Patent Grant
8846680
1. Technical Field
The invention relates to the field of animal health. In particular, the invention relates to novel oral pharmaceutical compositions comprising, as part of the pharmaceutically active compounds, pimobendan.
2. Background Information
Pimobendan, (4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-3(2H)-pyridazone) is disclosed in U.S. Pat. No. 4,361,563, herein incorporated by reference in its entirety. Pimobendan is a cardiotonic, hypotensive and anti-thrombotic. Said substance is useful in the treatment of congestive heart failure.
Pimobendan hardly dissolves in water. The resorption of pimobendan when administered orally is prone to considerable inter- and intra-individual fluctuations if the active substance is incorporated in known or conventional pharmaceutical forms for oral administration. The reason for this is that pimobendan is characterized by a low solubility in aqueous media and a very highly pH-dependent solubility. To overcome this, hard gelatine capsules were used containing pimobendan formulated with citric acid, in particular at a weight ratio of pimobendan to citric acid of between 1:10 and 1:20 (U.S. Pat. No. 5,364,646, herein incorporated by reference in its entirety). However, the high quantity of citric acid and the acidic taste of citric acid is not readily accepted by most animals—thus, such capsules have to be force-fed to the animals or mixed with food prior to application.
The problem underlying the present invention was to provide a pimobendan solid formulation readily acceptable by mammalian subjects, especially small animals.
The invention relates to novel solid formulations comprising as a pharmaceutically active compound pimobendan or a pharmaceutically acceptable salt thereof which is homogenously dispersed in a polyvalent acid and a flavor acceptable to small animals. Preferably, such solid formulations are granules or tablets. Most preferred is a tablet characterized in that the tablet comprises, 1.25 mg, 2.5 mg, 5 mg or 10 mg pimobendan, and further comprises lactose, corn starch, croscarmellose-sodium, citric acid, preferably at an amount of 50 mg/g of the solid formulation, artificial beef flavor, polyvidone, colloidal anhydrous silica and magnesium stearate.
The invention further relates to fluid-bed granulation processes for production of the solid formulations comprising the following steps:
Step g) is omitted if the solid formulation is a granule. If the solid formulation is a tablet, step g) is carried out.
Furthermore, the invention relates to a method of prevention and/or treatment of diseases wherein cardiotonic, hypotensive and anti-thrombotic substances have a therapeutic benefit, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a solid formulation prepared as described above.
Preferred is a method of prevention and/or treatment of congestive heart failure, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a solid formulation according to the invention as disclosed above. Most preferably, the method comprises administering a tablet according to the invention, as defined above.
Furthermore, the invention relates to a method for manufacturing a medicament for the prevention and/or treatment of congestive heart failure, Additionally, the invention relates to a method for manufacturing a medicament for the prevention and/or treatment of congestive heart failure, characterised in that a tablet comprising, 1.25 mg, 2.5 mg, 5 mg or 10 mg pimobendan and further comprising lactose, corn starch, croscarmellose-sodium, 50 mg/g citric acid, artificial beef flavor, polyvidone, colloidal anhydrous silica and magnesium stearate is made.
Reference signs: 1 Exhaust air ventilator; 2 Filter; 3 Pump; 4 Stirrer; 5 Aqueous Suspension of micronised pimobendan and binder solution (PVP, HPMC, starch, gelatine); 6 Heating device for inlet air; 7 Sieve; 8 Nozzle, aqueous suspension is sprayed onto powder bed (citric acid, lactose, starch, flavour); 9 Powder bed
Before the embodiments of the present invention it must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to “a tablet” includes a plurality of such tablets, reference to the “carrier” is a reference to one or more carriers and equivalents thereof known to those skilled in the art, and so forth. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. All given ranges and values may vary by 1 to 5% unless indicated otherwise or known otherwise by the person skilled in the art. Accordingly, the term “about” is not used in the description.
Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are described. All publications mentioned herein are incorporated herein by reference for the purpose of describing and disclosing the substances, excipients, carriers, and methodologies as reported in the publications which might be used in connection with the invention. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
The solution to the above technical problem is achieved by the description and the embodiments characterized in the claims.
To overcome the difficulties in the art, a process was invented. Only the invention of this novel, fluid-bed granulation process allowed the formulation of solid formulations according to the invention. With the process according to the invention, it was possible to formulate a long-term stable, capable of being produced on a large scale, homogenously dispersed, fast-releasing solid formulation. Despite the large size, pimobendan was homogenously dispersed. Such solid formulations comprise a flavor suitable for small animals, which surprisingly still allows a formulation having a polyvalent acid and yet have a palatibility rate of more than 70%—in many cases more than 90%. Thus, the solid formulations according to the invention are a major step forward in therapeutic application as they do not have to be force-fed to the animal.
In a first important embodiment, the invention relates to a solid formulation, comprising pimobendan or a pharmaceutically acceptable salt thereof, see e.g. U.S. Pat. Nos. 4,361,563 or 5,364,646 (both herein incorporated by reference in its entirety), which is homogenously dispersed in a polyvalent acid selected from the group consisting of citric acid, acetic acid, maleic acid, tartaric acid and the anhydride of any of said polyvalent acids and mixtures thereof, and a flavor acceptable to small animals. Such flavors according to the invention preferably are selected from artificial beef flavours, artificical chicken flavours, pork liver extract, artificial meat flavour, honey flavour and the like. Said flavors not only disguise the taste of the polyvalent acid, but also the taste of pimobendan.
Preferably, the solid formulation according to the invention is a tablet or granule formulation. The granule formulation according to the invention is explained in more detail below. More preferably, the solid formulation is chewable.
The invention preferably also relates to a solid formulation according to the invention, further comprising one or several pharmaceutically acceptable excipients. Excipients according to the invention are preferably selected from the group consisting of diluents, disintegrants, carriers, binders, flow regulators, lubricants and solvents. Any other excipients known to the skilled person and found suitable for the solid formulation according to the invention may also be comprised in the solid formulation according to the invention. See also Remington, J. P. The science and Practice of Pharmacy (2000). 20th ed. Lippincott Williams & Wilkins Publishers, Philiadelphia, US. More preferably, said excipients are carriers/disintegrants selected from the group lactose, starch, cellulose, microcrystalline cellulose and cellulose derivatives, e.g. methylcellulose, and the like. Any other carrier known to the skilled person and found suitable for the solid formulation according to the invention may also form part of the solid formulation according to the invention. See also Remington, J. P. The science and Practice of Pharmacy (2000). 20th ed. Lippincott Williams & Wilkins Publishers, Philiadelphia, US.
One or several binders according to the invention are preferably selected from the group consisting of polyvidone (used synonymously for povidone), methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxymethylcellulose, starch, gelatine, and the like. Any other binder known to the skilled person and found suitable for the solid formulation according to the invention may also be comprised in the solid formulation according to the invention. See also Remington, J. P. The science and Practice of Pharmacy (loc. cit.).
The solid formulation according to the invention may also comprise one or several flow regulators selected from the group consisting of silica, preferably colloidal anhydrous silica, calcium silicate, magnesium silicate, talc, and the like. Any other flow regulator known to the skilled person and found suitable for the solid formulation according to the invention may also be incorporated into the solid formulation according to the invention. See also Remington, J. P. The science and Practice of Pharmacy (loc. cit.).
The solid formulation according to the invention may also comprise one or several disintegrants selected from the group consisting of croscarmellose sodium, sodium starch glycolate, pregelatinised starch, cross-linked polyvinylpyrrolidone and the like. Any other disintegrant known to the skilled person and found suitable for the solid formulation according to the invention may also form part of the solid formulation according to the invention. See also Remington, J. P. The science and Practice of Pharmacy (loc. cit.).
The solid formulation according to the invention may also comprise one or several lubricants selected from the group consisting of magnesium stearate, calcium stearate, glyceryl behenate, polyethylene glycol, stearic acid, talc and the like. Any other lubricant known to the skilled person and found suitable for the solid formulation according to the invention may form part of the solid formulation according to the invention. See also Remington, J. P. The science and Practice of Pharmacy (loc. cit.).
The invention preferably also relates to a solid formulation according to the invention, characterized in that the carriers are starch and lactose. The invention preferably also relates to a solid formulation according to the invention, characterized in that the lactose consists of coarse particles greater than 200 μm in size. The person skilled in the art knows other types of lactose which are suitable as well as carrier according to the invention, e.g. fine lactose equal or smaller than 200 μm in size or spray-dried lactose. Preferred is lactose consisting of coarse particles greater than 200 μm in size.
The invention preferably also relates to a solid formulation according to the invention, characterized in that the starch or various starches are selected from the group consisting of native starch, gelatinized starch, partly gelatinized starch, starch powder, starch granules, chemically modified starch and swellable, physically modified starch.
The invention preferably also relates to a solid formulation according to the invention, characterized in that the starch is corn starch.
The invention preferably also relates to a solid formulation according to the invention, comprising 0.5 to 20 mg of pimobendan. The more preferred solid formulation contains 1 to 10 mg of pimobendan. The even more preferred solid formulation contains 1.25 to 5 mg of pimobendan. Most preferred solid formulations contain 1.25 mg, 2.5 mg, 5 mg or 10 mg of pimobendan.
The invention preferably also relates to a solid formulation according to the invention, comprising a content of 1:10-1:40 of pimobendan in relation to citric acid anhydride. The preferred ratio is 1:20.
The invention preferably also relates to a solid formulation according to the invention, characterized in that the weight of the whole solid formulation is in the range of 250 to 3000 mg, with a more preferred weight range of 500 mg to 2000 mg, and most preferred weight of 500 mg, 1000 mg or 2000 mg.
The invention preferably also relates to a solid formulation according to the invention, characterized in that the solid formulation is produced by a fluid-bed granulation process comprising or consisting of the steps:
Step g) is omitted if the solid formulation is a granule. If the solid formulation is a tablet, step g) is carried out.
The invention preferably also relates to a solid formulation according to the invention, characterized in that the solid formulation is produced by a fluid-bed granulation process comprising or consisting of the steps:
Step g) is omitted if the solid formulation is a granule. If the solid formulation is a tablet, step g) is carried out.
The invention preferably relates to a granule formulation as obtained by the process above that can either be administered in the granular form or as tablets after compressing the final granules to tablets. Therefore, the solid formulation according to the invention preferably is a granule (or a plurality of such granules) or a tablet. The administration of the granules can take place by mixing with food or by offering the granules directly to the animal, e.g. in a bowl. The application of the granular form will allow an individual dosing of pimobendan according to the body weight of the animal.
The tablets according to the invention have surprising advantages. The dissolution profile ensures immediate release of pimobendan. Surprisingly, it could be demonstrated that while compressing the final granules as mentioned above, a decrease in the dissolution characteristics is not observed. By ensuring an immediate release profile of pimobendan, the amount of drug to be administered can be kept as low as possible, thereby improving the safety profile, which is especially important for long-term treatment.
Furthermore, the dosing accuracy of the tablet is excellent. This is due to the fact that in accordance with the manufacturing process according to this invention, an excellent uniformity of pimobendan content is achieved. Furthermore, the tablets can be broken into two halves so that half the dose per tablet can be administered. Compared with the existing gelatine capsule, the dosing accuracy and compliance of both the animal and the animal owner are assured. This is even more important since the drug is administered for a chronic condition and long-term treatment.
Also, the palatability of the tablet is excellent. More than 90% of the dogs to whom the tablet according to this invention was given accepted the tablet voluntarily with only the tablet offered in a bowl. Compared with the existing gelatine capsule, the ease of administration has increased compliance with the prescribed treatment regime. This is important since the drug is administered for a chronic condition.
The invention preferably also relates to a tablet according to the invention, characterized in that the tablet is stable for at least 18 months at 25° C. and 60% relative humidity. In the examples, testing parameter assays are disclosed for degradation of pimobendan, dissolution, loss on drying, hardness and disintegration of the tablet. The tablets according to the invention are within the specification limits regarding degradation of pimobendan, dissolution, loss on drying, hardness and disintegration.
Suitable packaging materials for tablets according to the invention are selected from, but not limited to: aluminum/aluminum blisters, PVC/PVDC blisters, and HDPE (high density polyethylene bottles).
The invention preferably also relates to a tablet according to the invention, characterized in that the tablet is oblong in shape. For such a tablet, characteristics like crushing strength, disintegration, uniformity of weight and content uniformity fulfill the requirements of the European Pharmacopoeia (ISBN/ISSN 92-871-5106-7 of 4th Edition 2004, Vol. 4.8, European Directorate for the Quality of Medicines (EDQM), European Pharmacopoeia, 226 avenue de Colmar, F-67029 Strasbourg, France, http://www.pheur.org) and the United States Pharmacopoeia (http://www.usp.org; in print: USP-NF, catalog No. 2270001).
The invention preferably relates to a solid formulation, and most preferred a tablet according to the invention, characterized in that the solid formulation or tablet comprising 0.5-20 mg pimobendan, preferably of 1.25 mg, 2.5 mg, 5 mg or 10 mg pimobendan, and further comprises lactose (35-50% by weight relative to the dry mass of the solid formulation/tablet=(w/w)), corn starch (25-50% w/w), croscarmellose-sodium (1-5%), citric acid (2.5-10% w/w), artificial beef flavor (5-30% w/w), polyvidone (1-5% w/w), colloidal anhydrous silica (0.1-1, preferably 0.1-0.5% w/w) and magnesium stearate (0.25-1.5% w/w), wherein the percentage by weight of pimobendan contains preferably about 0.25% (w/w) and the sum of the percentages by weight of all ingredients of the solid formulation including pimobendan is 100% (w/w). A skilled man is in a position to prepare such solid formulations, preferably a tablet. Thus, the skilled man knows that he can add to 0.25% (w/w) pimobendan at most 32.625% (w/w) corn starch, 4% (w/w) croscarmellose-sodium 5% (w/w) citric acid, 20% (w/w) artificial beef flavor, 4% (w/w) polyvidone, colloidal, 0.5% (w/w) anhydrous silica, 1% (w/w) magnesium stearate if the amount of lactose to be 32.625% (w/w). Moreover, the skilled man also knows, that if he decided to reduce the amount of the artificial beef flavor, for example, to the minimum of 5% (w/w), he can increase the amount of lactose, for example, to 47.625% (w/w). The invention also relates to a solid formulation, preferably a tablet, comprising about 0.25% (w/w) pimobendan and any of the above other ingredients of the solid formulation, preferably the tablet, in the range given above so that the sum of the amounts by weight of the individual formulation ingredients is 100%.
The present invention is also directed to a solid formulation, preferably to a tablet, which comprises 1 mg pimobendan, 100-200 mg lactose, 100-200 mg corn starch, 4-20 mg croscarmellose-sodium, 10-40 mg citric acid anhydrous, 20-120 mg artificial beef flavor, 4-20 mg polyvidone, 0.4-4 mg colloidal anhydrous silica, and 1-6 mg magnesium stearate for each 400 mg of total weight of the solid formulation, preferably a tablet. According to a further embodiment of the present invention, the solid formulation, preferably the tablet, comprises 1 mg pimobendan, 120-180 mg lactose, 120-180 mg corn starch, 8-18 mg croscarmellose-sodium, 15-30 mg citric acid anhydrous, 40-100 mg artificial beef flavor, 8-18 mg polyvidone, 0.5-2 mg colloidal anhydrous silica, and 2-5 mg magnesium stearate for each 400 mg of total weight of the solid formulation/tablet. For example, the present invention relates to a solid formulation comprising for each 400 mg of total weight: 1 mg pimobendan, 20 mg citric acid anhydrous, 130.5 mg lactose, 130.5 mg corn starch, 16 mg polyvidone, 16 mg croscarmellose-sodium, 80 mg artificial beef flavor, 4 mg magnesium stearate, and 2 mg colloidal anhydrous silica. A skilled man is in a position to prepare such solid formulation/tablet. The skilled man also knows that he can vary the amount of each ingredient of the solid formulation/tablet within the ranges given above in that the total weight of the solid formulation/tablet for each 1 mg pimobendan is 400 mg. For example, the amount of lactose may be 100, 101, 102, . . . 108, 109, 110 etc.; 111, 112, . . . 118, 119, 120 etc; 121, 122, . . . 128, 129, 120 etc; 131, 132, . . . 138, 139, 140 etc; 141, 142, . . . 148, 149, 150 etc; 151, 152, . . . 158, 159, 160 etc; 161, 162, . . . 168, 169, 170 etc; 171, 172, . . . 178, 179, 180 etc; 108, 182, . . . 188, 189, 190 etc; 191, 192, . . . 198, 199, 200 mg for each 400 mg of total weight of the solid formulation, preferably a tablet, comprising about 1 mg pimobendan. In the same manner the amount of corn starch may be 100, 101, 102, . . . 108, 109, 110 etc.; 111, 112, . . . 118, 119, 120 etc; 121, 122, . . . 128, 129, 120 etc; 131, 132, . . . 138, 139, 140 etc; 141, 142, . . . 148, 149, 150 etc; 151, 152, . . . 158, 159, 160 etc; 161, 162, . . . 168, 169, 170 etc; 171, 172, . . . 178, 179, 180 etc; 108, 182, . . . 188, 189, 190 etc; 191, 192, . . . 198, 199, 200 mg for each 400 mg of total weight of the solid formulation, preferably a tablet, comprising about 1 mg pimobendan. Furthermore, the amount of citric acid anhydrous may be 10, 11, 12, . . . 18, 19, 20 etc.; 21, 22, . . . 28, 29, 30 etc; 31, 32, . . . 38, 39, 40 mg for each 400 mg of total weight of the solid formulation, preferably a tablet comprising about 1 mg pimobendan. Furthermore, the amount of artificial beef flavor may be 20, 21, 22, . . . 28, 29, 30 etc.; 31, 32, . . . 38, 39, 40 etc; 41, 42, . . . 48, 49, 50 etc; 50, 51, 52, . . . 58, 59, 60 etc.; 61, 62, . . . 68, 69, 70 etc; 71, 72, . . . 78, 79, 80 etc, 81, 82, 83, . . . 88, 89, 90 etc.; 91, 92, . . . 98, 99, 100 etc; 101, 102, . . . 108, 109, 110 etc; 111, 112, . . . 118, 119, 120 mg for each 400 mg of total weight of the solid formulation, preferably a tablet, comprising about 1 mg pimobendan. Furthermore, the amount of polyyidone may be 4, 5, 6, . . . 8, 9, 10 etc.; 11, 12, . . . 18, 19, 20 mg for each 400 mg of total weight of the solid formulation, preferably a tablet, comprising about 1 mg pimobendan. Furthermore, the amount of croscarmellose-sodium may be 4, 5, 6, . . . 8, 9, 10 etc.; 11, 12, . . . 18, 19, 20 mg for each 400 mg of total weight of the solid formulation, preferably a tablet, comprising 1 mg pimobendan. Furthermore, the amount of magnesium stearate may be 1.0, 1.1, 1.2, . . . 1.8, 1.9, 2.0 etc.; 2.1, 2.2, . . . 2.8, 2.9, 3.0 etc; 3.1, 3.2, . . . 3.8, 3.9, 40 etc; 4.0, 4.1, 4.2, . . . 4.8, 4.9, 5.0 etc.; 5.1, 5.2, . . . 5.8, 5.9, 6.0 mg for each 400 mg of total weight of the solid formulation, preferably a tablet, comprising about 1 mg pimobendan. Furthermore, the amount of colloidal anhydrous silica may be 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 1.0, 1.1, 1.2, . . . 1.8, 1.9, 2.0 etc.; 2.1, 2.2, . . . 2.8, 2.9, 3.0 etc; 3.1, 3.2, . . . 3.8, 3.9, 4.0 mg for each 400 mg of total weight of the solid formulation, preferably a tablet, comprising about 1 mg pimobendan. A skilled man is in a position to prepare any of such inventive solid formulation, preferably as a tablet.
In another important embodiment, the invention relates to a fluid-bed granulation process comprising the following steps:
Step g) is omitted if the solid formulation is a granule. If the solid formulation is a tablet, step g) is carried out.
The invention preferably relates to a fluid-bed granulation process comprising the following steps:
Step g) is omitted if the solid formulation is a granule. If the solid formulation is a tablet, step g) is carried out.
Another embodiment is a method of prevention and/or treatment of diseases wherein cardiotonic, hypotensive and anti-thrombotic substances have a therapeutic benefit, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a solid formulation according to the invention as disclosed above. Preferred is a method of prevention and/or treatment of congestive heart failure, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a solid formulation according to the invention as disclosed above. Most preferably, the method comprises administering a tablet according to the invention, characterized in that the tablet comprises 1.25 mg, 2.5 mg, 5 mg or 10 mg pimobendan, and further comprises lactose, corn starch, croscarmellose-sodium, citric acid preferably at an amount of 50 mg/g, artificial beef flavor, polyvidone, colloidal anhydrous silica and magnesium stearate. Preferably also, such treatment is by orally administering the solid formulation according to the invention.
The mammal according to the invention is preferably a mammal selected from the group consisting of dogs, cats and rodents such as rabbits.
Furthermore, the invention relates to a method for manufacturing a medicament for the prevention and/or treatment of congestive heart failure, characterised in that a solid formulation according to the invention is used. Preferably, the invention relates to a method for manufacturing a medicament for the prevention and/or treatment of congestive heart failure, characterised in that a tablet consisting of 1.25 mg, 2.5 mg, 5 mg or 10 mg pimobendan and further consisting of lactose, corn starch, croscarmellose-sodium, 50 mg/g citric acid, artificial beef flavor, polyvidone, colloidal anhydrous silica and magnesium stearate is used.
The present invention furthermore relates to a kit, which comprises a solid formulation, preferably a tablet according to the present invention described herein, and a package leaflet or user instruction including the information concerning how the solid formulation, preferably the tablet, is to used via the oral route for the prevention and/or treatment of congestive heart failure in a mammal in need of such prevention or treatment, preferably in a dog, cat or rodent.
The following examples serve to further illustrate the present invention; but the same should not be construed as limiting the scope of the invention disclosed herein.
Appearance: brownish, oblong tablets, with breakline.
1. Granulating
2. Screening
3. Final Mixing
4. Compression
5. Packaging
A study to investigate the palatability of pimobendan-containing tablets was carried out. For a period of four days, two products were given to twenty or ten dogs, respectively, for voluntary uptake. For example, the following formulations with a content of 5 mg/500 mg active ingredient were examined:
In case of Ch. 010123 in competition with the identical formulation in granulated format, a voluntary uptake was observed in 36 out of 40 possible opportunities (i.e. when offered to 10 dogs for 10 days),. This compares to an acceptance rate of 90.0%.
In case of Ch. 010222 in competition with a formulation in granulated format of equal quantity with 30% flavor, a voluntary uptake was observed in 31 out of 40 possible opportunities. This compares to an acceptance rate of 77.5%.
Examples for representative dissolution profiles of the tablet according to this invention are as disclosed in
Examples for representative dissolution profiles of the tablet according to this invention are as disclosed in
Examples for representative dissolution profiles of the tablet according to this invention are as disclosed in
Examples for representative dissolution profiles of the tablet according to this invention are as disclosed in
Examples for representative dissolution profiles of the tablet according to this invention are as disclosed in
Samples were taken from both the final blend before tabletting and from the tabletting process. The following results demonstrate the uniformity of pimobendan content.
The tablets according to this invention were part of an content uniformity test for the broken tablets. 10 tablets were taken from the beginning, middle and end of the tabletting process and broken into two halves. The pimobendan content was determined.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10 2004 011 512 | Mar 2004 | DE | national |
This application is a divisional of pending U.S. patent application Ser. No. 11/072,207 filed on Mar. 4, 2005, which is incorporated herein by reference. This application also claims priority under 35 U.S.C. 119 (a) German Patent Application No. 10 2004 011 512, filed on Mar. 8, 2004.
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| Number | Date | Country | |
|---|---|---|---|
| 20120148640 A1 | Jun 2012 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11072207 | Mar 2005 | US |
| Child | 13402292 | US |
