EP2432459A2 - Oral compositions of celecoxib - Google Patents
Oral compositions of celecoxibInfo
- Publication number
- EP2432459A2 EP2432459A2 EP10722778.7A EP10722778A EP2432459A2 EP 2432459 A2 EP2432459 A2 EP 2432459A2 EP 10722778 A EP10722778 A EP 10722778A EP 2432459 A2 EP2432459 A2 EP 2432459A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- pharmaceutical composition
- celecoxib
- sodium
- starch
- calcium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- 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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
Abstract
The present invention relates to disintegrant free oral compositions comprising celecoxib. It further relates to processes for preparing such compositions. It also relates to method of treating cyclooxygenase-2 mediated disorders using compositions of the present invention.
Description
ORAL COMPOSITIONS OF CELECOXIB
Technical Field of the Invention
The present invention relates to disintegrant free oral compositions of celecoxib. It also relates to the processes for preparing such compositions. Further, it relates to method of treating cyclooxygenase-2 mediated disorders using compositions of the present invention.
Background of the Invention
Celecoxib is a non-steroidal anti-inflammatory drug belonging to the class of selective cyclooxygenase-2 inhibitors. Chemically it is 4-[5-(4-methylphenyl)-3- (trifluoromethyl) pyrazol-1-yl] benzenesulfonamide.
Celecoxib, as a compound is disclosed in U.S. Patent No. 5,466,823 assigned to G.D. Searle & Co. This patent describes a class of 1,5-diaryl pyrazoles and their salts together with processes for the preparation of such compounds. U.S. Patent No. 5,760,068 assigned to G.D. Searle & Co. describes the use of 1,5- diaryl pyrazolyl benzenesulfonamide compounds (including celecoxib) in the treatment of pathological conditions associated with rheumatoid arthritis and osteoarthritis.
Celecoxib has unique physical and chemical properties, which present various problems in formulating effective oral compositions of celecoxib. Celecoxib has a low solubility in aqueous media. Further it is a fluffy material, with relatively low bulk and tap densities. In addition, celecoxib has certain undesirable flow characteristics, for example, it is sticky and can adhere to surfaces. Celecoxib shows a pH dependent solubility, wherein its solubility increases in highly basic pH. These properties present a challenge in developing a formulation of celecoxib effective for oral administration. Presently celecoxib is being marketed by Pharmacia Corporation under the trade name Celebrex® in a capsule dosage form containing either 100 mg or 200 mg of the drug.
EP Patent No. 1 049 467 Bl covers the marketed formulation of celecoxib. It describes orally deliverable compositions of celecoxib comprising particulate celecoxib in
an intimate mixture with one or more pharmaceutically acceptable excipients, wherein said pharmaceutically acceptable excipients include a diluent, binder, disintegrant, surfactant and lubricant. It has been stated in one of the examples of the present invention that the celecoxib availability from the wet granulated solid compositions can be improved by reducing the particle size, increasing the wetting properties of celecoxib (by including a wetting agent like sodium lauryl sulphate in the granulating fluid) and improving dispersibility (by including disintegrant like croscarmellose sodium in the granulation).
Disintegrants constitute an important part of the formulation of tablets and capsules of a poorly soluble, fluffy and sticky drug like celecoxib. A disintegrant facilitates break- up or disintegration of a tablet into particles after administration. Disintegrants also improve the drug dissolution from encapsulated dosage forms. Encapsulation of solid material often times results in a plug formation, which delays the disintegration and dissolution of the drug from the capsules. Disintegrants improve the dissolution of the contents of the capsule by promoting liquid penetration into the plug and breaking the plug into smaller particles. But the addition of another excipient (i.e. disintegrant) further leads to an increase in the cost of the dosage form.
The present inventors have developed a disintegrant free oral composition comprising celecoxib. It provides a reduction in total dosage form weight as well as decreasing the cost; without compromising the dissolution properties of the dosage form. The present formulation releases at least 70% of celecoxib in one-hour without the use of a disintegrant. The present invention provides a simple and economical method for preparing orally effective compositions of celecoxib.
Summary of the Invention
In one general aspect the present invention provides for a pharmaceutical composition, which includes celecoxib or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is free of disintegrant. Embodiments may include one or more of the following features. For example, the d09 of the celecoxib particles is less than 200 μm, less than 150 μm, or less than 25 μm.
The celecoxib is present in an amount of about 10 mg to about 1000 mg and may include one or more pharmaceutically acceptable excipients selected from one or more of
diluents, binders, wetting agents, lubricants, anti- adherents or mixtures thereof.
Suitable diluents may be lactose USP; lactose USP, anyhydrous; lactose USP, spray dried; starch USP; directly compressible starch; mannitol USP; sorbitol; dextrose monohydrate; microcrystalline cellulose NF; dibasic calcium phosphate dihydrate NF; sucrose-based diluents; confectioner's sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate NF; calcium lactate trihydrate granular NF; dextrates, NF (e.g., Emdex®); Celutab®; dextrose (e.g., Cerelose®); inositol; hydrolyzed cereal solids such as the Maltrons and Mor-Rex™; amylose; Rexcel®; powdered cellulose; calcium carbonate; glycine; bentonite; and/or polyvinylpyrrolidone. Suitable binders may be acacia; tragacanth; sucrose; gelatin; glucose; starch; cellulose materials such as, methylcellulose and sodium carboxymethylcellulose (e.g.,
Tylose®); alginic acid and salts of alginic acid; magnesium aluminum silicate; polyethylene glycol; guar gum; polysaccharide acids; bentonites; polyvinylpyrrolidone; polymethacrylates; hydroxypropylmethylcellulose (HPMC); hydroxypropylcellulose (Klucel®); ethylcellulose (Ethocel®); and/or pregelatinized starch (such as National 1511 and Starch 1500).
Suitable wetting agents may be oleic acid; glyceryl monostearate; sorbitan monooleate; sorbitan monolaurate; triethanolamine oleate; polyoxyethylene sorbitan monooleate; polyoxyethylene sorbitan monolaurate; sodium oleate; and sodium lauryl sulfate.
Suitable lubricants/ antidherents may be glyceryl behapate (Compritol® 888); stearates (magnesium, calcium, and sodium); stearic acid; hydrogenated vegetable oils (e.g., Sterotex®); talc; waxes: Stearowet™; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; polyethylene glycols (e.g., Carbowax® 4000 and Carbowax® 6000); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate.
The pharmaceutical composition is in the form of tablets, pills, capsules, lozenges, sachets or pastilles. For example, the pharmaceutical compositions may be tablets or capsules. The pharmaceutical composition should release not less than 70 % of celecoxib within one hour.
In another general aspect there is provided method for the treatment or prophylaxis of a cyclooxgenase-2 mediated condition or disorder. The method includes administering a pharmaceutical composition which includes celecoxib or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is free of disintegrant. Detailed Description of the Invention
The present invention is directed to disintegrant free oral compositions comprising celecoxib. It further relates to processes for preparing such compositions.
The phrase "pharmaceutically-acceptable salts", as used herein, includes salts commonly used to form alkali metal salts and addition salts of free acids or free bases. Suitable pharmaceutically acceptable acid addition salts of celecoxib may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
Appropriate organic acids include aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, such as formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic, p- hydroxybenzoic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, b-hydroxybutyric, salicyclic, galactaric and galacturonic acid.
Suitable pharmaceutically-acceptable base addition salts of celecoxib include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Particularly compositions of the invention comprise celecoxib in its free form.
The term "do 9" as used herein with reference to the size of celecoxib particles, indicate that about 90% of particles measured have a size less than the defined d0 9 value, and that about 10% of particles measured have a size greater than the defined d0 9 value.
The phrase "disintegrant free oral compositions" as used herein refers to the oral compositions of celecoxib, which do not contain any disintegrant. However, when the
compositions of the present invention are in the form of a tablet an extragranular disintegrant may be added.
The compositions of the present invention comprise celecoxib having a d0 9 less than 200 μm, particularly less than 150 μm, more particularly less than 50 μm and most particularly less than 25 μm.
Celecoxib is present in an amount of 10 mg to 1000 mg; 50 mg to 800 mg; 75 mg to 400 mg; and/or 100 mg to 200 mg in the compositions of the present invention.
The disintegrant free oral compositions of the present invention further include one or more pharmaceutically acceptable excipients selected from the group consisting of diluents, binders, wetting agents, lubricants and anti- adherents.
Suitable examples of diluents include, either individually or in combination, lactose USP; lactose USP, anyhydrous; lactose USP, spray dried; starch USP; directly compressible starch; mannitol USP; sorbitol; dextrose monohydrate; microcrystalline cellulose NF; dibasic calcium phosphate dihydrate NF; sucrose-based diluents; confectioner's sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate NF; calcium lactate trihydrate granular NF; dextrates, NF (e.g., Emdex®); Celutab®; dextrose (e.g., Cerelose®); inositol; hydrolyzed cereal solids such as the Maltrons and Mor-Rex™; amylose; Rexcel®; powdered cellulose; calcium carbonate; glycine; bentonite; polyvinylpyrrolidone; and the like. Lactose is the primary diluents used in the compositions of the present invention.
Suitable examples of binding agents include, either individually or in combination, acacia; tragacanth; sucrose; gelatin; glucose; starch; cellulose materials such as, methylcellulose and sodium carboxymethylcellulose (e.g., Tylose®); alginic acid and salts of alginic acid; magnesium aluminum silicate; polyethylene glycol; guar gum; polysaccharide acids; bentonites; polyvinylpyrrolidone; polymethacrylates; hydroxypropylmethylcellulose (HPMC); hydroxypropylcellulose (Klucel®); ethylcellulose (Ethocel®); pregelatinized starch (such as National 1511 and Starch 1500). Polyvinylpyrrolidone is a preferred binding agent.
Examples of wetting agents include, individually or in combination, oleic acid; glyceryl monostearate; sorbitan monooleate; sorbitan monolaurate; triethanolamine oleate;
polyoxyethylene sorbitan monooleate; polyoxyethylene sorbitan monolaurate; sodium oleate; and sodium lauryl sulfate. Wetting agents that are anionic surfactants are preferred. Compositions of the present invention include sodium lauryl sulfate.
Suitable lubricants and/or glidants include, either individually or in combination, glyceryl behapate (Compritol® 888); stearates (magnesium, calcium, and sodium); stearic acid; hydrogenated vegetable oils (e.g., Sterotex®); talc; waxes: Stear-o-wet™; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; polyethylene glycols (e.g., Carbowax® 4000 and Carbowax® 6000); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate. Magnesium stearate is a preferred lubricant being used in the compositions of the present invention.
Other carrier materials (such as anti-adherent agents, colorants, flavors, sweeteners and preservatives) that are known in the pharmaceutical art and can be included in compositions of the present invention.
According to one of the embodiments, the disintegrant free oral compositions of the present invention are in the form of tablets, pills, capsules, lozenges, sachets or pastilles.
The composition of the present invention may be prepared in accordance with methods well known to the person skilled in the field of pharmacy. For example, wet granulation, dry granulation, compaction or encapsulation method can be employed to prepare the compositions of the present invention. Particularly, the compositions of the present invention are prepared by wet granulation or dry compaction.
According to another embodiment, the disintegrant free oral compositions of the present invention show a similar release profile at four different pH values i.e., highly basic pH 12, very slightly acidic pH 6.8, slightly acidic pH 4.5 and highly acidic pH 1.2. The present invention also relates to a method of treating a disorder where treatment with cyclooxygenase-2 inhibitor is indicated (for example, osteoarthritis, rheumatoid arthritis and ankylosing spondylitis) by administering an effective amount of a composition of the present invention to a patient in need of such treatment.
The methods of utilizing the pharmaceutical compositions of the present invenction can include one or more of the following embodiments. For example in one
embodiment, the method further comprises concurrently or sequentially administering one or more of pregabalin, cyclophosphamide, capecitabine, temozolomide, statins and other anticancer agents. In another embodiment, the composition further comprises one or more of pregabalin, cyclophosphamide, capecitabine, temozolomide, statins and other anticancer agents.
The following examples represent various embodiments of the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
EXAMPLE
Oral Capsule Containing Celecoxib
Process:
1. Celecoxib, polyvinylpyrrolidone and lactose were sifted through a sieve.
2. Material of step 1 was then mixed in a high shear mixer.
3. Sodium lauryl sulphate was dissolved in purified water to prepare a solution. 4. Material of step 2 was granulated using the solution of step 3. 5. Wet mass of step 4 was then dried in a fluid bed dryer. 6. The dried granules were then sifted and milled.
7. Magnesium stearate was sifted through a sieve and blended with the granules of step 6.
8. Finally, the above blend was filled in hard gelatin capsules of suitable size.
Comparative dissolution data of the disintegrant free compositions of the present invention with the marketed formulation of celecoxib i.e. Celebrex® are given in Tables 1, 2, 3 and 4. Capsules were tested for drug release in four different media.
Table 1
Drug release was determined in 1000 ml of disodium phosphate buffer (containing 1% sodium lauryl sulphate; pH 12) at 37 0C using USP apparatus II with paddle speed at 50 rpm.
Table 2
Drug release was determined in 1000 ml of acetate buffer (containing 1% sodium lauryl sulphate; pH 4.5) at 37 0C using USP apparatus II with paddle speed at 50 rpm.
Table 3
Drug release was determined in 1000 ml of 0.1 N HCl (containing 1% sodium lauryl sulphate; pH 1.2) at 37 0C using USP apparatus II with paddle speed at 50 rpm.
Table 4
Drug release was determined in 1000 ml of sodium phosphate buffer (containing 1% sodium lauryl sulphate; pH 6.8) at 37 0C using USP apparatus II with paddle speed at 50 rpm.
While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the invention detailed in the text can be made without departing from the spirit and scope of the invention. Accordingly, it is not intended that the invention be limited, except as by the appended claims.
Claims
Claims 1. A pharmaceutical composition comprising celecoxib or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is free of disintegrant. 2. The pharmaceutical composition of claim 1, wherein the d09 of celecoxib particles is less than 200 μm. 3. The pharmaceutical composition of claim 2, wherein the do 9 of celecoxib particles is less than 150 μm. 4. The pharmaceutical composition of claim 2, wherein the d09 of celecoxib particles is less than 25 μm. 5. The pharmaceutical composition of claim 1, wherein celecoxib is present in an amount of about 10 mg to about 1000 mg. 6. The pharmaceutical composition of claim 1, further comprising one or more pharmaceutically acceptable excipients selected from one or more of diluents, binders, wetting agents, lubricants, anti-adherents, or mixtures thereof. 7. The pharmaceutical composition of claim 6, wherein the one or more diluents comprise lactose USP; lactose USP, anyhydrous; lactose USP, spray dried; starch USP; directly compressible starch; mannitol USP; sorbitol; dextrose monohydrate; microcrystalline cellulose NF; dibasic calcium phosphate dihydrate NF; sucrose-based diluents; confectioner's sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate NF; calcium lactate trihydrate granular NF; dextrates, NF (e.g., Emdex®); Celutab®; dextrose (e.g., Cerelose®); inositol; hydrolyzed cereal solids such as the Maltrons and Mor-Rex™; amylose; Rexcel®; powdered cellulose; calcium carbonate; glycine; bentonite; and/or polyvinylpyrrolidone. 8. The pharmaceutical composition of claim 6, wherein the one or more binders comprise acacia; tragacanth; sucrose; gelatin; glucose; starch; cellulose materials such as, methylcellulose and sodium carboxymethylcellulose (e.g., Tylose®); alginic acid and salts of alginic acid; magnesium aluminum silicate; polyethylene glycol; guar gum; polysaccharide acids; bentonites; polyvinylpyrrolidone; polymethacrylates; hydroxypropylmethylcellulose (HPMC); hydroxypropylcellulose (Klucel®); ethylcellulose (Ethocel®); and/or pregelatinized starch (such as National 1511 and Starch
1500). 9. The pharmaceutical composition of claim 6, wherein the one or more wetting comprise oleic acid; glyceryl monostearate; sorbitan monooleate; sorbitan monolaurate; triethanolamine oleate; polyoxyethylene sorbitan monooleate; polyoxyethylene sorbitan monolaurate; sodium oleate; and sodium lauryl sulfate. 10. The pharmaceutical composition of claim 6, wherein the one or more lubricants/ antidherents comprise glyceryl behapate (Compritol® 888); stearates (magnesium, calcium, and sodium); stearic acid; hydrogenated vegetable oils (e.g., Sterotex®); talc; waxes: Stear-o-wet™; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; polyethylene glycols (e.g., Carbowax® 4000 and Carbowax® 6000); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate. 11. The pharmaceutical composition of claim 1 , wherein said composition is in the form of tablets, pills, capsules, lozenges, sachets or pastilles. 12. The pharmaceutical composition of claim 11, wherein said composition is in the form of tablets or capsules. 13. The pharmaceutical composition of claim 1, wherein said composition release not less than 70% of celecoxib in one hour. 14. A method for the treatment or prophylaxis of a cyclooxgenase-2 mediated condition or disorder comprising administering the pharmaceutical composition of claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1036DE2009 | 2009-05-20 | ||
| PCT/IB2010/052210 WO2010134025A2 (en) | 2009-05-20 | 2010-05-18 | Oral compositions of celecoxib |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP2432459A2 true EP2432459A2 (en) | 2012-03-28 |
Family
ID=42536343
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP10722778.7A Withdrawn EP2432459A2 (en) | 2009-05-20 | 2010-05-18 | Oral compositions of celecoxib |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP2432459A2 (en) |
| AU (1) | AU2010250800A1 (en) |
| CA (1) | CA2762388A1 (en) |
| WO (1) | WO2010134025A2 (en) |
| ZA (1) | ZA201108413B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2761212A1 (en) * | 2011-12-07 | 2013-06-07 | Pharmascience Inc. | Disintegrant-free delayed release doxylamine and pyridoxine formulation and process of it manufacturing |
| WO2015044961A2 (en) * | 2013-09-30 | 2015-04-02 | Intas Pharmaceuticals Limited | Pharmaceutical composition comprising capecitabine and cyclophosphamide |
| CA2958332A1 (en) | 2014-09-26 | 2016-03-31 | Intas Pharmaceuticals Ltd. | Pharmaceutical composition having improved content uniformity |
| US10350171B2 (en) | 2017-07-06 | 2019-07-16 | Dexcel Ltd. | Celecoxib and amlodipine formulation and method of making the same |
| US11826462B2 (en) | 2019-12-09 | 2023-11-28 | Nicoventures Trading Limited | Oral product with sustained flavor release |
| US11793230B2 (en) | 2019-12-09 | 2023-10-24 | Nicoventures Trading Limited | Oral products with improved binding of active ingredients |
| US11872231B2 (en) | 2019-12-09 | 2024-01-16 | Nicoventures Trading Limited | Moist oral product comprising an active ingredient |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SA99191255B1 (en) * | 1998-11-30 | 2006-11-25 | جي دي سيرل اند كو | celecoxib compounds |
| US20020077328A1 (en) * | 2000-07-13 | 2002-06-20 | Fred Hassan | Selective cyclooxygenase-2 inhibitors and vasomodulator compounds for generalized pain and headache pain |
| WO2009063367A1 (en) * | 2007-11-15 | 2009-05-22 | Pfizer Products Inc. | Dosage forms comprising celecoxib providing both rapid and sustained pain relief |
-
2010
- 2010-05-18 CA CA2762388A patent/CA2762388A1/en not_active Abandoned
- 2010-05-18 EP EP10722778.7A patent/EP2432459A2/en not_active Withdrawn
- 2010-05-18 AU AU2010250800A patent/AU2010250800A1/en not_active Abandoned
- 2010-05-18 WO PCT/IB2010/052210 patent/WO2010134025A2/en active Application Filing
-
2011
- 2011-11-16 ZA ZA2011/08413A patent/ZA201108413B/en unknown
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2010134025A2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2010250800A1 (en) | 2012-01-12 |
| CA2762388A1 (en) | 2010-11-25 |
| WO2010134025A3 (en) | 2011-11-10 |
| WO2010134025A2 (en) | 2010-11-25 |
| ZA201108413B (en) | 2012-09-26 |
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