Specification
Improved Formulations of Fenofibrate
This application claims the benefit of U.S. Provisional Application No. 60/666,192, filed on March 30,2005, and is a continuation-in-part application of U.S. Non-Provisional Application No. 11/321,157, filed on December 28,2005, wherein the disclosures of these two earlier applications are incorporated by reference in their entirety.
Background
Fenofibrate, (2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester), is one of the fibrate class of drugs. It is available as both capsules and tablets. In the United States, fenofibrate is marketed under the trade name Tricor® in tablet forms at a strength of 48 mg, 145 mg, 54 mg and 160 mg. Fenofibrate is apparently a prodrug. The active moiety is reportedly the metabolite fenofibric acid which is reported to be produced in the body by esterases. When dosing fenofibrate, apparently no intact fenofibrate is found in the plasma (Physician's Desk Reference, 58th ed., 2004, pages 522 -525 (PDR 2004)).
Fenofibrate is a very poorly soluble drug. Despite its poor solubility, it is reported to be well absorbed when dosed in the "fed state" and less so in the "fasted state". It is unclear what the bioavailability of the fenofibric acid really is, since much of it is understood to be metabolized to the glucuronide in both presystemic and first pass sites. The absolute bioavailability of fenofibrate cannot supposedly be determined since the compound is insoluble in media suitable for intravenous injection. Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabelled fenofibrate appeared hi urine, primarily as fenofibric acid and its glucuronide conjugate, and 25% was excreted in the feces (PDR 2004). The absorption of fenofibrate administered as Tricor® 54 mg or Tricor® 160 mg tablets is understood to be increased when administered with food. With Tricor® 54 mg or Tricor® 160 mg tablets, the extent of fenofibrate absorption is increased by approximately 35% when dosed with food (PDR 2004; Martindale 33rd ed., page 889).
Tricor® 54 mg or Tricor® 160 mg tablets contain, other than fenofibrate, colloidal silicon dioxide, crospovidone, lactose monohydrate, lecithin, microcrystalline cellulose, polyvinyl alcohol, povidone, sodium lauryl sulfate, sodium stearyl furnarate, talc, titanium dioxide and xanthan gum (PDR 2004). In addition, Tricor® 54 mg tablets contain D&C
Yellow No. 10, FD&C Yellow No. 6 and FD&C Blue No. 2 (PDF 2004). Other than fenofibrate, Tricor® 48 mg or Tricor® 145 mg tablets, which received marketing approval from U.S. Food and Drug Administration in November 2004, contain hypromellose 2910 (3cps), docusate sodium, sucrose, sodium lauryl sulfate, lactose monohydrate, silicified microcrystalline cellulose, crospovidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc, soybean lecithin and xanthan gum (Prescribing Information Document 04K-030-F534-1, Revised November 2004, Abbott Laboratories, North Chicago, IL, U.S.A.). Tricor® 48 mg tablets also contain D&C Yellow 10 aluminum lake, FD&C Yellow No. 6/sunset yellow FCF aluminum lake and FD&C Blue No. 2/indigo carmine aluminum lake.
Much effort has been expended to improve the formulation of fenofibrate. U.S. Patent Nos. 4,895,726 and 5,880,148 disclose co-micronizing the fenofibrate with surface active agents. U.S. Patent Nos. 6,074,670,6,277,405 and others disclose micronized fenofibrate coated onto hydrosoluble carriers with optional surface active agents. U.S. Patent No. 6,814,977 discloses fenofibrate dissolved in a medium chain glycerol ester of fatty acid, U.S. PatentNo. 6,719,999 discloses fenofibrate dissolved in glycerin, propylene glycol, or dimethylisosorbide and U.S. Patent No. 5,827,536 discloses fenofibrate dissolved in diethyleneglycol monoethyl ether.
Several patents disclose specific formulations of micronized fenofibrate with specific polymeric or surface active agent additives while several others describe emulsions and suspensions. U.S. Patent Application Publication .No. 20040087656 discloses fenofibrate of particle size less than 2000 nm with an improved bioavailability. U.S. Patent Application Publication No. 20030224059 discloses microparticles of active pharmaceutical ingredients, drug delivery vehicles comprising same, and methods for making them. The disclosure of US 20030224059 is incorporated herein by reference in its entirety.
U.S. Patent Application Publication No. 20040198646 discloses compositions comprising solutions of drugs in menthol, especially drugs that are poorly soluble in water, and to methods for making such compositions. The disclosure of US 20040198646 is incorporated in its entirety by reference.
Micronization of the drug and the addition of surface active agents have moderately raised the bioavailability of fenofibrate allowing the amount of drug dosed to be reduced from 100 mg per dose to 67 mg per dose and then subsequently to 54 mg per dose, all with the same bioavailability in the fed state. Nanoparticle formulations of the drug have further allowed the reduction of the dose to 48 mg per dose with the bioavailability of the "fasted
state" being reported as similar to the fed state. There is still room for much improvement since it is posited that the true bioavailability of fenofibrate is still relatively low. The current inventors have surprisingly found that a composition of fenofibrate dissolved in menthol and comprising surface active agents gives a much enhanced bioavailability well beyond anything previously disclosed. The inventors have also surprisingly found formulations with or without menthol of increased solubility and drug release of fenofibrate
Summary of the mvention
The present invention encompasses a composition for the treatment of elevated levels of triglycerides that comprises a therapeutically effective amount of fenofibrate or another fibrate drug that is intimately associated with menthol. The intimate association may be in the form of a solution of the fenofibrate or other fibrate in menthol but would encompass compositions where at least part of the drug has come out of such a solution due to a process that induces the precipitation of the drug, e.g, saturation such as reducing the volume of the solvent or cooling. The composition may be optionally absorbed in, or adsorbed on a solid carrier by methods exemplified by the teachings in US 2003-0224059 and US0198646-2004 .
The present mvention encompasses a composition for the treatment of elevated levels of triglycerides that comprises a therapeutically effective amount of fenofibrate or another fibrate drug that is dissolved in menthol and further comprises at least one surface active agent. The composition may be optionally absorbed on a solid carrier.
The present invention encompasses a composition that comprises a therapeutically effective amount of fenofibrate or another fibrate drug that is dissolved in menthol and further comprises at least one surface active agent. The composition can have a dissolution property in that, when tested in 50 ml 0.1 NHC1 at37°Cand 150 rpm, at least about 10%, 30% or 80% of the fenofibrate or other fibrate drug dissolved in 15 minutes. The composition can also have a dissolution property in that, when tested in 500 ml 0.5% sodium lauryl sulfate (SLS) in water at 37° C and 50 rpm, at least about 70% of the fenofibrate or other fibrate drug dissolved in 5 minutes.
The present invention encompasses a composition that comprises a therapeutically effective amount of fenofibrate or another fibrate drug that is dissolved in menthol and further comprises at least one surface active agent that when administered orally to beagle dogs shows a bioavailability of fenofibric acid based on Area Under the Curve (AUC) of the concentration v. time profile in plasma that is at least three times that of the Tricor® 54 mg product on a per milligram basis (when normalized to equal weight).
The present invention also encompasses the method of preparing a composition of the invention, which method comprises:
a) heating menthol to about 60 °C in order to effect melting thereof,
b) adding at least one surface active agent to the melt,
c) cooling the product of step b) to about 50 °C,
d) dissolving fenofibrate or another fibrate drug in the product of step c) with stirring,
e) cooling the product of step d) to room temperature to obtain the composition of the
invention, and
f) if capsules are desired, (A) dispensing the product of step e) into capsules, or (B)
alternatively adding a solid carrier such as microcrystalline cellulose, lactose or sorbitol,
to the product of step e), mixing well, cooling to room temperature and filling the powder
thus obtained into capsules.
The present invention encompasses a composition that comprises a therapeutically effective amount of fenofibrate or another fibrate drag that is dissolved in a surfactant mixture, such as a surfactant mixture comprising polyethylene glycol and Poloxamer, e.g., a surfactant mixture comprising Polyethylene Glycol (PEG) 1000 and Poloxamer 407, or a surfactant mixture comprising PEG 6000 and Poloxamer 407. The composition may be optionally absorbed or adsorbed on a solid carrier.
The present invention encompasses a composition that comprises a therapeutically effective amount of fenofibrate or another fibrate drug that is intimately associated with a surfactant mixture, such as a surfactant mixture comprising polyethylene glycol and Poloxamer, e.g., a surfactant mixture comprising PEG 1000 and Poloxamer 407, or a surfactant mixture comprising PEG 6000 and Poloxamer 407. This composition can have a dissolution property in that, when tested in 900 ml 0.5% sodium lauryl sulfate (SLS) in water at 37 °C and 50 rpm, at least about 40% of the fenofibrate or the other fibrate drug dissolved in 15 minutes and/or about 80% dissolved in 30 minutes. The intimate association may be in the form of a solution but would encompass compositions where at least part of the drug has come out of such a solution or has not fully dissolved due to e.g. saturation. When administered orally to beagle dogs, this composition of the invention shows a bioavailability of fenofibric acid, based on Area Under the Curve (AUC) of the concentration vs. time profile in plasma, that is at least about two times that of the Tricor® 54 mg product on a per milligram basis (when normalized to equal weight).
The present invention also encompasses a method of treating a patient for elevated triglyceride levels comprising administering to the patient a composition of fenofibrate that comprises a therapeutically effective amount of fenofibrate that is dissolved in menthol.
The present invention also encompasses a method of treating a patient for elevated triglyceride levels comprising administering to the patient a composition of fenofibrate that comprises a therapeutically effective amount of fenofibrate that is dissolved in menthol and farther comprises at least one surface active agent.
The present invention also encompasses a method of treating a patient for elevated triglyceride levels comprising administering to the patient a composition of fenofibrate that comprises a therapeutically effective amount of fenofibrate that is dissolved in PEG 1000 and Poloxamer 407.
The present invention also provides a method of treating a subject for elevated triglyceride levels comprising administering to the subject a composition comprising a therapeutically effective amount of fenofibrate or another fibrate drug in intimate association
with a surfactant mixture comprising PEG 6000 and Poloxamer 407.
i
Detailed Description of the Invention
There is a need to improve pharmaceutical compositions of fenofibrate, a drug used in treating hypertriglyceridemia. The term "fenofibrate" includes the 1-methylethyl ester of 2-[4-(4-chlorobenzoyl)-phenoxy]-2-methyl-propanoic acid and any pharmaceutically acceptable salts thereof. One aspect of this invention is to compositions of fenofibrate that is dissolved in menthol. Fenofibrate dissolves up to about 37% in melted menthol at 60°C. Formulations may be made where all the fenofibrate is dissolved in the menthol or where only some of the fenofibrate is so dissolved and the rest present in a solid form in the fully saturated menthol medium. In a preferred embodiment of the invention, the fenofibrate is rally dissolved in the menthol. In one embodiment of the invention, the menthol melt maybe filled into capsules in the liquid state or may be solidified, optionally milled, and filled into capsules. The capsules used for the liquid fill in one embodiment maybe hard gelatin capsules. In a preferred embodiment, the hard gelatin capsules are banded to prevent leakage. In a more preferred embodiment, the liquid formulation may be filled into soft-gel capsules. In another embodiment, the solidified menthol solution is optionally milled and filled into hard gelatin capsules or equivalent capsules of other materials such as materials of vegetable origin (e.g., HPMC). In another preferred embodiment, the melted menthol formulations may be further adsorbed on a solid carrier. Such solid carriers can be water soluble (hydrosoluble)
carriers such as sucrose, lactose, mannitol or sorbitol or water insoluble carriers such as starch, cellulose, microcrystalline cellulose, or calcium phosphate. The so formed powder can optionally be mixed with standard pharmaceutical additives to help flow or other properties and can be rilled into hard gelatin capsules or their equivalents. In another preferred embodiment, these powders can be optionally mixed with standard pharmaceutical excipients and formulated for tablet formation in a tablet press.
In this instant patent application, the term "another fibrate drug" or "other fibrate drug" includes fenofibric acid, any salt of fenofibric acid, any ester of fenofibric acid except the 1-methylethyl ester which is encompassed by the term "fenofibrate" as defined above, bezafibrate, binifibrate, clinofibrate, ciprofihrate, clofibrate, clofibride, etofibrate, etofylline clofibrate, gemfibrozil, pirifibrate, ronifibrate and simfibrate.
In the patent application, where fenofibrate or another fibrate drug is "intimately associated with menthol", "in intimate association with menthol", "intimately associated with a surfactant mixture" or "in intimate association with a surfactant mixture", it is intended to include
a) a solution of fenofibrate or the other fibrate drug in menthol, menthol surfactant
mixture, or surfactant mixture whether the menthol, menthol mixture or surfactant mixture is
a liquid, melt or solid (a solid solution);
b) a precipitate of fenofibrate or the other fibrate drug, or a co-precipitate of
fenofibrate or the other fibrate drug and any additive(s) from the menthol solution, menthol
surfactant mixture solution or surfactant mixture solution, which is coated by or in contact
with the saturated or supersaturated solution; and/or
c) fenofibrate or the other fibrate drug coated by or in contact with a saturated
solution of fenofibrate or the other fibrate drug in menthol, the menthol surfactant mixture or
surfactant mixture, wherein the remaining fenofibrate or the other fibrate drug does not
dissolve because the amount of fenofibrate or the other fibrate drug present is above
saturation.
The expressions, "intimately associated" and "in intimate association", exclude a simple physical mixture of two solids by blending or by granulation in a granulation liquid which does not at least partially dissolve the fenofibrate or the other fibrate drug.
In this patent application, when a quantitative value is preceded with "about", it is intended to cover ± 5% of the value. For instance, "about 50%" means from 47.5% to 52.5%.
Another aspect of this invention is a composition for the treatment of elevated levels of triglycerides that comprises a therapeutically effective amount of fenofibrate that is
dissolved in menthol and further comprises at least one surface active agent. Formulations may be made where all the fenofibrate is dissolved in the menthol or where only some of the fenofibrate is so dissolved and the rest present in a solid form in the fully saturated menthol medium. In a preferred embodiment, the fenofibrate is dissolved in the menthol plus surface active agent medium. In a more preferred embodiment, the fenofibrate is fully dissolved in the menthol which also comprises the surface active agent. Surface active agents that can be used with this embodiment comprise the Tweens, most preferably Tween 80, sodium ducosate, sodium lauryl sulfate, Cremophor, polyethylene glycols (PEG), preferably PEG 1000 or PEG 6000, and poloxamers, most preferably poloxamer 407. Preferred embodiments comprise by weight fenofibrate 2% to 40%, more preferably 5% to 25%, menthol 10% to 90%, more preferably 15% to 40%, and surface active agents 10% to 80%, more preferably 30% to 70%. In another preferred embodiment the melted menthol formulations maybe further adsorbed on, or absorbed in, a solid carrier. Such solid carriers can be water soluble (hydrosoluble) carriers such as sucrose, lactose or sorbitol or water insoluble carriers such as starch, cellulose, microcrystalline cellulose, or calcium phosphate. The so formed powder can optionally be mixed with standard pharmaceutical additives to help flow or other properties and can be filled into hard gelatin capsules or their equivalents. In another preferred embodiment these powders can be optionally mixed with standard pharmaceutical excipients and formulated for tablet formation in a tablet press or formed into a melt tablet.
In a preferred embodiment of a composition of the invention, a formulation comprised about 25.2% fenofibrate, about 23.4% menthol, about 11.7% sodium ducosate and about 39.7 % Tween 80. When the drug release of this formulation was tested in a small volume drag release test of 50 ml 0.1N HC1 at 37°C and 150 rpm, about 11.9% of the fenofibrate in the composition were dissolved in 15 minutes.
Another preferred embodiment of the composition of the invention comprises about 20.5% fenofibrate, about 37.9% menthol, about 9.5% sodium ducosate and about 32.2% Tween 80. When the drug release of this composition was tested in a small volume drug release test of 50 ml 0.1N HC1 at 37°C and 150 rpm, about 31.7% of the fenofibrate in the composition were dissolved in 15 minutes.
Another preferred embodiment of the composition of the invention comprises about 12.4% fenofibrate, about 18.4% menthol, and about 69.1% Tween 80. When the drug release of this composition was tested in a small volume drug release test of 50 ml 0.1N HC1 at 37°C and 150 rpm, about 12.5% of the fenofibrate in the composition were dissolved in 15 minutes.
Another preferred embodiment of the composition of the invention comprises about 12.4% fenofibrate, about 18,4% menthol, and about 69.1% Cremophor. When the drug release of this composition was tested in a small volume drug release test of 50 ml 0. IN HC1 at 37°C and 150 rpm, about 17.9% of the fenofibrate in the composition were dissolved in 15 minutes.
Another preferred embodiment of the composition of the invention comprises about 10.9% fenofibrate, about 16.2% menthol, about 8.1% sodium ducosate, about 4.0% glycerine and about 60.7% Cremophor. When the drug release of this composition was tested in a small volume drug release test of 50 ml 0.1N HC1 at 37°C and 150 rpm, about 15.6% of the fenofibrate in the composition dissolved in 15 minutes.
In a most preferred embodiment of the composition of the invention comprises about 7.7% fenofibrate, about 19.2% menthol, about 7.7% sodium ducosate and about 65.4% Tween 80. When the drug release of this composition was tested in a small volume drug release test of 50 ml 0.1N HC1 at 37°C and 150 rpm, about 93.3% of the fenofibrate in the composition dissolved in 15 minutes. This most preferred embodiment was further tested in 500 ml 0.5% sodium lauryl sulfate (SLS) in water at 37°C and 50 rpm where it gave a release profile of 78.7% dissolved at 5 minutes and 92.5% dissolved at 10 minutes.
By comparison, the fenofibrate composition as taught in example 2 of U.S. application 10/400,100 (US 2003/0224059) when tested in less stringent, more conducive conditions for dissolution, in a USP Apparatus II dissolution tester in 900 ml 0.5% sodium lauryl sulfate (SLS) in water at 37°C and 100 rpm, displayed a rate of dissolution such that it took approximately 90 minutes for greater than 90% of the fenofibrate to dissolve . Thio most preferred embodiment was further tested for its pharmacokinetic profile in dogs vs. the micronized formulation of commercial Tricor® 54 mg (see example 3) and gave a bioavailability of the active metabolite fenofibric acid that was improved by a factor of more than four on a per milligram basis.
Another aspect of this invention encompasses the method of preparing the fenofibrate menthol compositions. In one preferred embodiment, this method comprises the heating of menthol to about 50 - 70°C, most preferably about 60°C, in order to effect melting of the menthol. The menthol melt is stirred at a convenient rate. The method further comprises adding a surface active agent or more than one agent to the melt. The melt is stirred gently until a full solution has been achieved. In a preferred embodiment, the surface active agent is Tween 80. In a more preferred embodiment the surface active agent comprises both Tween 80 and Sodium ducosate. ha one embodiment, fenofibrate is added to the melt at this point. In
a more preferred embodiment the melt is cooled to between 45°C and 55°C, moat preferably to about 50°C, before adding the fenofibrate. The melt is stirred at about the same temperature until all the fenofibrate dissolves. In one preferred embodiment the solution thus obtained is dispensed into either hard or soft capsules. More preferably the solution (or melt) is first cooled to room temperature and then dispensed into either hard or soft capsules. The hard capsules are preferably sealed by "banding" to prevent leakage. In another preferred embodiment of this method a solid carrier such as microcrystalline cellulose, lactose or sorbitol or a combination thereof is added to the melt either before or after cooling to room temperature. The mixture is mixed well, cooled to room temperature if necessary, and filled into capsules. Optionally, other excipients may be added to the powder such as flow aids. In another preferred embodiment the powder so obtained is further formulated with additives that allow it to be pressed into a tablet in a tablet press.
Another aspect of this invention relates to compositions of fenofibrate or another fibrate drug that are menthol free but comprise a therapeutically effective amount of the fenofibrate or other fibrate drug that is dissolved in, or in intimate association with a surfactant mixture comprising polyethylene glycol (PEG) and Poloxamer. PEG useful for this embodiment are all PEG's that are liquid at room temperature or that melt up to about 70°C. The most preferred PEG is PEG 1000 or PEG 6000. The most preferred Poloxamer is Poloxamer 407. In an embodiment, the composition can comprise by weight fenofibrate from about 5% to about 50%, PEG 1000 from about 5% to about 50% and Poloxamer 407 from about 5% to about 50%. In another embodiment, the composition comprises between about 15% and about 25% by weight of the fibrate drug, preferably fenofibrate, between about 7% and about 13% by weight of PEG 6000, and between about 7% and about 13% by weight of Poloxamer 407, wherein the fibrate drug preferably is fenofibrate. In yet another preferred embodiment the compositions further comprise at least one pharmaceutically acceptable carrier, wherein the at least one pharmaceutically acceptable carrier may be solid and the fibrate drug may be adsorbed on or absorbed in the at least one solid carrier. Such solid carriers can be water soluble (hydrosoluble) carriers such as sucrose, lactose or sorbitol or water insoluble carriers such as starch, cellulose, microcrystalline cellulose, or calcium phosphate. The so formed powder can optionally be mixed with standard pharmaceutical additives to help flow or other properties and can be filled into hard gelatin capsules or their equivalents, hi another preferred embodiment these powders can be optionally mixed with standard pharmaceutical excipients and formulated for tablet formation in a tablet press.
The present invention also provides a composition comprising about 19% by weight of fenofibrate, about 10.9% by weight of Poloxamer 407, about 10.9% by weight of PEG 6000 by weight, about 15.3% by weight of microcrystalline cellulose, about 18% by weight of crospovidone, about 12% by weight of sodium bicarbonate and about 12% by weight of citric acid, wherein the fenofibrate is dissolved in or intimately associated with the PEG 6000 and Poloxamer 407.
The invention further provides a composition comprising about 19% by weight of fenofibrate, about 10.9% by weight of Poloxamer 407, about 10.9% by weight of PEG 6000 by weight, about 15.3% by weight of microcrystalline cellulose, about 18% by weight of crospovidone, about 12% by weight of sodium bicarbonate and about 12% by weight of tartaric acid, wherein the fenofibrate is dissolved in or intimately associated with the PEG 6000 and Poloxamer 407.
The pharmaceutical composition of the present invention comprising a fibrate drug, preferably fenofibrate, in a therapeutically effective amount, that is intimately associated with a surfactant mixture, such as polyethylene glycol and Poloxamer, e.g., PEG 6000 and Poloxamer 407, can optionally be adsorbed on or absorbed in a solid carrier. The pharmaceutical composition can have a dissolution property in that, when tested using a USP type II dissolution tester filled with 1000 ml 0.5% sodium lauryl sulfate (w/v) in water at 37 °C and 50 rpm, at least about 50%, preferably about 50-80%, e.g., about 55-76% (such as about 68%) or about 70-80%, is released in 10 minutes; at least about 73%, preferably about 73-93%, e.g., about 77-89% (such as about 83%) or about 86-93%, is released in 15 minutes; and at least about 85%, preferably about 85-99%, e.g., about 87-97% (such as about 90%) or about 93-100%, is released in 30 minutes.
The pharmaceutical composition of the present invention comprising a therapeutically effective amount of fenofibrate or another fibrate drug intimately associated with a surfactant mixture comprising PEG 6000 and Poloxamer 407 can be used to make formulations such as tablets or capsules. For tablets comprising about 145 mg fenofibrate administered orally to humans in a fed state, when the pharmacokinetics based on the plasma concentration of fenofibric acid is determined, the average area under the plasma concentration versus time curve from time zero to about 48 hours, i.e., AUC
Documents
Application Documents
| # |
Name |
Date |
| 1 |
7011-DELNP-2007-Petition-138-(05-08-2009).pdf |
2009-08-05 |
| 1 |
7011-DELNP-2007_EXAMREPORT.pdf |
2016-06-30 |
| 2 |
7011-DELNP-2007-Form-3-(05-08-2009).pdf |
2009-08-05 |
| 2 |
7011-delnp-2007-abstract.pdf |
2011-08-21 |
| 3 |
7011-DELNP-2007-Correspondence-Others-(05-08-2009).pdf |
2009-08-05 |
| 3 |
7011-delnp-2007-claims.pdf |
2011-08-21 |
| 4 |
7011-delnp-2007-correspondence-others 1.pdf |
2011-08-21 |
| 4 |
7011-delnp-2007-assignment-(05-08-2009).pdf |
2009-08-05 |
| 5 |
7011-delnp-2007-Form-3-(31-03-2010).pdf |
2010-03-31 |
| 5 |
7011-delnp-2007-correspondence-others.pdf |
2011-08-21 |
| 6 |
7011-delnp-2007-description (complete).pdf |
2011-08-21 |
| 6 |
7011-delnp-2007-Correspondence-Others-(31-03-2010).pdf |
2010-03-31 |
| 7 |
7011-delnp-2007-pct-308.pdf |
2011-08-21 |
| 7 |
7011-delnp-2007-form-1.pdf |
2011-08-21 |
| 8 |
7011-delnp-2007-pct-304.pdf |
2011-08-21 |
| 8 |
7011-delnp-2007-form-18.pdf |
2011-08-21 |
| 9 |
7011-delnp-2007-pct-237.pdf |
2011-08-21 |
| 9 |
7011-delnp-2007-form-2.pdf |
2011-08-21 |
| 10 |
7011-delnp-2007-form-3.pdf |
2011-08-21 |
| 10 |
7011-delnp-2007-pct-220.pdf |
2011-08-21 |
| 11 |
7011-delnp-2007-form-5.pdf |
2011-08-21 |
| 11 |
7011-delnp-2007-pct-210.pdf |
2011-08-21 |
| 12 |
7011-delnp-2007-form-5.pdf |
2011-08-21 |
| 12 |
7011-delnp-2007-pct-210.pdf |
2011-08-21 |
| 13 |
7011-delnp-2007-form-3.pdf |
2011-08-21 |
| 13 |
7011-delnp-2007-pct-220.pdf |
2011-08-21 |
| 14 |
7011-delnp-2007-form-2.pdf |
2011-08-21 |
| 14 |
7011-delnp-2007-pct-237.pdf |
2011-08-21 |
| 15 |
7011-delnp-2007-form-18.pdf |
2011-08-21 |
| 15 |
7011-delnp-2007-pct-304.pdf |
2011-08-21 |
| 16 |
7011-delnp-2007-form-1.pdf |
2011-08-21 |
| 16 |
7011-delnp-2007-pct-308.pdf |
2011-08-21 |
| 17 |
7011-delnp-2007-Correspondence-Others-(31-03-2010).pdf |
2010-03-31 |
| 17 |
7011-delnp-2007-description (complete).pdf |
2011-08-21 |
| 18 |
7011-delnp-2007-correspondence-others.pdf |
2011-08-21 |
| 18 |
7011-delnp-2007-Form-3-(31-03-2010).pdf |
2010-03-31 |
| 19 |
7011-delnp-2007-correspondence-others 1.pdf |
2011-08-21 |
| 19 |
7011-delnp-2007-assignment-(05-08-2009).pdf |
2009-08-05 |
| 20 |
7011-DELNP-2007-Correspondence-Others-(05-08-2009).pdf |
2009-08-05 |
| 20 |
7011-delnp-2007-claims.pdf |
2011-08-21 |
| 21 |
7011-DELNP-2007-Form-3-(05-08-2009).pdf |
2009-08-05 |
| 21 |
7011-delnp-2007-abstract.pdf |
2011-08-21 |
| 22 |
7011-DELNP-2007_EXAMREPORT.pdf |
2016-06-30 |
| 22 |
7011-DELNP-2007-Petition-138-(05-08-2009).pdf |
2009-08-05 |