similar polysaccharides or other film forming polymers, such as, for example, shellac or whey protein.
  • the capsule shell is a multi-layer composite of an outer layer and at least one inner layer.
  • the composite may be a bi-layer, a tri- layer, or a quad-layer shell.
  • the shell may be multi ⁇ layer composite having more than four layers.
  • the particular properties of the desired final product may be altered by using such combinations. Examples of these alternative combinations are the following: Outer layer Inner layers gelatin barrier gelatin barrier barrier gelatin barrier gelatin barrier gelatin gelatin barrier gelatin barrier gelatin barrier gelatin barrier gelatin barrier agar barrier gelatin agar gelatin barrier
  • the multilayer ribbons for use in the invention are from about 0.01 to 0.07, preferably from about 0.02 to 0.05, and more preferably from about 0.03 to 0.035, inches in thickness.
  • the layer in contact with the fill material may be a layer of gelatin, optionally modified as described below, to protect and isolate the barrier layer during manufacturing of the ribbon and the final gelatin capsule.
  • This gelatin layer may be a protective or lubricating layer isolating the tacky barrier from the encapsu ⁇ lation apparatus.
  • the outer layer comprises gelatin and a plasticizer for the gelatin.
  • the gelatin mass used to prepare the capsule shell is made according to conventional methods using traditional compo ⁇ nents.
  • the gelatin may optionally include an embrittlement inhibiting composition comprising materials such as a mixture of sorbitol and one or more sorbitans. See U.S. Patent No. 4,780,316.
  • the gelatin may optionally include a tackifier or a viscosity modifier. Examples of tackifiers and viscosity modifiers are ethylene acrylic acid copolymer and amylose, respectively.
  • a preferred gelatin outer layer comprises gelatin, glycerin as a plasticizer, and water.
  • glycerin as a plasticizer
  • water in preferred embodiments of a dry
  • the gelatin present in the outer layer is about 40-70% by weight of the outer layer; glycerin is from about 20-40% by weight of the outer layer; and water is about 5-15% by weight of the outer layer.
  • the layer in contact with the fill material is a layer of gelatin
  • that gelatin layer may optionally be modified by the addition of hydrophobic components.
  • suitable hydrophobic components include colloidal silicas, modified silicas, silicones, modified silicones, magnesium stearate, oxidized polyethylene homopolymer, polyethylene homopolymer, paraffin wax, or mixtures of these materials.
  • the barrier layer of the shell comprises any of a variety of homopolymers or copolymers.
  • Such polymers can be derived from the polymerization of a monomer from the group consisting of acryl- amide, acrylic acid, acrylonitrile, caprolactones, ethylene, furan, maleic anhydride, methacrylate, methacrylic acid, methacry ⁇ late, methylpropylene, styrene, vinyl acetate, vinyl alcohol, vinyl chloride, vinyl ethylether, vinyl propylether, vinyl pyrrolidone, salts of any of the above-mentioned acids or mixtures of these materials.
  • the inner layer may also comprise a paraffin wax.
  • the barrier layer further may comprise hydrocarbons such as polyethylene waxes or microcrystalline waxes, synthetic esters such as isopropyl myristate, natural esters such as vegetable oils, animal fats, or lanolin, natural long-chain alcohols, synthetic long-chain alcohols, natural long-chain fatty acids, synthetic long-chain fatty acids, ethers such as for example polyoxypropylenes, silicones, mixed plant waxes, mixed animal waxes such as bees wax or mixtures thereof.
  • hydrocarbons such as polyethylene waxes or microcrystalline waxes, synthetic esters such as isopropyl myristate, natural esters such as vegetable oils, animal fats, or lanolin, natural long-chain alcohols, synthetic long-chain alcohols, natural long-chain fatty acids, synthetic long-chain fatty acids, ethers such as for example polyoxypropylenes, silicones, mixed plant waxes, mixed animal waxes such as bees wax or mixtures thereof.
  • microcrystalline wax is meant a solid
  • Such solid hydrocarbons have molecular weights from about 490 to 800 and viscosities from about 45 to 120 Saybolt Universal Seconds (SUS) at 210°F (99°C) .
  • Preferred inner layers of the shell comprise paraffin waxes, polyethylene homopolymers or polyethylene copolymers.
  • a parti ⁇ cularly preferred inner layer comprises ethylene acrylic acid copolymer available from Allied Signal, Inc., Morristown, N.J. and microcrystalline wax available from Witco Corporation, Greenwich, CT.
  • ethylene acrylic acid copolymer is about 50-90% by weight of the inner layer and a microcrystalline wax is about 10- 50% by weight of the inner layer.
  • Other preferred inner layers have the following compositions:
  • the shell is formed in a manner such that each layer adheres securely to every other layer.
  • the gelatin layer i.e., the outer layer
  • adheres to the inner layer i.e., the barrier layer.
  • the shell according to the invention is prepared from a multi-layer, e.g., a bi-layer or tri-layer, ribbon that comprises materials that allow for processing into a soft gelatin capsule on a rotary die encapsulation machine without delamination or separa ⁇ tion of the various layers of the multilayer ribbon.
  • a multi-layer e.g., a bi-layer or tri-layer, ribbon that comprises materials that allow for processing into a soft gelatin capsule on a rotary die encapsulation machine without delamination or separa ⁇ tion of the various layers of the multilayer ribbon.
  • ⁇ 10- adhesion is defined as adhesion between the layers sufficient to prevent separation or delamination during all stages of the encapsulation process.
  • the barrier layer material is selected such that it is impervious to hydrophilic materials such as for example water, polyethylene glycols, glycerol, propylene glycol, various C ⁇ -C 3 alcohols, etc.
  • the barrier layer must also be impervious to a variety of hydrophobic or lipophilic vehicles such as fractionated coconut oil, light mineral oil, petrolatum, etc.
  • the materials forming the shell must act as a uniform single ribbon of shell material, i.e., the materials must possess properties similar to that of a typical gelatin ribbon.
  • Each inner layer, including the barrier layer, when adhered to the outer layer must have suffi ⁇ cient elasticity, strength and heat sealing abilities to allow processing of the multilayer material into a capsule on a rotary die encapsulating machine.
  • each layer to another layer may be enhanced by incorporat ⁇ ing tackifiers into the gelatin mass, or the inner layer or barrier layer formulations, or each layer material; alternatively, it may be enhanced by physically modifying the layers during the manufacturing process.
  • tackifiers and viscosity modifiers include ethylene acrylic acid copolymer and amylose, respectively.
  • suitable material for preparing a multi-layer shell of gelatin and at least one barrier material either the gelatin mass or barrier material may be modified by the addition of viscosity modifiers in either the gelatin mass or the barrier fill formulation.
  • -11- these materials may be modified by physically changing the manufacturing process.
  • the apparatus to prepare the inventive gelatin capsules are rotary die encapsulation machines modified such that the inner and outer layers of the capsule shell simultaneously are formed by coextrusion on a casting drum using a coextrusion feedblock and a single manifold, single exit sheet die.
  • Preferred embodiments include machines modified such that the inner and outer layers are coextruded on a casting drum using a multi manifold, multi exit sheet die.
  • Another alternative includes preparing the inner and outer layers sequentially by extruding onto casting drum using a single-manifold, single exit coat-hanger slot die.
  • the gelatin ribbon is formed by simultaneously coextruding the inner and outer layers on a casting drum.
  • extrusion dies suitable for preparing the multilayer films of the invention are typically capable of (1) forcing the melted gelatin and barrier materials into thin films, (2) maintaining the melted materials at a constant temperature; and (3) metering the melted materials at a constant pressure and rate to the die land to prepare a film of a uniform gauge.
  • extrusion dies suitable for use in the invention include those listed in the following table:
  • a coextrusion feedblock such as that shown in Figure 2 is mounted on a coat-hanger type die such as the one shown in Figure 1, such that the exit port 3 is adjacent the feed port 2.
  • the coextrusion feedblock and die are mounted adjacent a casting drum to provide the drum with a film of material .
  • the ports provide the die lip with single-layer, bi-layer or multilayer material, depending on the configuration.
  • the die is mounted on a rotary die encapsulation apparatus such that the die lips are adjacent a casting drum and provides the casting drum with a thin film of material .
  • ⁇ 13- Bi-layer soft gelatin capsules are manufactured on a rotary die encapsulation apparatus using the materials shown below in Table I.
  • the bi-layer (gelatin-barrier) ribbons are formed by a coextrusion technique.
  • This bi-layer ribbon is formed by a multi- manifold multi-exit die.
  • Formulation 1 A PEG 400 solution containing 20% w/w of water was encapsulated in the bi-layer capsule with the shell composition described in Table I. Soft gelatin capsules with good seals were obtained.
  • Formulation 2 A PEG solution containing 40% w/w of water was encapsulated in the bi-layer capsule with the shell composition described in Table I. Soft gelatin capsules with good seals were obtained.
  • Formulation 3 A bi-layer capsule with the shell composition described in Table I containing a 100% purified water as fill was prepared. Soft gelatin capsules with good seals were obtained.
  • Formulation 4 A bi-layer capsule with the shell composition
  • Formulation 7 A water-in-oil emulsion containing 56.3% w/w of water, 10% w/w POE glycerol sorbitan, isostearate, 3% w/w beeswax, 3% w/w lanolin, 11% w/w cap- rylic/capric triglyceride, 11% w/w squalane, 3% w/w
  • 1% w/w hydroxypropyl cellulose, and 41% w/w ethoxy- diglycol was encapsulated in a bi-layer capsule having the shell composition described in Table 1. Soft gelatin capsules with good seals were ob ⁇ tained.
  • Bilayer and gelatin-barrier composite ribbons are prepared to comprise a barrier layer containing a 70:30 blend of ethylene acrylic acid copolymer and microcrystalline wax where the gelatin and barrier layers have thicknesses of 0.019 and 0.033 inches, respectively.
  • a gelatin layer 0.032 inches thick is prepared utilizing conventional gelatin ribbon casting methods. Water vapor permeation rates for each ribbon are shown in Tables II and III below:

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Laminated Bodies (AREA)
  • Manufacturing Of Micro-Capsules (AREA)
  • Materials For Medical Uses (AREA)
  • Artificial Filaments (AREA)
EP96919128A 1995-06-07 1996-06-06 Methods and compositions for preparing soft gelatin capsules having shells resistant to permeation by fill materials Withdrawn EP0837675A2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US47289595A 1995-06-07 1995-06-07
US472895 1995-06-07
PCT/US1996/009145 WO1996040083A2 (en) 1995-06-07 1996-06-06 Methods and compositions for preparing soft gelatin capsules having shells resistant to permeation by fill materials

Publications (1)

Publication Number Publication Date
EP0837675A2 true EP0837675A2 (en) 1998-04-29

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ID=23877340

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96919128A Withdrawn EP0837675A2 (en) 1995-06-07 1996-06-06 Methods and compositions for preparing soft gelatin capsules having shells resistant to permeation by fill materials

Country Status (14)

Country Link
EP (1) EP0837675A2 (ja)
JP (1) JPH11506785A (ja)
KR (1) KR19990022443A (ja)
CN (1) CN1186429A (ja)
AU (1) AU6154696A (ja)
BR (1) BR9608608A (ja)
CA (1) CA2222120A1 (ja)
CZ (1) CZ381897A3 (ja)
HU (1) HUP9900858A2 (ja)
IL (1) IL122422A0 (ja)
NZ (1) NZ310708A (ja)
PL (1) PL323790A1 (ja)
SK (1) SK164897A3 (ja)
WO (1) WO1996040083A2 (ja)

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US6333047B1 (en) 1997-05-09 2001-12-25 Daiichi Kasei Co., Ltd. Molded capsule superior in strength and stability and method for preparing same
JP3188649B2 (ja) * 1997-05-09 2001-07-16 株式会社第一化成 カプセル
ES2235337T3 (es) * 1997-07-09 2005-07-01 Swiss Caps Rechte Und Lizenzen Ag Procedimiento y dispositivo para fabricar una forma farmaceutica multicapa, fisiologicamente tolerable.
GB2398499B (en) * 2000-02-16 2004-11-24 Bioprogress Technology Ltd Two layer capsules
CN1111419C (zh) * 2000-07-05 2003-06-18 宋令春 一种治疗心脑血管中风和中风先兆症状的药物及其制备方法
EP1498117A1 (en) * 2003-07-15 2005-01-19 Pfizer GmbH Arzneimittelwerk Gödecke A pharmaceutical gelatin-capsule or gelatin containing capsule preparation showing an improved stability, a process for making the capsules and a process for improving the stability of gelatin-capsules
NL2000247C2 (nl) * 2006-09-25 2008-03-26 Drie Mollen Holding B V Vloeistofhoudende capsule.
CN101596174B (zh) * 2009-07-13 2011-04-06 北京航洋胶囊技术有限公司 一种软胶囊及其制备方法
CN102552209A (zh) * 2012-01-06 2012-07-11 安徽黄山胶囊股份有限公司 一种双层空心胶囊和多层肠溶空心胶囊
CN103550065B (zh) * 2013-10-26 2015-01-28 中山市凯博思淀粉材料科技有限公司 一种复合挤出法生产淀粉基软胶囊的方法
US20150209360A1 (en) * 2014-01-30 2015-07-30 Orbz, Llc Oral caffeine delivery composition
CN107361392B (zh) * 2017-07-26 2019-10-25 云南芯韵科技开发有限公司 一种三层含水胶囊及其制备方法
US11298336B2 (en) 2019-05-30 2022-04-12 Soluble Technologies, Inc. Water soluble formulation
CN113367379A (zh) * 2020-03-09 2021-09-10 深圳波顿香料有限公司 一种烟草制品
US11786475B2 (en) 2020-07-22 2023-10-17 Soluble Technologies Inc. Film-based dosage form
CN115721627B (zh) * 2022-11-10 2024-08-30 南通华山药业有限公司 一种益母草软胶丸及其制备方法

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JPH0761948B2 (ja) * 1986-05-08 1995-07-05 フロイント産業株式会社 腸内有用細菌含有カプセル
GB2290965A (en) * 1994-07-11 1996-01-17 Therapicon Srl Multiple layer capsules for drugs
DE4432557A1 (de) * 1994-09-13 1996-03-14 Hoechst Ag Kapseln mit innenseitig hydrophober Beschichtung zur Aufnahme von matrixadsorbierten wäßrigen (radioaktiven) Lösungen und Verfahren zur Herstellung obiger Kapseln

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Also Published As

Publication number Publication date
JPH11506785A (ja) 1999-06-15
SK164897A3 (en) 1998-12-02
BR9608608A (pt) 1999-12-07
WO1996040083A3 (en) 1997-02-06
AU6154696A (en) 1996-12-30
CZ381897A3 (cs) 1998-05-13
HUP9900858A2 (hu) 1999-08-30
NZ310708A (en) 1999-11-29
KR19990022443A (ko) 1999-03-25
IL122422A0 (en) 1998-06-15
PL323790A1 (en) 1998-04-27
CA2222120A1 (en) 1996-12-19
WO1996040083A2 (en) 1996-12-19
CN1186429A (zh) 1998-07-01
MX9709198A (es) 1998-03-31

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