CA2175091C - Controlled release naproxen tablets - Google Patents
Controlled release naproxen tabletsInfo
- Publication number
- CA2175091C CA2175091C CA002175091A CA2175091A CA2175091C CA 2175091 C CA2175091 C CA 2175091C CA 002175091 A CA002175091 A CA 002175091A CA 2175091 A CA2175091 A CA 2175091A CA 2175091 C CA2175091 C CA 2175091C
- Authority
- CA
- Canada
- Prior art keywords
- controlled release
- hpmc
- naproxen
- tablet
- release
- 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.)
- Expired - Fee Related
Links
Classifications
-
- 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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
Abstract
A controlled release pharmaceutical tablet suitable for daily dosing comprising naproxen and about 3 weight percent of HPMC having a number average molecular weight of about 190,000.
Description
2l7snsl CONTROLLED RELEASENAPROXENTABLETS
Field of the Invention The present invention relates to controlled release preparations of naproxen for oral ~lministration. Specifically, it relates to a tablet comprising naproxen and hydrox~lo~yllllethylcellulose (HPMC), which provides a release profile suitable for daily dosing.
Description of Related Art Naproxen is a well known and widely used anti-inflf~mm:~tory medication with analgesic and antipyretic properties. It is used for the relief of pain and infl~mm~tion generally, and for specific conditions such as arthritis and dysmenorrhea.
15 Hydro2~l0~ylmethylcelluloses are commercially available in various grades, under several kadenames~ including Methocel* E, F, J, and K (all previously designated as Methocel EG) from The Dow Chemical Co., U.S.A., HPM* from British Celanese, Ltd., England, and Metolose SH* from Shin-Etsu, Ltd., Japan. The various grades available under a given tradename represent differences in methoxy and hydroxypropoxyl content as well as molecular weight and viscosity. Commercial designations of the various HPMCs reflect their individual viscosity types and are based on the viscosities of 2% aqueous solutions at 20~ C as determined according to the method described in the United States Pharmacopoeia Rev. 23. The viscositiesrange from 15 cps to 100,000 cps and represent number average molecular weights of from about 10,000 to about 190,000. Each of the various grades under a given tradename is a HPMC of a single viscosity type, e.g. 50 cps, 100 cps, 4,000 cps,15,000 cps, etc.
* trade-marks The area of controlled release ph~rm~ceuticals is increasingly important in the formulation, manufacture and marketing of new ph:~rm~ceutical products. The technologies and corresponding products of this art are variously described as, among others, sustained release, controlled release, prolonged action, depot, delayed action, 5 retarded release, and timed release pharmaceuticals. In describing the presentinvention, the term "controlled release" is used to indicate that control is exercised over the duration and profile of the in vivo drug release curve.
Controlled release drug dosage forms offer many advantages over conventional 10 dosage forms for particular drugs. Of major importance both practically and therapeutically is the decrease in frequency of a-lmini~tration required to achieve the desired effect. A dosage form which is taken only once-a-day greatly improves patient compliance, and by extending the drug's activity through the night, permits the patient to sleep undisturbed until the morning. By enhancing the acceptability of a 15 medication regime, patient compliance, and hence therapy, is improved.
Another important therapeutic advantage of controlled release drug dosage forms is a reduction in the fluctuation of plasma drug concentrations.
20 Conventional immediate-release dosage forms of naproxen are a(1mini~tered two or three times daily in order to m:~int~in therapeutic blood levels, and to minimi7e the differentiai between peak and trough blood levels during multiple dose therapeutic regimens. Peak to trough blood level ratios of about 2:1 are generally achieved with these regimens. In the interest of m~imi~ing the therapeutic effectiveness of the 25 drug, it is desirable to minimi7e as much as possible the ratio of peak to trough blood levels obtamed during multiple dose therapy. Controlled release formulations generally permit less frequent dosing intervals to obtain acceptable peak to trough ratios.
2l7snsl Many different types of controlled release oral dosage forms have been developed, but each has disadvantages which affect its suitability to a particular drug and therapeutic objective. Wide variations in the chemical and ph~ cokinetic properties of different drugs impose such varied requirements on the design of controlled drugdelivery formulations, that formulations which are suitable for one drug cannot generally be predictably applied to other drugs. A formulation which incorporates the drug in a soluble or erodible matrix is desirable due to its ease of manufacture, low incidence of lot to lot variability, and relative low cost. The use of hydrophilic gums such as HPMC as sustained release matrix materials is known and has been demonstrated with a variety of active agents.
Christenson and Dale (U.S. Pat. No. 3,065,143) disclosed the use of certain hydrophilic gums, including HPMC, as carrier base materials in the preparation of sustained release pharmaceutical tablets. The tablets consisted essentially of amixture of a drug in combination with at least one-third part by weight of the hydrophilic gum.
Schor and Nigalaye (U.S. Pat. No. 4,369,172, 1983) have disclosed the use of certain HPMCs for "prolonged release therapeutic compositions." In that case, the carrier base is low viscosity HPMC having a number average molecular weight below 50,000and a hydroxypropyl content of 9-12%. Specifically cited as examples corresponding to these criteria are Methocel* E50 and Metolose* 60HS50, which are 50 cps viscosity grade HPMCs having number average molecular weights in the range of 23,000. Examples 1-4 describe tablets consisting essentially of about 57% by weight of one or the other of these two materials in combination with lithium carbonate. The tablets weigh about 700 mg and release the active agent for up to 14 hours in vitro.
Further examples in U.S. Pat. No. 4,369,172 show tablets cont~ining 16-20% by weight of the polymer.
* trade-marks The Dow Chemical Company publishes a brochure entitled "Formulating for Controlled Release with Methocel Premium Cellulose Ethers" which describes the various commercially available Methocel~ polymers, identifying their relative 5 viscosities, rates of hydration and gel strength properties. The brochure also gives guidance for formulating sustained release ph~rm:~ceutical products.
C:~n~ n Patent 1204671 discloses a controlled release tablet for a daily oral a-lmini~tration in the form of a matrix comprising about 4 to 9 weight per cent of HPMC having a number average molecular weight in the range of from about 80,000 to about 130,000. In the compositions of C~n~ n Patent 1204671, the HPMC acts both as an agent to control the rate of release of the naproxen and as a binder to enable formulation of a tablet of sufficient hardness.
While the concept of lltili~ing HPMC in oral dosage forms to prolong the rate ofrelease of drugs into the blood stream is known, and prolonged release of various active agents from such dosage forms has been demonstrated, the art available toformulate oral controlled release forms of naproxen has certain disadvantages. First, it is ~pa~en~ from the foregoing discussion of the relevant art that presently known sustained release tablet formulations rely on levels of HPMC of at least about 4percent by weight to achieve adequate duration of drug release. A problem with using any of these formulations is the additional bulk of the resulting tablet. There is an approximate upper limit to the tablet bulk that will be tolerated by the patient. This limit varies from patient to patient, but can be as low as 650 mg. Thus, with drugs such as naproxen, for which the therapeutic dosage range is 500-1000 mg/day, theadditional tablet bulk which is created by inclusion of substantial amounts of matrix material will render the tablets unacceptable to many patients.
Additionally, HPMC is relatively expensive, and the inclusion of an excessive quantity increases the cost of the composition.
2l7~nsl Description of the Invention The present invention is a controlled release tablet for once-daily oral ~lmini.~tration of 500-1000 mg of naproxen which is formed as a matrix comprising, in addition to 5 naproxen, about 3 weight percent of HPMC having a number average molecular weight of about 190,000.
It has been surprisingly found that a tablet exhibiting both an adequately-slow rate of release and an adequate hardness can be achieved using HPMC at a level of only 10 about 3 weight percent, provided that the HPMC that is used has a number average molecular weight of about 190,000, and provided that it is incorporated into thematrix with naproxen in a wet granulation process, as explained further hereinafter.
The tablet matrix preferably further includes a minor amount of a pharmaceutically 15 acceptable lubricant such as magnesium stearate to aid in the process of making tablets. This amount will vary between about 0.1 to 3% generally, and preferablyrepresents about 1% of the total weight of the tablet. Suitable lubricants include magnesium stearate, stearic acid, calcium stearate and the like, or mixtures thereof.
Magnesium stearate is preferred.
Optionally, the tablet matrix may include minor amounts of other pharmaceutically acceptable excipients, such as colorants and glidants. Suitable colorants include, but are not limited to, yellow #6 lake pigment, and generally represent 1% or less of the tablet weight. Suitable glidants include, but are not limited to, pharmaceutical grades 25 of talc and fused silica.
In accordance with the present invention, the amount of naproxen that is incorporated in a tablet may range between about 500 and about 1000 mg. The therapeutic rangeof about 500 - 1000 mg per tablet is indicated for the treatment of pain of arthritis, 30 dysmenorrhea and other conditions. The tablet of the present invention provides a release period suitable for once-daily dosing, i.e. once within a 24-hour period.
release period suitable for once-daily dosing, i.e. once within a 24-hour period.
Naproxen is generally ~(lmini.~tered at levels of 500, 750, or 1000 mg/day, depending on the physician' s judgement of the needs of the patient.
HPMC is a water soluble cellulose ether, and is commercially available in various grades under the tradenames mentioned about in the DESCRIPTION OF RELATED
ART. The physicochemical properties of these polymers vary over a wide range.
The number average molecular weight (Mn) of the hydroxypropyl methylcellulose isthe sum of the individual molecular weights of a representative sample population of molecules divided by the number of molecules in that sample. Compositions of this invention use HPMC having number average molecular weight of about 190,000.
Hydroxpropylmethylcellulose which has number average molecular weight of about 190,000 is available as a single viscosity type polymer. As used herein, the term "single viscosity type" refers to commercially available grades of HPMC whose commercial designations reflect their individual viscosity type. A single viscosity type HPMC suitable for use in the present invention is Methocel~ Premium KlOOM
(Dow Chemical Co., U.S.A.) which is a 100,000 cps viscosity polymer having number average molecular weight of about 190,000.
The controlled release tablet of the present invention provides therapeutic blood levels of naproxen for at least 24 hours, and is thus suitable for once-daily ~lmini~tration.
Fluctuations in blood levels during multi-dose therapeutic regimens are minimi7e~1 by 25 the tablets of the present invention, such that the ratio of mean peak plasma concenkation to mean trough plasma concentration is 2:1 or lower.
2175n91 -The following example serves to further illustrate the invention, but is not to be interpreted as limiting the scope of the appended claims in any way:
EXAMPLE
Sustained Release Naproxen Tablets, 750 mg Tablets were prepared from the following ingredients:
Ingredients mg/tablet naproxen 750.0 2 HPMC (Methocel KlOOM) 24.0 3 colorants 3.0 4 water 200.0 5. magnesium stearate 3.0 TOTAL WEIGHT is 780 mg per tablet excluding the water.
The process used was as follows: The naproxen, Methocel~ KlOOM and colorants were well blended, and then granulated with the water. The granulation was tray-dried in a 65~ C oven for 12 hours, passed through a #20 screen, and then mixed with the magnesium stearate. The resulting material was compressed into tablets of 25 weight 780 mg.
The tablets of this example were found to have good hardness. Furthermore, the tablets were found to exhibit release rate comparable to commercially available naproxen controlled release tablets sold under the tradename Naprosyn~ SR
2l7sn~l As used herein, the term "about 3" when used in relation to the weight percent of HPMC is intended to mean between 2 and 3.6. Also, as used herein the term "about190,000" when used in relation to number average molecular weight is intended tomean between 150,000 and 230,000.
Field of the Invention The present invention relates to controlled release preparations of naproxen for oral ~lministration. Specifically, it relates to a tablet comprising naproxen and hydrox~lo~yllllethylcellulose (HPMC), which provides a release profile suitable for daily dosing.
Description of Related Art Naproxen is a well known and widely used anti-inflf~mm:~tory medication with analgesic and antipyretic properties. It is used for the relief of pain and infl~mm~tion generally, and for specific conditions such as arthritis and dysmenorrhea.
15 Hydro2~l0~ylmethylcelluloses are commercially available in various grades, under several kadenames~ including Methocel* E, F, J, and K (all previously designated as Methocel EG) from The Dow Chemical Co., U.S.A., HPM* from British Celanese, Ltd., England, and Metolose SH* from Shin-Etsu, Ltd., Japan. The various grades available under a given tradename represent differences in methoxy and hydroxypropoxyl content as well as molecular weight and viscosity. Commercial designations of the various HPMCs reflect their individual viscosity types and are based on the viscosities of 2% aqueous solutions at 20~ C as determined according to the method described in the United States Pharmacopoeia Rev. 23. The viscositiesrange from 15 cps to 100,000 cps and represent number average molecular weights of from about 10,000 to about 190,000. Each of the various grades under a given tradename is a HPMC of a single viscosity type, e.g. 50 cps, 100 cps, 4,000 cps,15,000 cps, etc.
* trade-marks The area of controlled release ph~rm~ceuticals is increasingly important in the formulation, manufacture and marketing of new ph:~rm~ceutical products. The technologies and corresponding products of this art are variously described as, among others, sustained release, controlled release, prolonged action, depot, delayed action, 5 retarded release, and timed release pharmaceuticals. In describing the presentinvention, the term "controlled release" is used to indicate that control is exercised over the duration and profile of the in vivo drug release curve.
Controlled release drug dosage forms offer many advantages over conventional 10 dosage forms for particular drugs. Of major importance both practically and therapeutically is the decrease in frequency of a-lmini~tration required to achieve the desired effect. A dosage form which is taken only once-a-day greatly improves patient compliance, and by extending the drug's activity through the night, permits the patient to sleep undisturbed until the morning. By enhancing the acceptability of a 15 medication regime, patient compliance, and hence therapy, is improved.
Another important therapeutic advantage of controlled release drug dosage forms is a reduction in the fluctuation of plasma drug concentrations.
20 Conventional immediate-release dosage forms of naproxen are a(1mini~tered two or three times daily in order to m:~int~in therapeutic blood levels, and to minimi7e the differentiai between peak and trough blood levels during multiple dose therapeutic regimens. Peak to trough blood level ratios of about 2:1 are generally achieved with these regimens. In the interest of m~imi~ing the therapeutic effectiveness of the 25 drug, it is desirable to minimi7e as much as possible the ratio of peak to trough blood levels obtamed during multiple dose therapy. Controlled release formulations generally permit less frequent dosing intervals to obtain acceptable peak to trough ratios.
2l7snsl Many different types of controlled release oral dosage forms have been developed, but each has disadvantages which affect its suitability to a particular drug and therapeutic objective. Wide variations in the chemical and ph~ cokinetic properties of different drugs impose such varied requirements on the design of controlled drugdelivery formulations, that formulations which are suitable for one drug cannot generally be predictably applied to other drugs. A formulation which incorporates the drug in a soluble or erodible matrix is desirable due to its ease of manufacture, low incidence of lot to lot variability, and relative low cost. The use of hydrophilic gums such as HPMC as sustained release matrix materials is known and has been demonstrated with a variety of active agents.
Christenson and Dale (U.S. Pat. No. 3,065,143) disclosed the use of certain hydrophilic gums, including HPMC, as carrier base materials in the preparation of sustained release pharmaceutical tablets. The tablets consisted essentially of amixture of a drug in combination with at least one-third part by weight of the hydrophilic gum.
Schor and Nigalaye (U.S. Pat. No. 4,369,172, 1983) have disclosed the use of certain HPMCs for "prolonged release therapeutic compositions." In that case, the carrier base is low viscosity HPMC having a number average molecular weight below 50,000and a hydroxypropyl content of 9-12%. Specifically cited as examples corresponding to these criteria are Methocel* E50 and Metolose* 60HS50, which are 50 cps viscosity grade HPMCs having number average molecular weights in the range of 23,000. Examples 1-4 describe tablets consisting essentially of about 57% by weight of one or the other of these two materials in combination with lithium carbonate. The tablets weigh about 700 mg and release the active agent for up to 14 hours in vitro.
Further examples in U.S. Pat. No. 4,369,172 show tablets cont~ining 16-20% by weight of the polymer.
* trade-marks The Dow Chemical Company publishes a brochure entitled "Formulating for Controlled Release with Methocel Premium Cellulose Ethers" which describes the various commercially available Methocel~ polymers, identifying their relative 5 viscosities, rates of hydration and gel strength properties. The brochure also gives guidance for formulating sustained release ph~rm:~ceutical products.
C:~n~ n Patent 1204671 discloses a controlled release tablet for a daily oral a-lmini~tration in the form of a matrix comprising about 4 to 9 weight per cent of HPMC having a number average molecular weight in the range of from about 80,000 to about 130,000. In the compositions of C~n~ n Patent 1204671, the HPMC acts both as an agent to control the rate of release of the naproxen and as a binder to enable formulation of a tablet of sufficient hardness.
While the concept of lltili~ing HPMC in oral dosage forms to prolong the rate ofrelease of drugs into the blood stream is known, and prolonged release of various active agents from such dosage forms has been demonstrated, the art available toformulate oral controlled release forms of naproxen has certain disadvantages. First, it is ~pa~en~ from the foregoing discussion of the relevant art that presently known sustained release tablet formulations rely on levels of HPMC of at least about 4percent by weight to achieve adequate duration of drug release. A problem with using any of these formulations is the additional bulk of the resulting tablet. There is an approximate upper limit to the tablet bulk that will be tolerated by the patient. This limit varies from patient to patient, but can be as low as 650 mg. Thus, with drugs such as naproxen, for which the therapeutic dosage range is 500-1000 mg/day, theadditional tablet bulk which is created by inclusion of substantial amounts of matrix material will render the tablets unacceptable to many patients.
Additionally, HPMC is relatively expensive, and the inclusion of an excessive quantity increases the cost of the composition.
2l7~nsl Description of the Invention The present invention is a controlled release tablet for once-daily oral ~lmini.~tration of 500-1000 mg of naproxen which is formed as a matrix comprising, in addition to 5 naproxen, about 3 weight percent of HPMC having a number average molecular weight of about 190,000.
It has been surprisingly found that a tablet exhibiting both an adequately-slow rate of release and an adequate hardness can be achieved using HPMC at a level of only 10 about 3 weight percent, provided that the HPMC that is used has a number average molecular weight of about 190,000, and provided that it is incorporated into thematrix with naproxen in a wet granulation process, as explained further hereinafter.
The tablet matrix preferably further includes a minor amount of a pharmaceutically 15 acceptable lubricant such as magnesium stearate to aid in the process of making tablets. This amount will vary between about 0.1 to 3% generally, and preferablyrepresents about 1% of the total weight of the tablet. Suitable lubricants include magnesium stearate, stearic acid, calcium stearate and the like, or mixtures thereof.
Magnesium stearate is preferred.
Optionally, the tablet matrix may include minor amounts of other pharmaceutically acceptable excipients, such as colorants and glidants. Suitable colorants include, but are not limited to, yellow #6 lake pigment, and generally represent 1% or less of the tablet weight. Suitable glidants include, but are not limited to, pharmaceutical grades 25 of talc and fused silica.
In accordance with the present invention, the amount of naproxen that is incorporated in a tablet may range between about 500 and about 1000 mg. The therapeutic rangeof about 500 - 1000 mg per tablet is indicated for the treatment of pain of arthritis, 30 dysmenorrhea and other conditions. The tablet of the present invention provides a release period suitable for once-daily dosing, i.e. once within a 24-hour period.
release period suitable for once-daily dosing, i.e. once within a 24-hour period.
Naproxen is generally ~(lmini.~tered at levels of 500, 750, or 1000 mg/day, depending on the physician' s judgement of the needs of the patient.
HPMC is a water soluble cellulose ether, and is commercially available in various grades under the tradenames mentioned about in the DESCRIPTION OF RELATED
ART. The physicochemical properties of these polymers vary over a wide range.
The number average molecular weight (Mn) of the hydroxypropyl methylcellulose isthe sum of the individual molecular weights of a representative sample population of molecules divided by the number of molecules in that sample. Compositions of this invention use HPMC having number average molecular weight of about 190,000.
Hydroxpropylmethylcellulose which has number average molecular weight of about 190,000 is available as a single viscosity type polymer. As used herein, the term "single viscosity type" refers to commercially available grades of HPMC whose commercial designations reflect their individual viscosity type. A single viscosity type HPMC suitable for use in the present invention is Methocel~ Premium KlOOM
(Dow Chemical Co., U.S.A.) which is a 100,000 cps viscosity polymer having number average molecular weight of about 190,000.
The controlled release tablet of the present invention provides therapeutic blood levels of naproxen for at least 24 hours, and is thus suitable for once-daily ~lmini~tration.
Fluctuations in blood levels during multi-dose therapeutic regimens are minimi7e~1 by 25 the tablets of the present invention, such that the ratio of mean peak plasma concenkation to mean trough plasma concentration is 2:1 or lower.
2175n91 -The following example serves to further illustrate the invention, but is not to be interpreted as limiting the scope of the appended claims in any way:
EXAMPLE
Sustained Release Naproxen Tablets, 750 mg Tablets were prepared from the following ingredients:
Ingredients mg/tablet naproxen 750.0 2 HPMC (Methocel KlOOM) 24.0 3 colorants 3.0 4 water 200.0 5. magnesium stearate 3.0 TOTAL WEIGHT is 780 mg per tablet excluding the water.
The process used was as follows: The naproxen, Methocel~ KlOOM and colorants were well blended, and then granulated with the water. The granulation was tray-dried in a 65~ C oven for 12 hours, passed through a #20 screen, and then mixed with the magnesium stearate. The resulting material was compressed into tablets of 25 weight 780 mg.
The tablets of this example were found to have good hardness. Furthermore, the tablets were found to exhibit release rate comparable to commercially available naproxen controlled release tablets sold under the tradename Naprosyn~ SR
2l7sn~l As used herein, the term "about 3" when used in relation to the weight percent of HPMC is intended to mean between 2 and 3.6. Also, as used herein the term "about190,000" when used in relation to number average molecular weight is intended tomean between 150,000 and 230,000.
Claims (2)
1. A controlled release tablet for once-daily oral administration of naproxen, said tablet comprising, in addition to naproxen, from 2 to 3.6 weight percent of HPMC having a number average molecular weight of from 150,000 to 230,000.
2. The controlled release tablet of Claim 1 which further comprises from 0.1 to 3 weight percent of a pharmaceutically acceptable lubricant.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002175091A CA2175091C (en) | 1996-04-26 | 1996-04-26 | Controlled release naproxen tablets |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002175091A CA2175091C (en) | 1996-04-26 | 1996-04-26 | Controlled release naproxen tablets |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2175091A1 CA2175091A1 (en) | 1997-10-27 |
| CA2175091C true CA2175091C (en) | 1999-01-05 |
Family
ID=4158074
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002175091A Expired - Fee Related CA2175091C (en) | 1996-04-26 | 1996-04-26 | Controlled release naproxen tablets |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2175091C (en) |
-
1996
- 1996-04-26 CA CA002175091A patent/CA2175091C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2175091A1 (en) | 1997-10-27 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |