GB2048671A - Pharmaceutical composition containing dihydroergotoxine - Google Patents
Pharmaceutical composition containing dihydroergotoxine Download PDFInfo
- Publication number
- GB2048671A GB2048671A GB8012357A GB8012357A GB2048671A GB 2048671 A GB2048671 A GB 2048671A GB 8012357 A GB8012357 A GB 8012357A GB 8012357 A GB8012357 A GB 8012357A GB 2048671 A GB2048671 A GB 2048671A
- Authority
- GB
- United Kingdom
- Prior art keywords
- dihydroergotoxine
- weight
- coating
- composition according
- hours
- 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.)
- Granted
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Pharmaceutical compositions contain dihydroergotoxine and comprise non-toxic carrier particles provided with a coating of a mixture containing dihydroergotoxine, said coating being covered with a coating of a methacrylic acid polymer, a poly(alkylmethacrylate) or a mixture of these polymers have sustained/delayed release properties.
Description
SPECIFICATION
Pharmaceutical composition containing dihydroergotoxine
The present invention is concerned with a pharmaceutical composition containing dihydroergotoxine.
Dihydroergotoxine is a combination of equal parts of dihydroergocornine, dihydroergocristine and dihydroergocryptine, which are alkaloids from ergot of rye. The methanesulphonate of d ihydroergotoxine (DHET) is known for its activity in vascular and cerebral pathology. It is administered either parenterally in the form of an injectable solution or orally in the form of a solution or tablet, the customary daily doses being 3 mg. for perfusion or intravenous injection, 0.3 mg. to 0.6 mg. for intra-arterial administration and 4.5 mg. for drops to be taken orally or tablets.
The present invention provides a new pharmaceutical composition containing DHETwhich permits a controlled release of the active principle.
Thus, according to the present invention, there is provided a pharmaceutical composition containing dihydroergotoxine, said composition comprising non-toxic carrier particles provided with a coating of a mixture containing dihydroergotoxine, said coating being covered with a coating of a methacrylic acid polymer, a poly-(alkyl methacrylate) or a mixture of these polymers.
The compositions according to the present invention have a delayed action and have the advantage of releasing the DHET gradually and uniformly over the course of 12 hours. Consequently, the utilisation of the active material is improved and a therapeutic protection is thus obtained throughout the nycthemeron, the controlled release ensuring a stable plasma level which is sustained for a long time.
In order to achieve this object, the contents of the compositions with a delayed action must make it
possible to obtain dissolution kinetics having charac
teristics which are such that, under the experimental
conditions chosen, i.e. in artificial aqueous media,
from 15 to 20% of the total amount of the DHET pres
ent in each dosage unit is released in the course of 1
hour; the dissolution kinetics must then make it pos
sible to obtain the release of 40 to 50% and especially
of about 45% in the course of 4 hours, the amount of
active principle released reaching about 80 to 90%
and especially 85% after 4 hours and 100% after 12
hours.
In order to obtain the DHET microgranules for con
trolled release, the active principle is fixed to carrier
particles of about 800 to 1,000, diameter, these carr
ier particles being obtained, for example, by success
ively coating grains of sugar with an aqueous
alcoholic solution containing sucrose, an excipient,
such as polyvidone, pharmaceutical industrial-grade alcohol and water. After drying, the particles are
graded and only those with a diameter of from 800 to 1,000cm are retained. These carrier particles are then coated with a solution of polyvidone in a mixture of water and pharmaceutical industrial-grade alcohol.
The particles are sprinkled with a mixture of DHET and lactose and left to dry, the finished particles hav
ing a diameter of from 900 to 1 ,250,a. The content of active material is calculated. Finally, these particles are coated with a solution, in ethyl phthalate and pharmaceutical industrial-grade alcohol, of a polymer based on methacrylic acid and/or methyl methacrylate. They are sprinkled with talc and these operations are repeated until the release control corresponds to the dissolution kinetics described above. The microgranules finished in this way are again checked and are then made up into dosage units so that each dosage unit contains 2.5 mg. of DHET, the weight of the contents being of the order of 0.250 gram.
The following Example is given for the purpose of illustrating the present invention: Example.
Carrier particles are prepared, using the following proportions:
General range Preferred range kg. kg.
sucrose 30 to 70 50 maize starch 5 to 20 10 talc 5 to 20 10 polyvidone excipient 1 to 4 2 the intermediate solvents used being water and pharmaceutical industrial-grade alcohol. After drying and grading, the resulting particles have a diameter of from 800 to 1,000eel.
These carrier particles are coated with an aqueous-alcoholic solution of polyvidone and then sprinkled with a mixture of DHET and lactose so that 260 mg. of dosage unit contents contain 2.5 mg. of
DHET, the lactose representing from 0.06 to 0.4 parts by weight for each part by weight of DHET. The particles are left to dry and only those with a diameter of from 900 to 1250cm are retained. The amount of DHET present can be determined colorimetrically or, preferably, spectrophotometrically. These particles are coated with a solution, in ethyl phthalate and alcohol, of a polymer based on methacrylic acid and/or methyl methacrylate, the coating representing from 0.002 to 0.1% of the weight of the rest of the composition.The particles are sprinkled with talc in an amount of one tenth by weight, referred to the total weight, these operations being repeated until the desired release control has been obtained. The dosage units are then divided up, the weight of the contents being 0.263 gram.
The determination ofthe dissolution kinetics in an
artificial aqueous medium give the following results:
after 1 hour 15-20%; preferablyl8% after 4hours 40-50%; preferably 46% after 8 hours 80-90%; preferably 86% after 12 hours 100% Atoxicoligical study of the DHET dosage units for controlled release was carried out and compared with non-controlled DHET dosage units.After pulverising the contents of the dosage units and suspending the powder obtained in a 5% by weight aqueous solution of gum arabic, the suspension thus obtained was administered through a stomach tube to
Sprague-Dawley rats, the animals being equally divided between the two sexes, each dose studied being administered to batches of 5 males and 5 females, the bodyweightofthe males being from 220 to 250 grams and that of the females being frdm 180 to 200 grams. The maximum dose administered was 100 dosage units per kg. of body weight, corresponding, in terms of active material, to 250 mg. of DHET/kg. The animals were placed under observation for 8 days following administration of the dosage units and no symptoms of intolerance were seen.It should be pointed out that the above-mentioned dose could not be increased for reasons of consistency and volume of the compositions. The tolerance, was, therefore, the same, whether or not the cdmpo- sition in question was for controlled release.
Further experiments were carried out with male beagle dogs having a body weight of from 11 to 14.5 kg. Above 30 dosage units 1keg., i.e. 75 mg. of DHET, vomiting was observed in the 30 minutes following oral administration, this vomiting then disappearing and the animals showing no other local or general intolerance.
Experiments on the rate of release of DHET were carried out in vitro with tablets containing 4.5 mg. of
DHET, dosage units containing 2.5 mg. of DHET and 10 mg. of lactose and DHET dosage units containing 2.5 mg. of active principle for controlled release according to the present invention, each experiment being carried out with 20 mug. of DHET for each of the 3 compositions studied.
A continuous flow cell, such as that described by
Bastide, Michaud and Rouffiac (Labo. Pharma.,249, 1170-1174/19i5) was used, the volume of the bath being 200 ml., the rate of circulation being 30 ml./minute and the tests being carried out at pH 1.2 and pH 5.6. The amount of DHET released was determined continuously by spectrophotometry using ultra-violet light, the optical density being read at 281 nm.
The experimental results obtained are given in the following Table I, which indicates the percentages of
DHET released as a function of time.
TABLE I
pH 1.2 pH 5.6 tablets DHET DHET with tablets DHET DHET with containing + lactose delayed containing + lactose delayed 4.5 mg. (dosage action 4.5 mg. (dosage action DHET units) (dosage DHET units) (dosage units) units) 1 hour 80 73 23 52 35 10 2hours 94 88 38 70 53 14 3 hours 97 93 48 78 65 16 4 hours 100 96 57 85 72 18 5 hours 64 90 78 21 6 hours 68 94 82 23 7 hours 72 96 87 25 8 hours 75 1 98 91 27 It is thus apparent that, at pH 1.2, the tsC% (i.e. the time required to obtain the release of 50% of the
active material) is less than 30 minutes for the 2
compositions without delayed action, whereas the t1, is more than 3 hours for the cmposition with
delayed action; at pH 5.6, the t50% is of the order of 60
minutes for the tablets containing 4.5 mg. of DHET
and of the order of 100 minutes of the dosage units
containing DHET + lactose; as regards the DHET
composition for controlled release, only 27% of the
active principle is released after 8 hours and this con
firms the delayed effect of the preparation which,
therefore, enables the blood level of DHET to be
maintained satisfactorily. At pH 1.2, the two compos
itions without delayed action have released virtually
all of their active material content after 4 hours, whe
reas only 75% of the active material content in the
composition with delayed action has been released
after 8 hours. At pH 5.6, after 8 hours, the amount of
DHET released is 98% in the case of the tablets conta
ining 4.5 mg. of DHET, 91% in the case of the DHET
dosage units without delayed action and only 27% in
the case of the DHET dosage units for controlled rel
ease. The level of DHET released in the case of the
composition with delayed action is 3.62 times lower
than in the case of the tablets containing 4.5 mg. of
DHET and 3.37 times lower than in the case of the
dosage units without delayed action.
Experiments were carried out on humans, the pri
nciple being based on the increase, caused by DHET, in the venous vasoconstriction induced by dihydroe rgotamine (DHE), which is known to bring about an intense venous vasoconstriction when it is administered orally. The experiment was carried out on several subjects in the following manner:
The process is based on the optical determination of the calibre of a surface vein in the hand, at a standard congestive pressure. The culminating point of a suitable vein in the back of the hand is marked with a cross, using Indian ink. The subject, who is in a room kept at a constant temperature, remains stretched out, his arm, which rests on a rigid splint, forming an angle of 30C with the horizontal so that the surface veins are entirely collapsed.A binocular microscope, the optical axis of which is located exactly perpendicular to the surface of the skin, is focused on the cross forming the reference point. One to two minutes after applying a tourniquet, the microscope is focused and the appropriate surface vein is considered as being totally vasodilated; the diameter of the vein in question is then arbitrarily given the value 100.
Then (time 0), a loading dose of 2 mg. of DHE is administered and, after 90 minutes (i.e. time 1.5), 0.5 mg. of DHE is administered every 30 minutes throughoul the duration of the experiment (7 hours).
These doses were chosen during prior experiments which made it possible to obtain a permanent vasoconstriction without the subject showing secondary manifestations. At time 1.5, 2.5 mg. of DHET are administered to the subject in a single dose and all at once, either in the form of drops taken orally or in the form of dosage units for controlled release. The diameter of the surface vein is measured every half hour for 7 hours. The results obtained are given in the following Tables, these results being given by way of illustration but without implying any limitat
ion, each figure being calculated relative to time 0.
Table II shows the residual vasodilation, with time, as a percentage relative to the value of 100% for the starting time 0. Table Ill shows the percentage vasoconstriction resulting from the action of DHE, partia
lly neutralised by DHET, the figures being obtained relative to time 0 when the vasoconstriction was zero.
If the time 5.5 hours is considered, for example, it is found that, due to the action of DHE by itself, the residual vasodilation is only 26.2% relative to time 0, it is 25.0% due to the action of DHE + DHET without delayed action and it reaches 90% of the maximum vasodilation after the action of DHE + controlled
DHET. Still at time 5.5 hours, the resultant vasoconstriction, after administration of DHE by itself, is 73.8%, referred to time 0, at which, by definition, there is no vaso-constriction; with DHE + DHET without delayed action, the resulting vasoconstriction is 75% and with DHE + DHET with delayed action, it is only 10%; in other words, whereas DHET without delayed action provides virtually no neutralisation of the vasoconstrictive effect of DHE, the controlled
DHET composition according to the present invention virtually nullifies the vaso-constrictive effect of
DHE.
Experimental proof of the controlled delayed effect of the pharmaceutical composition of the present invention has thus been provided both in vitro and in vivo.
TABLE Il Percentage residual vasodilation
Time O 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 DHE 100 52.5 43.5 33.7 33.7 26.2 33.7 31.2 26.2 25.0 26.2 25.0 25.0 27.5 DHE + DHET without 100 62.5 50.0 38.7 51.2 73.7 87.5 63.7 53.7 37.5 25.0 21.2 16.2 18.7 delayed action DHE+ DHET with 100 61.2 43.7 33.7 27.5 48.7 72.5 77.5 85.0 87.5 90.0 72.5 52.5 36.2 delayed action TABLE 111 Percentage vasoconstriction
Time 1 1.5 2 2.5 3 3.5 4 4.5 5 5 6 5 7 DHE 47.5 56.5 66.3 66.3 73.8 66.3 68.8 73.8 75.0 73.8 75.0 75.0 72.5 DHE+ DHET without 37.5 50.0 61.3 48.8 26.3 12.5 36.3 46.3 62.5 75.0 78.8 83.8 81.3 delayed action DHE + DHET with 38.8 56.3 66.3 1 72.5 51.3 27.5 22.5 15.0 12.5 10.0 27.5 47.5 63.8 delayed action
Claims (13)
1. A pharmaceutical composition containing dihydroergotoxine, said composition comprising nontoxic carrier particles provided with a coating of a mixture containing dihydroergotoxine, said coating being covered with a coating of a methacrylic acid polymer, a poly-(alkyl methacrylate) or a mixture of these polymers.
2. A composition according to claim 1, comprising several pairs of the two types of coating, separated by layers of talc, so that 15 to 20% of the weight of the dihydroergotoxine is released in water in the course of 1 hour.
3. A composition according to claim 1, compris- ing several pairs of the two types of coating, separated by layers of talc, so that from 40 to 50% of the weight of the dihydroergotoxine is released in water in the course of4 hours.
4. A composition according to claim 1, comprising several pairs of the two types of coating, separated by layers of talc, so that from 80 to 90 of the weight of the dihydroergotoxine is released in water in the course of 8 hours.
5. A composition according to claim 1, comprising several pairs of the two types of coating, separated by layers of talc, so that all the dihydroergotoxine is dissolved in water in the course of 12 hours.
6. A composition according to any of the preceding claims, wherein the carrier particles comprise sugar, preferably in an amount of from 30 to 70 parts by weight, and starch, preferably maize starch, preferably in an amount of from 5 to 20 parts by weight, and preferably talc, preferably in an amount of from 5 to 20 parts by weight, the carrier particles having a diameter of from about 800 to 1000 microns.
7. A composition according to any of the preceding claims, wherein the mixture containing dihydroergotoxine comprises lactose, preferably in an amount of from 0.06 to 0.4 part by weight for each part by weight of dihydroergotoxine, the particles covered with the first coating having an overall diameter of from about 900 to 1250 microns.
8. Acomposition according to anyofclaims2to 7, wherein the intermediate layer of talc represents about one tenth of the weight of the rest of the composition.
9. A composition according to any of the preceding claims, wherein the coating represents from 0.002 to 0.1% of the weight of the rest of the composition.
10. A pharmaceutical composition according to claim 1 containing dihydroergotoxine, substantially as hereinbefore described and exemplified.
11. A process for the preparation of a composition according~to any of the preceding claims, comprising moistening non-toxic carrier particles with a diameter of from 800 to 1000 microns with an aqueous-alcoholic solution of polyvidone, sprinkling the moistened carrier particles with a mixture of dihydroergotoxine and lactose and leaving the particles to dry, the amount of mixture being such that the particles coated with the mixture having a diameter of from 900 to 1250 microns, covering the dried coated particles with an alcoholic solution of a methacrylic acid polymer, of a polyalkyl methacrylate or of a mixture of these polymers, sprinkling the coated grain with talc and repeating the above operations on the particles coated with talc until a composition isobtained frdm which 15 to 20% of the dihydroergos toxine is released in the course of 1 hour, from 40 to 50% is released in the course of4 hours, from 80 to 90% is released in the course of 8 hours and 100% is released in the course of 12 hours, in an aqueous medium.
12. A process according to claim 10 for the preparation of a composition according to any of claims 1 to 10, substantially as hereinbefore described and exemplified.
13. A composition according to any of claims 1 to 10, whenever prepared by the process according to claim 11 or 12.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR7910620A FR2454804B1 (en) | 1979-04-26 | 1979-04-26 | DIHYDROERGOTOXIN-BASED MEDICINAL PRODUCT AND PROCESS FOR PREPARING THE SAME |
Publications (2)
Publication Number | Publication Date |
---|---|
GB2048671A true GB2048671A (en) | 1980-12-17 |
GB2048671B GB2048671B (en) | 1983-07-13 |
Family
ID=9224784
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB8012357A Expired GB2048671B (en) | 1979-04-26 | 1980-04-15 | Pharmaceutical composition containing dihydroegotoxine |
Country Status (6)
Country | Link |
---|---|
BE (1) | BE882913A (en) |
ES (1) | ES8103970A1 (en) |
FR (1) | FR2454804B1 (en) |
GB (1) | GB2048671B (en) |
IL (1) | IL59764A (en) |
IT (1) | IT1130109B (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2129301A (en) * | 1982-10-07 | 1984-05-16 | Claude Laruelle | Sustained release microgranules containing sulpiride |
US5069911A (en) * | 1985-02-05 | 1991-12-03 | Sandoz Ltd. | Pharmaceutical 9,10-dihydrogenated ergot alkaloid containing compositions |
WO1992017165A1 (en) * | 1991-03-26 | 1992-10-15 | Csl Limited | A single dose vaccination system |
CN102266310A (en) * | 2011-07-21 | 2011-12-07 | 佛山市隆信医药科技有限公司 | Dihydroergotoxine mesylate sustained-release capsule and preparation method thereof |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4411882A (en) | 1978-12-21 | 1983-10-25 | Sandoz Ltd. | Galenical compositions |
FR2539995B1 (en) * | 1983-01-28 | 1985-08-16 | Sanofi Sa | PROGRAMMED RELEASE MEDICINE BASED ON ACETYLSALICYLIC ACID |
FR2539989B1 (en) * | 1983-01-28 | 1985-08-09 | Sanofi Sa | PROGRAMMED RELEASE MEDICINE COMBINING ACETYLSALICYLIC ACID WITH DIHYDROERGOTAMINE |
FR2554718B1 (en) * | 1983-11-14 | 1986-04-04 | Ethypharm Sa | NEW ORAL SULPIRIDE FORMS FOR SULPIRIDE |
FR2556964A1 (en) * | 1983-12-23 | 1985-06-28 | Ile De France | NEW GALENIC FORMS OF SULPIRIDE USED ORALALLY |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR1347413A (en) * | 1963-01-29 | 1963-12-27 | Italnysco S P A | Broad-acting spherules or globules and method for their preparation |
GB1175430A (en) * | 1966-04-07 | 1969-12-23 | Sandoz Ltd | Pharmaceutical Compositions containing Ergot Alkaloids |
DE2010416B2 (en) * | 1970-03-05 | 1979-03-29 | Hoechst Ag, 6000 Frankfurt | Orally applicable dosage form with sustained release effect |
DE2336218C3 (en) * | 1973-07-17 | 1985-11-14 | Byk Gulden Lomberg Chemische Fabrik Gmbh, 7750 Konstanz | Oral dosage form |
DE2546577B2 (en) * | 1975-10-17 | 1981-04-02 | Sandoz-Patent-GmbH, 7850 Lörrach | Solid substances made from polyvinylpyrrolidone and ergot alkaloids |
LU77353A1 (en) * | 1977-05-16 | 1979-01-19 |
-
1979
- 1979-04-26 FR FR7910620A patent/FR2454804B1/en not_active Expired
-
1980
- 1980-04-03 IL IL59764A patent/IL59764A/en unknown
- 1980-04-04 IT IT67531/80A patent/IT1130109B/en active
- 1980-04-15 GB GB8012357A patent/GB2048671B/en not_active Expired
- 1980-04-22 BE BE0/200324A patent/BE882913A/en not_active IP Right Cessation
- 1980-04-25 ES ES491455A patent/ES8103970A1/en not_active Expired
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2129301A (en) * | 1982-10-07 | 1984-05-16 | Claude Laruelle | Sustained release microgranules containing sulpiride |
US5069911A (en) * | 1985-02-05 | 1991-12-03 | Sandoz Ltd. | Pharmaceutical 9,10-dihydrogenated ergot alkaloid containing compositions |
WO1992017165A1 (en) * | 1991-03-26 | 1992-10-15 | Csl Limited | A single dose vaccination system |
US5593697A (en) * | 1991-03-26 | 1997-01-14 | Csl Limited | Single dose vaccination system |
CN102266310A (en) * | 2011-07-21 | 2011-12-07 | 佛山市隆信医药科技有限公司 | Dihydroergotoxine mesylate sustained-release capsule and preparation method thereof |
Also Published As
Publication number | Publication date |
---|---|
FR2454804A1 (en) | 1980-11-21 |
IT1130109B (en) | 1986-06-11 |
IT8067531A0 (en) | 1980-04-04 |
IL59764A (en) | 1984-06-29 |
GB2048671B (en) | 1983-07-13 |
FR2454804B1 (en) | 1986-11-21 |
ES491455A0 (en) | 1981-04-16 |
ES8103970A1 (en) | 1981-04-16 |
BE882913A (en) | 1980-08-18 |
IL59764A0 (en) | 1980-06-30 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PE20 | Patent expired after termination of 20 years |
Effective date: 20000414 |