CA2101095C - Enteric coated soft capsules and method of preparation thereof - Google Patents
Enteric coated soft capsules and method of preparation thereof Download PDFInfo
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- CA2101095C CA2101095C CA002101095A CA2101095A CA2101095C CA 2101095 C CA2101095 C CA 2101095C CA 002101095 A CA002101095 A CA 002101095A CA 2101095 A CA2101095 A CA 2101095A CA 2101095 C CA2101095 C CA 2101095C
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- capsule
- methyl
- mixture
- plasticizer
- enteric coating
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4891—Coated capsules; Multilayered drug free capsule shells
Abstract
Soft capsules coated with an enteric coating comprising a 1:1 copolymer of methacrylic acid and methyl or ethyl acrylate or methyl or ethyl methacrylate and a plasticizer without need for a subcoating and optionally additionally coated with a protective coating comprising hydroxypropyl methylcellulose or hydroxypropyl cellulose or a mixture thereof and a plasticizer and method of preparation thereof are disclosed.
Description
-1- D.N. 1098 BACKGROUND OF TIE INVENTION
' 1 f h~ Invention The invention relates to soft capsules coated with an enteric coating without need for a subcoating and optionally additionally coated with a protective coating and method of preparation thereof.
Information Disclosure Statement Enteric coating of soft capsules has heretofore required a glidant such as talc to prevent agglomeration of the capsules and a subcoating to stiffen the capsules and thereby prevent distortion thereof during coating. The prior art does not describe or suggest any means of overcoming either problem. The presently described and claimed invention overcomes both of them.
A Rohm Pharma product brochure entitled "Eudragir L 30 D - Aqueous Acrylic Resin Dispersion - Application in the Froduction of Pharmaceutical Preparations" (Info LD-1/e, pages 1-7 and Info LD-2/e, two pages) describes EUDRAGTT L 30 D and use thereof as follows:
EUDRAGIT L 30 D is utilised predominantly for covering orally administered pharmaceutical dosage forms, particularly tablets, pills and capsules, with coatings which are resistant to gastric juice but soluble in intestinal juice.
...
*Trade-mark -2- D.A1. 1098 EUDRAGIT L 30 D is a copolymer, anionic in character, based on polymethylacrylic acid and acrylic acid esters.
The ratio of the free carboxyl groups to the ester groups is 1:1.
The mean molecular weight is 250 000.
EUDRAGIT L 30 D is supplied as an aqueous dispersion containing 30% w/w of dry lacquer substance.
To achieve coatings which are resistant to gastric juice, it is necessary to apply lacquer containing 3 to 6 mg of dry, substance per sq. cm of tablet surface. For enteric coatings with delayed drug release in the intestine, larger quantities of lacquer will possibly need to be applied.
In certain cases, EUDRAGIT L 30 D containing 30%
w/w of dry lacquer substance can be employed undiluted, possibly for granulation purposes, to isolate porous cores or in fraction application.
Uniform and smooth film coatings are obtained by spray application; this process requires that the dispersion be diluted to some 20% w/w with water.
T~ enhance the elasticity of the EUDItAGIT L
D elms, the addition of plasticisers is str~ngly reeoanrnended. Polyethylene glycols, propylene glycol, triacetin and dibutyl phthalate, citric 30 acid esters have proved suitable as plasticisers. The addition of 10% w/w of plasticiser, calculated on the dry lacquer substance content, is generally adequate. Where required, this can be increased to 20-25% without ~~~~.~~J
' 1 f h~ Invention The invention relates to soft capsules coated with an enteric coating without need for a subcoating and optionally additionally coated with a protective coating and method of preparation thereof.
Information Disclosure Statement Enteric coating of soft capsules has heretofore required a glidant such as talc to prevent agglomeration of the capsules and a subcoating to stiffen the capsules and thereby prevent distortion thereof during coating. The prior art does not describe or suggest any means of overcoming either problem. The presently described and claimed invention overcomes both of them.
A Rohm Pharma product brochure entitled "Eudragir L 30 D - Aqueous Acrylic Resin Dispersion - Application in the Froduction of Pharmaceutical Preparations" (Info LD-1/e, pages 1-7 and Info LD-2/e, two pages) describes EUDRAGTT L 30 D and use thereof as follows:
EUDRAGIT L 30 D is utilised predominantly for covering orally administered pharmaceutical dosage forms, particularly tablets, pills and capsules, with coatings which are resistant to gastric juice but soluble in intestinal juice.
...
*Trade-mark -2- D.A1. 1098 EUDRAGIT L 30 D is a copolymer, anionic in character, based on polymethylacrylic acid and acrylic acid esters.
The ratio of the free carboxyl groups to the ester groups is 1:1.
The mean molecular weight is 250 000.
EUDRAGIT L 30 D is supplied as an aqueous dispersion containing 30% w/w of dry lacquer substance.
To achieve coatings which are resistant to gastric juice, it is necessary to apply lacquer containing 3 to 6 mg of dry, substance per sq. cm of tablet surface. For enteric coatings with delayed drug release in the intestine, larger quantities of lacquer will possibly need to be applied.
In certain cases, EUDRAGIT L 30 D containing 30%
w/w of dry lacquer substance can be employed undiluted, possibly for granulation purposes, to isolate porous cores or in fraction application.
Uniform and smooth film coatings are obtained by spray application; this process requires that the dispersion be diluted to some 20% w/w with water.
T~ enhance the elasticity of the EUDItAGIT L
D elms, the addition of plasticisers is str~ngly reeoanrnended. Polyethylene glycols, propylene glycol, triacetin and dibutyl phthalate, citric 30 acid esters have proved suitable as plasticisers. The addition of 10% w/w of plasticiser, calculated on the dry lacquer substance content, is generally adequate. Where required, this can be increased to 20-25% without ~~~~.~~J
-3- D.N. 1098 adversely affecting the specifc solubility characteristics of the lacquer film.
The addition of a small quantity of talc seduces the tendency of EUDRAGIT L 30 D to agglutinate during the application process and helps to make the surface of the film smooth.
Belanger et al. U.S. Pat. 5,047,258, which issued September 10, 1991, describes (a] method of preventing pharmaceutical dosage forms from adhering during spray coating, comprising:
spraying said pharmaceutical dosage forms in the absence of glidant [especially talc] with a mixture consisting essentially of a one to one copolymer of ethyl acrylate and methacrylic acid and a plasticizes in air having an inlet dew point below about 10°C. and an inlet temperature between about 35°C. and about 60°C.
The term "pharmaceutical dosage forms" is not explicitly defined. The specification states that the invention relates to a process for the spray-coating of "tablets, pills, and the like" and illustrates the invention only by tablets in the examples.
Matthews et al. U.S. Pat. 4,816,259, which issued March 28, 1989, describes a process for making coated soft gelatin capsules including enteric coated soft gelatin capsules comprising first coating the capsule shell with a subcoating composition consisting essentially of hydroxypropyl methyl cellulose about 4%-9%, polyethylene glycol about 0.5%-1% with the remainder water in an [a]mount sufficient to increase the total weight of said shell by about 8%-10%, and thereafter applying one or more continuous coating layers to said :~. ~. ~ ~ ~3 -4- D.N. 1098 S
shell comprising a known hard tables coating composition selected from the group consisting of:
waterproofing and sealing compounds, smoothing compounds, coloring and finishing compounds, polishing compounds, cellulose polymer film compositions, compression coating compositions, arid enteric coating compounds, wherein said subcoating is applied to said capsule shell using standard spraying techniques at a temperature below the distortion temperature of the capsule shell thereby essentially eliminating deformation of the capsule shell during the manufacturing process and capsules prepared by the process. The preferred enteric coating composition is 12-18% of polyvinyl acetate phthalate, 0.25-0.35% concentrated ammonium hydroxide 1S and water to make 100%.
SUMMARY OF THE INVENTION
In a first composition of matter aspect the invention is a filled soft capsule not having a subcoating and coated with from about 1 to about 20 mg./cm.2 of an enteric coating consisting essentially of by weight from about 60% to about 90% of a 1:1 copolymer of methacrylic acid and methyl or ethyl acrylate or methyl or ethyl methacrylate and from about 10% to about 40% of a plasticizer selected from the group consisting of triacedn, a polyethylene glycol having a molecular weight in the range from 400 to 3350, propylene glycol, dibutyl phthalate and triethyl citrate or mixture 2S thereof.
In a second composition of matter aspect the invention is a capsule in accordance with the first composition of matter aspect of the invention additionally -5- D.Al. 1098 coated with from about 1 to about 10 mg./cm.2 of a protective coating consisting essentially of by weight from about 60% to about 90% of a cellulose derivative which is hydroxypropyl methylcellulose or hydroxypropyl cellulose or a mixture thereof and from about 10% to about 40% of a plasticizes selected from the group consisting of triacetin, a polyethylene glycol having a molecular weight in the range from 400 to 3350, propylene glycol, dibutyl phthalate, triethyl citrate, glycerin and diacetylated monoglycerides or a mixture thereof.
In a first process aspect the invention is the process of preparing a capsule in accordance with the first composition of matter aspect of the invention which comprises mixing the 1:1 copolymer of methacrylic acid and methyl or ethyl acrylate or methyl or ethyl methacrylate and the plasticizes in from about 2 times to about 8 times the combined weight thereof of water, spraying a filled soft capsule not having a subcoating using air at a temperature in the range from 30°C. to 60°C. with the resulting mixture in sufficient amount to produce from about 1 to about 20 mg./cm 2 of enteric coating on the capsule after drying, and then drying the capsule with air at a temperature in the range from 30°C. to 60°C.
In a second process aspect the invention is the process of preparing a capsule in accordance with the second composition of matter aspect of the invention which comprises mixing the hydroxypropyl methylcellulose or hydroxypropyl cellulose or mixture thereof and the plasticizes in from about 5 to about 15 times the combined weight thereof of water, spraying a capsule prepared in accordance with the first process aspect of the invention using air at a temperature in the range from 30°C. to 60°C. with the resulting mixture in sufficient amount to produce from about 1 to about -6- D.N. 1098 mg./cm.2 of protective coating on the capsule after drying, and then drying the capsule with air at a temperature in the range from 30°C. to 60°C.
DETAILED DESCRIPTION OF THE INVENTION
Enteric coated soft gelatin capsules of the prior art have needed a 5 subcoating to stiffen them and thereby to prevent distortion during the coating process, which has been carried out at or above the distortion temperature (65-75°C.). The manufacturer of the 1:1 copolymer of methacrylic acid and methyl or ethyl acrylate or methyl or ethyl methacrylate has recommended that due to its tacky nature an agent such as talc be used to prevent adherence of capsules during the coating process.
Talc 10 however tends to clog the spray nozzles used in the coating process. The invention overcomes both of these problems by allowing use of a coating temperature below the distortion temperature of the capsules and thereby avoiding use of subcoated capsules and allowing omission of an antiadherent agent in the coating process and thereby avoiding clogged spray nozzles.
The soft capsule shell of the composition of matter aspects of the invention can be any pharmaceutically acceptable soft capsule shell but is preferably a soft gelatin capsule shell and is of suitable size for containing from about 40 milligrams or about 0.04 milliliter to about 800 milligrams or about 0.8 milliliter of filling. Soft gelatin capsule shells are commercially available and generally contain in addition to gelatin a plasticizer, a preservative and a colorant. Conventional machinery and technique are used in filling the soft capsule shells.
The capsule filling can be any liquid, solid or semi-solid pharmaceutical composition suitable for oral administration but is preferably a liquid or semi-solid composition since soft capsules, which are more expensive to make than hard capsules, -7- D.N. I098 are generally used when a pharmaceutical substance cannot be fozmulated as a solid.
Pharmaceutical substance means any drug for treating or preventing any disease or disorder or mixture thereof or any nutritional aid. A pharmaceutical substance used to illustrate the invention is an antiviral agent described by Diana U.S. Pat.
4,843,087 issued June 27, 1989, which is the compound described as 5-[5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole in part (c) of example thereof and which cannot be formulated as a solid. The amount of pharmaceutical substance in the capsule filling depends on the dose needed. A drug for treating or preventing a disease or disorder can constitute from as little as 0.1% to as much as 90%
by weight of the capsule filling. A nutritional aid, for example garlic oil, can constitute the entire capsule filling. Conventional excipients, if any, constitute the remainder of the capsule filling, which is prepared using conventional equipment and methods.
The excipients used to prepare the capsule filling and the substances used to prepare the enteric coating and the protective coating of the invention are known pharmaceutical ingredients and are described by manufacturers' product brochures and pharmaceutical texts, for example The United States Pharmacopeia, Twenty-second Revision and The National Formulary, Seventeenth Edition (a single volume also entitled 1990 USP XXII NF XVII; copyright by United States Pharmacopeial Convention, Inc., 12601 Twinbrook Parkway, Rockville, IvE7 20852, 1989). A set of monographs is presented and arranged alphabetically by name in each of the United States Pharmacopeia (USP) and National Formulary (NF) sections thereof. The convention followed thereby in naming the substances described is that the first letter of each word of the name is capitalized. The substances used to prepare the below-described example are described under the following names (section, page(s)):
The addition of a small quantity of talc seduces the tendency of EUDRAGIT L 30 D to agglutinate during the application process and helps to make the surface of the film smooth.
Belanger et al. U.S. Pat. 5,047,258, which issued September 10, 1991, describes (a] method of preventing pharmaceutical dosage forms from adhering during spray coating, comprising:
spraying said pharmaceutical dosage forms in the absence of glidant [especially talc] with a mixture consisting essentially of a one to one copolymer of ethyl acrylate and methacrylic acid and a plasticizes in air having an inlet dew point below about 10°C. and an inlet temperature between about 35°C. and about 60°C.
The term "pharmaceutical dosage forms" is not explicitly defined. The specification states that the invention relates to a process for the spray-coating of "tablets, pills, and the like" and illustrates the invention only by tablets in the examples.
Matthews et al. U.S. Pat. 4,816,259, which issued March 28, 1989, describes a process for making coated soft gelatin capsules including enteric coated soft gelatin capsules comprising first coating the capsule shell with a subcoating composition consisting essentially of hydroxypropyl methyl cellulose about 4%-9%, polyethylene glycol about 0.5%-1% with the remainder water in an [a]mount sufficient to increase the total weight of said shell by about 8%-10%, and thereafter applying one or more continuous coating layers to said :~. ~. ~ ~ ~3 -4- D.N. 1098 S
shell comprising a known hard tables coating composition selected from the group consisting of:
waterproofing and sealing compounds, smoothing compounds, coloring and finishing compounds, polishing compounds, cellulose polymer film compositions, compression coating compositions, arid enteric coating compounds, wherein said subcoating is applied to said capsule shell using standard spraying techniques at a temperature below the distortion temperature of the capsule shell thereby essentially eliminating deformation of the capsule shell during the manufacturing process and capsules prepared by the process. The preferred enteric coating composition is 12-18% of polyvinyl acetate phthalate, 0.25-0.35% concentrated ammonium hydroxide 1S and water to make 100%.
SUMMARY OF THE INVENTION
In a first composition of matter aspect the invention is a filled soft capsule not having a subcoating and coated with from about 1 to about 20 mg./cm.2 of an enteric coating consisting essentially of by weight from about 60% to about 90% of a 1:1 copolymer of methacrylic acid and methyl or ethyl acrylate or methyl or ethyl methacrylate and from about 10% to about 40% of a plasticizer selected from the group consisting of triacedn, a polyethylene glycol having a molecular weight in the range from 400 to 3350, propylene glycol, dibutyl phthalate and triethyl citrate or mixture 2S thereof.
In a second composition of matter aspect the invention is a capsule in accordance with the first composition of matter aspect of the invention additionally -5- D.Al. 1098 coated with from about 1 to about 10 mg./cm.2 of a protective coating consisting essentially of by weight from about 60% to about 90% of a cellulose derivative which is hydroxypropyl methylcellulose or hydroxypropyl cellulose or a mixture thereof and from about 10% to about 40% of a plasticizes selected from the group consisting of triacetin, a polyethylene glycol having a molecular weight in the range from 400 to 3350, propylene glycol, dibutyl phthalate, triethyl citrate, glycerin and diacetylated monoglycerides or a mixture thereof.
In a first process aspect the invention is the process of preparing a capsule in accordance with the first composition of matter aspect of the invention which comprises mixing the 1:1 copolymer of methacrylic acid and methyl or ethyl acrylate or methyl or ethyl methacrylate and the plasticizes in from about 2 times to about 8 times the combined weight thereof of water, spraying a filled soft capsule not having a subcoating using air at a temperature in the range from 30°C. to 60°C. with the resulting mixture in sufficient amount to produce from about 1 to about 20 mg./cm 2 of enteric coating on the capsule after drying, and then drying the capsule with air at a temperature in the range from 30°C. to 60°C.
In a second process aspect the invention is the process of preparing a capsule in accordance with the second composition of matter aspect of the invention which comprises mixing the hydroxypropyl methylcellulose or hydroxypropyl cellulose or mixture thereof and the plasticizes in from about 5 to about 15 times the combined weight thereof of water, spraying a capsule prepared in accordance with the first process aspect of the invention using air at a temperature in the range from 30°C. to 60°C. with the resulting mixture in sufficient amount to produce from about 1 to about -6- D.N. 1098 mg./cm.2 of protective coating on the capsule after drying, and then drying the capsule with air at a temperature in the range from 30°C. to 60°C.
DETAILED DESCRIPTION OF THE INVENTION
Enteric coated soft gelatin capsules of the prior art have needed a 5 subcoating to stiffen them and thereby to prevent distortion during the coating process, which has been carried out at or above the distortion temperature (65-75°C.). The manufacturer of the 1:1 copolymer of methacrylic acid and methyl or ethyl acrylate or methyl or ethyl methacrylate has recommended that due to its tacky nature an agent such as talc be used to prevent adherence of capsules during the coating process.
Talc 10 however tends to clog the spray nozzles used in the coating process. The invention overcomes both of these problems by allowing use of a coating temperature below the distortion temperature of the capsules and thereby avoiding use of subcoated capsules and allowing omission of an antiadherent agent in the coating process and thereby avoiding clogged spray nozzles.
The soft capsule shell of the composition of matter aspects of the invention can be any pharmaceutically acceptable soft capsule shell but is preferably a soft gelatin capsule shell and is of suitable size for containing from about 40 milligrams or about 0.04 milliliter to about 800 milligrams or about 0.8 milliliter of filling. Soft gelatin capsule shells are commercially available and generally contain in addition to gelatin a plasticizer, a preservative and a colorant. Conventional machinery and technique are used in filling the soft capsule shells.
The capsule filling can be any liquid, solid or semi-solid pharmaceutical composition suitable for oral administration but is preferably a liquid or semi-solid composition since soft capsules, which are more expensive to make than hard capsules, -7- D.N. I098 are generally used when a pharmaceutical substance cannot be fozmulated as a solid.
Pharmaceutical substance means any drug for treating or preventing any disease or disorder or mixture thereof or any nutritional aid. A pharmaceutical substance used to illustrate the invention is an antiviral agent described by Diana U.S. Pat.
4,843,087 issued June 27, 1989, which is the compound described as 5-[5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole in part (c) of example thereof and which cannot be formulated as a solid. The amount of pharmaceutical substance in the capsule filling depends on the dose needed. A drug for treating or preventing a disease or disorder can constitute from as little as 0.1% to as much as 90%
by weight of the capsule filling. A nutritional aid, for example garlic oil, can constitute the entire capsule filling. Conventional excipients, if any, constitute the remainder of the capsule filling, which is prepared using conventional equipment and methods.
The excipients used to prepare the capsule filling and the substances used to prepare the enteric coating and the protective coating of the invention are known pharmaceutical ingredients and are described by manufacturers' product brochures and pharmaceutical texts, for example The United States Pharmacopeia, Twenty-second Revision and The National Formulary, Seventeenth Edition (a single volume also entitled 1990 USP XXII NF XVII; copyright by United States Pharmacopeial Convention, Inc., 12601 Twinbrook Parkway, Rockville, IvE7 20852, 1989). A set of monographs is presented and arranged alphabetically by name in each of the United States Pharmacopeia (USP) and National Formulary (NF) sections thereof. The convention followed thereby in naming the substances described is that the first letter of each word of the name is capitalized. The substances used to prepare the below-described example are described under the following names (section, page(s)):
-8- D.N. 1098 Hydroxypropyl Methylcellulose (USP, pp. 670-671), Triacetin (USP, p. 1392), Methacrylic Acid Copolymer (NF, pp. 1946-1947), Polyethylene Glycol (NF, pp.
1961-1963), Polysorbate 80 (NF, p. 1968).
Hydroxypropyl Methylcellulose is described as "[c]ellulose, 2-hydroxypropyl methyl ether" and as "a propylene glycol ether of methylcellulose'°.
When dried it contains "methoxy (OCH3) and hydroxypropoxy (OCH2CHOHCH3) groups" conforming to certain limits. Hydroxypropyl Methylcellulose 2910 for example has a minimum of 28.0% and a maximum of 30.0% of methoxy groups and a minimum of 7.0% and a maximum of 12.0% of hydroxypropoxy groups.
Triacetin is described as well by the names "1,2,3-[p]ropanetriol triacetate" and "[g]lycerin triacetate°' and by the structural formula CH2(OCOCH3)CH(OCOCH3)CH20COCH3.
Methacrylic Acid Copolymer is described as "a fully polymerized copolymer of methacrylic acid and an acrylic or methacrylic ester." Types A, E
and C
are specifically described in terms of percent methacrylic acid units and viscosity units.
Type C is specified as having a methacrylic acid content of 46.0-50.6% and a viscosity of 100-200 cps and is the dry polymer corresponding to the aqueous dispersion thereof described as EUDRAG1T 1. 30 D by the above-cited Rohm Pharma product brochure.
Polyethylene Glycol is described as "an addition polymer of ethylene oxide and water, represented by the formula H(OCH2CH~)nOH
in which n represents the average number of oxyethylene groups." The variants are designated by "nominal value" of "average molecular weight". Polyethylene glycols having nominal average molecular weights in the range from 300 to 8000 are described.
1961-1963), Polysorbate 80 (NF, p. 1968).
Hydroxypropyl Methylcellulose is described as "[c]ellulose, 2-hydroxypropyl methyl ether" and as "a propylene glycol ether of methylcellulose'°.
When dried it contains "methoxy (OCH3) and hydroxypropoxy (OCH2CHOHCH3) groups" conforming to certain limits. Hydroxypropyl Methylcellulose 2910 for example has a minimum of 28.0% and a maximum of 30.0% of methoxy groups and a minimum of 7.0% and a maximum of 12.0% of hydroxypropoxy groups.
Triacetin is described as well by the names "1,2,3-[p]ropanetriol triacetate" and "[g]lycerin triacetate°' and by the structural formula CH2(OCOCH3)CH(OCOCH3)CH20COCH3.
Methacrylic Acid Copolymer is described as "a fully polymerized copolymer of methacrylic acid and an acrylic or methacrylic ester." Types A, E
and C
are specifically described in terms of percent methacrylic acid units and viscosity units.
Type C is specified as having a methacrylic acid content of 46.0-50.6% and a viscosity of 100-200 cps and is the dry polymer corresponding to the aqueous dispersion thereof described as EUDRAG1T 1. 30 D by the above-cited Rohm Pharma product brochure.
Polyethylene Glycol is described as "an addition polymer of ethylene oxide and water, represented by the formula H(OCH2CH~)nOH
in which n represents the average number of oxyethylene groups." The variants are designated by "nominal value" of "average molecular weight". Polyethylene glycols having nominal average molecular weights in the range from 300 to 8000 are described.
-9- D.N. 1098 Polyethylene Glycol 600 and Polyethylene Glycol 1000 were used to prepare the below-described example.
Polysorbate 80 is described as a poly(oxy-1,2-ethanediyl) derivative of sorbitan mono-9-octadecenoate, as "an oleate ester of sorbitol and its anhydrides copolymerized with approximately 20 moles of ethylene oxide for each mole of sorbitol and sorbitol anhydrides", and as "[p]olyoxyethylene 20 sorbitan monaoleate".
The mixing, spraying and drying steps of the process aspects of the invention are carried out using conventional equipment. The 1:1 copolymer of methacrylic acid and methyl or ethyl acrylate or methyl or ethyl methacrylate, plasticizer and water of the first process aspect of the invention are preferably mixed at room temperature. The hydroxypropyl methylcellulose or hydroxypropyl cellulose oa mixture thereof, plasticizer and water of the second process aspect of the invention are preferably mixed with warming, preferably to about 80°C., using part of the water and then cooled, preferably to room temperature, using the remainder of the water to complete the mixture and aid in cooling. Spraying is carried out with batches of capsules in a coating pan using one or more spray nozzles with warm air flow to remove water from the coated capsules as the coating proceeds. The inlet air temperature is in the above-stated range from 30°C. to 60°C., preferably from 40°C. to 50°C. The amount of enteric coating applied to the capsules as stated above is from about 1 to about 20 mg./cm.2, preferably from about 5 to about 15 mg./cm.2 and most preferably from about 8 to about 12 mg./cm.2. The relative weight of the 1:1 copolymer of methacrylic acid and methyl or ethyl acrylate or methyl ar ethyl methacrylate in the enteric coating is as stated above from about 60% to about 90%
thereof and is preferably from about 75% to about 85% thereof. The relative weight of ~~.~~.OJS
Polysorbate 80 is described as a poly(oxy-1,2-ethanediyl) derivative of sorbitan mono-9-octadecenoate, as "an oleate ester of sorbitol and its anhydrides copolymerized with approximately 20 moles of ethylene oxide for each mole of sorbitol and sorbitol anhydrides", and as "[p]olyoxyethylene 20 sorbitan monaoleate".
The mixing, spraying and drying steps of the process aspects of the invention are carried out using conventional equipment. The 1:1 copolymer of methacrylic acid and methyl or ethyl acrylate or methyl or ethyl methacrylate, plasticizer and water of the first process aspect of the invention are preferably mixed at room temperature. The hydroxypropyl methylcellulose or hydroxypropyl cellulose oa mixture thereof, plasticizer and water of the second process aspect of the invention are preferably mixed with warming, preferably to about 80°C., using part of the water and then cooled, preferably to room temperature, using the remainder of the water to complete the mixture and aid in cooling. Spraying is carried out with batches of capsules in a coating pan using one or more spray nozzles with warm air flow to remove water from the coated capsules as the coating proceeds. The inlet air temperature is in the above-stated range from 30°C. to 60°C., preferably from 40°C. to 50°C. The amount of enteric coating applied to the capsules as stated above is from about 1 to about 20 mg./cm.2, preferably from about 5 to about 15 mg./cm.2 and most preferably from about 8 to about 12 mg./cm.2. The relative weight of the 1:1 copolymer of methacrylic acid and methyl or ethyl acrylate or methyl ar ethyl methacrylate in the enteric coating is as stated above from about 60% to about 90%
thereof and is preferably from about 75% to about 85% thereof. The relative weight of ~~.~~.OJS
-10- D.N.1098 plasticizer in the enteric coating is as stated above from about 10% to about 40% thereof and is preferably from about 15% to about 25% thereof. The amount of protective coating as stated above is from about 1 to about 10 mg./cm 2, preferably from about 2 to about 4 mg./cm.2. The relative weight of hydroxypropyl methylcellulose or hydroxypropyl cellulose or mixture thereof in the protective coating is as stated above from about 60% to about 90% thereof and is preferably from about 75% to about 85%
thereof. The relative weight of plasticizer in the protective coating is as stated above from about 10% to about 40% thereof and is preferably from about 15% to about 25%
thereof. After completion of spraying drying is preferably carried out in the same coating pan with the same warm air flow at the same inlet air temperature.
EXAMPLE
(_:apsule Filling In Tent Weieht (ke.l %, b x, Wei h 5-{5-[2,6-Dichloro-4-(4,S-dihydro-2-oxazolyl)-phenoxy]pentyl }-3-methylisoxazole19.1 50.0 Polyethylene Glycol 600 9.55 25.0 Polyethylene Glycol 1000 7.64 20.0 Polysorbate 80 1.91 5.00 Total 38.2 100.0 The two polyethylene glycols and the Polysorbate 80 were combined and heated with occasional stirnng to 50°C. until the Polyethylene Glycol 1000 was melted. The 5-{5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole was added with heating and occasional mixing at 46°C.
until the ~1U~.0~~
thereof. The relative weight of plasticizer in the protective coating is as stated above from about 10% to about 40% thereof and is preferably from about 15% to about 25%
thereof. After completion of spraying drying is preferably carried out in the same coating pan with the same warm air flow at the same inlet air temperature.
EXAMPLE
(_:apsule Filling In Tent Weieht (ke.l %, b x, Wei h 5-{5-[2,6-Dichloro-4-(4,S-dihydro-2-oxazolyl)-phenoxy]pentyl }-3-methylisoxazole19.1 50.0 Polyethylene Glycol 600 9.55 25.0 Polyethylene Glycol 1000 7.64 20.0 Polysorbate 80 1.91 5.00 Total 38.2 100.0 The two polyethylene glycols and the Polysorbate 80 were combined and heated with occasional stirnng to 50°C. until the Polyethylene Glycol 1000 was melted. The 5-{5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole was added with heating and occasional mixing at 46°C.
until the ~1U~.0~~
-11- D.N. 1098 miacure was uniform (40 minutes). Heating was discontinued and occasional mixing was continued until the mixture congealed to an off white, opaque semi-solid.
The temperature was then 27°C. The mixture was filled with continuous mixing thereof at 27-30°C. into soft gelatin capsules so that each filled capsule contained 206 milligrams of the mixture and weighed in total 350 milligrams.
Capsule Coatine ' " Wed; ht~ l~ l Weieht (mg./cansule) Filled Capsules of this Example 7.00 350.
Enteric Coating Methacrylic Acid Copolymer (Type C, 30% Dispersion by Weight in Water) 1,23 16.8 (dry) Triacetin 0.092 4.20 Water 0.988 0.0 Protective Coatin Hydroxypropyl Methylcellulose 2910 0.123 5.60 Triacetin 0.031 1.40 Water 1.390 Total 378.
The weights in the left column include 10% overage for losses in carrying out the process steps. The weights in the right column are target weights. The 1:1 methacrylic acid-ethyl acrylate copolymer, triacetin and water for the enteric coating ~~.~~.0~
The temperature was then 27°C. The mixture was filled with continuous mixing thereof at 27-30°C. into soft gelatin capsules so that each filled capsule contained 206 milligrams of the mixture and weighed in total 350 milligrams.
Capsule Coatine ' " Wed; ht~ l~ l Weieht (mg./cansule) Filled Capsules of this Example 7.00 350.
Enteric Coating Methacrylic Acid Copolymer (Type C, 30% Dispersion by Weight in Water) 1,23 16.8 (dry) Triacetin 0.092 4.20 Water 0.988 0.0 Protective Coatin Hydroxypropyl Methylcellulose 2910 0.123 5.60 Triacetin 0.031 1.40 Water 1.390 Total 378.
The weights in the left column include 10% overage for losses in carrying out the process steps. The weights in the right column are target weights. The 1:1 methacrylic acid-ethyl acrylate copolymer, triacetin and water for the enteric coating ~~.~~.0~
-12- D.N. 1098 were mixed at room temperature. The hydroxypropyl methylcellulose, triacetin and about half the water for the protective coating were mixed with heating to 80°C., the remaining water was added, and the resulting solution was cooled to 25°C. The coatings were carned out in a twenty four-inch side-vented coating pan using a rotation rate of 14 r.p.m., two spray nozzles at atomizing air pressure of 60-65 p.s.i., a coating application rate of 40 ml./min., an inlet air temperature of 40-44°C., an exhaust air temperature of 30-34°C., a distance of 6.5 inches from nozzle to capsule bed, and water rinsing of the nozzles between coatings. The enteric coating time was approximately 60 minutes. The protective coating time was approximately 40 minutes.
Drying was carried out at the same inlet and exhaust air temperatures. Drying time was 5 minutes. The capsules obtained were coated with 9 mg./cm.2 of enteric coating and 3 mg./cm 2 of protective coating.
Drying was carried out at the same inlet and exhaust air temperatures. Drying time was 5 minutes. The capsules obtained were coated with 9 mg./cm.2 of enteric coating and 3 mg./cm 2 of protective coating.
Claims (24)
1. A filled soft capsule not having a subcoating and coated with from 1 to 20 mg./cm.2 of an enteric coating consisting essentially of by weight from 60% to 90% of a 1:1 copolymer of methacrylic acid and methyl or ethyl acrylate or methyl or ethyl methacrylate and from 10% to 40% of a plasticizer selected from the group consisting of triacetin, a polyethylene glycol having a molecular weight in the range from 400 to 3350, propylene glycol, dibutyl phthalate and triethyl citrate or mixture thereof.
2. A capsule according to claim 1, wherein the capsule shell is a gelatin capsule shell.
3. A capsule according to claim 2, wherein the amount of enteric coating is from 5 to 15 mg./cm.2.
4. A capsule according to claim 3, wherein the amount of enteric coating is from 8 to 12 mg./cm.2.
5. A capsule according to any one of claims 1 to 4, wherein the plasticizer is triacetin.
6. A capsule according to any one of claims 1 to 5, wherein the relative weight of the 1:1 copolymer of methacrylic acid and methyl or ethyl acrylate or methyl or ethyl methacrylate in the enteric coating is from 75% to 85%
thereof and the relative weight of triacetin in the enteric coating is from 15% to 25% thereof.
thereof and the relative weight of triacetin in the enteric coating is from 15% to 25% thereof.
7. A capsule according to any one of claims 1 to 6, wherein the capsule is filled with a liquid or semi-solid composition containing a drug for treating or preventing a disease or disorder or mixture thereof or a nutritional aid.
8. A capsule according to claim 7, wherein the capsule is filled with a semi-solid composition of 5-{5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole, polyethylene glycol of molecular weight 600, polyethylene glycol of molecular weight 1000 and an oleate ester of sorbitol and its anhydrides copolymerized with approximately 20 moles of ethylene oxide for each mole of sorbitol and sorbitol anhydrides.
9. A filled soft capsule not having a subcoating and coated with from 1 to 20 mg./cm.2 of an enteric coating consisting essentially of by weight from 60% to 90% of a 1:1 copolymer of methacrylic acid and methyl or ethyl acrylate or methyl or ethyl methacrylate and from 10% to 40% of a plasticizer selected from the group consisting of triacetin, a polyethylene glycol having a molecular weight in the range from 400 to 3350, propylene glycol, dibutyl phthalate and triethyl citrate or mixture thereof and additionally coated with from 1 to 10 mg./cm.2 of a protective coating consisting essentially of by weight from 60% to 90% of a cellulose derivative which is hydroxypropyl methylcellulose or hydroxypropyl cellulose or a mixture thereof and from 10% to 40% of a plasticizer selected from the group consisting of triacetin, a polyethylene glycol having a molecular weight in the range from 400 to 3350, propylene glycol, dibutyl phthalate, triethyl citrate, glycerin and diacetylated monoglycerides or a mixture thereof.
10. A capsule according to claim 9, wherein the capsule shell is a gelatin capsule shell.
11. A capsule according to Claim 9 or 10, wherein the amount of enteric coating is from 5 to 15 mg./cm.2.
12. A capsule according to claim 9, 10 or 11, wherein the amount of the enteric coating is from 8 to 12 mg./cm.2.
13. A capsule according to any one of claims 9 to 12, wherein the plasticizer of both coatings is triacetin and the cellulose derivative is hydroxypropyl methylcellulose.
14. A capsule according to any one of claims 9 to 13, wherein the relative weight of the 1:1 copolymer of methacrylic acid and methyl or ethyl acrylate or methyl or ethyl methacrylate in the enteric coating is from 75% to 85%
thereof and the relative weight of triacetin in the enteric coating is from 15% to 25% thereof.
thereof and the relative weight of triacetin in the enteric coating is from 15% to 25% thereof.
15. A capsule according to any one of claims 9 to 14, wherein the amount of the protective coating is from 2 to 4 mg./cm.2.
16. A capsule according to any one of claims 9 to 15, wherein the relative weight of hydroxypropyl methylcellulose in the protective coating is from 75% to 85% thereof and the relative weight of triacetin in the protective coating is from 15% to 25% thereof.
17. A capsule according to any one of claims 9 to 16, wherein the capsule is filled with a liquid or semi-solid composition containing a drug for treating or preventing a disease or disorder or mixture thereof or a nutritional aid.
18. A capsule according to claim 17, wherein the capsule is filled with a semi-solid composition of 5-{5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole, polyethylene glycol of molecular weight 600, polyethylene glycol of molecular weight 1000 and an oleate ester of sorbitol and its anhydrides copolymerized with approximately 20 moles of ethylene oxide for each mole of sorbitol and sorbitol anhydrides.
19. The process of preparing a capsule according to claim 1 which comprises:
mixing the 1:1 copolymer of methacrylic acid and methyl or ethyl acrylate or methyl or ethyl methacrylate and the plasticizer in from 2 times to 8 times the combined weight thereof of water, spraying a filled soft capsule not having a subcoating using air at a temperature in the range from 30°C.
to 60°C. with the resulting mixture in sufficient amount to produce from 1 to 20 mg./cm.2 of enteric coating on the capsule after drying, and then drying the capsule with air at a temperature in the range from 30°C. to 60°C.
mixing the 1:1 copolymer of methacrylic acid and methyl or ethyl acrylate or methyl or ethyl methacrylate and the plasticizer in from 2 times to 8 times the combined weight thereof of water, spraying a filled soft capsule not having a subcoating using air at a temperature in the range from 30°C.
to 60°C. with the resulting mixture in sufficient amount to produce from 1 to 20 mg./cm.2 of enteric coating on the capsule after drying, and then drying the capsule with air at a temperature in the range from 30°C. to 60°C.
20. The process of preparing a capsule according to claim 9 which comprises:
mixing the 1:1 copolymer of methacrylic acid and methyl or ethyl acrylate or methyl or ethyl methacrylate and the plasticizer in from 2 times to 8 times the combined weight thereof of water, spraying a filled soft capsule not having a subcoating using air at a temperature in the range from 30°C.
to 60°C. with the resulting mixture in sufficient amount to produce from 1 to 20 mg./cm.2 of enteric coating on the capsule after drying, -16a-mixing the hydroxypropyl methylcellulose or hydroxypropyl cellulose or mixture thereof and the plasticizer in from 5 to 15 times the combined weight thereof of water, spraying the capsule using air at a temperature in the range from 30°C. to 60°C. with the resulting mixture in sufficient amount to produce from 1 to 10 mg./cm.2 of protective coating on the capsule after drying, and then drying the capsule at a temperature in the range from 30°C. to 60°C.
mixing the 1:1 copolymer of methacrylic acid and methyl or ethyl acrylate or methyl or ethyl methacrylate and the plasticizer in from 2 times to 8 times the combined weight thereof of water, spraying a filled soft capsule not having a subcoating using air at a temperature in the range from 30°C.
to 60°C. with the resulting mixture in sufficient amount to produce from 1 to 20 mg./cm.2 of enteric coating on the capsule after drying, -16a-mixing the hydroxypropyl methylcellulose or hydroxypropyl cellulose or mixture thereof and the plasticizer in from 5 to 15 times the combined weight thereof of water, spraying the capsule using air at a temperature in the range from 30°C. to 60°C. with the resulting mixture in sufficient amount to produce from 1 to 10 mg./cm.2 of protective coating on the capsule after drying, and then drying the capsule at a temperature in the range from 30°C. to 60°C.
21. The process according to claim 19, wherein the filled soft capsule has a capsule shell made of gelatin.
22. The process according to claim 21, wherein the spraying of the filled soft capsule with the mixture of the 1:1 copolymer and the plasticizer and the drying are conducted using air at a temperature of 40°C to 50°C.
23. The process according to claim 20, wherein the filled soft capsule has a capsule shell made of gelatin.
24. The process according to claim 23, wherein the spraying of the filled soft capsule with the mixture of the 1:1 copolymer and the plasticizer, the spraying of the capsule with the mixture of hydroxypropyl methylcellulose or hydroxypropyl cellulose and the plasticizer and the drying are all conducted using air at a temperature of 40 to 50°C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/935,505 US5330759A (en) | 1992-08-26 | 1992-08-26 | Enteric coated soft capsules and method of preparation thereof |
| US935,505 | 1992-08-26 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2101095A1 CA2101095A1 (en) | 1994-02-27 |
| CA2101095C true CA2101095C (en) | 2004-01-20 |
Family
ID=25467257
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002101095A Expired - Lifetime CA2101095C (en) | 1992-08-26 | 1993-07-22 | Enteric coated soft capsules and method of preparation thereof |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US5330759A (en) |
| EP (1) | EP0587220B1 (en) |
| JP (1) | JP3983823B2 (en) |
| AT (1) | ATE152618T1 (en) |
| AU (1) | AU672982B2 (en) |
| CA (1) | CA2101095C (en) |
| DE (1) | DE69310461T2 (en) |
| DK (1) | DK0587220T3 (en) |
| ES (1) | ES2104044T3 (en) |
| GR (1) | GR3024351T3 (en) |
| HU (1) | HUT64833A (en) |
| MX (1) | MX9305108A (en) |
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| US5914132A (en) * | 1993-02-26 | 1999-06-22 | The Procter & Gamble Company | Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery |
| US5843479A (en) * | 1993-02-26 | 1998-12-01 | The Procter & Gamble Company | Bisacodyl dosage form with multiple enteric polymer coatings for colonic delivery |
| US5651983A (en) * | 1993-02-26 | 1997-07-29 | The Procter & Gamble Company | Bisacodyl dosage form for colonic delivery |
| US6224911B1 (en) * | 1993-03-16 | 2001-05-01 | Syntex (U.S.A.) Llc | Process for the preparation of enteric coated pharmaceutical dosage forms |
| EE03305B1 (en) * | 1994-07-08 | 2000-12-15 | Astra Aktiebolag | Multiparticulate tableted dosage form I |
| SE9500422D0 (en) * | 1995-02-06 | 1995-02-06 | Astra Ab | New oral pharmaceutical dosage forms |
| US5686106A (en) * | 1995-05-17 | 1997-11-11 | The Procter & Gamble Company | Pharmaceutical dosage form for colonic delivery |
| SE9600072D0 (en) * | 1996-01-08 | 1996-01-08 | Astra Ab | New oral formulation of two active ingredients II |
| SE512835C2 (en) * | 1996-01-08 | 2000-05-22 | Astrazeneca Ab | Dosage form containing a plurality of units all containing acid labile H + K + ATPase inhibitors |
| SE9600070D0 (en) | 1996-01-08 | 1996-01-08 | Astra Ab | New oral pharmaceutical dosage forms |
| SE9600071D0 (en) | 1996-01-08 | 1996-01-08 | Astra Ab | New oral formulation of two active ingredients I |
| JP3625940B2 (en) * | 1996-01-29 | 2005-03-02 | 信越化学工業株式会社 | Aqueous liquid capsule and method for producing the same |
| US5919481A (en) * | 1996-06-28 | 1999-07-06 | Ncneil-Ppc, Inc. | Fill material for soft gelatin pharmaceutical dosage form |
| US5891474A (en) * | 1997-01-29 | 1999-04-06 | Poli Industria Chimica, S.P.A. | Time-specific controlled release dosage formulations and method of preparing same |
| US6440448B1 (en) | 1998-03-16 | 2002-08-27 | Joseph Intelisano | Food supplement/herbal composition for health enhancement |
| US6139875A (en) * | 1998-09-29 | 2000-10-31 | Eastman Chemical Company | Aqueous enteric coating composition and low gastric permeability enteric coating |
| DK1126826T6 (en) * | 1998-11-02 | 2019-06-24 | Alkermes Pharma Ireland Ltd | Multiparticulate modified release of methylphenidate |
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| US20090149479A1 (en) * | 1998-11-02 | 2009-06-11 | Elan Pharma International Limited | Dosing regimen |
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| US20090297597A1 (en) * | 1998-11-02 | 2009-12-03 | Gary Liversidge | Modified Release Ticlopidine Compositions |
| GB9824658D0 (en) * | 1998-11-11 | 1999-01-06 | Brown Malcolm D | A capsule based drug delivery system |
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| US7842308B2 (en) * | 2001-01-30 | 2010-11-30 | Smithkline Beecham Limited | Pharmaceutical formulation |
| HUE031650T2 (en) | 2002-10-01 | 2017-07-28 | Banner Life Sciences Llc | Enteric composition for the manufacture of soft capsule wall |
| US20080220074A1 (en) * | 2002-10-04 | 2008-09-11 | Elan Corporation Plc | Gamma radiation sterilized nanoparticulate docetaxel compositions and methods of making same |
| US20050152969A1 (en) * | 2004-01-08 | 2005-07-14 | Chiprich Timothy B. | Colored liquid-filled soft capsules and method of manufacture thereof |
| US20060121112A1 (en) * | 2004-12-08 | 2006-06-08 | Elan Corporation, Plc | Topiramate pharmaceutical composition |
| US20070298098A1 (en) * | 2005-02-16 | 2007-12-27 | Elan Pharma International Limited | Controlled Release Compositions Comprising Levetiracetam |
| WO2006110807A1 (en) * | 2005-04-12 | 2006-10-19 | Elan Pharma International Limited | Controlled release compositions comprising a cephalosporin for the treatment of a bacterial infection |
| US20100136106A1 (en) * | 2005-06-08 | 2010-06-03 | Gary Liversidge | Modified Release Famciclovir Compositions |
| US20070148248A1 (en) | 2005-12-22 | 2007-06-28 | Banner Pharmacaps, Inc. | Gastric reflux resistant dosage forms |
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| KR101783945B1 (en) * | 2009-05-12 | 2017-10-10 | 비피에스아이 홀딩스, 엘엘씨. | Enhanced moisture barrier immediate release film coating systems and substrates coated therewith |
| EP2429504A4 (en) * | 2009-05-12 | 2013-05-01 | Bpsi Holdings Llc | Film coatings containing fine particle size detackifiers and substrates coated therewith |
| US8663671B2 (en) | 2009-11-05 | 2014-03-04 | Philip Morris Usa Inc. | Methods and compositions for producing hydrogel capsules coated for low permeability and physical integrity |
| RU2014141201A (en) | 2012-03-29 | 2016-05-20 | ТЕРАБАЙОМ, ЭлЭлСи | COMPOSITIONS FOR GASTROINTESTINAL SITE-SPECIFIC ORAL VACCINATION, MANIFESTING ACTIVITY IN THE IOLIC GUT AND APPENDIX |
| JP6464142B2 (en) * | 2013-03-14 | 2019-02-06 | セラバイオーム，エルエルシー | Targeted gastrointestinal delivery of probiotic organisms and / or therapeutic agents |
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| CN104825418B (en) * | 2015-05-07 | 2018-05-15 | 上海信谊万象药业股份有限公司 | A kind of nifedipine soft capsule and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3234331C2 (en) * | 1982-09-16 | 1986-06-05 | A. Nattermann & Cie GmbH, 5000 Köln | Processes and solutions for coating gelatin capsules with enteric coatings |
| US4816259A (en) * | 1987-02-12 | 1989-03-28 | Chase Chemical Company, L.P. | Process for coating gelatin capsules |
| EP0313845A1 (en) * | 1987-09-29 | 1989-05-03 | Warner-Lambert Company | Stabilization of enteric coated dosage form |
| US5047258A (en) * | 1989-07-14 | 1991-09-10 | Sterling Drug Inc. | Aqueous spray-coating process |
| NL9002336A (en) * | 1990-10-24 | 1992-05-18 | Leuven K U Res & Dev | COATING OR MATRIX MATERIAL FOR MEDICINES. |
-
1992
- 1992-08-26 US US07/935,505 patent/US5330759A/en not_active Expired - Lifetime
-
1993
- 1993-07-22 CA CA002101095A patent/CA2101095C/en not_active Expired - Lifetime
- 1993-08-21 ES ES93202463T patent/ES2104044T3/en not_active Expired - Lifetime
- 1993-08-21 AT AT93202463T patent/ATE152618T1/en active
- 1993-08-21 DK DK93202463.1T patent/DK0587220T3/en active
- 1993-08-21 DE DE69310461T patent/DE69310461T2/en not_active Expired - Lifetime
- 1993-08-21 EP EP93202463A patent/EP0587220B1/en not_active Expired - Lifetime
- 1993-08-23 MX MX9305108A patent/MX9305108A/en unknown
- 1993-08-25 JP JP21029693A patent/JP3983823B2/en not_active Expired - Fee Related
- 1993-08-25 AU AU44888/93A patent/AU672982B2/en not_active Expired
- 1993-08-26 HU HU9302426A patent/HUT64833A/en unknown
-
1997
- 1997-08-01 GR GR970401997T patent/GR3024351T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPH06157295A (en) | 1994-06-03 |
| MX9305108A (en) | 1994-02-28 |
| AU672982B2 (en) | 1996-10-24 |
| HU9302426D0 (en) | 1993-11-29 |
| GR3024351T3 (en) | 1997-11-28 |
| EP0587220A1 (en) | 1994-03-16 |
| EP0587220B1 (en) | 1997-05-07 |
| US5330759A (en) | 1994-07-19 |
| DE69310461T2 (en) | 1997-12-11 |
| AU4488893A (en) | 1994-03-03 |
| ATE152618T1 (en) | 1997-05-15 |
| ES2104044T3 (en) | 1997-10-01 |
| JP3983823B2 (en) | 2007-09-26 |
| DE69310461D1 (en) | 1997-06-12 |
| HUT64833A (en) | 1994-03-28 |
| DK0587220T3 (en) | 1997-12-01 |
| CA2101095A1 (en) | 1994-02-27 |
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