The present invention relates in general to the field of targeted drug delivery of anti-cancer drugs. More precisely, the present invention concerns polymer drug conjugates, namely, conjugates of poly(organo)phosphazenes and anti-cancer drugs, wherein the conjugates are suitable to selectively release anti-cancer drugs in tumor tissue. In addition, the present invention relates to a method for manufacturing such poly(organo)phosphazene molecule conjugates, to poly(organo)phosphazene molecule conjugates for use in medicine, in particular, to poly(organo)phosphazene molecule conjugates for use in the treatment of cancer, and to pharmaceutical compositions comprising such poly(organo)phosphazene molecule conjugates.

Anti-cancer drugs used to control the growth of cancerous cells are commonly known to have severe side effects, since healthy tissue is always affected by these drugs.
For instance, anthracycline antibiotics, such as epirubicin, doxorubicin, daunorubicin, idarubicin and valrubicin, are a group of highly effective DNA intercalators derived from Streptomyces bacteria. Anthracycline antibiotics as some of the most effective anti-cancer drugs are used to treat a wide range of cancers, including leukemias, lymphomas, breast, uterine, ovarian, and lung cancers. However, anthracycline antibiotics also exhibit severe side effects due to their high toxicity towards healthy tissue. One of the main side effects of anthracycline antibiotics are cardiotoxicity, which considerably limits their usefulness, and vomiting.
Similar, taxanes and vinca alkaloids are anti-cancer drugs interfering with microtubule and mitotic spindle, respectively, and therefore, always affect both tumor and healthy tissue.
Beyond that, anti-cancer drugs are usually highly hydrophobic and, therefore, exhibit poor aqueous solubility. Thus, administration via blood stream is always critical. In addition, most anti-cancer drugs are rapidly eliminated from the body and therefore, have to be administered repeatedly in order to ensure constant therapeutic levels.
In order to avoid damage of healthy tissue in an effective way, it would be of great advantage to provide drug delivery systems suitable to selectively deliver and release anti-cancer drugs in tumor tissue. It would be of further advantage, if the desired drug delivery system were also suitable to enhance water solubility of hydrophobic anti-cancer drugs and to improve blood circulation time of anti-cancer drugs, and thus, suitable to be administered into the blood stream.
From the state of the art, it is known that water solubility of hydrophobic anti-cancer drugs generally can be improved and their toxicity reduced through conjugation to macromolecules. For instance, macromolecular drug carriers have been shown to improve the therapeutic index of anti-cancer drug molecules, improving their blood solubility and circulation time (Greco, F. et al, 2009, Haag, R. et al., 2006, Lee, C. C. et al., 2006, and Lammers, T. et al., 2010).
Furthermore, it is known that polymers with molecular weights above 30-50 kDa have decreased renal clearance and hence increased blood circulation time. In this respect, studies have also shown that an increased number of arms of the macromolecular carrier decrease renal filtration (Fox, M. E., et al., 2009).
Beyond that, macromolecules have been observed to accumulate in tumor tissue (Maeda, H. et al., 2000). This phenomenon is also known as the so-called enhanced permeability and retention (EPR) effect, which can regarded as passive tumor targeting.
The main reason for the EPR effect is thought to be higher vascular permeability of tumor tissue (tumor vasculature is, in principle, more permeable than healthy tissue), which allows large macromolecules to penetrate into the tumor. The haphazard structure of tumor tissue due to the fast growth of the cells and its poor lymphatic system means removal is slow, particularly for larger macromolecules, and therefore, leads to accumulation of these molecules. In addition, accumulation is observed to increase with increasing molecular weight (Maeda, H. et al., 2000).
However, at a particular threshold molecular weight (hydrodynamic volume)—depending on the used polymer and its macromolecular architecture—the macromolecules become too large to penetrate even porous tumor vasculature resulting in no further increase of the EPR effect.
In summary, choice and design of the macromolecule is of particular significance for its potential as drug delivery system of anti-cancer drugs.
Poly(organo)phosphazenes are a class of macromoleculare polymers of inorganic/organic hybrid type. Due to their synthetic flexibility, hydrolytic degradability and non-toxic degradation products, poly(organo)phosphazenes have been reported to have tremendous potential as materials for biomedical applications (El-Amin, S. F. et al., 2006). The polymer backbone of such poly(organo)phosphazenes consists of alternating phosphorus and nitrogen atoms (scheme 1), wherein organic substituents are linked to the phosphorus atoms as side chain groups.

In this respect, U.S. Pat. No. 6,319,984 concerns biodegradable and thermosensitive poly(organo)phosphazenes having depsipeptide and amino acid ethylester side groups for use as drug delivery system in general. More specific poly(organo)phosphazenes are disclosed in US 2009/0181088 teaching poly(organo)phosphazene-bioactive molecule conjugates. These conjugates containing various bioactive molecules are biodegradable and thermosensitive poly(organo)phosphazenes with a functional group showing sol-gel phase transition upon temperature alteration. Due to this specific functional group the poly(organo)phosphazenes of US 2009/0181088 forms (after administration to the human body) a gel-phase at body temperature and, therefore, allows controlled release of the bioactive molecules. However, gel-phase forming properties at body temperature means that these poly(organo)phosphazenes are not suitable to be administered into the blood stream.
US 2004/0219127 teaches polyphosphazene-platinum(II) conjugates having enhanced permeability and retention (EPR) effect to tumor tissues due to poly(ethylene glycol) and dispeptide ethyl esters introduced into the polyphosphazene backbone.
Beyond that Zheng et al., 2009, discloses self-assembly of polyphosphazenes into vesicle-like polymersomes and their encapsulation of water-soluble anti-cancer drug. However, these polyphosphazenes do not covalently link anti-cancer drugs.
All the above-mentioned conjugates of poly(organo)phosphazenes and anti-cancer drugs or polymersomes of polyphosphazenes encapsulating anti-cancer drugs accumulate in tumor tissues due to the EPR effect, in a more or less pronounced manner. Such accumulation in tumor tissue reduces side effects of the administered anti-cancer drugs, i.e. toxicity towards healthy tissue. However, in order to be effective against cancer, anti-cancer drugs also need to be selectively released from such conjugates and/or polymersomes while accumulating in tumor tissue.
Therefore, treatment of cancer would be much more effective and less toxic, if a drug delivery system could be provided suitable to selectively deliver and, additionally, to selectively release anti-cancer drugs in tumor tissue.
For this reason, it was an object of the present invention to provide novel poly(organo)phosphazene molecule conjugates suitable to selectively deliver and release anti-cancer drugs in tumor tissue. Furthermore, it was an object of the present invention to provide a process for preparing such poly(organo)phosphazene molecule conjugates and pharmaceutical compositions comprising such poly(organo)phosphazene molecule conjugates.
The object of the present invention, in one preferred embodiment thereof, is solved by a poly(organo)phosphazene molecule conjugate wherein the anti-cancer drug is covalently linked to the polymer backbone via a pH-sensitive linker.
Therefore, in a first aspect the present invention relates to a poly(organo)phosphazene molecule conjugate represented by formula 1:
                wherein,        a represents a degree of polymerisation of the poly(organo)phosphazenes in the range of 1 and 150;        m is an integer between 1 and 150;        n and l are the same or different and each of n and l is independently from one another is an integer between 0 and 149;        X represents O, S or NH;        Y represents a pH sensitive functional group, wherein the pH sensitive functional group is selected from the group consisting of hydrazide, hydroxamate, imine, cyclic acetal and aconityl;        R1 is selected from the group consisting of (C1 to C10)-alkyl, (C1 to C10)-alkenyl, (C1 to C10)-alkinyl, (C1 to C10)-alkoxy, (C1 to C10)-alkenoxy, (C1 to C10)-acyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, arylalkenyl, (C1 to C10)-heteroalkyl, (C1 to C10)-heteroalkenyl, (C1 to C10)-heteroalkinyl, (C1 to C10)-heteroalkoxy, (C1 to C10)-heteroalkenoxy, (C1 to C10)-heteroacyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarykalkenyl, heteroarylalkyls, and polyalkylene oxide;        R2 represents an anti-cancer drug;        R3, R4, R5, R6 and R7 are the same or different and each of R3, R4, R5, R6 and R7 is independently from one another selected from the group consisting of R1—Y—R2, polyalkylene oxide, depsipeptide, amino acid alkyl ester, and a tumor targeting ligand.
Due to the functional group "Y" the poly(organo)phosphanes molecule conjugates of the present invention are suitable to selectively release anti-cancer drugs in tumor tissue. The extracellular pH of tumor tissue has a pH of about 4-6 and is, therefore, significantly lower than the extracellular pH of healthy tissue, which is approximately around 7.4. Since the poly(organo)phosphazene molecule conjugates of the present invention covalently link anti-cancer drugs via the pH sensitive functional group "Y", the anti-cancer drug of the conjugate will be only released in an acidic (tumor) environment. Thus, covalently linking of anti-cancer drugs via a pH sensitive functional group to poly(organo)phosphazenes allows the drug to be selectively released when the polymer-drug conjugate is transported and accumulated in tumor tissue.
Drugs can also be loaded onto macromolecular carriers via non-covalent interactions (for example hydrophobic or hydrogen-bonding interactions). However, a major problem of this method is that the drug molecules can leak out prematurely from the macromolecular carrier before it has reached the site of action. Some may leak out prior to the site of action and affect healthy tissue (Lee, MacKay et al. 2005)
Being able to covalently bind the drug to the polymer according to the present invention is therefore of significant advantage. However, the polymer must also be able to release its load rapidly when it reaches the site of action. If the drug molecule is directly bound to the polymer then biodegradation of the polymer is required before the drug is released (US Patent 20091811088). A polymer that degrades too quickly, however, will partially release its payload before reaching the site of action. In addition, employing a polymer that degrades more slowly, will lead to a slower release of the drug and delayed therapeutic action and a reduced efficacy, if polymer degradation is relied upon as the drug release mechanism.
Thus, the employment of an acid-sensitive linkage according to the present invention ensures—for the first time utilising poly(organo)phosphazenes—rapid release of the drug exclusively in the required environment, i.e. tumor tissue.
In this respect, a "pH-sensitive functional group" according to the present invention means any functional group which will respond to a pH lower than 6.5, i.e. which will be hydrolysed by a pH of lower than 6.5. Preferably, the pH-sensitive functional group of the present invention will respond to a pH lower than 6.5, 6.4, 6.3, 6.4, 6.3, 6.2, 6.1, 6.0, 5.9, 5.8, 5.7, 5.6, 5.5, 5.4, 5.3, 5.2, 5.1, 5.0, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1 and 4.0. More preferably, the pH-sensitive functional group of the present invention will respond to a pH in the range of 4.0 to 6.5, preferably, in the range of 4.5 to 6.0, more preferably, in the range of 4.5 to 6.0, and most preferably, in the range of 5.0 to 6.0. Thus, any functional group cleavable in an acidable environment (pH lower than 6.5, preferably lower than 6.0) known to the person skilled in the art would be suitable for the present invention. Preferably, the pH sensitive functional group is selected from the group consisting of hydrazide, hydroxamate, imine, cyclic acetal and aconityl.
In one preferred embodiment of the poly(organo)phosphazene molecule conjugate according to the present invention the pH sensitive group "Y" within formula 1 is represented by one formula 2 to 7 selected from the group consisting of

In order to receive such pH sensitive functional group "Y" a pH sensitive linker is reacted with the polymeric backbone selected from the group consisting of formula 8 to 13:
wherein X and R1 are defined as above.
In another preferred embodiment of the poly(organo)phosphazene molecule conjugate according to the present invention R1 is selected from the group consisting of (C1 to C9)-alkyl, (C1 to C9)-alkenyl, (C1 to C9)-alkinyl, (C1 to C9)-alkoxy, (C1 to C9)-alkenoxy, (C1 to C9)-acyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, arylalkenyl, (C1 to C9)-heteroalkyl, (C1 to C10)-heteroalkenyl, (C1 to C9)-heteroalkinyl, (C1 to C9)-heteroalkoxy, (C1 to C9)-heteroalkenoxy, (C1 to C9)-heteroacyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarykalkenyl, heteroarylalkyls, and polyalkylene oxide. Preferably, R1 is selected from the group consisting of (C1 to C8)-alkyl, (C1 to C8)-alkenyl, (C1 to C8)-alkinyl, (C1 to C8)-alkoxy, (C1 to C8)-alkenoxy, (C1 to C8)-acyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, arylalkenyl, (C1 to C8)-heteroalkyl, (C1 to C8)-heteroalkenyl, (C1 to C8)-heteroalkinyl, (C1 to C8)-heteroalkoxy, (C1 to C9)-heteroalkenoxy, (C1 to C8)-heteroacyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarykalkenyl, heteroarylalkyls, and polyalkylene oxide. More preferably, R1 is selected from the group consisting of (C1 to C7)-alkyl, (C1 to C7)-alkenyl, (C1 to C7)-alkinyl, (C1 to C7)-alkoxy, (C1 to C7)-alkenoxy, (C1 to C7)-acyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, arylalkenyl, (C1 to C7)-heteroalkyl, (C1 to C7)-heteroalkenyl, (C1 to C7)-heteroalkinyl, (C1 to C7)-heteroalkoxy, (C1 to C7)-heteroalkenoxy, (C1 to C7)-heteroacyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarykalkenyl, heteroarylalkyls, and polyalkylene oxide.
In the context of this invention, the term "alkyl" is understood as saturated, linear or branched hydrocarbons, which can occur unsubstituted, mono- or polysubstituted. In this respect, (C1 to C7)-alkyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl, (C1 to C8)-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8-alkyl, (C1 to C9)-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8 or C9-alkyl, and (C1 to C10)-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10-alkyl. Alkyls of the present invention are, for example, methyl, ethyl, propyl, isopropyl, methylethyl, butyl, tert-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-methylpentyl, if substituted also CHF2, CF3 or CH2OH etc.
In connection with the present invention—unless defined otherwise—the term "substituted" is understood as meaning replacement of at least one hydrogen radical by F, Cl, Br, I, NH2, SH or OH. In this respect "monosubstituted" means the replacement of one hydrogen radical by F, Cl, Br, I, NH2, SH or OH, wherein "polysubstituted" (more than once substituted) is means that the replacement takes effect both on different and on the same atoms several times, e.g. at least two times, with the same or different substituents, for example three times on the same C atom, as in the case of CF3, or at different places, as in the case of e.g. —CH(OH)—CH═CH—CHCl2. "Optionally at least monosubstituted" means either "monosubstituted", "polysubstituted" or—if the option is not fulfilled—"unsubstituted".
The term "alkenyl" as used herein is understood as unsaturated, linear or branched hydrocarbons containing at least one double bond, which can be unsubstituted, mono- or polysubstituted. In this respect, (C1 to C7)-alkenyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7-alkenyl, (C1 to C8)-alkenyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8-alkenyl, (C1 to C9)-alkenyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8 or C9-alkenyl, and (C1 to C10)-alkenyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10-alkenyl. "Alkenyls" of the present invention are, for example, methenyl, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, tert-butenyl, pentenyl, hexenyl, octenyl, butadienyl, and allenyl groups.
The term "alkinyl" as used herein is understood as unsaturated, linear or branched hydrocarbons containing at least one triple bond, which can be unsubstituted, mono- or polysubstituted. In this respect, (C1 to C7)-alkinyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7-alkinyl, (C1 to C8)-alkinyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8-alkinyl, (C1 to C9)-alkinyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8 or C9-alkinyl, and (C1 to C10)-alkinyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10-alkenyl. "Alkinyls" of the present invention are, for example, methinyl, ethinyl, propinyl, isopropinyl, butinyl, isobutinyl, tert-butinyl, pentinyl, hexinyl, octinyl, and allinyl groups.
The terms "alkoxy" and "alkenoxy" as used herein refers to an alkyl and alkenyl, respectively, as defined above, which is linked to oxygen and which can be unsubstituted, mono- or polysubstituted. In this respect, (C1 to C7)-alkoxy represents C1-, C2-, C3-, C4-, C5-, C6- or C7-alkoxy, (C1 to C8)-alkoxy represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8-alkoxy, (C1 to C9)-alkoxy represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8 or C9-alkoxy, and (C1 to C10)-alkoxy represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10-alkoxy. In addition, (C1 to C7)-alkenoxy represents C1-, C2-, C3-, C4-, C5-, C6- or C7-alkenoxy, (C1 to C8)-alkenoxy represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8-alkenoxy, (C1 to C9)-alkenoxy represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8 or C9-alkenoxy, and (C1 to C10)-alkenoxy represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10-alkenoxy. Examples of "alkoxy" and "alkenoxy" of the present invention are methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, octoxy, groups, methenoxy, ethenoxy, propenoxy, butenoxy, pentenoxy, hexenoxy, octenoxy groups, etc.
The term "acyl" as used herein refers a functional group of R—(C═O)—, wherein R is an alkyl, alkenyl, alkinyl, cycloalkyl or cycloalkenyl as defined herein which can be unsubstituted, mono- or polysubstituted. Thus, the term "acyl" comprises linear, branched, cyclic, saturated or unstaturated hydrocarbons containing the functional group R—(C═O)—. In this respect, (C1 to C7)-acyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7-acyl, (C1 to C8)-acyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8-acyl, (C1 to C9)-acyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8 or C9-acyl, and (C1 to C10)-acyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10-acyl. Examples of "acyl" are methanoyl-, acetoyl-, ethanoyl, propanoyl-, butanoyl-, malonyl-, benzoyl-groups, etc.
The term "cycloalkyl" or "cycloalkenyl" as used herein is a subdefinition of "alkyl" or "alkenyl" as defined above and is a carbon ring which can be unsubstituted, mono- or polysubstituted. The term "cycloalkyl" or "cycloalkenyl" typically refers to C3, C4, C5, C6, C7, C8, C9 or C10 cycloalkyl or cycloalkenyl, preferably refers to C4, C5, C6, C7, or C8 cycloalkyl or cycloalkenyl and may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cyclooctenyl groups.
A "heteroalkyl", "heteroalkenyl", "heteroalkinyl", "heteroyalkoxy", "heteroalkenoxy", "heteroacyl", "heterocycloalkyl", "heterocycloalkenyl", "heteroaryl", "heteroarylalkenyl", or a "heteroarylalkyls" are defined as an alkyl, an alkenyls an alkinyl, an alkoxy, an alkenoxy, an acyl, a cycloalkyl, a cycloalkenyl, an aryl, an arylalkenyl or an arylalkyl, as defined above, wherein said structures contain 0-7 heteroatoms selected from O, N or S, which replace at least one carbon atom in the alkyl, an alkenyls an alkinyl, an alkoxy, an alkenoxy, an acyl, a cycloalkyl or a cycloalkenyl as defined above.
The term "aryl" or "heteroaryl" as used herein refers to a 5- or 6-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N or S, a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system ring containing 0-5 heteroatoms selected from O, N or S, or a tricyclic 13- or 14 membered aromatic or heteroaromatic ring system containing 0-7 heteroatoms selected from O, N or S and which can be unsubstituted, mono- or polysubstituted. The aromatic 6- to 14-membered ring systems include e.g. phenyl, naphthalene, indane, tetraline, and fluorene and the 5- to 10-membered aromatic heterocycloc ringsystems include e.g. imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furane, benzimidazole, chinolin, isochinoline, chinoxaline, pyrimidine, pyrazine, tetrazole, pyrazole, pyrrole, imidazole, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, and indoline.
Arylalkyl, arylalkenyls, heteroarylalkyl, heteroalkylalkenyl, heterocycloalkyl, heterocycloalkenyl moieties are each defined as their corresponding basic structures alkyl, alkenyl, aryl, heteroaryl, heteroalkyl, or heterocycloalkyl.
Any of the above alkyl, alkenyl, alkinyl, alkoxy, alkenoxy, acyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, arylalkenyls, heteroalkyl, heteroalkenyl, heteroalkinyl, heteroalkenyl, heteroalkoxy, heteroalkenoxy, heteroacyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl groups may either be unsubstituted or (mono- or poly-) substituted with one or more non-interfering substituents, e.g., halogen, alkoxy, acyloxy, hydroxy, mercapto, carboxy, benzyloxy, phenyl, benzyl, or other functionality which may or has been suitably blocked with a protecting group so as to render the functionality non-interfering. Each substituent may be optionally substituted with additional non-interfering substituents. The term "non-interfering" characterizes the substituents as not adversely affecting any reactions to be performed in accordance with the process of this invention.
"Anti-cancer drugs" (also commonly known as "cytostatics") according to the present invention are any drug known in the art suitable to treat cancer, i.e. to treat malignancies, or cancerous growths in order to control the growth of cancerous cells.
In one preferred embodiment of the poly(organo)phosphazene molecule conjugate according to the present invention the anti-cancer drug of the present invention is selected from the group consisting of antibiotics, si-RNA, antisense RNA, alkylating agents, platinum analogues, intercalating drugs, antibiotics, mitotic inhibitors, taxanes, topoisomerase inhibitors, anti-metabolites, hydroxycarbamid, podophyllotoxin, enzymes, hormones, tumor necrosis factor, biological response modifiers and any other known cytostatic.
Preferably, the anti-cancer drug of the poly(organo)phosphazene molecule conjugate according to the present invention is selected from the group consisting of aminolevulinic acic, abarelix, abiraterone, aclacinomycins, agatolimoc, alitretinoin, altretamine, americium, amifostine, aminoglutethimice, aminopterin, amrubicin, amsacrine, anastrozole, ancitabine, aplicine, aprinocarsen, arsenic trioxice, arzoxifene, asparaginase, atrasentan, axitinib, azaciticine, batimastat, belinostat, belotecan, bencamustine, bevacizumab, bexarotene, bicalutamice, biricocar, bisantrene, bleomycins, bortezomibm bosutinib, brostallicin, broxuricine, buserelin, busulfan, cabazitaxel, cactinomycin, calcitriol, californium, canertinib, canfosfamice, capecitabine, carboplatin, carboquone, carmofur, carmustine, carubicin, cetrorelix, cetuximab, chlorambucil, chlormacinone acetate, chlornaphazine, chlorozotocin, chromic phosphate, cilengitice, cintrecekin besucotox, cisplatin, clacribine, clofarabine, cobalt, contusugene lacenovec, cositecan, cyclophosphamice, cytarabine, cacarbazine, cactinomycin, casalini, caunorubicin, cecitabine, cegarelix, cehycroequol, cenileukin ciftitox, cenopterin, ciaziquone, ciethylstilbestrol, cimesna, cocetaxel, coxifluricine, coxorubicin, croloxifene, cromostanolone, ecteinascicins, ecatrexate, ecotecarin, ecotreotice, ecrecolomab, efaproxiral, eflornithine, elliptinium acetate, eniluracil, enocitabine, enzastaurin, epirubicin, epitiostanol, epratuzumab, eribulin, erlotinib, estramustine, etanicazole, ethiocizec oil, etoglucic, etoposice, everolimus, exatecan, exemestane, facrozole, fenretinice, flavopiricol, floxuricine, flucarabine, fluorouracil, flutamice, folinic acic, formestane, fosfestrol, fotemustine, fulvestrant, gallium nitrate, gefitinib, gemcitabine, gemtuzumab ozogamicin, glufosfamice, golc, racioactive, colloical, goserelin, hexestrol, histamine, histrelin, homoharringtonine, hycroxyurea, ibritumomab tiuxetan, icarubicin, icoxifene, ifosfamice, imatinib, imiquimoc, improsulfan, incisulam, interferon-, interleukin-2, iobenguane, irinotecan, irofulven, ixabepilone, kahalalice f, lanreotice, lapatinib, laromustine, lentinan, letrozole, leuprolice, liarozole, lobaplatin, lomustine, lonafarnib, lonicamine, marimastat, mechlorethamine oxice hycrochlorice, mechlorethamine, mecroxyprogesterone, megestrol acetate, melphalan, mepact, mepitiostane, mesna, methotrexate, methyl aminolevulinate, micostaurin, miltefosine, mitobronitol, mitoguazone, mitolactol, mitomycins, mitotane, mitoxantrone, mofarotene, motesanib, motexafin gacolinium, motexafin lutetium, nelarabine, Neovastat® (aeterna), nilutamice, nimustine, ninopterin, nitra crine, nolatrexec, norcihycroguaiaretic acic, oblimersen socium, ofatumumab, olaparib, olivomycins, onapristone, oregovomab, oxaliplatin, paclitaxel poliglumex, paclitaxel, palifermin, panitumumab, panobinostat, pazopanib, pemetrexec, pentostatin, peplomycin, perfosfamice, perifosine, pertuzumab, picoplatin, pipobroman, piposulfan, pirarubicin, piritrexim, pixantrone, plicamycin, polyestraciol phosphate, porfimer socium, porfiromycin, potassium arsenite, precnimustine, prinomastat, procarbazine, propagermanium, Psk® (kureha chemical incustry co., ltc. pharmaceutical civ.; kureha), pteropterin, racium, racon, raltitrexec, ranimustine, ranpirnase, razoxane, retinoic acic, rituximab, romicepsin, roquinimex, rubitecan, samarium 153sm lexicronam, satraplatin, seliciclib, seocalcitol, sipuleucel-t, sizofiran, sobuzoxane, socium iocice, racioactive, socium phosphate, radioactive, sorafenib, spirogermanium, streptozocin, strontium chlorice, strontium, sunitinib, talaporfin, tamibarotene, tamoxifen, tariquicar, tegafur, temoporfin, temozolomice, temsirolimus, teniposice, tesmilifene, testolactone, thiamiprine, thioguanine, tiazofurin, tipifarnib, tirapazamine, topotecan, toremifene, tositumomab, trabecersen, trastuzumab, trichlormethine, triethylenemelamine, triethylenephosphoramice, triethylenethiophosphoramice, trilostane, trimetrexate, triptorelin, trofosfamice, troxacitabine, ubenimex, uracil mustarc, urecepa, valrubicin, valspocar, vancetanib, catalani, vinblastine, vincristine, vincesine, vinflunine, vinorelbine, vorinostat, vorozole, zinostatin, zorubicin, zosuquicar, 6-azauricine, 6-mercaptopurine and 9-aminocamptothecin.
More preferably, the anti-cancer drug of the poly(organo)phosphazene molecule conjugate according to the present invention is selected from the group consisting of epirubicin, doxorubicin, daunorubicin, idarubicin and valrubicin.
In one particular preferred embodiment of the poly(organo)phosphazenes of the present invention the anti-cancer drug is epirubicin. In this respect the release of epirubicin from the polymer-drug conjugates was simulated under physiological conditions at 37° C. in a pH 7.4 phosphate buffer and in an acidic medium at pH 5 in an acetate buffer solution. At pH 5 a steady release of the drug molecule from the polymer was observed, with 100% release from the polymer-drug conjugate being observed within 15 hours. Meanwhile, only minimal release was observed within a period of 24 h from the polymers at pH 7.4 (FIG. 2).
The term "polyalkylene oxide" according to the present invention is a polymer composed of repeating oxyalkylene units (—OR—), for example CH2O, C2H6O, C3H6O, C4H8O, or combinations thereof, from 2 to 800 repeat units, preferably 10-50 repeat units. They can be linear or branched, but must be overall hydrophilic. Preferred polymers comprise majority (>50%) —C2H6O— units. The polymers should be end-capped with a non-nucleophilic group at one end, preferably CH3O or C2H7O and a nucleophilic moeity at the other end, preferably NH2.
Poly(organo)phosphazenes comprising polyalkylene oxides exhibit enhanced water solubility, hydrodynamic volume and number of arms to the polymers. As already mentioned above an increased number of arms of the macromolecular carrier decrease renal filtration and therefore, exhibit increased blood circulation time (Fox, M. E., et al., 2009).
Therefore, in one preferred embodiment of the poly(organo)phosphazenes of the present invention, R3 and/or R4 and/or R5 and/or R6 and/or R7 represents a polyalkylene oxide as defined above.
In one preferred embodiment of the poly(organo)phosphazene molecule conjugate according to the present invention the polyalkylene oxide is selected from the group consisting of polyether, methoxypolyether, ethoxypolyether, polyethylene oxide, polypropylene oxide, polybutylene oxide, polyethylene glycol, polypropylene glycol, polybutylene glycol, methoxypolyethylene oxide, methoxypolypropylene oxide, methoxypolybutylene oxide, methoxypolyethylene glycol, methoxypolypropylene glycol, methoxypolybutylene glycol, ethoxypolyethylene oxide, ethoxypolypropylene oxide, ethoxypolybutylene oxide, ethoxypolyethylene glycol, ethoxypolypropylene glycol, ethoxypolybutylene glycol, poly(ethylene oxide-co-propylene oxide), poly(ethylene glycol-co-propylene glycol), poly(ethylene oxide-co-butylene oxide), poly(ethylene glycol-co-butylene glycol), poly(propylene oxide-co-butylene oxide), poly(propylene glycol-co-butylene glycol), methoxypoly(ethylene oxide-co-propylene oxide), methoxypoly(ethylene glycol-co-propylene glycol), methoxypoly(ethylene oxide-co-butylene oxide), methoxypoly(ethylene glycol-co-butylene glycol), methoxypoly(propylene oxide-co-butylene oxide), methoxypoly(propylene glycol-co-butylene glycol), ethoxypoly(ethylene oxide-co-propylene oxide), ethoxypoly(ethylene glycol-co-propylene glycol), ethoxypoly(ethylene oxide-co-butylene oxide), ethoxypoly(ethylene glycol-co-butylene glycol), ethoxypoly(propylene oxide-co-butylene oxide) and ethoxypoly(propylene glycol-co-butylene glycol).
"Depsipetide" according to the present invention means a peptide, wherein one or more peptide linkages are substituted by ester linkages, i.e. a peptide in which one or more of the amide (—CONHR—) bonds are replaced by ester (COOR) bonds. In one preferred embodiment of the poly(organo)phosphazene molecule conjugate according to the present invention depsipeptide is selected from the group consisting of beativericin, morpholinedione, valinomycin, Depsipeptide A, Depsipeptide B, ethyl-2-(O-glycyl)glycolate and ethyl-2-(O-glycyl)lactate.
The term "amino acid alkyl ester" according to the present invention is an alkyl derivative of an amino acid, i.e. an ester formed by an amino acid and an alkanol, wherein the alkanol is an alkyl, as defined above, carrying an OH-moiety, preferably an (C1 to C10)-alkyl. In this respect, an amino acid is any natural or non-natural amino acid selected from the group consisting of Alanine, Arginine, Asparagine, Aspartic Acid, Cysteine, Glutamic Acid, Glutamine, Glycine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Proline, Serine, Threonine, Tryptophan, Tyrosine, Valine, 2-Aminoadipic acid, 3-Aminoadipic acid, beta-Alanine, beta-Aminopropionic acid, 2-Aminobutyric acid, 4-Aminobutyric acid, piperidinic acid, 6-Aminocaproic acid, 2-Aminoheptanoic acid, 2-Aminoisobutyric acid, 3-Aminoisobutyric acid, 2-Aminopimelic acid, 2,4 Diaminobutyric acid, Desmosine, 2,2′-Diaminopimelic acid, 2,3-Diaminopropionic acid, N-Ethylglycine, N-Ethylasparagine, Hydroxylysine, allo-Hydroxylysine, 3-Hydroxyproline, 4-Hydroxyproline, Isodesmosine, allo-Isoleucine, N-Methylglycine, sarcosine, N-Methylisoleucine, 6-N-Methyllysine, N-Methylvaline, Norvaline, Norleucine, Ornithine Selenocysteine, and Taurine.
It is known that polymers with a molecular weight above the renal clearance limit will accumulate in the body, and, therefore, lead to damaging side effects. Thus, it is extremely desirable that polymers used for drug delivery applications degrade under physiological conditions. However, a major disadvantage of many organic polymers is their lack of biodegradability. In this respect, it is well-reported that poly(organo)phosphanes degrade to biocompatible products under physiological conditions. The rate of degradation can vary greatly, depending on the properties of the side-substituents and hydrophilicity of the polymer. (Allock, H. R. et al., 1977; Ibim, S.E.M. et al., 1997). This can be readily utilized to give a broad spectrum of polymers with very different rates of degradation. In addition to the corresponding side groups, polyphosphazenes have been shown to degrade to low toxicity compounds including ammonia and phosphates (Allock, H. R. et al., 1994). In particular, hydrophilic amino substituted polyphosphazenes are known to be hydrolytically unstable and the stability can be tailored by careful choice of substituents such as depsipeptides or amino acid esters.
Therefore, in one preferred embodiment of the poly(organo)phosphazenes of the present invention, R3 and/or R4 and/or R5 and/or R6 and/or R7 represents a depsipeptide as defined above.
In another preferred embodiment of the poly(organo)phosphazenes of the present invention, R3 and/or R4 and/or R5 and/or R6 and/or R7 represents an amino acid alkyl ester as defined above.
It has been reported that the rate of degradation of polyphosphazenes can be altered significantly by careful choice of substituents. In particular, the incorporation of amino acid side chains has been shown to considerably decrease the hydrolytic stability of hydrophilic poly(organo)phosphazenes (Vandorpe, J. et al., 1996, Andrianov, A. K. et al., 2006). In this respect, a series of polymers were synthesised via sequential addition of linker, PEO-PPO-NH2 and then ethyl glycinate ester side chains in varying ratios. As shown in FIG. 3, the degradation is considerably accelerated upon incorporation of ethyl glycinate side groups. After 2 weeks, the Mn of polymer 7, in which around 47% of the chlorine atoms were substituted with ethyl glycinate groups, was reduced to 66% of its original value, whereby polymer 2 had a Mn value 80% of its original.
A "tumor targeting ligand" according to the present invention means any substance specifically targeting tumor-specific antigens and/or tumor-specific receptors. For instance, the folate receptor has been shown to be over-expressed in many human cancers (Lu, Y. and Low, P. S., 2002). Thus, folic acid binding to the folate receptor is a "tumor targeting ligand".
Therefore, in one preferred embodiment of the poly(organo)phosphazenes of the present invention, R3 and/or R4 and/or R5 and/or R6 and/or R7 represents an amino acid alkyl ester as defined above.
Poly(organo)phosphazene molecule conjugates of the present invention comprising at least one tumor targeting ligand have the advantage to selectively target tumor tissue. In one preferred embodiment of the poly(organo)phosphazene molecule conjugate according to the present invention the tumor targeting ligand is selected from the group consisting of biotin, folic acid, vitamin B12, riboflavin, hyaluronic acid, monoclonal antibodies targeting tumor-specific antigens and/or tumor-specific receptors and variants thereof, polyunsaturated fatty acids, aptamers targeting tumor-specific antigens and/or tumor-specific receptors, oligopeptides targeting tumor-specific antigens and/or tumor-specific receptors. In this respect "tumor-specific antigen or receptor" means any antigen and/or receptor which specifically is expressed within tumor tissue.
In one preferred embodiment of the poly(organo)phosphazene molecule conjugate according to the present invention the sum of a, m, n and l is ≦150, preferably the sum of a, m, n and l is ≦140, ≦130, ≦120, ≦110, ≦100, ≦90, ≦80. More preferably, the sum of a, m, n and l is in the range of 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 90, 1 to 80, and 1 to 75, alternatively, the sum of a, m, n and l is in the range of 5 to 150, 5 to 140, 5 to 130, 5 to 120, 5 to 110, 5 to 100, 5 to 90, 5 to 80, and 5 to 75, alternatively, the sum of a, m, n and l is in the range of 10 to 150, 10 to 140, 10 to 130, 10 to 120, 10 to 110, 10 to 100, 10 to 90, 10 to 80, and 10 to 75, alternatively, the sum of a, m, n and l is in the range of 15 to 150, 15 to 140, 15 to 130, 15 to 120, 15 to 110, 15 to 100, 15 to 90, 15 to 80, and 15 to 75, alternatively, the sum of a, m, n and l is in the range of 20 to 150, 20 to 140, 20 to 130, 20 to 120, 20 to 110, 20 to 100, 20 to 90, 20 to 80, and 20 to 75, alternatively, the sum of a, m, n and l is in the range of 25 to 150, 25 to 140, 25 to 130, 25 to 120, to 110, 25 to 100, 25 to 90, 25 to 80, and most preferably, the sum of a, m, n and l is in the range of 25 to 75.
In one preferred embodiment of the poly(organo)phosphazene molecule conjugate according to the present invention "a" represents a degree of polymerisation of the poly(organo)phosphazenes in the range of 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 90, 1 to 80, and 1 to 75, alternatively, "a" represents a degree of polymerisation of the poly(organo)phosphazenes in the range of 5 to 150, 5 to 140, 5 to 130, 5 to 120, 5 to 110, 5 to 100, 5 to 90, 5 to 80, and 5 to 75, alternatively, "a" represents a degree of polymerisation of the poly(organo)phosphazenes in the range of 10 to 150, 10 to 140, 10 to 130, 10 to 120, 10 to 110, 10 to 100, 10 to 90, 10 to 80, and 10 to 75, alternatively, "a" represents a degree of polymerisation of the poly(organo)phosphazenes in the range of 15 to 150, 15 to 140, 15 to 130, 15 to 120, 15 to 110, 15 to 100, 15 to 90, 15 to 80, and 15 to 75, alternatively, "a" represents a degree of polymerisation of the poly(organo)phosphazenes in the range of 20 to 150, 20 to 140, 20 to 130, 20 to 120, 20 to 110, 20 to 100, 20 to 90, 20 to 80, and 20 to 75, alternatively, "a" represents a degree of polymerisation of the poly(organo)phosphazenes in the range of 25 to 150, 25 to 140, 25 to 130, 25 to 120, 25 to 110, 25 to 100, 25 to 90, 25 to 80, and most preferably, "a" represents a degree of polymerisation of the poly(organo)phosphazenes in the range of 25 to 75.
In another preferred embodiment of the poly(organo)phosphazene molecule conjugate according to the present invention "m" represents an integer between 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 90, 1 to 80, and 1 to 75, alternatively, "m" represents an integer between 5 to 150, 5 to 140, 5 to 130, 5 to 120, 5 to 110, 5 to 100, 5 to 90, 5 to 80, and 5 to 75, alternatively, "m" represents an integer between 10 to 150, 10 to 140, 10 to 130, 10 to 120, 10 to 110, 10 to 100, 10 to 90, 10 to 80, and 10 to 75, alternatively, "m" represents an integer between 15 to 150, 15 to 140, 15 to 130, 15 to 120, 15 to 110, 15 to 100, 15 to 90, 15 to 80, and 15 to 75, alternatively, "m" represents an integer between 20 to 150, 20 to 140, 20 to 130, 20 to 120, 20 to 110, 20 to 100, 20 to 90, 20 to 80, and 20 to 75, alternatively, "m" represents an integer between 25 to 150, 25 to 140, 25 to 130, 25 to 120, 25 to 110, 25 to 100, 25 to 90, 25 to 80, and most preferably, "m" represents an integer between 25 to 75.
In one preferred embodiment of the poly(organo)phosphazene molecule conjugate according to the present invention "n" and "l" are the same or different and each of n and l is independently from one another an integer between 1 and 149, preferably, between 1 to 139, 1 to 129, 1 to 119, 1 to 109, 1 to 99, 1 to 89, 1 to 79, and 1 to 74, alternatively, "n" and "l" are the same or different and each of n and l is independently from one another an integer between 1 to 145, 1 to 140, 1 to 135, 1 to 130, 1 to 125, 1 to 120, 1 to 115, 1 to 110, 1 to 105, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 75, and 1 to 70, alternatively, "n" and "l" are the same or different and each of n and l is independently from one another an integer between 5 to 145, 5 to 140, 5 to 135, 5 to 130, 5 to 125, 5 to 120, 5 to 115, 5 to 110, 5 to 105, 5 to 100, 5 to 95, 5 to 90, 5 to 85, 5 to 75, and 5 to 70, alternatively, "n" and "l" are the same or different and each of n and l is independently from one another an integer between 10 to 145, 10 to 140, 10 to 135, 10 to 130, 10 to 125, 10 to 120, 10 to 115, 10 to 110, 10 to 105, 10 to 100, 10 to 95, 10 to 90, 10 to 85, 10 to 75, and 10 to 70, alternatively, "n" and "l" are the same or different and each of n and l is independently from one another an integer between 15 to 145, 15 to 140, 15 to 135, 15 to 130, 15 to 125, 15 to 120, 15 to 115, 15 to 110, 15 to 105, 15 to 100, 15 to 95, 15 to 90, 15 to 85, 15 to 75, and 15 to 70, alternatively, "n" and "l" are the same or different and each of n and l is independently from one another an integer between 20 to 145, 20 to 140, 20 to 135, 20 to 130, to 125, 20 to 120, 20 to 115, 20 to 110, 20 to 105, 20 to 100, 20 to 95, 5 to 90, 20 to 85, 20 to 75, and 20 to 70, alternatively, "n" and "l" are the same or different and each of n and l is independently from one another an integer between 25 to 145, 25 to 140, 25 to 135, 25 to 130, 25 to 125, 25 to 120, 25 to 115, 25 to 110, 25 to 105, 25 to 100, 25 to 95, to 90, 25 to 85, 25 to 75, and 25 to 70.
In another preferred embodiment of the poly(organo)phosphazene molecule conjugate according to the present invention X is NH.
In another preferred embodiment of the poly(organo)phosphazenes of the present invention, R3 and/or R4 and/or R5 and/or R6 and/or R7 represents R1—Y—R2, wherein R1—Y—R2 is defined as above.
As already outlined above, the molecular architecture and hydrodynamic volume of the polymer plays a crucial role in the pharmacokinetics and in-vivo distribution of polymeric drug carriers (Fox, M. E., et al., 2009), accurate control of both molecular weight and dispersity is an important factor for polymer therapeutics.
In this respect, the polydispersity index (PDI) is the weight average molecular weight divided by the number average molecular weight and, therefore, a measure of the distribution of molecular mass in a given polymer sample. Thus, the PDI indicates the distribution of individual molecular masses in a batch of polymers. A PDI equal to or little above 1 indicates that the distinct polymer chains in a given polymer sample approach uniform chain length, i.e. only one length of polymer is present. In contrast, a PDI around 10 to 20 refers to a batch of polymers having polymer chains varying in chain lengths over a wide range of molecular masses.
Therefore, in one preferred embodiment of the poly(organo)phosphazenes of the present invention the poly(organo)phosphazene has a polydispersity of 1.8 or less, preferably, the poly(organo)phosphazene has a polydispersity of 1.7 or less, more preferably of 1.6 or less, even more preferably of 1.5 or less and most preferably of 1.4 or less.
In this respect, it should be noted that the major precursor of poly(organo)phosphazenes is dichloropolyphosphazene. Dichloropolyphosphazene is extremely hydrolytically unstable, however, can be readily substituted to give a wide range of stable poly(organo)phosphazenes with an extremely wide range of properties.
So far, the most developed method of synthesis for preparation of dichloropolyphosphazene is the so-called thermal ring-opening polymerisation of hexachlorophosphazene at 250° C. This method does not allow any controlling of the molecular weight of the synthesized polymers. Therefore, dichloropolyphosphazenes synthesized by thermal ring-opening polymerisation generally have high molecular weights (Mw>106 daltons) and, in addition, broad polydispersities, i.e. polydispersity indexes (PDI) up to 19. Limited control of the molecular weight utilizing thermal ring-opening polymerisation can be achieved by the use of catalysts such as OP(OPh)3/BCl3 or AlCl3. However, high temperatures are still required which also result in broad polydispersity, as it is the case, for example, for the condensation polymerisation of Cl3P═(O)Cl2. By high temperature reaction of PCl5 with NH4Cl (Allcock, H. R., et al., 1996) only low molecular weight dichloropolyphosphazene with limited molecular weight control can be achieved.
To date synthesis of the precursor polymer dichloropolyphosphazene with controlled molecular weights and narrow molecular weight distribution, i.e. narrow polydispersities, such as, for example PDIs in the range of 1.1-1.8, preferably, 1.1-1.6, more preferably, 1.1-1.4 according to the present invention, is enabled by the room temperature living cationic polymerisation of chlorophosphoranimine, pioneered by Allcock and Manners, (Allcock, H. R., et al., 1996 and Blackstone, V. et al., 2009) and unavailable by any other methods as disclosed in U.S. Pat. No. 5,698,664 or U.S. Pat. No. 5,914,388.
Thus, the development of a living polymerisation route to polyphosphazenes was a key advancement allowing access to block copolymers (Nelson, J. M., et al., 1998 and Matyjaszewski, K. et al., 1993) star-branched and dendritic polymers based on polyphosphazenes (Nelson, J. M., et al., 1997 and Cho, S. Y., et al. 2007).
Therefore, in a second aspect the present invention concerns a process for preparing a poly(organo)phosphazenes conjugates according to the present invention, comprising cationic living polymerisation of chlorophosphoramines.
In one preferred embodiment, the present invention relates to a process for preparing a poly(organo)phosphazene molecule conjugate according to the present invention, comprising the steps of:                a) preparation of dichloropolyphosphazenes by living cationic polymerisation of chlorophosphoranimes;        b) substitution of at least one chlorine atom of the dichloropolyphosphazenes of step a) with a pH sensitive linker; and        c) covalently binding an anti-cancer drug to the pH sensitive linker.
"Living cationic polymerisation" is known in the art. In one preferred embodiment of the process for preparing a poly(organo)phosphazene conjugate according to the present invention, dichloropolyphosphazenes are synthesised by the polymerisation of chlorophosphoranime utilising living polymerisation according to Allock, H. R., 1996 and U.S. Pat. No. 5,698,664. This simple room temperature polymerisation results in polymers with narrow polydispersities, i.e. polydispersities of 1.8 or less.
In one preferred embodiment of the process according to the present invention, the polymerised dichloropolyphosphazene of step a) of the process of the present invention has a polydispersity of 1.8 or less, preferably, of 1.7 or less, more preferably, of 1.6 or less, even more preferably of 1.5 or less and most preferably of 1.4 or less. In one preferred embodiment the polymerised dichloropolyphosphazene of step a) of the process of the present invention has a polydispersity in the range of 1.0 to 1.8, preferably, 1.1 to 1.7, more preferably, in the range of 1.2 to 1.6 and most preferably, in the range of 1.3 to 1.5.
The polymers in this state are very hydrolytically unstable, due to the labile chlorine groups and must be stored in a dry, inert atmosphere. It is also critical that all reagents used in the polymerisation and subsequent reactions are extremely dry as H2O reacts readily with dichloropolyphosphazenes.
However, the advantage of these labile chlorine atoms is that they can then be readily substituted with the desired nucleophilic substituents, such as alcohols, thiols or amines. In one preferred embodiment of the present invention, amine-capped organic reagents in THF (wherein any dry polar solvent, such as dioxane would be also suitable) and with an equimolar amount of triethylamine as a scavenger for the HCl by-product are used.

In one preferred embodiment of the process of the present invention the pH sensitive linker can be any linker resulting in a "pH sensitive functional group" as defined above, i.e a "pH-sensitive functional group" which will respond to a pH lower than 6.5, i.e. which will be hydrolysed by a pH of lower than 6.5. Preferably, the pH-sensitive functional group of the present invention will respond to a pH lower than 6.5, 6.4, 6.3, 6.4, 6.3, 6.2, 6.1, 6.0, 5.9, 5.8, 5.7, 5.6, 5.5, 5.4, 5.3, 5.2, 5.1, 5.0, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1 and 4.0. More preferably, the pH-sensitive functional group of the present invention will respond to a pH in the range of 4.0 to 6.5, preferably, in the range of 4.5 to 6.0, more preferably, in the range of 4.5 to 6.0, and most preferably, in the range of 5 to 6.0. Thus, any functional group cleavable in an acidable environment (pH lower than 6.5, preferably lower than 6.0) known to the person skilled in the art would be suitable for the present invention. Preferably, the pH sensitive functional group is selected from the group consisting of hydrazide, hydroxamate, imine, cyclic acetal and aconityl.
In one particular preferred embodiment for preparing a poly(organo)phosphazene molecule conjugate according to the present invention the pH sensitive linker is selected from the group consisting of formula 8 to 13
wherein X and R1 are defined as above.
In one particular preferred embodiment for preparing a poly(organo)phosphazene molecule conjugate according to the present invention the pH sensitive linker is selected from the group consisting of formula 14 to 19

In another preferred embodiment for preparing a poly(organo)phosphazene molecule conjugate according to the present invention the pH sensitive linker is protected before step b).
The term "protected" as used herein and unless otherwise defined refers to a group that is added to an oxygen or nitrogen atom to prevent its further reaction during the course of derivatization of other moieties in the molecule in which the oxygen or nitrogen is located. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis. Preferably, the protecting group is selected from the group consisting of allyloxycarbonyl (Aloc), benzyl (Bn), benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), tert-butoxycarbonyl (Boc), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), p-methoxybenzyl (PMB), methoxymethyl (MOM), p-methoxyphenyl (PMP), tosyl (Ts), 2-tosylethoxycarbonyl (Tsoc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), triisopropylsilyl (TIPS), trityl (Tr), fluorenylmethyl carbamate, fmoc, t-butyl carbamate, benzyl carbamate, acetamide, tosylamide, triphenylmethylamine, benzylamine, acetonide, benzylidene acetal, benzoic acid ester, benzoate ester, benzoate, pivalic acid ester, pivalate ester, pivalate, acetic acid ester, acetate ester, acetate, t-butyldiphenylsilyl ether, TBDPS ether, t-butyldimethylsilyl ether, TBDMS ether, benzyl ether, allyl ether, t-butyl ether, tetrahydropyranyl ether, THP ether, methoxymethyl ether, MOM ether, methyl ester, t-Butyl ester, benzyl ester and 2-alkyl-1,3-oxazoline.
In one preferred embodiment of the process of the present invention the protected pH sensitive linkers are selected from the group consisting of formula 20 to 25:
wherein PG is a protecting group as defined above.
In one particular preferred embodiment of the process of the present invention the protected pH sensitive linkers are selected from the group consisting of formula 26 to 31

For instance, a hydrazone-containing linker capped with an ethylamine group and a boc protecting group (King, H. D. et al., 1999) could be used for the present invention. Such linker has a free amine group, for reaction with the polymer backbone.

The boc-protected hydrazide linker could be then added to the dichloropolyphosphazene.

Synthesis of any other pH sensitive functional group (as defined above) covalently linked to the polymeric backbone of the poly(organo)phosphazenes of the present invention are described below in the examples.
In another preferred embodiment the process for preparing poly(organo)phosphazenes of the present invention further comprises the step of substitution of at least one chlorine atom with a polyalkylene oxide between steps b) and c).
In one preferred embodiment the process for preparing poly(organo)phosphazenes of the present invention further comprises the step of substitution of at least one chlorine atom with a depsipeptide between steps b) and c).
In another preferred embodiment the process for preparing poly(organo)phosphazenes of the present invention further comprises the step of substitution of at least one chlorine atom with an amino acid alkyl ester between steps b) and c).
In one preferred embodiment the process for preparing poly(organo)phosphazenes of the present invention further comprises the step of substitution of at least one chlorine atom with a tumor targeting ligand between steps b) and c). In this respect any tumor-targeting ligand known in the art and suitable to be covalently bound to polyalkylene oxide oligomers could be used.
In one particular preferred embodiment of the process for preparing poly(organo)phosphazenes according to the present invention, polyethylene glycol oligomers were synthesised with an additional folic acid tumor-targeting ligand in a separate reaction, wherein the diamino polyethylene glycol oligomers were firstly protected on one end. The remaining amino group was then allowed to react with folic acid via a well-reported coupling procedure with EDCl.

Following simple deprotection in TFA/CH2Cl2, the chosen amount (1-5 mol %) of the boc-protected was then added to the dichloropolyphosphazene, previously substituted with the hydrazide linker. This substitution was allowed to continue to completion (10-24 h) before further steps.

In another preferred embodiment of the process for preparing poly(organo)phosphazenes according to the present invention, chlorine atoms of the polyphosphazenes were substituted in order to enhance the aqueous solubility of the poly(organo)phosphazenes. In this respect any hydrophilic polyalkylene oxide based chain with an amine end group could be used, wherein the length of the chain could be varied.
In a particular preferred embodiment of the process for preparing poly(organo)phosphazenes according to the present invention step d) was performed by replacing the remaining chlorine atoms with mono amine-capped polyalkylene oxide oligomers. These mono amine-capped polyalkylene oxide oligomers add water solubility, hydrodynamic volume and number of arms to the polymers (in this respect it should be noted that a large number of arms might also be an important factor for renal clearance). Preferably, amine-capped Jeffamines® are used for this purpose. The excess PEO-PPO-NH2 and remaining salts are then removed by dialysis.

In a third aspect, the present invention relates to the polyorganophosphazene molecule conjugates obtainable by the process according to the present invention.
In a fourth aspect, the present invention relates to the polyorganophosphazene molecule conjugates according to the present invention or to the polyorganophosphazene molecule conjugates obtainable by the process according to the present invention for use in medicine, preferably for use in the treatment of cancer.
In a fifth aspect, the present invention relates to pharmaceutical compositions comprising a polyorganophosphazene molecule conjugate according to present invention or a polyorganophosphazene molecule conjugate obtainable by the process according to the present invention and a pharmaceutically active carrier.
Pharmaceutical compositions as defined herein typically can be formulated by methods known to those skilled in the art preferably utilizing pharmaceutically acceptable components. The term "pharmaceutically acceptable" refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding factors such as formulation, stability, patient acceptance and bioavailability.
In this context, a pharmaceutically acceptable carrier and/or vehicle typically includes the liquid or non-liquid basis of the inventive pharmaceutical composition. If the inventive pharmaceutical composition is to be provided in liquid form as it is preferred in the present invention the carrier will be typically pyrogen-free water; isotonic saline or buffered (aqueous) solutions, e.g. phosphate, citrate etc. buffered solutions. The injection buffer may be hypertonic, isotonic or hypotonic with reference to the specific reference medium, i.e. the buffer may have a higher, identical or lower salt content with reference to the specific reference medium, wherein preferably such concentrations of the afore mentioned salts may be used, which do not lead to damage of cells due to osmosis or other concentration effects. Reference media are e.g. liquids occurring in "in vivo" methods, such as blood, lymph, cytosolic liquids, or other body liquids, or e.g. liquids, which may be used as reference media in "in vitro" methods, such as common buffers or liquids. Such common buffers or liquids are known to a skilled person. Ringer-Lactate solution is particularly preferred as a liquid basis.
In another aspect, the present invention concerns a method of treatment of cancer comprising administering a poly(organo)phosphazene according to the present invention. Preferably, the poly(organo)phosphazene according to the present invention is administered into the blood stream, i.e. intravenously.

Biodegradable, water soluble and pH responsive poly(organo)phosphazenes


The present disclosure relates to the technical field of semiconductors, and in particular to a semiconductor chip, a semiconductor wafer and a method for manufacturing a semiconductor wafer. The semiconductor chip comprises: a substrate, devices provided on a side of the substrate, via holes running through the substrate, conductive material filled in the via holes and contacted with the devices, and a backside metal layer provided on the other side of the substrate away from the devices, the backside metal layer coming into contact with the conductive material so as to be electrically connected to the devices via the conductive material. The semiconductor chip, the semiconductor wafer and the method for manufacturing a semiconductor wafer of the present disclosure reduce the ground resistance and improve the heat dissipation of devices with via holes structure during the operation.

Compared with the first-generation semiconductor Si and the second-generation semiconductor GaAs, GaN semiconductor material is more suitable for manufacturing of electronic devices of high temperature, high voltage, high frequency and high power due to its distinct advantages such as wide band gap, high saturated electron drift velocity, high breakdown field strength and high temperature-resistance. The GaN semiconductor material has great application prospect and thus has become a hot spot for research in the semiconductor industries.
GaN high electron mobility transistors (HEMT), as GaN devices formed by two dimensional electron gas at AlGaN/GaN heterojunctions, may be applied in situations requiring high frequency, high voltage and high power. When a GaN device is packaged, a throughhole structure is generally employed to increase the device gain and reduce the ground resistance. Via holes in such a structure are generally introduced by etching from a backside of a substrate, and the semiconductor device is grounded by grounding the backside of the substrate. Specifically, via holes run through a substrate and a semiconductor layer made of nitrides and to a source electrode, so that the source electrode is connected with the backside of the grounded substrate by the via holes.
At present, there are mainly two approaches of positioning the via holes for a GaN device. One approach is to form the via holes in a metal PAD area. In this approach, since the via holes are located on a same side of an active area, the current in the active area entirely flows in a same direction without being dispersed although the influence of the via holes on heat dissipation of the devices is weakened. As a result, mutual inductance is generated between metal fingers in the active area. Furthermore, this approach allows the distance from the source electrode within the active area to the ground to be increased as well. That is to say, the ground resistance of the source electrode is increased, and thus the properties of the devices such as gain are influenced. The other approach is to form the via holes below the source electrode located in the active area. As for this approach, because the source electrodes within each active area may be directly grounded by the via holes, the distance from source electrode within the active area to the ground is reduced and the ground resistance is thus reduced. However, this approach which arranges all the via holes in the active area will severely affect the heat dissipation of the devices, thus restricting the power design for the devices. This is because the active area is an area where heat is generated intensively in the devices and a throughhole structure is generally a hollow one, and the hollow throughhole structure will destroy the heat dissipation of the substrate.

Semiconductor chip, semiconductor wafer and method for manufacturing semiconductor wafer


A stringed musical instrument, such as a guitar, mandolin, or a violin, has an elongated frame to which modular components such as necks, electronic pick-ups, electronic control boxes, bridges, tail pieces, decorative components, or body parts can be adjustably placed and clamped. This not only allows the position of many such components to be customized, but also allows different components to be easily substituted for each others; allows the instrument to be quickly taken apart for more compact storage or shipment; and allows the instrument to be changed so as to produce a different sound or look. Preferably some the components, including the body parts, are rotatably mounted relative to the frame, so their angle relative to the plane of the fingerboard can be adjusted to suit a user's tastes or physical disabilities, such as carpel-tunnel stress syndrome. In some embodiments, an entire string assembly, comprised of a set of strings connected between a head and a bridge or tail piece, can be modularly attached to or replaced from the instrument.

Stringed musical instruments, such as guitars, mandolins, bass guitars and violins, have been used for many years. Their sounds have brought most humans many hours of enjoyment and they are among the most important of all musical instruments. Although many prior-art stringed musical instruments work very well, there are, however, certain features which they lack.
For example, some people would find it desirable to make it easier to customize the look, feel, properties, and performance of a stringed instrument to suit an individual user's long term preference or his current desires. Normally with prior art stringed instruments it is difficult or virtually impossible to change most aspects of the instrument once it has been purchased.
In certain cases it would be desirable to be able to more compactly carry and ship a stringed instrument. This is particularly true for a player who would like to take with him the equipment necessary to provide different musical qualities, such as the different qualities of a twelve-string and a six-string guitar, or different tonal qualities, such as mellow, bright, loud, and brassy tonal qualities.
For some players the angle of the fingerboard of the neck along its major axis relative to the player's body and hands is awkward. This can be particularly true for players with certain physical handicaps, such as carpal-tunnel stress syndrome.
Finally, many musicians, particularly rock musician, desire to have guitars which have a look which is different from that of traditional stringed instruments, and they may often desire to change that look at different times.


A data transfer method realizing a function similar to Unix's FORK by the following operations: allowing a parent process on a server to issue a request for intermission of communication to a process on a client and allowing the process on the client to issue a report of completion of intermission; allowing the parent process to issue, to a child process created on the server and the process on the client, a request for establishment of a new communication line connection between them; and, if the parent process has received data from the process on the client before the establishment of the new connection, coping the data to the child process.

1. Field of the Invention
This invention relates to a data transfer method including fork emulation in TCP/IP socket communication, and particularly to a data transfer method by which a child process created by a fork takes over the network connection between the parent process and client in a data processing system which performs data transfer between user-spaces without any operating system involvement.
2. Description of Related Art
In a distributed data processing system of the server-client model, TCP/IP socket communication is very common and there exist enormous software assets. FIG. 2 shows an example of a data processing system of the server-client model. In this example, a host 210 and a host 260 are connected by a communication line 30 and a server application 211 and a client application 261 communicate with each other via sockets.
In the conventional socket communication method, when a parent process 212 in the server application 211 receives a request from a process 262 in the client application 261, the parent process 212 creates a child process 213 through UNIX's fork function and the child process 213 deals with the request from the process 262. In socket communication, however, data to be communicated is once buffered in buffers inside the space of an operating system (a buffer 231 in an OS 230 and a buffer 281 in an OS 280). This has been a bottleneck in improving the throughput.
As a solution to this problem, next-generation high speed IO methods, such as VIA (Virtual Interface Architecture) which enables direct data transfer between user-spaces without the need for copying into the OS space, have been proposed in recent years. One example of such known art is "High-Performance Local Area Communication With Fast Socket" (Proceedings of the USENIX, 1997) by Steven H. Rodrigues et al. According to this art, connection of the server and client by a high speed network permits performance improvement and also emulation of some of the socket communication functions by the API of the high speed network enables an effective use of existing software assets. Regarding this emulation, it is well known that the original function can be replaced by a new function through UNIX's rename capability.

Data transfer and intermission between parent and child process


A disclosed optical semiconductor element includes: a semiconductor substrate having a first main surface and a second main surface in which a plurality of first grooves are formed; a first optical waveguide defined by portions of the semiconductor substrate between the first grooves and having side faces defined by the first grooves; and a photoelectric converter configured to transmit or receive an optical signal propagating through the first optical waveguide. Moreover, the first grooves define part of a guide hole.

With the arrival of an advanced information society, optical communication technologies capable of transferring information at high speed are about to be realized. These optical communication technologies use an optical semiconductor element for converting optical signals transferred through optical fibers into electric signals or, conversely, converting electric signals into optical signals.
In order to reduce the loss of optical signals, it is effective to couple the optical fibers to optical waveguides included in the optical semiconductor element, and also to improve the accuracy of alignment of the optical fibers and the optical waveguides so that the optical signals transferred through the optical fibers may mostly be introduced into the optical semiconductor element.
Further, reducing the size of a mechanism coupling the optical fibers and the optical waveguides may contribute to reduction of the size of an electronic device on which these components are mounted.
Note that technologies related to the present application are disclosed in Japanese Laid-open Patent Publication Nos. 2006-323317, 2002-131565, 05-264832, 2006-71801, and 59-7910.

Optical semiconductor element and method of manufacturing the same


A golf swing assistance device has a base having a flat upper surface with a hitting spot, a shallow lower surface indented adjacent to a hitting spot of the upper surface. The hitting spot is located in the middle of a golf swing that a user takes. A rear position sensor is located behind the golf swing, and behind the hitting spot. A front position sensor is located after the swing and in front of the hitting spot. A ball holder has a ball holding plate, a ball holding arm and a ball holder connector. A block receives the ball holder connector. An adjusting mechanism allows vertical adjustment of the ball holder connector. A ball target has a ball end, a ball target arm and a ball target connector. Also, position sensors mounted on stands can monitor other sections of the golf swing.

1. Field of the Invention
This invention relates generally to the field of apparatus for a golf training, practice, and coaching device.
2. Discussion of Related Art
A variety of golf assistance devices had been invented. For example, Golf 'Swing For Accuracy' Mat U.S. Pat. No. 6,554,716 patented Apr. 29, 2003 shows a device having a mat and a pair of connecting arms holding ball targets that assist the user in improving a golf swing. The disclosure of U.S. Pat. No. 6,554,716 is incorporated herein by reference.


In a dry cleaning process, breakage of a gas supply pipe can be prevented, and maintenance efficiency can be increased. There is provided a method of manufacturing a semiconductor device, comprising: (a) loading a substrate into a process chamber; (b) forming a silicon film or a silicon compound film on the substrate loaded in the process chamber by supplying a raw-material gas to a gas supply pipe disposed in the process chamber to introduce the raw-material gas into the process chamber; (c) unloading the substrate from the process chamber; (d) heating an inside of the process chamber after unloading the substrate to generate a crack in a thin film formed inside the process chamber; (e) decreasing an inside temperature of the process chamber after carrying out the step (d) with the substrate unloaded from the process chamber; and (f) introducing a cleaning gas into the process chamber by supplying the cleaning gas to the gas supply pipe after the step (e) with the substrate unloaded from the process chamber.

1. Field of the Invention
The present invention relates to a method of manufacturing a semiconductor device, and more particularly, to a method of manufacturing a semiconductor device by processing a substrate while removing films formed on parts of a semiconductor manufacturing apparatus.
2. Description of the Prior Art
In a process of forming a silicon (Si)-based film by using a hot wall type chemical vapor deposition (CVD) apparatus, source gas and etch gas are supplied to the inside of a reaction furnace through a gas supply pipe. However, when gas is supplied from a gas supply source, films are deposited on quartz components (e.g., a reaction tube, a boat, and the gas supply pipe (including a nozzle)) as well as wafers, and if the thickness of the films exceeds 3 μm, the films may be stripped off and form particles.
Therefore, it is necessary to clean the quartz components periodically, and moreover, it is necessary to replace the quartz components with new components according to the wear of the quartz components. Wet etching can be performed (to remove Si-based films by using an etchant such as fluoroacetic acid and hydrogen fluoride) each time wafers are processed. However, in this case, since washing and drying processes are also necessary, maintenance time increases, and thus maintenance efficiency decreases. In addition, when a quartz component is detached, the inside of the reaction furnace is exposed to the outside atmosphere and thus can be contaminated. Therefore, it is not preferable to maintain a highly clean state.
For these reasons, dry etching may be alternatively performed to remove Si-based films by introducing cleaning gas (e.g., ClF3) into the reaction furnace in a state where the quartz components are disposed in the apparatus in a nitrogen (N2) atmosphere.
However, when an Si-based film forming process is performed, since the inside pressure of the gas supply pipe (including a nozzle) used for supplying source gas is higher than the inside pressure of the reaction furnace, a thicker film is deposited on the inside of the source gas supply pipe as compared with the inside of the reaction furnace. Therefore, stresses are accumulated in the gas supply pipe due to the thicker film. If cleaning gas is supplied through the gas supply pipe in which stresses are accumulated, the film deposited on the inside of the gas supply pipe is rapidly etched, and thus the accumulated stresses are rapidly released. This causes breakage of the gas supply pipe such as cracking of the gas supply pipe. Moreover, due to resultant particles and replacement of the gas supply pipe after a dry cleaning process, maintenance efficiency decreases.

Method of manufacturing semiconductor device


Injection molding is carried out by using styrene-based resin composition. As to the styrene-based resin composition, styrene-based resin, in which melt flow index is 3.0-40.0 g/10 minutes, a Rockwell hardness is M38 or more, an Izod impact strength is 2.0 Kg.multidot.cm/cm or more, a bending elastic modulus is 20,000 Kg/cm.sup.2 or more, and a Vicat softening point is 78.degree. C. or more, is 50 wt. % or more, total of at least two kinds selected from lubricant or surfactant is 0.01-20 wt. %, a thermoplastic resin having experienced twice or more heat histories at 150.degree. C. or more is 3 wt. % or more, and total of at least one of antioxidant, deodorant and an agent imparting fragrance is 0.01-20 wt. %. Styrene-based resin composition having melt flow index of 1-50 g/10 minutes, and including ethylbenzene of 0.001-1 wt. %, rubber-like material of 0.1-15 wt. %, and light shielding material of 0.1-10 wt. %, may be used.

1. Field of the Invention
The present invention relates to a injection molded article used with photosensitive material, for example, a photo film cartridge, a photo sheet film case, a lens-fitted film unit, a container for photo film cassette, a photo film spool, a photo film cassette made of resin (a cassette for so-called advanced photo system and so on), an instant film unit, an instant film pack, a cartridge for photo disc film, a winding spool, a cassette shell, a core for film-like photosensitive material, a sheet film pack and a sheet film unit.
2. Description of the Related Art
Conventionally, injection molded articles used with photosensitive material, for example, 135-type photo film spool, a core for film-like photosensitive material, a lens-fitted film unit in which a photo film is built beforehand, and a photo film cassette made of resin (for Advanced Photo System, hereinafter, APS), are molded by injection with various resin compositions in order to improve light shielding property, impact resistance, abrasion resistance and so forth.
Japanese Utility Model Publication No. 61-36995 discloses that a photo film spool is made of polystyrene resin or impact resistance polystyrene resin. In this case, when a film end engages with a claw provided on the photo film spool, excellent engaging force of 11.3 Kg is obtained.
Japanese Utility Model Publication No. 2-37799 discloses that a core for film-like photosensitive material is molded by using impact resistance polystyrene resin including rubber-like material, and a gate position of which is restricted. In this case, generation of weld line is reduced and compression strength is improved. Further, injection molding property is improved because gate processing is not required.
Japanese Patent Laid-open publication No. 63-226643 discloses that a lens-fitted film unit is molded by using resin composition in which carbon black is added in impact resistance polystyrene resin of low melt flow index. In this case, necessary light shielding property is obtained.
Japanese Patent laid-open Publication No. 1-312538 discloses that an outer case of a photo film cassette (APS) is molded by resin composition in which carbon black is added to impact resistance polystyrene resin of low melt flow index. In this case, necessary light shielding property is obtained.
Resin composition having light shielding property for a lens-fitted film unit, a photo film cassette made of resin and so forth are disclosed in Japanese Patent Laid-open Publication No. 7-295150. In the resin composition, at least one kind of organic compound having number average molecular weight of less than 10,000 is 0.001-45 wt. %, at least two kinds of antioxidant are 0.002-1 wt. %, and at least one kind of thermoplastic having number average molecular weight of 10,000 or more is 50 wt. % or more.
However, when the photo film spool is molded with above-described resin composition, scatter due to molding tends to be generated and engaging force and physical strength are sometimes greatly different. Further, injection molding property, heat resistance, dimensional accuracy, slip property, antistatic and abrasion resistance are not sufficient and there arises a problem with respect to photographic property.
When a core for film-like photosensitive material is molded by injection with resin composition including rubber-like material or the like, a wound photosensitive material roll is hard to slip due to property of the rubber-like material so that good winding is obtained. However, friction force of the core surface becomes large so that injection molding property and abrasion resistance are not sufficient. Further, when the core surface becomes slippy due to lubricant, surfactant and so forth added thereto, winding property of the roll film becomes bad. It is hard to obtain good winding, injection molding property and abrasion resistance at the same time.
As to the above-described lens-fitted film unit, carbon black is added in conventional impact resistance polystyrene resin of low melt flow index so that it is necessary to increase the resin temperature because flowability of the resin decreases. Therefore, pyrolysis of the resin and the additive tends to be generated so that it is hard to obtain a good photographic property. Further, molding cycle is long and appearance is not good because many weld lines are generated. Moreover, physical strength is low. This is caused due to lack of consideration about the resin composition. Accordingly, further improvement of the resin is desired.
Due to the resin composition used for the photo film cassette, sufficient light shielding property is obtained. However, molding cycle is long and it is expensive. The improvement of slipping property, antistatic, photographic property, heat resistance, appearance and physical strength are desired to be improved. Moreover, many weld lines are generated.
On the other hand, due to the above-described conventional injection molding material, it is possible to reduce generation of micro grid and deterioration of photographic property. Further, generation of trouble due to burned resin is a little so that it is possible to perform successive molding. However, in order to obtain perfect light shielding by adding light shielding material of 2 wt. % or less, further improvement is desired. The light shielding material is fine particle and tends to cohere such as carbon black having a mean particle size of 100 m.mu. or less and oil absorption of 50 ml/100 g or more. Moreover, in order to improve the physical strength of injection molded article and to reduce the generation of weld lines, further improvement is desired.

Injection molded article used with photosensitive material


Embodiments relate to systems and methods for generating a machine state verification using a number of installed package objects. A physical or virtual client machine can host a set of installed software packages, including operating system, application, and/or other software. A package manager installed on the client machine can track the installed package complement, and updates available for those packages. To verify that a target of a package update is prepared and in the correct state to receive the update, the package manager inventory the set of package objects installed on the client machine. The resulting sum can be reported to a remote management platform, such as a package server. The counted package objects can be the packages themselves, and/or their set of component files. Machines having a package sum that does not match an expected target number can have a package re-installation performed, and/or other diagnostics carried out.

Users of physical or virtual machines commonly install software packages, including package updates, to those machines. The software packages can contain a set of related files chosen to perform a given application or task, such as, for example, a group of software applications, drivers, and/or other resources used to install and use messaging or media applications. In instances, a software package can contain application software, operating system software, drivers, patches, and/or other software components grouped as a logical set.
Software package managers exist to help a user initiate and perform software package updates, such as, for example, the "yum" (Yellowdog update manager) package update manager available from Red Hat, Inc., Raleigh, N.C., and others. In general, available software package managers are configured to interact with the set of installed packages on a client and with one or more software package repositories and associated package servers, to directly connect to those databases and download available package updates.
The process of initiating software package updates can involve, however, the risk or possibility of software-related faults, instabilities, bugs, or other errors or irregular conditions. Some of those potential faults or irregular conditions can be the result of a target machine that was not in the correct or expected machine state to receive a package update or updates. For instance, a client machine scheduled to receive a package update may not contain the correct version, or correct number, of previous packages needed to support that update. Irregularities in the package complement can in one regard be caused, for example, by users in the managed network performing unauthorized package updates to client machines, resulting in an unexpected total package sum on those machines. The client machine in addition or instead might be missing one or more component files that are necessary to the operation of the existing package complement. Missing files from a package complement can for instance can be due to further causes hard drive corruption, malicious software intrusions, or other issues. Beyond issues of that nature, an administrator in a managed network may also not have an up-to-date or complete inventory of the machines on the network that represent identical images of desired configurations, and therefore be ready to receive a collective package update, or other collective maintenance.
Existing package update managers may contain facilities to interrogate the state of client machines in a network, but typically need to extract package name, version, and/or other attributes from client machines to attempt to identify the installed package complements on managed machines and reconcile package sets, group related machines together, and/or perform other package-related maintenance and administration. It may be desirable to provide systems and methods for generating a machine state verification using a number of installed package objects, in which a package server or other management platform can interrogate client machines using a comparatively lightweight census or reporting mechanism, but which is nevertheless sensitive to changes in target machine state.

Generating machine state verification using number of installed package objects


A semiconductor device includes: a circuit unit including a semiconductor chip; a plurality of pin terminals formed in a rod shape extending in a same direction from the circuit unit and electrically connected to the circuit unit; a sealing resin portion sealing the circuit unit and first portions of the plurality of pin terminals positioned on a side of the circuit unit; and a plurality of covering resin portions integrally extending from an outer surface of the sealing resin portion from which second portions of the plurality of pin terminals protrude, the plurality of covering resin portions being formed in a cylindrical shape respectively covering base end portions of the second portions of the plurality of pin terminals, which are positioned on a side of the sealing resin portion.

Patent Document 1 discloses a semiconductor device in which a semiconductor chip (power semiconductor element) and one ends, in the longitudinal direction, of a plurality of pin terminals (external connection terminals) formed in a rod shape are joined to one surface of a substrate (power module substrate), and the substrate, the semiconductor device, and a portion on the one end side of each pin terminal are sealed with a sealing resin portion (sealing resin). In this semiconductor device, a portion on the other end side of each pin terminal protrudes from a flat outer surface of the sealing resin portion.

Semiconductor device and semiconductor device manufacturing method

SHINDENGEN ELECTRIC MANUFACTURING CO., LTD.


A process for forming a vertical DMOS device with an ESD protection transistor that is configured for carrying a breakdown current includes the steps of masking a substrate of a first polarity type and forming spaced apart surface isolation regions. An insulated gate is formed between the spaced apart surface isolation regions. Selected portions of the surface regions between the gate and the surface isolation regions are heterodoped to form p-n junctions having retrograde doping profiles beneath the substrate surface thereby lowering the breakdown voltage beneath the heterodoped portions in order to direct a substantial portion of the breakdown current below the surface of the substrate and into the body of the substrate between the heterodoped regions. Source and drain regions are formed in the substrate surface on opposite sides of the gate.

The Field Effect Transistor (FET) has become the most common device used in integrated circuitry, providing a wide variety of electronic tasks, e.g., analog signal processing, memory functions, high speed, low power logic operations and power switching.
During the last decade the semiconductor industry has more fully embraced the use of protection circuitry to shield FET's and other circuitry from damage associated with brief, high power voltage spikes such as the ESD. Because the FET is in many instances the prevalent device type on such circuitry it is often most convenient to form transistor protection devices coincident with the fabrication of FETs. This allows economy, i.e., avoidance of extra fabrication steps.
Although formation of the protection device follows the process fabrication sequence of functional circuit FETs, the transistor operation which provides the over voltage protection is often based on bipolar action. That is, inherent in most FET structures there is a bipolar structure, sometimes termed a parasitic, which can be placed into conduction when certain minimum voltages are applied across input terminals of the integrated circuit.
In the past, parasitic devices associated with functional circuitry have sometimes provided unintended conduction paths that carry the ESD surge and create thermal damage along that path. As a solution, transistor devices are configured to form circuit paths which shunt the majority of damaging power to a ground terminal while avoiding more sensitive conduction paths through which transient, yet high current, high voltage conditions would cause damage.
Generally, efforts to economically incorporate ESD protection devices on an integrated circuit require compromises either in performance or manufacturing costs. As trends continue for increased circuit density and lower operating voltages it is becoming more of a challenge to avoid compromises between performance of functional circuitry and ESD circuitry. More specifically, these trends make it increasingly difficult to effectively shunt heat away from thermally sensitive regions. With decreased operating voltages, the provision of optimal protection should require that the ESD circuitry be tuned to more quickly respond to ESD events. While it is desirable to optimize the ESD device turn-on voltage in order to provide maximum protection before damaging the functional circuitry, it is recognized that when the parasitic devices are optimized to provide ESD protection, there can be less satisfactory performance of the functional circuitry.
CMOS integrated circuits with ESD protection transistors are shown in U. S. Pat. Nos. 5,559,352 and 6,444,511. Both patents show examples where the source and drain of the ESD device is provided with a p-implant beneath the source and drain. The p-implant is supposed to lower the breakdown voltage of the ESD device so that it triggers before the CMOS device fails. However, I found that the narrow p-implant tends to shift the ESD current laterally so that the ESD device directs the current beneath the gate and has too high a current density. That defect is caused in part by the making the p-implant late in the process where the contact opening is used as a mask for the P-type ions. The relatively narrow contact opening results in a narrow p-implant beneath the source and drain of the ESD device. This causes a high current density proximate the surface of the device, although it would be better if the current peaked deeper in the device.
Another trend which limits the performance of ESD protection circuitry relates to marked decreases in gate breakdown voltages. For device designs in the 0.25 micron regime it is common for gate thicknesses to be less than 60 Angstroms. To avoid damage to the FET gate insulator it is necessary to assure fast and satisfactory bipolar conduction during the transient event. It is also necessary to reduce the trigger-on voltage of the ESD device to values substantially lower than the gate breakdown voltage to conduct current along a path which avoids inflicting damage on the gate structure. Solutions which address this concern should have application in a wide variety of semiconductor products including those manufactured with CMOS, BiCMOS and power processes.

ESD protection for semiconductor products