Title of Invention

"AN ADHESIVE PATCH FOR TREATMENT AND COMPOSITION THEREOF"

Abstract

Compounds of formula (1) (in which R<1>; R<2>, R<3> and R<4> are the s"ame as or different from each other and each represents an oxo group, a hydroxy group, a mercapto group, a hydrogen atom, a halogen atom, an alkoxy group or an aryloxy group; and the dotted line indicates that there may be a single or dour e bond between one of the respective pairs of carbon atoms) and esters thereof can be administered by transdermal administration. They are particularly effective when applied as a patch, preferably with an adhesive comprising a copolymer of from 40 to 60% by weight of methoxyethyl acrylate, from 30 to 40% by weight of lauryl acrylate or lauryl methacrylate and from 10 to 25% by weight of a polar monomer.

Full Text

TRANSDERMAL STEROID FORMULATION The present invention relates to a transderraal formulation for the treatment, inter alia., of osteoporosis and related ailments. Osteoporosis, a condition in which bone mass decreases, resulting in the bone losing some of its structural integrity, is a condition particularly prevalent in post-menopausal women. It is often treated by the administration of steroids, such as oestrogen. EP69S612 discloses that certain 11-hydroxy steroids are particularly useful for the treatment and prevention of osteoporosis and for osteogenesis, without mam' of the side effects of known treatments, There is no indication in this specification as to the route by which the steroids are to he administered. However, the Examples show the use of the compounds b}r inj ection. WO 02/00224 and WO 02/00225 disclose the use of certain 7-hydroxy-steroid compounds, especially 3-h3droxy-7J!>-hydroxy-steroid compounds, for protection against neuronal cell death. These suggest mat. in order to achieve a rapid effect, the compounds should be administered by intravenous injection. WO 03/0-15791 discloses tile use of 3-hydroxy-7-hydroxy steroids and 3-oxo-7- -hydroxy steroids, especially the 7/3-isomers thereof, and pharmaceutically acceptable esters thereof for protection against ischaeniia-irid.tj.ced damage to peripheral organs, such as the heart or kidneys. Although the two most common methods of administering medication are orally or by injection, both methods have serious disadvantages. Oral administration of a drug depends on the drug being stable to the acid environment of the stomach as well as to the intestinal mechanism, or on the drug being protected from that environment. Moreover, people differ in the rate and manner in which drugs are absorbed, and so the amount of the drug actually reaching the bloodstream via the oral route can vary enormously from person to person, Injection avoids these disadvantages but has to be done by £ skilled or trained person, is after), disliked sometimes intensely., by the patient and can caust damage if done too often. Traditionally, transdermal administration (i.e. administration through the slin, but without breaking the sldn) has been used only for those drugs which affect the sldn or immediately underlying muscle tissue. However, it can be used with other drugs provided thai, those; drugs can pass through the skin sufficiently efficiently and sufficiently predictably. We have now surprisingly found that transdermal deliver)' can be used with certain steroids, including those of EP698612, WO 02/00224 and WO 02/00225. Thus, the present invention consists in the use of compounds of formula (I): (Figure Remove) (in which R*; R^, R^ and R^ are the same as or different from each other and each represents an oxo group, a hydroxy group, a mercapto group, a hydrogen atom, a halogen atom, an alkoxy group or an aryloxy group; and the dotted line indicates that there may be a single or double bond between one or two of the respective non-adjacent pairs of carbon atoms) and esters thereof for the manufacture of a medicament for transdermal administration. The invention also consists in a pharmaceutical formulation for transdermal administration having as the active ingredient a compound of formula (I), as defined above, or an ester thereof. The invention further consists in an adhesive patch for the transdermal administratian of atompounc of formula (I) or an ester thereof, as defined above, said patch comprising a substrate and a layer of adhesive on the substrate, said adhesive hashing dispersed therein at least one compound of formula (T) or an ester thereof. Among the compounds of the present invention, preferred compounds include those compounds of formula (IT): (Figure Remove) i ^ *^ / (in which R , R^.R-1 and R"7 are as defined, above) and esters thereof. Another preferred class of compounds of the present invention are those compounds of formula (HI): (Figure Remove) (in which R1 a represents an oxo group, a hydroxy group, a mercapto group or a halogen atom: and R^, R^ and R • are as defined above) and esters thereof. A still further preferred class of compounds of the present invention are those compounds of formula (IV): (Figure Remove) (in which pJ3 R.^, E.^ and R^ are as defined above) and esters thereof. Examples of compounds of formula (H) include 1 l/5-hydroiry-4-arj.drostene-3;17-dione5 which has the formula (Eta); (Figure Remove) and esters thereof. This compound. -which is the preferred compound for use in the Examples of compounds of formula (IE) include 7a-hydroxy-dehydroepiandrosterone (7a-hydroxy-DHEA), which has tie formula (da): (Figure Remove) and esters thereof. Examples of compounds of formula (IV) include 7jS-hydraxy-epiandrosterane; hereinafter referred to as 7/S-OE EPIA. which ha? the formula (IVa): (Figure Remove) and esters thereof. In the compounds of the present invention, where R*.. fj-a. 1L~. Rp or g_4 represents a. halogen atom, this ma3rbe a fluorine, chlorine, bromine or iodine, atom. preferably a chlorine atom. Other usefal steroids which may be used as the compound of formula (I) include such androgens as testosterone and 3/6,17/S-dihydroxyandrostane. Of the compounds referred to above, the. most preferred are Va-hydroxy-dehydroepiandrosteiDne, 7/S-hydToxy-epiandrosterone (7jS-OEEPIA) and 11/5-hydroxy-4-androstene-3.17-dione (HAD). . Patches for transdermal admnn'srration of medication nonoally comprise a substrate of a medically acceptable fabric or film on which is a layer of an adhesive impregnated with the medication. Any substrate commonly used in the field ma}' be used in the present invention. It may, for example, be a woven fabric., non-woven fabric, porous film or moulded film, ideally 10-100um thick. Woven fabrics, non-woven fabrics and porous fUms are useful in that they allow the passage of water vapour, while moulded films are useful for providing a barrier to bacteria and for waterproofing. However, it will be appreciated that the natore of the adhesive may nave a sienificani effect OD the utility of the patch, and so this nesds to be chosen with some care, Thus; the adhesive must be capable of adhering to the akin, it must permit sustained drug release and it must not cause irritation to the sirin. In general, it must maintair these properties over a relatively long period: e.g. 3 to 7 days, after attachment despite the normal flexing of foe skin and possibly washing. Moreover, the adhesive must not be so strong that it causes damage to the skin when the patch is removed, We have now found that a particular class of adhesives is especially useful with me steroid compounds of formula (I) and esters thereof used in the present invention. These new adhesives comprise a copolymer of from 40 to 60% by weight of msfhoxyethyl acrylate, from 30 to 40% by weight of lauryl acrylate or lauryl methacrylate and from 10 to 25% by weight of a polar monomer. The amount of units derived from methojiyethyl acrylate in the copolymer should be from 40 to 60% by weight more preferably from 45 to 55% by weight. If this amount is greater than 60% by weight, gelling occurs during polymerisation and the resulting copolymer becomes insoluble. Moreover, the viscosity of the copolymsr is poor. On the other hand, if the amount of methoryethyl methacrylate is less than 40%, drug solubility in the adhesive is reduced and the relatively high drug loadings otherwise achievable are not achieved. ~~~The second cD=monomerrlamyl-ac:r^^ an amount of from 30 to 40% by weight .of .the. monomer units in the.copolym.er. Jts_ ..... . presence enhances the adhesion of the adhesive and, when combined with the methoxyemyl acrylate, it provides suitable conditions for dissolving the steroids used in the present invention as well as absorption promoters, where these are used. If the amount of lauryl acrylate and/or lauryl methacrylate units in the copolymer is less than 30% by weight, adequate hydrophobicity is not achieved. On the other hand, if the amount is greater than 40%, the copolymer becomes too hydrophobic and drug solubility is reduced. If 2-ethyIhexyl acrylate or 2-ethylhexyl methacrylate were used in place of the lauryl analogue, since the chain length of the 2-etb.ylhexyl group is less than that of the lauiyl group, the ability of the resulting copoiymer to dissolve, hydrophobic dings and absorption promoters would be reduced. OB the other hand, if steary] acrylate or methacrylate: with a longer chain length were used in place of the iauryl analogue., the adhesion of the adhesive would be poor. The third necessary monomer in the copo^iaers used in the present invention is a polar monomer, This serves to impart to the copolymer higher cohesion without damaging the other desirable properties mentioned above and it can improve the cross-linking of the polymer. It should be present in the copotymer in an amount of from 1 0 to 25% by wsight of the copolymer units. Less than 10% by weight of the polar monomer will not give adequate cohesion, while more than 25% -will result in the copolyme: becoming too polar and the adhesiveness being reduced, Examples of suitable polar monomers include acrylic acid: methacrylic acid, acrylamide, methacrylamide, N-vinyl-2-pyrrolidone, KN-dimernylacrylamide, 2-hydroxystiiyi acrylate and vinyl acetate. A single one of these or a combination of two or more may be used, Of these, acrylic acid, N-vmyl-2-pyrrolidone and 2-hydroxyethyl acrylate are preferred, N-vinyl-2-pvrrolidone being most preferred, either alone or in combination with at least one other polar monomer. In any event we particularly prefer that units derived from N-vinyl-2-pyrrolidone should constitute at 5% by weight of the copolymer, provided that the total amount of polar monomer is. as stated above, from 1 0 to 25 % by weight of the copolymer. As mentione. • aove, an asorpton proneTT!ia.y cmuuc composition, according to_the,present mventjon. ..Examples of such absorption promoters include: fatty acid esters, such as isopropyl palmitate and isopropyl myristate; glycerol esters, such as glyeeryl monolaiirate and glyceryl monooleate; acid amides, such, as lauric acid diethanolamide; and neutral surfactants, such as polyethylene glycol dilauryl ether. However, such materials are well known in the art, and any common absorption promoter may be used. The preferred absorption promoter is isopropyl myristate. Clearly, the amount of the absorption promoter must be sufficient to enhance transdennal absorption of the drug. However, too much may have the effect of reducing the adhesiveness of the patch. Accordingly, we prefer that the amount of absorption promoter should be from 3 to 40 parts by weight per 1 00 parts by weight of the copolymer, IT is also preferred that the copolymer used in the adhesive composition should be cross-linked by means of a cross-linking agent in order to enhance cohesion. Examples of such cross-linking agents include isocyanateE and cheiamag agents. The amount of the cross-linking agent used is preferably from 0.1 to 2 parts by weight. If the amount used is less than 0.1 parts by weight, little cross-linking takes place and there is no significant benefit from its addition. On the other hand, if the amount added is more than 2 parts by weight, adhesiveness is reduced. The copolymer may be prepared by methods well known in the art for the preparation of polymers of this type, for example by free radical polymerisation using the monomers defined above. Any conventional process, such as solution polymerisation, suspension polymerisation or emulsion polymerisation, ma}' be used. Solution polymerisation is particularly preferred, since the resulting molecular weight distribution is relatively narrow and there is, as a. result, little variability in adhesiveness. 'Surprisingly, we have found that the copolymers suggested above, whsn used as the adhesive, actually enhance the absorption of the compounds of formula (I) through the skin. The active ingredient may be mixed with the adhesive copolymer by adding it, and. if desired, an absorption promoter and/or a cross-linking agent to a solution the copolvmer in a suitable solvent. The resulting mixture may then be laminated onto the desired support using, for example, a knife or roll coater, and then dried in an oven, for example at a temperature of from 50 t6~lOO"°C, to remove the solvent and cause the adhesive composition containing the active ingredient to adhere to the substrate. The amount of the mixture applied to the substrate is preferably such that the thickness of the composition after drying is from 30 to 120 um. If the thickness is less than 30 jim, adhesion of the composition is weak and it may be difficult to incorporate an adequate amount of the active ingredient. On the other hand, if the amount is greater than 120am, it is difficult to form a layer of the composition and to dry it. The present invention is further illustrated by the following non-limiting Examples, of which Examples 1 to 3 illustrate fee preparation of the adhesive copolymers and Examples 4, 5. 6 and Comparative Examples 1 to 10 illustrate the preparation and use of patches of the present invention. EXAMPLES 1-3 200 g of ethyl acetate (solvent), 0.05 g of azobisisobutjTonitrile (initiator) and the monomers shown in the following Table 1 were charged into a reaction vessel, which was then sparged with nitrogen, Pol3Tjierisation was then carried out for 15 hours at 20°C. The resulting copolymer solution was coaied with s. knife coater onto a polyethylene terephthalate film to a dried thickness of lOOum. and then dried at a temperature of 90°C for 15 minute 10 produce adhesive sheets. The resulting sheets were attached to the keratin layer of the shaven sltin on the abdomen of Wistar rats. They were left there for 24 hours, after which they were removed, and the adhesiveness and state of the adhesive layer were observed with the naked eye. The results are shown in Table 1. Table 1 Monomer Amouat of monomer Adhesion Cohesion ~Bxample-l — • — - -iBBtbGK-yeteyl-aEPi'lal-e- -4s- -P ' ;7~ - THV~~ — HA TPurfViip -~ — la.imrLacrtfla.te 3_&:g_:_- detachment - left on body- - N-vinylpyrrolidone 6g within 24 acrylic acid 3g hours hydroxyethyl acetate 10g Example 2 methoxyethyl acrylate 48 g no no residue lauryl acrylate 34 g detachment left on body N-vinylpyrrolidone 15 g within 24 acrylic acid 3g hours Example 3 methoxyethyl acrylate 50 g no 110 residue lauryl acryiate 36 g detachment left on body N-vinylpyrr o lidone Sg within 24 hydroxyethyl acetate 10 g nours EXAMPLES 4 & 5 & COMPARATIVE EXAMPLES 1-10 Preparation of adhesive patch Into the adhesive solution, (copolymer solution) of Example 1 and into the adhesive solutions used in the Comparative Examples, the drug specified below, and. where used, isopropyl myristate and/or a crosshnker, were added and dissolved. The resulting compositions containing the dissolved drag were coated onto a poiy(ethylene terephthalate) film to give a thickness when dry of 100 urn, and dried at a temperature of 90DC for 15 minutes, to produce drug-containing adhesive sheets. The adhesives used for the Comparative Examples were obtained from National Starch, and are sold under fhe designations DT2287, DT2516, DT2051, DT2052,. and DT2074. The compositions of the adhesive mixtures are shown in Tables 2 and 3. Table 2 Example No. 4 Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Ingredien.: i Example No. 1 Solid, mg 250 - - ~ - - DT22B7 Solid, mg - 250 * - - DT2516 Solid, mg •" — 250 ** - - DT2051 Solid, mg ' - 250 - - DT2052 Soiad. mg ~ — ~ _ 250 - DT2074 Solid, mg ~ ~ - 250 IPM mg 100 — ™ — 100 100 HAD mg 7.0 5.0 7.5 7.0 6.0 5,5 urDsslmker* ' mg 250 " " *~ - - 0.05% of aluminium acstylaretate/tetraliydroBiraii solufcioiL. Table 3 Example No, 5 Comp 6 Comp 7 Comp Si Comp 9 Comp 10 Ingredient ! Example No. 1 Solid, mg 250 - - "~ ~ "• DT22S7 Solid, mg 250 "* " — DT2516 Solid, mg - ~ 250 *" •• — DT2051 Solid, mg - - - 250 - - DT2052 Solid, mg - - " - 250 - DT2C74 Solid, mg " ^ ~ - — - 250 IPM me 100 •~ 100 — 100 100 7jS-OH EP3A me 0 8.0 6.5 12.0 10.5 7.0 9.0 Crosslinker* mg L 0.0-02 1 • — . - .- _ PEG 400 mg 30 *" •* •• •• - * 0.05% of aluminium acetylacetate/tetrahydro&ran solution.. As shown in Table 2 and Table 3, the various adhesives were loaded with the satarah^m concentration of ^^^ "(PM) was "used as an enhancer, since it is an excellent pharmaceutical excipielit ~for the" transdermal delivery ol a drug because of its marked~enhancing effecTa5d~lBw^l^~" irritation. However, most of the conventional adhesives could not load enough IPM because it resulted in a decrease in cohesion. EXAMPLE 6 1. Saturation concentration of SAD in adhesives The adhesive patches described in Example 4 and Comparative Examples 1-5 were mixed with progressively increasing concentrations of HAD and were stored (adhesive side up) at room temperature for 8 weeks. At the end of this time, the patches were examined to determine whether HAD had crystallised, on the surfaces of the patches. The saturation concentrations of HAD in the adhesives are shown b Table 4. Table 4 Adhesives Saturation of HAD (% of patch weight) Example 4 2.0 Comp 1 2.0 Comp2 3.0 Comp3 2.0 Comp 4 1.5 Comp 5 2.0 2. Saturation concentration of 75-OH EPIA in adbesives The adhesive patches described in Example 5 and Comparative Examrjles 6-10 were mixed with progressively increasing concentrations of 7/S-OH EPLA. and were stored (adhesive side up) at room temperature for 8 weeks. At the end of this time, the patches were examined to determine whether 7/S-OH EPIA had crystallised on the surfaces of the natches. The saturation concentrations of 7/3-OH EPIA in the adhesives are shown in Table 5. Table. 5 Adhesives Saturation of 7/J-OH EPLA. (% of patch weight) Example 5 2.0 Comp 6 2.5 Comp 7 3.3 Comp 6 4.0 Comp 9 2.0 Comp 10 2.5 3. Permeation behaviour The materials used wsre as follows: Animals: Wistar rats (male, body -weight 240 ~ 250g) Jest patches: Examples 4 and 5 and Comparative Examples 1-10 Commercial estradiol patch as permeation marker (Estrat Hisamitsu Pharmaceutical Co.) Patch size: 8 mm diameter for HAD andfOmm diameter for 7fi-OR~EF]jC Receptor solution: PEG400:water (1:3) HPLC conditions Column Mobile Flow rate Ul7 detector ODS water : acstonitrile 240 nm for HAD, 300mnfar 7&-OEEPIA ' um, 4.6% 150 mm 55:45) r. Column temperature The excised abdominal rat skin was mounted on a Franz type cell (receiver volume: 3ml) with a water jacket connected to a water bath at 37DC. The patch was adhered to the stratum corneum side of the slrm. The receiver compartment was filled with a mixture of PEG400 and wate: (1:3 by volume) and stirred with a star head magnetic bead driven by a constant speed motor. At predeiennined times, IQOid of sample was withdrawn from the receiver compartment, and the same volume of receptor solution was added to keep the volume constant. The drug concentration was analysed byHPLC. For all adhesives, the amount of the drug which had permeated increased .rr^ra^n-i.'Tnifh tjmp Th-p T°gTi1tg afi-RT-14 Vimire arp. shown in Tahlp, f. aTiH TaVilp. 7 Table 6 Adhesive Permeated amount jig/crrf Example 4 30 Comp 1 2£ | Comp2 20 Comp 3 30 Comp 4 50 Comp 5 60 Estradiol 15 Adhesive Permeated amount fig/cm2 Example 5 162 (..ni'ip ft JU - • • — •"" 1 — Comp 7 110' Comp S 52 Comp 9 74 Comp 10 73 Estradiol 13 Table 7 All patches showed that £ much higher amount of HAD and 7jS-OH EPIA had permeated than thai of the permeation marker, esiradiol. This means that HAD 7/3-OH EPIA have a potential skin permeability. It was surprisingly found that the skin permeation of HAD was best "with, adhssives having the functional group -COOH or a combination of the functional groups -COOH/'-OH. which make the adhesive highly hydrophilic. This allows HAD ID be released into the skin. Adhesives having just the-OH group, such as DT2516, did not allow good permeation, whereas adhesives with a combination of groups —COOH / -OH, such as Example 1 and DT2074. allowed good permeation. Allowing for experimental variations due to variations in individual rats, the adhesive of Example ! is as good as, if not better than, the known adhesives DT2Q52 and DT2074 for HAD permeation. 4. Permeation in human skin The protocol in 3 above was repeated with HAD on human skin using the composition of Example 4 (Table 2) together with 5% w/w of lactic acid as enhancer. A penetration flu?: of 1.l/ig/cm2/hr in human skin was achieved.. We claim: 1. An adhesive patch for treatment, inter alia, of osteoporosis and related ailments which comprises a substrate having a layer of adhesive thereon, said adhesive comprising a copolymer of from 40 to 60% by weight of methoxyethyl acrylate, from 30 to 40% by weight of lauryl acrylate or methacrylate and from 10 to 25% by weight of a polar monomer, said adhesive being dispersed therein at least one compound of formula (I) (Formula Removed) in which R1, R2, R3 and R4 are the same as or different from each other and each represents an oxo group, a hydroxy group, a mercapto group, a hydrogen atom, a halogen atom, an alkoxy group or an aryloxy group; and the dotted line indicates that there may be a single or double bond between one of the respective pairs of carbon atoms or an ester thereof. 2. A patch as claimed in claim 1, in which said compound is a compound of formula (II): (Formula Removed) in which R1, R2, R3 and R4 are as defined in claim 1 or an ester thereof. 3. A patch as claimed in claim 1, in which said compound is a compound of formula (III): (Formula Removed) in which R1a represents an oxo group, a hydroxy group, a mercapto group or a halogen atom; and R2, R3 and R4 are as defined in claim 1 or an ester thereof. 4. A patch as claimed in claim 1, in which said compound is a compound of formula (IV) (Formula Removed) in which R1, R2, R3 and R4 are as defined in claim 1 or an ester thereof. 5. A patch as claimed in claim 1, in which said compound is 11 ß-hydxoxy-4-androstene-3,17-dione. 6. A patch as claimed in claim 1, in which said compound is 7α-hydroxyy dehydroepiandrosterone. 7. A patch as claimed in claim 1, in which said compound is 7ß-hydroxy-epiandrosterone. 8. A patch as claimed in claim 1, in which the amount of units derived from methoxyethyl acrylate in the copolymer is from 45 to 55% by weight. 9. A patch as claimed in claimsl to 8, in which the polar monomer is acrylic acid, methacrylic acid, acrylamide, methacrylamide, N-vinyl-2-pyrrolidone, N,N-dimethylacrylamide, 2-hydroxyethyl acrylate or vinyl acetate. 10. A patch as claimed in claim 9, in which the polar monomer is acrylic acid, N-vinyl-2-pyrrolidone or 2-hydroxyethyl acrylate. 11. A patch as claimed in claim 10, in which the polar monomer is N-vinyl-2-pyrrolidone. 12. A patch as claimed in claims 1 to 11, in which the adhesive additionally contains an absorption promoter. 13. A patch as claimed in claim 12, in which said absorption promoter is isopropyl myristate. 14. A patch as claimed in claim 12 or claim 13, in which said absorption promoter is present in an amount from 3 to 40 parts by weight per 100 parts by weight of the copolymer. 15. A patch as claimed in any one of claims 1 to 14, in which the adhesive layer has a thickness of from 30 to 120µm. 16. A patch as claimed in any one of claims, for use in the treatment or prevention by transdermal application of osteoporosis, osteogenesis, neuronal cell death, or ischaemia-induced damage to peripheral organs. 17. An adhesive composition consisting of a copolymer a copolymer of from 40 to 60% by weight of methoxyethyl acrylate, from 30 to 40% by weight of lauryl acrylate or methacrylate and from 10 to 25% by weight of a polar monomer, said adhesive being dispersed therein at least one compound of formula (I) (Formula Removed) or ester thereof, said adhesive composition being intended for use in an adhesive patch as claimed in any one of claims 1 to 16. 18. An adhesive composition as claimed in claim 17, for use in the treatment or prevention by transdermal application of osteoporosis, osteogenesis, neuronal cell death, or ischaemia-induced damage to peripheral organs.

Documents:

6256-delnp-2006-abstract.pdf

6256-DELNP-2006-Claims-(06-08-2012).pdf

6256-delnp-2006-claims.pdf

6256-DELNP-2006-Correspondence Others-(06-08-2012).pdf

6256-delnp-2006-correspondence-others (23-04-2008).pdf

6256-delnp-2006-Correspondence-Others-(21-08-2012).pdf

6256-DELNP-2006-Correspondence-Others-(21-12-2011).pdf

6256-delnp-2006-correspondence-others.pdf

6256-delnp-2006-description (complete).pdf

6256-delnp-2006-form-1.pdf

6256-delnp-2006-form-18 (23-04-2008).pdf

6256-delnp-2006-form-2.pdf

6256-DELNP-2006-Form-3-(21-12-2011).pdf

6256-delnp-2006-form-3.pdf

6256-delnp-2006-form-5.pdf

6256-delnp-2006-GPA-(21-08-2012).pdf

6256-delnp-2006-pct-237.pdf

6256-delnp-2006-pct-304.pdf

6256-delnp-2006-pct-326.pdf

6256-delnp-2006-pct-373.pdf

6256-delnp-2006-pct-search report.pdf

6256-DELNP-2006-Petition-137-(06-08-2012).pdf