CA2076983A1 - Taste masking of ibuprofen by fluid bed coating - Google Patents
Taste masking of ibuprofen by fluid bed coatingInfo
- Publication number
- CA2076983A1 CA2076983A1 CA002076983A CA2076983A CA2076983A1 CA 2076983 A1 CA2076983 A1 CA 2076983A1 CA 002076983 A CA002076983 A CA 002076983A CA 2076983 A CA2076983 A CA 2076983A CA 2076983 A1 CA2076983 A1 CA 2076983A1
- Authority
- CA
- Canada
- Prior art keywords
- ibuprofen
- tablet according
- chewable
- coating
- copolymer
- 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.)
- Abandoned
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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
A chewable taste-masked ibuprofen tablet having controlled release characteristics.
Description
~ v ~
WO 91/15194 PCT/US91/0l089 TASTL MASKING OF IBUPROFEN BY FLUID BED COATING
BACKGROUND OF THE INVENTION
Ibuprofen is a well-known therapeutic agent. Its therapeutic activities include analgesia and anti-pyretic attack. As with most medicines, one of the difficulties with 5 ibuprofen is in making it palatable to children. This difficulty has been overcome with most medicines by preparing formulations such as syrups and drops. The present invention relates to chewable tablets that are palatable to children and a process for making the tablets.
From a manufacturing cost standpoint, it is desirable to have chewable, taste-10 masked microcapsules that are large (0.25-1 mm in diameter), because larger microcapsules are easier to manufacture and package, and are less expensive to produce than are small microcapsules. However, an increase in size makes fracture duringchewing and the release of drug from the microcapsule more likely to occur especially when there is an inadequate amount of plasticizer or other component included to provide 15 elasticity. A larger sized microcapsule requires greater elasticity to minimize the likelihood that a fracture will occur and active agent will be released. There is therefore a need in the art of pharmaceutical forrnulation to provide encapsulating coatings capable of being formulated into chewable microcapsules as large as about 1.5 mm. that will not release drugs during chewing.
INFORMATION DISCLOSURE
Ibuprofen and its use for treatment of analgesia is disclosed in U.S. patent 3,385,886. Compositions containing ibuprofen and methods for using them are described in U.S. patent 3,228,831. New crystalline and high dose forrnulations of ibuprofen are disclosed in U.S. patents 4,476,248 and 4,609,675 respectively.
Microencapsulation is described by J.A. Bakan, Part Three of ''The Theory and Practice of Industrial Pharmacy", 1986, pp. 413-429.
EUDRAGIT L30D is a known polymer useful for coating orally administered pharmaceutical dosage forms, particularly tablets, capsules and pills, with coatings which are resistant to gastric juices but solvent in intestinal juices.
Chewable taste-masked pharmaceutical compositions, including some containing - ibuprofen, are described in U.S. patent 4,800,087. However, the compositions described therein require a coating consisting of a mixture of polymers. The use of fluidized bed for coating pharmaceutical products is described in U.S. Patent 4,800,û87.
:
WO 91/15194 PCT/US91/0l089 TASTL MASKING OF IBUPROFEN BY FLUID BED COATING
BACKGROUND OF THE INVENTION
Ibuprofen is a well-known therapeutic agent. Its therapeutic activities include analgesia and anti-pyretic attack. As with most medicines, one of the difficulties with 5 ibuprofen is in making it palatable to children. This difficulty has been overcome with most medicines by preparing formulations such as syrups and drops. The present invention relates to chewable tablets that are palatable to children and a process for making the tablets.
From a manufacturing cost standpoint, it is desirable to have chewable, taste-10 masked microcapsules that are large (0.25-1 mm in diameter), because larger microcapsules are easier to manufacture and package, and are less expensive to produce than are small microcapsules. However, an increase in size makes fracture duringchewing and the release of drug from the microcapsule more likely to occur especially when there is an inadequate amount of plasticizer or other component included to provide 15 elasticity. A larger sized microcapsule requires greater elasticity to minimize the likelihood that a fracture will occur and active agent will be released. There is therefore a need in the art of pharmaceutical forrnulation to provide encapsulating coatings capable of being formulated into chewable microcapsules as large as about 1.5 mm. that will not release drugs during chewing.
INFORMATION DISCLOSURE
Ibuprofen and its use for treatment of analgesia is disclosed in U.S. patent 3,385,886. Compositions containing ibuprofen and methods for using them are described in U.S. patent 3,228,831. New crystalline and high dose forrnulations of ibuprofen are disclosed in U.S. patents 4,476,248 and 4,609,675 respectively.
Microencapsulation is described by J.A. Bakan, Part Three of ''The Theory and Practice of Industrial Pharmacy", 1986, pp. 413-429.
EUDRAGIT L30D is a known polymer useful for coating orally administered pharmaceutical dosage forms, particularly tablets, capsules and pills, with coatings which are resistant to gastric juices but solvent in intestinal juices.
Chewable taste-masked pharmaceutical compositions, including some containing - ibuprofen, are described in U.S. patent 4,800,087. However, the compositions described therein require a coating consisting of a mixture of polymers. The use of fluidized bed for coating pharmaceutical products is described in U.S. Patent 4,800,û87.
:
2 ~ 7 6 ~ ~ ~3 PCI'/US91/01089 ~
SUMMARY OF THE INVEI~ION
This invention involves:
A chewable taste-masked tablet having controlled release characteristics comprising a microcapsule of about 100 microns to about 0.8 mm in diameter having (a) 5 a pharmaceutical core including crystalline ibuprofen and (b) a methacrylic acid copolymer coating having sufficient elasticity to withstand chewing.
urhile chewable taste masked formulations of ibuprofen are referred to in ~he prior art, among the advantages of the compositions of this invention over the closest prior art compositions is that the coating used consists of a single copolymer rather than 10 a mixture of copolymers.
DETAII,ED 12E5~IP~ION OF l~ INVENTION
The present invention comprises formulations of taste-masked microcapsules which further comprise (a) a pharrnaceutical core of crystalline ibuprofen and (b) a methacrylic acid copolymer coating that may provide chewable taste-masked charactens-15 tics. Both the polymeric coating and the pharmaceutical core may further comprisediluents, fillers and other pharmaceutical additives which may effect the rate of release of active ibuprofen from the microcapsule.
The methacrylic acid copolymer is preferably dispersable in water so as to take advantage of aqueous formulation techniques and has a rapid rate of dissolution at a pH
20 of about 5.5.. Aqueous-based coating systems are safe and make regulatory compliance (EPA) relativ~ly easy compared to non-aquaous based coating systems. An elastic microcapsule which will not release ibuprofen in the mouth when chewed is contemplated by the present invention.
A preferred coating composition is a high temperature film forming polymer or 25 ~hard" polymer. A hard polymer is defined as a polymer that will forrn a filrn on a pharmaceutical core at a temperature of at least about 30C. E:~arnples of high tempe~ature film forming polymers useful in this invention include hydroxypropylmethyl cellulose, for example, Pharmacoat' 606 brand from Shinetro Corp., Tokyo, Japan,hydro~cypropyl cellulose, for e~ample, Klucel' brand from Hercules Corp., Wilmington, 30 Del., methylcellulose for e~ample Methocel A', from Dow Chernical, Midland, Mich., - ethylcellulose, for example, Ethocel' brand from ~ow Chemical Corp., and other aqueous polymerie dispersions such as Aquacost' Brand from FMC, Philadelphia, PA., and Surelease' brand from Colorcon, West PoLnt, PA., polyvinyl alcohol, polyvinyl ~-~^ Wo 91/15194 ~ ; 9 ~ ~ Pcr/us9l/olo89 acetate, cellulose acetate butyrate, styrene acylate copolymers, for example Janocryl 138 (61C. film forming copolymer from S.C. Johnson, Racine, Wis.) and copolymers ofacrylic acid esters, for example, the EUDRAGIT Copolymers (Rohm Pharma GmbH
Westerstadt, W. Germany): Eudragit' L30D, Eudragit' L100 55, Eudragit' RS(30D and 5 lûO).
Eudragit' copolymers that are preferred in embodiments of this invention includeL30D, an anionic copolymer based of polymethacrylic and acrylic acid esters (Methacrylic Acid Copolymer, I~pe C in USP X~JNF XVI) with a mean molecular weight of 250,000.
The polymeric coating should provide for immediate release characteristics, i.e., rapid release of the active agents in the duodenum within a period of about one hour.
When the microcapsules are formulated into chewable, taste-masked oral tablets or capsules, the formulations provide for immediate, rapid release in the stomach.
The chewable polymeric coadng providing immediate release upon reaching the 15 duodenum i.e., within one hour after ingestion may be comprised of a pharmaceutically compadble high temperature film forming polymer that is water insoluble or not swellable within the pH range (about 5.5-6.5) and/or the liquid content of the mouth and will not release the actdve agent in the mouth, but will dissolve or change in physical character in the duodenum, for example, swell or become more porous, thus releasing 20 drug.
The most preferred film forrning acrylic resin polymer that releases active agent rapidly in duodenum is EUDRAGlT L30D. EUDRAGIT L30D is a copolymer anionic in character, based on polymethacrylic acid and acrylic acid esters. Although EUDRAGIT L30D is soluble at pH's in the mouth and insoluble at pH's of the stomach, 25 it has found usefulness in chewable, taste-maske~ immediate release formulations of the present invention. This usefulness may stem from the lack of liquid in the mouth, or may be the result of elastic qualities that EUDRAGl'r L3OD acquires when formulated in combination with a plasticizer, or preferably, wi~h EUD~AGlT E303).
Any of the above described high-temperature film-forming polymers may be used 30 for microencapsulation. However, to make capsules of the required elasticity using the above described high temperature film forming polymers, plasticizers may be incorporat~d into the coatings. Plasticizers useful to provide the requisi~e elasticity include propylene glycol and polyalkylene glycols, for example, polye~ylene glycol, Wo 91/tS194 2 ~ ~ 6 3 8 ~ pcr/us91/o1o89 triacetin, tglyceryl triacetate from Eastman Kodak, Rochester, NY vinyl pyrrolidone, diethyl phthallate, dibutylsebacate, and esters of citric acid among others. Generally, the plasticizers comprise between about 25G and about 50% by weight of polyrner and plasticizer combined, preferably between about 5~0 and 15% by weight and most 5 preferably about lO~o by weight of the polymer and plasticizer combined.
The chewable tablets of this invention are prepared by spraying a solution of the methacrylic acid copolymer on to a fluidized bed of crystalline ibuprofen.
Crystalline ibuprofen can be prepared by the process described in U.S. Patent 4,476,248. The particle size of the ibuprofen should be about 80 to SOO microns and it 10 it may contain excipients such as starch, lactose, hydro~ypropyl methylcellulose, microcrystalline cellulose PVP, sucrose and fructose.
The residence time should be such that the ratio of copolymer to ibuprofen of each chewable tablet is about eight percent by weight.
The temperature of the inlet and outlet air should be maintained between 40 and 15 60 C. 20 and 40 C. respec~vely. The preferred inlet and outlet air temperatures are between 45 and S5 and 33 and 27C respectively.
The temperature of the fluidized bed should be maintained between 60 and 20p respectively. The preferred temperature of the bed is about 35 C.
The arnount of ENDRAGlT L3OD in the encapsulation formulation should be 20 between about 10% to 60% by weight of ibuprofen, preferably about 14%.
`~0 91/15194 2 ~ 7 ~ 3 Pcr/US9"0,089 .
EMBODIMENT OF THE INVENTION
Exam~le 1 Preparation of chewable ibuprofen tablet (#13, p 23) A. Enca~sula~ed IbuDrofen Ibuprofen 4 Kg Eudragit L30D 2.33 Kg (coating polymer) Propylene Glycol 140 gm (plastici~er) Talc 200 gm Purified Water 200 gm Ibuprofen crystals (particle size #40 105) are ~ur suspended in a closed chamber 10 (Glatt GPCG5). An aqueous dispersion of Eudragit L 30D and talc is sprayed onto the fluidized bed of ibuprofen at a rate of 60gm/min. The inlet and outlet air temperature are maintained at 50C. and 2~22C. respectively. The air rate is adjusted so as to maintain the particles in a suspended state and to maintain the fluidized bed at a tempera-ture of 35C.
Air Atomizing Pressure 3.5 bar B. Pre~aration of Chewable Tablet~
Per Tab Per 1000 Tab Mannitol 5~4 mg 544 Gm Malic Acid 4 mg 4 Gm Aspartatne 12 mg 12 Gm Spray Dried Orange Flavor 18 mg 18 Gm Encapsulated Ibuprofen 127 mg 127 Gm Ac-Di-Sol 24 mg 24 Gm Avicel pH102 60 mg 60 Gm F.D.C. Yellow 6 I~lce 0.2 mg 0.2 Gm Citric Acid 4 mg 4 Gm Talc 20 mg 20 Gm The compression mix of above was tabletted on a Manesty beta press with 112" flat face 30 tooling. Tabletwdght: 813 mg. Hardness: 9- 13 Strong Cobert(SC). Disintegration Time in water: 2 minutes.
Table 1 shows a comparison of dissoluhon data between MOTRIN IB Tablet in PH 7.2 and the MOTRIN Chewable Tablets of this invention.
Wo 91/15194 ~! 0 7 ~ c3 ~ ~ PCI/US91/OtO89 ,f Table 2 shows a comparison of dissolution data between MOTRIN IB Tablets in PH 5.8 and the MOTRIN Chewable Tablets of this invention.
,"~~~ WO 9l~15l94 2 0 7 ~ 9 8 ~ Pcr/usgl/01o89 TABLE I
Com~anson of Dissolution Data between Motrin IB
and Motrin Chewa~le Tablets S Buffer 7.2 PH
Motnn IB #12 #13 Recrystallized IbuprofenRaw Material Flask 1 Flask 2 Flask 3 Flask 4 Time % Released Time % Released Time 9G Released Time % Released 0.10-0.02 0.20 0.00 0.30 0.04 0.40 -0.02 2.101.21 2.20 lO.S0 2.30 9.40 2.40 0.48 4.1038.77 4.20 63.24 4.30 53.61 4.40 18.34 6.1071.49 6.20 89.31 6.30 84.02 6.40 40.63 8.1084.88 8.20 97.65 8.30 89.89 8.40 54.00 10.1090~0 10.20 95.85 10.30 90.91 10.40 63.24 12.1092.79 12.20 93.61 1~.30 91.45 12.40 71.12 14.1093.80 14.20 91.77 14.30 91.45 14.40 78.23 16.1094.36 16.20 91.38 16.30 91.62 16.40 8~.25 18.1094.58 18.20 ~1.64 18.30 91.66 18.40 87.75 20.1094.67 20.20 91.86 20.30 91.68 20.40 94.43 22.1094.75 22.20 91.88 22.30 91.M 22.40 96.05 24.1094.77 24.20 92.01 24.30 91.79 24.40 99.24 26.1094.82 26.20 92.16 26.30 91.77 26.40 100.63 28.1094.88 28.20 92.40 28.30 91.79 28.40 101.32 30.1094.92 30.20 92.57 30.30 91.81 30.40 101.~8 32.1094.95 32.20 92.79 32.30 91.88 32.40 101.71 34.1095.01 34.20 92.83 34.30 91.90 34.40 102.14 36.1094.99 36.20 92.92 36.30 91.86 36.40 102.20 38.1095.03 38.20 92.96 38.30 91.86 38.40 102.35 40.1094.99 4~.20 93.00 40.30 91.84 40.40 102.46 42.1095.05 42.20 93.09 42.30 91.90 42.40 102.61 44.109S.10 44.20 93.15 44.30 91.92 44.40 102.66 46.1095.08 46.20 93.20 46.30 91.97 46.40 102.72 48.1095.10 48.20 93.24 48.30 91.97 48.40 102.74 50.1095.08 50.20 93.26 50.30 91.94 50.40 102.76 52.1095.14 52.20 93.26 52.30 91.94 52.40 102.79 54.1095.12 54.20 93.33 54.30 92.01 54.40 102.7-9 S6.1095.14 56.20 93.35 56.30 92.03 56.40 102.89 58.1095.18 58.20 93.37 58.30 92.05 58.40 102.85 60.1095.18 60.20 93.41 60.30 92.05 60.40 102.92 45 In PH7.2 buffer: Forrnula #12 shows fus~c reline than Motrin IB.
E;ormula #12, #13 and Motrin IB shows the same reline forte ~ter 10 minutes.
WO 91/15194 2 ~ PCl tUS91/01089 Formula ~12, ~13 all pass U.S.P. Tablets specification 20 minutes 785%.
Flask 1: Motrin IB. .
Flask : Motnn chewable experiment Lot 12.
Flask 3: Motrin chewable experiment Lot 13.
Flask 4: Recrystallized Ibuprofen.
~vo gt/l5l94 2 0 7 ~ ~ ~ 3 PCl/US91/01089 .
TABLE II
Buffer: 5-8 PH
5Motrin IB A~12 #13 Recrystallized Ibuprofen Raw Material Fla k 1 Flask 2 Flack 3 Fla.sk 4 10 Time% Released Time % Released Time % Released Time % Released 0.10 0.04 0.20 0.02 0.30 0.00 0.400.04 2.10 0.13 2.20 2.76 2.30 2.20 2.400.78 4.10 2.25 4.20 9.78 4.30 7.90 4.409.18 6.10 19.40 6.20 18.68 6.30 15.726.4~ 36.26 8.10 36.48 8.20 28.10 8.30 25.338.40 53.71 10.10 48.08 10.20 36.05 10.30 34.6910.40 65.90 12.10 57.28 12.20 43.30 12.30 47.1112.40 75.08 14.10 64.34 14.20 51.49 I4.30 56.5414.40 82.38 16.10 70.09 16.20 58.83 16.30 64.0216.40 87.39 18.10 74.82 18.20 65.33 18.30 69.9118.40 91.40 20.10 78.S7 20.20 71.02 20.30 74.8620.40 94.41 22.10 81.73 22.20 76.16 22.30 78.5322.40 96.78 24.10 84.47 24.20 80.43 24.30 81.5124.40 98.47 26.10 86.74 26.20 84.02 26.30 83.8926.40 99.72 28.10 88.68 28.20 86.80 28.30 86.1128.40 100.65 30.10 90.24 30.20 89.05 3~.30 87.7830.40 101.51 32.10 91.56 32.20 90.99 32.30 89.0932.40 102.03 34.10 92.70 34.20 92.53 34.30 90.0634.40 102.53 36.10 93.59 36.20 93.78 36.30 90.9536.40 103.09 38.10 94.43 38.20 94.79 38.30 91.7338.40 103.52 40.10 95.21 40.20 95.62 40.30 92.4640.40 103.91 42.10 95.75 42.20 96.26 42.30 93.0042.40 104.34 44.10 96.29 44.20 96.76 44.30 93.5044.40 104.67 46.10 96.67 46.20 97.17 46.30 93.8446.40 105.08 48.10 96.95 48.20 97.45 48.30 94.1548.40 105.25 50.10 97.21 50.20 97.65 50.3~ 94.3650.40 105.46 52.10 97.54 52.20 97.88 52.30 94.6052.40 105.72 54.10 97.75 54.20 98.12 54.30 94.77S4.40 105.94 56.10 97.97 56.20 98.25 56.30 94.9756.40 106.11 58.10 98.12 58.20 98.38 58.30 95.0858.40 106.29 60.10 98.27 60.20 98.47 6~.30 95.1860.40 106.37 PH 5-8: After 10 minutes about 1~12% difference ætion compare #12, #13 with Motnn IB.
After 20 n~inutes about 7-896 difference when compared #12, and #13 with Mot~in IB.
After 30 minutes shows no significant difference among them.
WO 91/lS194 2 ~ PCI/US91/0108~
Flask 1: Motrin IB.
Flask 2: Motrin chewable experiment Lot 12.
Flask 3: Motrin chewable experiment Lot 13.
Flask 4: Recrystallized Ibuprofen.
SUMMARY OF THE INVEI~ION
This invention involves:
A chewable taste-masked tablet having controlled release characteristics comprising a microcapsule of about 100 microns to about 0.8 mm in diameter having (a) 5 a pharmaceutical core including crystalline ibuprofen and (b) a methacrylic acid copolymer coating having sufficient elasticity to withstand chewing.
urhile chewable taste masked formulations of ibuprofen are referred to in ~he prior art, among the advantages of the compositions of this invention over the closest prior art compositions is that the coating used consists of a single copolymer rather than 10 a mixture of copolymers.
DETAII,ED 12E5~IP~ION OF l~ INVENTION
The present invention comprises formulations of taste-masked microcapsules which further comprise (a) a pharrnaceutical core of crystalline ibuprofen and (b) a methacrylic acid copolymer coating that may provide chewable taste-masked charactens-15 tics. Both the polymeric coating and the pharmaceutical core may further comprisediluents, fillers and other pharmaceutical additives which may effect the rate of release of active ibuprofen from the microcapsule.
The methacrylic acid copolymer is preferably dispersable in water so as to take advantage of aqueous formulation techniques and has a rapid rate of dissolution at a pH
20 of about 5.5.. Aqueous-based coating systems are safe and make regulatory compliance (EPA) relativ~ly easy compared to non-aquaous based coating systems. An elastic microcapsule which will not release ibuprofen in the mouth when chewed is contemplated by the present invention.
A preferred coating composition is a high temperature film forming polymer or 25 ~hard" polymer. A hard polymer is defined as a polymer that will forrn a filrn on a pharmaceutical core at a temperature of at least about 30C. E:~arnples of high tempe~ature film forming polymers useful in this invention include hydroxypropylmethyl cellulose, for example, Pharmacoat' 606 brand from Shinetro Corp., Tokyo, Japan,hydro~cypropyl cellulose, for e~ample, Klucel' brand from Hercules Corp., Wilmington, 30 Del., methylcellulose for e~ample Methocel A', from Dow Chernical, Midland, Mich., - ethylcellulose, for example, Ethocel' brand from ~ow Chemical Corp., and other aqueous polymerie dispersions such as Aquacost' Brand from FMC, Philadelphia, PA., and Surelease' brand from Colorcon, West PoLnt, PA., polyvinyl alcohol, polyvinyl ~-~^ Wo 91/15194 ~ ; 9 ~ ~ Pcr/us9l/olo89 acetate, cellulose acetate butyrate, styrene acylate copolymers, for example Janocryl 138 (61C. film forming copolymer from S.C. Johnson, Racine, Wis.) and copolymers ofacrylic acid esters, for example, the EUDRAGIT Copolymers (Rohm Pharma GmbH
Westerstadt, W. Germany): Eudragit' L30D, Eudragit' L100 55, Eudragit' RS(30D and 5 lûO).
Eudragit' copolymers that are preferred in embodiments of this invention includeL30D, an anionic copolymer based of polymethacrylic and acrylic acid esters (Methacrylic Acid Copolymer, I~pe C in USP X~JNF XVI) with a mean molecular weight of 250,000.
The polymeric coating should provide for immediate release characteristics, i.e., rapid release of the active agents in the duodenum within a period of about one hour.
When the microcapsules are formulated into chewable, taste-masked oral tablets or capsules, the formulations provide for immediate, rapid release in the stomach.
The chewable polymeric coadng providing immediate release upon reaching the 15 duodenum i.e., within one hour after ingestion may be comprised of a pharmaceutically compadble high temperature film forming polymer that is water insoluble or not swellable within the pH range (about 5.5-6.5) and/or the liquid content of the mouth and will not release the actdve agent in the mouth, but will dissolve or change in physical character in the duodenum, for example, swell or become more porous, thus releasing 20 drug.
The most preferred film forrning acrylic resin polymer that releases active agent rapidly in duodenum is EUDRAGlT L30D. EUDRAGIT L30D is a copolymer anionic in character, based on polymethacrylic acid and acrylic acid esters. Although EUDRAGIT L30D is soluble at pH's in the mouth and insoluble at pH's of the stomach, 25 it has found usefulness in chewable, taste-maske~ immediate release formulations of the present invention. This usefulness may stem from the lack of liquid in the mouth, or may be the result of elastic qualities that EUDRAGl'r L3OD acquires when formulated in combination with a plasticizer, or preferably, wi~h EUD~AGlT E303).
Any of the above described high-temperature film-forming polymers may be used 30 for microencapsulation. However, to make capsules of the required elasticity using the above described high temperature film forming polymers, plasticizers may be incorporat~d into the coatings. Plasticizers useful to provide the requisi~e elasticity include propylene glycol and polyalkylene glycols, for example, polye~ylene glycol, Wo 91/tS194 2 ~ ~ 6 3 8 ~ pcr/us91/o1o89 triacetin, tglyceryl triacetate from Eastman Kodak, Rochester, NY vinyl pyrrolidone, diethyl phthallate, dibutylsebacate, and esters of citric acid among others. Generally, the plasticizers comprise between about 25G and about 50% by weight of polyrner and plasticizer combined, preferably between about 5~0 and 15% by weight and most 5 preferably about lO~o by weight of the polymer and plasticizer combined.
The chewable tablets of this invention are prepared by spraying a solution of the methacrylic acid copolymer on to a fluidized bed of crystalline ibuprofen.
Crystalline ibuprofen can be prepared by the process described in U.S. Patent 4,476,248. The particle size of the ibuprofen should be about 80 to SOO microns and it 10 it may contain excipients such as starch, lactose, hydro~ypropyl methylcellulose, microcrystalline cellulose PVP, sucrose and fructose.
The residence time should be such that the ratio of copolymer to ibuprofen of each chewable tablet is about eight percent by weight.
The temperature of the inlet and outlet air should be maintained between 40 and 15 60 C. 20 and 40 C. respec~vely. The preferred inlet and outlet air temperatures are between 45 and S5 and 33 and 27C respectively.
The temperature of the fluidized bed should be maintained between 60 and 20p respectively. The preferred temperature of the bed is about 35 C.
The arnount of ENDRAGlT L3OD in the encapsulation formulation should be 20 between about 10% to 60% by weight of ibuprofen, preferably about 14%.
`~0 91/15194 2 ~ 7 ~ 3 Pcr/US9"0,089 .
EMBODIMENT OF THE INVENTION
Exam~le 1 Preparation of chewable ibuprofen tablet (#13, p 23) A. Enca~sula~ed IbuDrofen Ibuprofen 4 Kg Eudragit L30D 2.33 Kg (coating polymer) Propylene Glycol 140 gm (plastici~er) Talc 200 gm Purified Water 200 gm Ibuprofen crystals (particle size #40 105) are ~ur suspended in a closed chamber 10 (Glatt GPCG5). An aqueous dispersion of Eudragit L 30D and talc is sprayed onto the fluidized bed of ibuprofen at a rate of 60gm/min. The inlet and outlet air temperature are maintained at 50C. and 2~22C. respectively. The air rate is adjusted so as to maintain the particles in a suspended state and to maintain the fluidized bed at a tempera-ture of 35C.
Air Atomizing Pressure 3.5 bar B. Pre~aration of Chewable Tablet~
Per Tab Per 1000 Tab Mannitol 5~4 mg 544 Gm Malic Acid 4 mg 4 Gm Aspartatne 12 mg 12 Gm Spray Dried Orange Flavor 18 mg 18 Gm Encapsulated Ibuprofen 127 mg 127 Gm Ac-Di-Sol 24 mg 24 Gm Avicel pH102 60 mg 60 Gm F.D.C. Yellow 6 I~lce 0.2 mg 0.2 Gm Citric Acid 4 mg 4 Gm Talc 20 mg 20 Gm The compression mix of above was tabletted on a Manesty beta press with 112" flat face 30 tooling. Tabletwdght: 813 mg. Hardness: 9- 13 Strong Cobert(SC). Disintegration Time in water: 2 minutes.
Table 1 shows a comparison of dissoluhon data between MOTRIN IB Tablet in PH 7.2 and the MOTRIN Chewable Tablets of this invention.
Wo 91/15194 ~! 0 7 ~ c3 ~ ~ PCI/US91/OtO89 ,f Table 2 shows a comparison of dissolution data between MOTRIN IB Tablets in PH 5.8 and the MOTRIN Chewable Tablets of this invention.
,"~~~ WO 9l~15l94 2 0 7 ~ 9 8 ~ Pcr/usgl/01o89 TABLE I
Com~anson of Dissolution Data between Motrin IB
and Motrin Chewa~le Tablets S Buffer 7.2 PH
Motnn IB #12 #13 Recrystallized IbuprofenRaw Material Flask 1 Flask 2 Flask 3 Flask 4 Time % Released Time % Released Time 9G Released Time % Released 0.10-0.02 0.20 0.00 0.30 0.04 0.40 -0.02 2.101.21 2.20 lO.S0 2.30 9.40 2.40 0.48 4.1038.77 4.20 63.24 4.30 53.61 4.40 18.34 6.1071.49 6.20 89.31 6.30 84.02 6.40 40.63 8.1084.88 8.20 97.65 8.30 89.89 8.40 54.00 10.1090~0 10.20 95.85 10.30 90.91 10.40 63.24 12.1092.79 12.20 93.61 1~.30 91.45 12.40 71.12 14.1093.80 14.20 91.77 14.30 91.45 14.40 78.23 16.1094.36 16.20 91.38 16.30 91.62 16.40 8~.25 18.1094.58 18.20 ~1.64 18.30 91.66 18.40 87.75 20.1094.67 20.20 91.86 20.30 91.68 20.40 94.43 22.1094.75 22.20 91.88 22.30 91.M 22.40 96.05 24.1094.77 24.20 92.01 24.30 91.79 24.40 99.24 26.1094.82 26.20 92.16 26.30 91.77 26.40 100.63 28.1094.88 28.20 92.40 28.30 91.79 28.40 101.32 30.1094.92 30.20 92.57 30.30 91.81 30.40 101.~8 32.1094.95 32.20 92.79 32.30 91.88 32.40 101.71 34.1095.01 34.20 92.83 34.30 91.90 34.40 102.14 36.1094.99 36.20 92.92 36.30 91.86 36.40 102.20 38.1095.03 38.20 92.96 38.30 91.86 38.40 102.35 40.1094.99 4~.20 93.00 40.30 91.84 40.40 102.46 42.1095.05 42.20 93.09 42.30 91.90 42.40 102.61 44.109S.10 44.20 93.15 44.30 91.92 44.40 102.66 46.1095.08 46.20 93.20 46.30 91.97 46.40 102.72 48.1095.10 48.20 93.24 48.30 91.97 48.40 102.74 50.1095.08 50.20 93.26 50.30 91.94 50.40 102.76 52.1095.14 52.20 93.26 52.30 91.94 52.40 102.79 54.1095.12 54.20 93.33 54.30 92.01 54.40 102.7-9 S6.1095.14 56.20 93.35 56.30 92.03 56.40 102.89 58.1095.18 58.20 93.37 58.30 92.05 58.40 102.85 60.1095.18 60.20 93.41 60.30 92.05 60.40 102.92 45 In PH7.2 buffer: Forrnula #12 shows fus~c reline than Motrin IB.
E;ormula #12, #13 and Motrin IB shows the same reline forte ~ter 10 minutes.
WO 91/15194 2 ~ PCl tUS91/01089 Formula ~12, ~13 all pass U.S.P. Tablets specification 20 minutes 785%.
Flask 1: Motrin IB. .
Flask : Motnn chewable experiment Lot 12.
Flask 3: Motrin chewable experiment Lot 13.
Flask 4: Recrystallized Ibuprofen.
~vo gt/l5l94 2 0 7 ~ ~ ~ 3 PCl/US91/01089 .
TABLE II
Buffer: 5-8 PH
5Motrin IB A~12 #13 Recrystallized Ibuprofen Raw Material Fla k 1 Flask 2 Flack 3 Fla.sk 4 10 Time% Released Time % Released Time % Released Time % Released 0.10 0.04 0.20 0.02 0.30 0.00 0.400.04 2.10 0.13 2.20 2.76 2.30 2.20 2.400.78 4.10 2.25 4.20 9.78 4.30 7.90 4.409.18 6.10 19.40 6.20 18.68 6.30 15.726.4~ 36.26 8.10 36.48 8.20 28.10 8.30 25.338.40 53.71 10.10 48.08 10.20 36.05 10.30 34.6910.40 65.90 12.10 57.28 12.20 43.30 12.30 47.1112.40 75.08 14.10 64.34 14.20 51.49 I4.30 56.5414.40 82.38 16.10 70.09 16.20 58.83 16.30 64.0216.40 87.39 18.10 74.82 18.20 65.33 18.30 69.9118.40 91.40 20.10 78.S7 20.20 71.02 20.30 74.8620.40 94.41 22.10 81.73 22.20 76.16 22.30 78.5322.40 96.78 24.10 84.47 24.20 80.43 24.30 81.5124.40 98.47 26.10 86.74 26.20 84.02 26.30 83.8926.40 99.72 28.10 88.68 28.20 86.80 28.30 86.1128.40 100.65 30.10 90.24 30.20 89.05 3~.30 87.7830.40 101.51 32.10 91.56 32.20 90.99 32.30 89.0932.40 102.03 34.10 92.70 34.20 92.53 34.30 90.0634.40 102.53 36.10 93.59 36.20 93.78 36.30 90.9536.40 103.09 38.10 94.43 38.20 94.79 38.30 91.7338.40 103.52 40.10 95.21 40.20 95.62 40.30 92.4640.40 103.91 42.10 95.75 42.20 96.26 42.30 93.0042.40 104.34 44.10 96.29 44.20 96.76 44.30 93.5044.40 104.67 46.10 96.67 46.20 97.17 46.30 93.8446.40 105.08 48.10 96.95 48.20 97.45 48.30 94.1548.40 105.25 50.10 97.21 50.20 97.65 50.3~ 94.3650.40 105.46 52.10 97.54 52.20 97.88 52.30 94.6052.40 105.72 54.10 97.75 54.20 98.12 54.30 94.77S4.40 105.94 56.10 97.97 56.20 98.25 56.30 94.9756.40 106.11 58.10 98.12 58.20 98.38 58.30 95.0858.40 106.29 60.10 98.27 60.20 98.47 6~.30 95.1860.40 106.37 PH 5-8: After 10 minutes about 1~12% difference ætion compare #12, #13 with Motnn IB.
After 20 n~inutes about 7-896 difference when compared #12, and #13 with Mot~in IB.
After 30 minutes shows no significant difference among them.
WO 91/lS194 2 ~ PCI/US91/0108~
Flask 1: Motrin IB.
Flask 2: Motrin chewable experiment Lot 12.
Flask 3: Motrin chewable experiment Lot 13.
Flask 4: Recrystallized Ibuprofen.
Claims (6)
1. A chewable taste-masked tablet having controlled-release characteristics, comprising microcapsules, 100 to 800 µm in diameter, having (a) a pharmaceutical core including crystalline ibuprofen and (b) a methacrylic acid copolymer coating having sufficient elasticity to withstand chewing.
2. A tablet according to claim 1, wherein the copolymer is an anionic copolymer of methacrylic and acrylic acid having a mean molecular weight of 250,000.
3. A tablet according to claim 1 or claim 2, that releases the ibuprofen in the duodenum but not in the mouth.
4. A tablet according to any preceding claim, wherein the coating further comprises a plasticiser.
5. A tablet according to claim 4, wherein the plasticiser is selected from glyceryl triacetate, triethyl citrate, acetyl triethyl citrate, dibutyl sebacate, acetyl tributyl citrate, diethyl phthalate, dibutyl phthalate, glycerine, propylene glycol and polyethylene glycol.
6. A tablet according to claim 5, wherein the plasticiser is propylene glycol.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US50819390A | 1990-04-11 | 1990-04-11 | |
| US508,193 | 1990-04-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2076983A1 true CA2076983A1 (en) | 1991-10-12 |
Family
ID=24021750
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002076983A Abandoned CA2076983A1 (en) | 1990-04-11 | 1991-02-26 | Taste masking of ibuprofen by fluid bed coating |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US5552152A (en) |
| EP (1) | EP0524180B1 (en) |
| JP (1) | JPH05506011A (en) |
| AT (1) | ATE121619T1 (en) |
| AU (1) | AU639988B2 (en) |
| CA (1) | CA2076983A1 (en) |
| DE (1) | DE69109282T2 (en) |
| DK (1) | DK0524180T3 (en) |
| ES (1) | ES2071986T3 (en) |
| FI (1) | FI924589A (en) |
| HU (2) | HUT64220A (en) |
| NO (1) | NO300758B1 (en) |
| RU (1) | RU2101010C1 (en) |
| WO (1) | WO1991015194A1 (en) |
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| DE19648576C2 (en) * | 1996-11-23 | 1999-08-12 | Lohmann Therapie Syst Lts | Lozenge for modified release of active substances in the gastrointestinal tract |
| FR2766089B1 (en) * | 1997-07-21 | 2000-06-02 | Prographarm Lab | IMPROVED MULTIPARTICULAR TABLET WITH RAPID DELIVERY |
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| FR2785538B1 (en) * | 1998-11-06 | 2004-04-09 | Prographarm Laboratoires | PERFECTED QUICK DELIVERY TABLET |
| FR2785539B1 (en) | 1998-11-06 | 2004-04-09 | Prographarm Laboratoires | PARTICLES COATED WITH GRANULATED CRYSTALLINE IBUPROFENE |
| US6270807B1 (en) | 1999-03-02 | 2001-08-07 | L. Perrigo Company | Taste-masked pharmaceutical composition |
| WO2000059467A1 (en) | 1999-04-06 | 2000-10-12 | Laboratoires Des Produits Ethiques Ethypharm | Drinkable ibuprofen pharmaceutical suspension |
| TR200200313T2 (en) | 1999-08-17 | 2002-04-22 | Novartis Consumer Health S.A. | Rapidly dissolving dosage form and its production process. |
| BR0016236A (en) | 1999-12-09 | 2002-12-24 | Boots Co Plc | Therapeutic agents |
| US6551617B1 (en) | 2000-04-20 | 2003-04-22 | Bristol-Myers Squibb Company | Taste masking coating composition |
| EP1276470B1 (en) | 2000-04-20 | 2007-05-02 | Novartis AG | Taste masking coating composition |
| WO2002089808A1 (en) * | 2001-05-09 | 2002-11-14 | Bayer Healthcare Ag | Novel use of 2-phenyl-substituted imidazotriazinones |
| AU2002327418A1 (en) * | 2001-08-01 | 2003-02-17 | Bristol-Myers Squibb Company | Taste masking composition |
| US20190328679A1 (en) | 2001-10-12 | 2019-10-31 | Aquestive Therapeutics, Inc. | Uniform films for rapid-dissolve dosage form incorporating anti-tacking compositions |
| US7357891B2 (en) | 2001-10-12 | 2008-04-15 | Monosol Rx, Llc | Process for making an ingestible film |
| US8765167B2 (en) | 2001-10-12 | 2014-07-01 | Monosol Rx, Llc | Uniform films for rapid-dissolve dosage form incorporating anti-tacking compositions |
| US20110033542A1 (en) | 2009-08-07 | 2011-02-10 | Monosol Rx, Llc | Sublingual and buccal film compositions |
| US10285910B2 (en) | 2001-10-12 | 2019-05-14 | Aquestive Therapeutics, Inc. | Sublingual and buccal film compositions |
| US8603514B2 (en) | 2002-04-11 | 2013-12-10 | Monosol Rx, Llc | Uniform films for rapid dissolve dosage form incorporating taste-masking compositions |
| US11207805B2 (en) | 2001-10-12 | 2021-12-28 | Aquestive Therapeutics, Inc. | Process for manufacturing a resulting pharmaceutical film |
| JP5069395B2 (en) | 2002-02-21 | 2012-11-07 | ヴァレアント インターナショナル （バルバドス） エスアールエル | Pharmaceutical composition with improved release of at least one form of tramadol |
| CO5400144A1 (en) | 2002-03-11 | 2004-05-31 | Novartis Ag | ORGANIC COMPOUNDS |
| DE10232113A1 (en) * | 2002-07-16 | 2004-01-29 | Bayer Ag | Medicinal products containing vardenafil hydrochloride trihydrate |
| FR2850275B1 (en) | 2003-01-24 | 2005-04-08 | Scherer Technologies Inc R P | SOFT MACHINE CAPSULES CONTAINING AN ACTIVE ACTIVE SUBSTANCE WITH MASK TASTE |
| JP2007031281A (en) * | 2003-06-25 | 2007-02-08 | Kowa Co | Ibuprofen-containing film-coated tablet |
| US20050220825A1 (en) * | 2004-03-10 | 2005-10-06 | Adrian Funke | Molecular dispersions of drospirenone |
| DE102004023069A1 (en) * | 2004-05-11 | 2005-12-08 | Bayer Healthcare Ag | New dosage forms of the PDE 5 inhibitor vardenafil |
| DE102005001989A1 (en) * | 2005-01-15 | 2006-07-20 | Bayer Healthcare Ag | Intravenous formulations of PDE inhibitors |
| DE102005009241A1 (en) * | 2005-03-01 | 2006-09-07 | Bayer Healthcare Ag | Dosage forms with controlled bioavailability |
| DE102005009240A1 (en) * | 2005-03-01 | 2006-09-07 | Bayer Healthcare Ag | Dosage forms with improved pharmacokinetic properties |
| AU2006299232A1 (en) * | 2005-09-29 | 2007-04-12 | Bayer Schering Pharma Aktiengesellschaft | PDE inhibitors and combinations thereof for the treatment of urological disorders |
| US20070134493A1 (en) * | 2005-12-08 | 2007-06-14 | Kanji Meghpara | Compositions and capsules with stable hydrophilic layers |
| US7767248B2 (en) | 2007-02-02 | 2010-08-03 | Overly Iii Harry J | Soft chew confectionary with high fiber and sugar content and method for making same |
| US20100184769A1 (en) * | 2007-06-13 | 2010-07-22 | Bayer Schering Pharma Aktiengesellschaft | Pde inhibitors for the treatment of hearing impairment |
| US8404275B2 (en) | 2007-07-01 | 2013-03-26 | Vitalis Llc | Combination tablet with chewable outer layer |
| WO2009005803A1 (en) * | 2007-07-01 | 2009-01-08 | Joseph Peter Habboushe | Combination tablet with chewable outer layer |
| ES2363964B1 (en) | 2009-11-20 | 2012-08-22 | Gp Pharm, S.A. | CAPSULES OF PHARMACEUTICAL ACTIVE PRINCIPLES AND ESTERS OF POLYINSATURATED FATTY ACIDS. |
| US9149959B2 (en) | 2010-10-22 | 2015-10-06 | Monosol Rx, Llc | Manufacturing of small film strips |
| CN107296798A (en) | 2011-10-28 | 2017-10-27 | 维塔利斯公司 | Resist rubescent composition |
| PT2833880T (en) * | 2012-04-02 | 2017-12-06 | Pharma Seeds Create Llc | Ibuprofen solid oral dosage composition comprising a methacrylic acid copolymer |
| US8993041B2 (en) | 2012-10-15 | 2015-03-31 | New Jersey Institute Of Technology | Taste masked active pharmaceutical powder compositions and processes for making them |
| WO2014194872A1 (en) | 2013-06-04 | 2014-12-11 | Zentiva, K.S. | Taste masking of water soluble drugs using poloxamers |
| RU2576236C1 (en) * | 2014-08-22 | 2016-02-27 | Александр Александрович Кролевец | Method of producing antibiotic nanocapsules in agar-agar |
| RU2577689C1 (en) * | 2014-08-26 | 2016-03-20 | Александр Александрович Кролевец | Method of producing antibiotic nanocapsules in agar-agar |
| RU2578408C1 (en) * | 2014-09-10 | 2016-03-27 | Александр Александрович Кролевец | Method of producing nanocapsules of alkaloids |
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| BR112018072539A2 (en) | 2016-05-05 | 2019-03-26 | Aquestive Therapeutics, Inc. | increased administration epinephrine compositions |
| RU2688148C1 (en) * | 2016-05-10 | 2019-05-20 | Александр Александрович Кролевец | Method of producing ecocide nanocapsules in carrageenan |
| CN110917165A (en) * | 2019-12-26 | 2020-03-27 | 北京鑫开元医药科技有限公司海南分公司 | Ibuprofen orally disintegrating tablet and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB971700A (en) * | 1961-02-02 | 1964-09-30 | Boots Pure Drug Co Ltd | Anti-Inflammatory Agents |
| US4476248A (en) * | 1983-02-28 | 1984-10-09 | The Upjohn Company | Crystallization of ibuprofen |
| US4609675A (en) * | 1984-08-17 | 1986-09-02 | The Upjohn Company | Stable, high dose, high bulk density ibuprofen granulations for tablet and capsule manufacturing |
| DE3678644D1 (en) * | 1985-08-16 | 1991-05-16 | Procter & Gamble | ACTIVE PARTICLES WITH A CONTINUOUS THAN FASTER RELEASE. |
| IT1214629B (en) * | 1985-08-29 | 1990-01-18 | Formenti Farmaceutici Spa | MICRO-ENCAPSULATION PROCEDURE OF A MEDICATION, MEDICATION SO PREPARED, AND PHARMACEUTICAL COMPOSITIONS THAT INCLUDE IT |
| US4800087A (en) * | 1986-11-24 | 1989-01-24 | Mehta Atul M | Taste-masked pharmaceutical compositions |
| US4835186A (en) * | 1987-06-15 | 1989-05-30 | American Home Products Corporation | Spray dried ibuprofen |
| US5084278A (en) * | 1989-06-02 | 1992-01-28 | Nortec Development Associates, Inc. | Taste-masked pharmaceutical compositions |
-
1991
- 1991-02-26 EP EP91904188A patent/EP0524180B1/en not_active Expired - Lifetime
- 1991-02-26 RU SU5053248A patent/RU2101010C1/en active
- 1991-02-26 AU AU72560/91A patent/AU639988B2/en not_active Ceased
- 1991-02-26 WO PCT/US1991/001089 patent/WO1991015194A1/en active IP Right Grant
- 1991-02-26 CA CA002076983A patent/CA2076983A1/en not_active Abandoned
- 1991-02-26 DK DK91904188.9T patent/DK0524180T3/en active
- 1991-02-26 AT AT91904188T patent/ATE121619T1/en not_active IP Right Cessation
- 1991-02-26 HU HU9203193A patent/HUT64220A/en unknown
- 1991-02-26 JP JP91504575A patent/JPH05506011A/en active Pending
- 1991-02-26 DE DE69109282T patent/DE69109282T2/en not_active Expired - Fee Related
- 1991-02-26 ES ES91904188T patent/ES2071986T3/en not_active Expired - Lifetime
-
1992
- 1992-10-09 FI FI924589A patent/FI924589A/en not_active Application Discontinuation
- 1992-10-09 NO NO923947A patent/NO300758B1/en unknown
-
1995
- 1995-06-06 US US08/469,715 patent/US5552152A/en not_active Expired - Fee Related
- 1995-06-23 HU HU95P/P00418P patent/HU211247A9/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI924589A0 (en) | 1992-10-09 |
| DE69109282D1 (en) | 1995-06-01 |
| HU9203193D0 (en) | 1992-12-28 |
| ATE121619T1 (en) | 1995-05-15 |
| NO923947L (en) | 1992-10-09 |
| EP0524180A1 (en) | 1993-01-27 |
| NO923947D0 (en) | 1992-10-09 |
| DK0524180T3 (en) | 1995-09-04 |
| ES2071986T3 (en) | 1995-07-01 |
| JPH05506011A (en) | 1993-09-02 |
| FI924589A (en) | 1992-10-09 |
| WO1991015194A1 (en) | 1991-10-17 |
| US5552152A (en) | 1996-09-03 |
| EP0524180B1 (en) | 1995-04-26 |
| HU211247A9 (en) | 1995-11-28 |
| HUT64220A (en) | 1993-12-28 |
| DE69109282T2 (en) | 1995-09-28 |
| AU7256091A (en) | 1991-10-30 |
| AU639988B2 (en) | 1993-08-12 |
| RU2101010C1 (en) | 1998-01-10 |
| NO300758B1 (en) | 1997-07-21 |
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| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |