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US 4675381 A Abstract Biodegradable acyloxymethyl polyaspartate and polyglutamate as drug carrier in an encapsulated or incorporated state in the matrix of the copolymer. The polypeptide loaded in this way decomposes enzymatically in the organ where it has been placed and thus progressively releases the drug which it contains.
Claims(11) 1. A poilypeptide selected from the group consisting of (a) biodegradable polymers with the formula ##STR11## in which R.sup.1 and R.sup.2 are selected from the group consisting of lower alkyl and hydrogen; and R is lower alkyl or an aromatic radical; or R.sup.2 is lower alkyl or hydrogen and R and R.sup.1 are interlinked in the form of a substituted or non-substituted ethylene or vinylene bridge; and (b) polymers with the formula ##STR12## in which groups R, R.sup.1 and R.sup.2 have the values given above and where R' is a free or partially or completely esterified amino-acid radical; y and z are integers, n is 1 or 2; and x is equal to y+z and is selected so that the molecular mass of the polypeptide is not lower than 5000D.
2. Polypeptide according to claim 1 wherein R is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl, tert-butyl, phenyl and benzyl radicals.
3. Polypeptide according to claim 1 wherein R and R.sup.1 are interconnected to form a link selected from the following formulae: --CH.sub.2 --; --C═CH--; --CH(CH.sub.3)--CH(CH.sub.3); --C(CH.sub.3)═C(CH.sub.3)--; 1.2-phenylene; cyclohexenylene; cyclopentenylene, cyclopentadienylene.
4. Polypeptide according to claim 1 wherein polymer (I) is selected from acyl- and aryloxymethyl glutamates and aspartates and polymers (II) is selected from acyl- and aryloxymethyl glutamate or aspartate copolymers with one or more other amino-acids selected from alanine, leucine, valine and phenylalaline.
5. Polypeptide according to claim 1 wherein polymers (II) is a glutamate or aspartate copolymer with at least one member of the group consisting of glutamic acid, lower alkyl glutamates, aspartic acid and lower alkyl aspartates.
6. Polypeptide according to claim 4 wherein the acyl groups are selected from acetyl, propionyl, butyryl, isobutyryl, pivaloyl, benzoyl, and phenylacetyl groups.
7. A drug composition comprising a polypeptide selected from the group consisting of (a) biodegradable polymers with the formula ##STR13## in which R.sup.1 and R.sup.2 are selected from the group consisting of lower alkyl and hydrogen; and R is lower alkyl or an aromatic radical; or R.sup.2 is lower alkyl or hydrogen and R and R.sup.1 are interlinked in the form of a substituted or non-substituted ethylene or vinylene bridge; and (b) polymers with the formula ##STR14## in which groups R, R.sup.1 and R.sup.2 have the values given above and where R.sup.1 is a free or partially or completely esterified amino-acid radical; y and z are integers, n is 1 or 2, and x is equal to y+z and is selected so that the molecular mass of the polypeptide is not lower than 5000D, and a drug, the polypeptide serving as a drug reservoir with a delay effect, the drug being released progressively to its destination consequent upon the biodegradation of the polypeptide.
8. A composition according to claim 7 wherein the drug and the said polypeptide are mixed homogeneously and shaped in a pharmaceutically acceptable form.
9. A composition according to claim 8 which includes polyalkylene glycol to plasticise the polypeptide.
10. A biodegradable implant or prosthetic comprising the composition of claim 7.
11. In a method of administering a drug by release from a biodegradable polymer carrying the drug, the improvement which comprises using a polypeptide selected from the group consisting of (a) biodegradable polymers with the formula ##STR15## in which R.sup.1 and R.sup.2 are selected from the group consisting of lower alkyl and hydrogen; and R is lower alkyl or an aromatic radical; or R.sup.2 is lower alkyl or hydrogen and R and R.sup.1 are interlinked in the form of a substituted or non-substituted ethylene or vinylene bridge; and (b) polymers with the formula ##STR16## in which groups R, R.sup.1 and R.sup.2 have the values given above and where R.sup.1 is a free or partially or completely esterified amino-acid radical; y and z are integers, n is 1 or 2, and x is equal to y+z and is selected so that the molecular mass of the polypeptide is not lower than 5000D, as the carrier for the drug.
Description The subject of the present invention is a new biodegradable esterified polypeptide in which drugs can be incorporated, the drugs then being gradually released in proportion to the biochemical degradation of the polymer. Non-toxic biodegradable polymers have been known for several years which can act as a reservoir of drugs and which allow for the controlled gradual release of the latter into the organism at the time of the degradation of the carrier polymer. General information on products of this type can be found in the work: "Fundamental Aspects of Biocompatibility" by D. F. WILLIAMS. CRC Press (1981). See also U.S. Pat. No. 4,093,709. Of these polymers, those which are referred to in particular are synthetic polypeptides (polyamino acids), the structure of which is related to that of proteins. These polypeptides are biocompatible and the products of their degradation (amino acids) can be reabsorbed by the organism. Thus SIDMAN et al (J. Membr. Sci (1980), 7(3), 277-91) disclosed a copolymer of glutamic acid and of ethyl γ-glutamate, of which the rate of degradation is a function of the composition of the copolymer (molar proportions of the esterified segments as a ratio of the non-esterified segments) and which can store numerous medicinal products, more particularly steroids, peptides, and anti-malaria, anti-cancer and other products. Polymers of this type can be used in the form of sticks containing, mixed therewith, the desired drug, or in the form of capsules enclosing the drug if the latter cannot be mixed with the polymer. In spite of the interest attached to the above product, there is still a search for a product with improved qualities which has the following properties in particular: 1. Excellent solubility in most conventional harmless solvents suitable for drugs (in fact known derivatives of polyaminoacids are not generally soluble in certain specific solvents (DMF, pyridine, F.sub.3 CCOOH), the use of which is not suitable for pharmaceutical products). 2. Thermoformability. The synthetic polypetides which are known at present cannot in fact be generally mixed with conventional biocompatible plasticizers (polyalkylene glycols) and are consequently not thermoplastic. 3. Improved control of the process of degradation. In fact, the rate of degradation of known synthetic polypeptides is linked in a manner which is difficult to reproduce to their chemical structure, more particularly to the rate of esterification. Thus in a given case (see SIDMAN K. R. et al., Publication PB 81-132136 NTIS (1980) p. 42) a variation in the rate of esterification of the order of 10% causes the rate of degradation to increase from 1 to a hundredfold (see also the reference: SIDMAN mentioned above). The polymer of the invention allows these improvements to be put into effect. It is an esterified polypeptide with the formula: ##STR1## in which R.sup.1 and R.sup.2 are alkyl groups or hydrogen and R a substituted or non-substituted aliphatic or aromatic residue, or R.sup.2 is hydrogen and an alkyl and R.sup.1 and R linked to one another are substituted or non-substitued methylene or methenyl groups, n being equal to 1 or 2 and x being such that the molecular weight is at least 5000 D. As can be seen from formula 1, the polymer of the invention is a polyaspartate or polyglutamate esterified by a derivative of acyloxymethanol (HO--CR.sup.1 R.sup.2 --OOCR) in which R is either any organic residue, or is linked to R.sup.1 so as to form a cycle. The use of the word "any" means that the nature and the structure of the R group is not critical and, for instance, there has been no case in which if R is part of the conventional compound with an RCOO-group the corresponding constituent of the invention could not be obtained. However, it is preferred to use compounds in which R is a substituted or non-substituted aliphatic or aromatic group, the substitutes being chosen from amongst the biocompatible organic groups. From amongst the preferred R groups, are the groups methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, phenyl, benzyl and other similar groups. Of course, other groups are possible, but it is clear that the inventor has not been able to consider them all during the limited period of time available to him. When R and R.sup.1 are linked together so as to form a carbon-carbon link which may or may not be saturated, these carbon atoms may or may not be substituted by aliphatic or aromatic residues. Below are some non-limitative examples of these ester-lactal groups ##STR2## which are substituted or not corresponding to the above-mentioned definition: dimethylene group --CH.sub.2 --CH.sub.2 --; dimethylethylene group --CH(CH.sub.3)--CH(CH.sub.3)--; vinylene group --CH═CH--; and others. The polymer of the invention may also be in the form of a copolymer with other polyaminoacids. In this case, there would be a copolymer with the formula: ##STR3## in which R is a residue of any amino acid which may or may not be esterified, the R' groups of the units --(NH--CHR'--CO)-- may be identical or different in the copolymer chain, with y+z=x, y and z being integers and the value of x being always chosen so that the copolymer has an average molecular mass of at least 5000 D. Of course, if R' is identical to the group --(CH.sub.2)--COO--CR.sup.1 R.sup.2 --OOC--R, the n's being different however (one of them being equal to 1 and the other being equal to two), an esterified copolymer of a glutamic and aspartic acid would be obtained. However, in general it is preferred to have different groupings for R', such as, for example, methyl (alanine), isopropyl (valine). isobutyl (leucine and isoleucine), benzyl (phenylalaline), etc. All other amino acids are, in principle, possible although for obvious reasons, it has not been possible to try all of them. R' can also designate a residue of glutamic or aspartic acid which is not esterified or partially esterified by any alcohol for example MeOH or EtOH, that is, for example, --(CH.sub.2)--.sub.n --COOH or --(CH.sub.2).sub.n --COOMe. It is equally possible to have amino acids of the L or D series. The amino acids of the L series (or natural acids) are the most interesting since the polypeptides which contain them are degradable by enzymes (proteases) of the human body, whilst the polypeptides consisting of D units are not. This difference can be exploited using copolymers comprising D and L amino acids with the aim of obtaining polymers of which the rate of degradation has been altered. Returning to more general considerations, it should be noted that the molar ratio, in the copolymer II, of the other free or partially esterified polyamino acid, also allows for the regulation to a considerable degree of the rate of biodegradation of the copolymer as a function of the agents present in the organism at the target site of the mixture of copolymer and of the drug to be administered, (i.e. in the organ where the drug is to act). Thus, for example, if the copolymer is a copolymer of polyglutamate I and of leucine, the relative molar preparation of the two consituents as a function of the relative rate of degradation would be selected, at the place in question, from polyglutamate and polyleucine. In general, the ratio z/y can vary by 1 to 30, but these limits may be exceeded if necessary. Of course, in cases where the R' group does not designate a single natural group in the copolymer chain. that is for example when one R' designates a residue of free amino acid and another R' designates a residue of esterified amino acid. For greater convenience the variants of R' could be designated by the signs R', R'", etc. The general formula of a copolymer of this type can be illustratd as follows: ##STR4## where the sum of y, z, u, v, . . . , etc. is equal to x; u, v, etc. may of course be nil if the residue designated by R' is of the natural type. A typical case where the copolymer has R' and R" distinct is that in which these groups designate residues of glutamic and/or aspartic acid which may be esterified or non-esterified, the diagrammatic formula of a polymer of this type (in special cases partially methylated) is as follows: ##STR5## The nature of the R group can also influence the rate of degradation of the polymer I. Thus, for example, if R is a large or crowded group (for example tert-butyl), the degradation will be slower than with a methyl or ethyl group. It is understood that, from the point of view of optical isomerism, the polymers of the invention may comprise elements of L or D configuration or racemic mixtures or even polymers where one of the configurations is dominant. The biochemical properties of these various combinations are not, of course, identical, the polymers in which the natural forms (L) are dominant being more open to enzymatic degradation. It is thus possible to control their degradation by measuring the relative proportions of one form and the other in the copolymer. The polymer I and copolymer II are insoluble in water and usually soluble in one or more conventional solvents such as acetone, methyl ethyl ketone (MEK). tetrahydrofuran (THF), dioxan, ethyl acetate, monoglyme, diglyme and others, which can be easily transformed into balls, pellets, fibres, filaments, micro capsules. films, etc. Depending on their structure polymers I and II may be insoluble or soluble in chlorinated solvants, such as chloroform. In certain cases of insolubility in chloroform, this can be remedied by adding a small amount of acetone to a solvent of this type. This ability to dissolve in a number of solvents which may or may not be mixable with water, makes them compatible without any other with numerous liquid drugs or drugs which are soluble in the same solvants. Thus, for example, in order to encapsulate a water-soluble product in polymer micro-balls, it is possible to use the known, well-established technique of dispersing an aqueous solution of the drug into a polymer solution, the latter comprising a solvent which cannot be mixed with water, then evaporating this solvent so that solid polymer capsules form. Furhermore, according to its structure, polymer I is often perfectly compatible with polyalkylene glycols (polyethylene glycol and polypropylene glycol), which means that glycol polyethers can be used as polymer I plasticizers and to thus provide a homogeneous mixture with a low fusion point. It is easy to incorporate a whole gram of thermolabile drugs in a mixture of this type (fusion at temperatures of approximately 40 therefrom. Furthermore, the presence of very hydrophilic polyalkylene glycols means that it is possible to increase the susceptibility of the polymer and the copolymer to biological aqueous liquids and to facilitate their in situ enzymatic degradation. It should be noted that known synthetic polypeptides do not have these favourable properties of solubility and of compatibility with PEGs. Thus, for example, to form films of polyglutamate acid having an appreciable mechanical resistance and a certain degree of insolubility in water, it is necessary to use solvents which are relatively awkward to handle and which are not well liked in pharmaceutical circles such as dimethyl formamide (DMF) and dichloroacetic and trifluoroacetic acids (DCA and TFA). The films of polyglutamic acid obtained from aqueous solutions (at pH 7.4, i.e. when the acid is at least partially salified) do not have any mechanical resistance and are quickly dissolved in water, which makes the polymer entirely unsuitable as a carrier of delayed release drugs in the sense of the present invention. The same applies to polyglutamic-polyethylene glycol acid mixtures which are immediately soluble in water. The biodegradation of polymer I can be represented diagramatically as: ##STR6## The reaction (2) follows reaction (1) and consequently the rate of polymer biodegradation increases as the rate of the hydrolysis of the lactal or acyloxyalkylic ester increases. The hydrolysis mechanism of esters of this type is known per se and was demonstrated during the study of esters of ampicillin (for example pivampicillin), in this matter see the following references: "Design of biopharmaceutical properties through prodrugs and Analogs", B. Roche, editor, American Pharmaceutical Association (ISBN 0-917330-16-1). page 212 and 354 (1977). It should be noted that, since R.sup.2 is hydrogen and R.sup.1 an alkyl (for example methyl), the compound resulting from the reaction (1) is an R.sup.1 ---CHO aldehyde (for example acetaldehyde), these aldehydes being biologically more advantageous than the metaldehyde obtained when R.sup.1 =R.sup.2 =H for reasons of toxicity. As far as this aspect of the invenrion is concerned, the products resulting from the reaction (1) where R and R.sup.1 are interlinked (the ketonic acids or acid aldehydes) are also most advantageous as a result of their negligible toxicity. Thus, if the association R-R.sup.1 corresponds to the ethylene or 1,2-phenylene groups, the products of degradation will be respectively, 3-formyl-propionic acid and O-formyl-benzoic acid slowly eliminated by the organism without secondary reactions. The polymer I can be prepared by direct esterification of a corresponding poly amino acid salt with an acyloxymethyl halide (X--CR.sup.1 R.sup.2 --OCO--R (III)) where X may be chlorine, bromine or iodine. The polyamino acid is preferably a tertiary amino salt (for example of tributylamine or triethylamine). This type of method is known per se by W. V. DACHNE; J. Med chem. 13, 607-12, 1971). Furthermore, the synlhesls of the compounds III (X =Cl) is known (see Z. H. ULICH, J.A.C.S. 43, 662 (1921)) and consists in reacting the acid chloride RCOCl with formaldehyde in the presence of a catalytic quantity of anhydrous ZnCl.sub.2. The polyamino acid or co-polyamino acid of which the esterification products the polymer I or the copolymer II is easily obtained by conventional means consisting of the esterification by a lower alcohol of the lateral carboxyl of an acid having the formula: ##STR7## the transfromation of the ester into the corresponding N-carboxyanhydride (NCA) by phosgene in a medium of dioxan or THF, the polymerisation of NCA into esterifed polyamino acid and the hydrolysis of the protector ester group in an alkaline medium or by trifluoroacetic acid. These methods are known per se (see for example Encyclopedia of polymer Science and Technology; N-carboxyanhydrides, vol II, page 837). If it desired to obtain a copolymer where R' designates a partially esterified lateral carboxyl (R'=--(CH.sub.2)n--COOH and R"=--(CH.sub.2)n--COOAlk) care is taken to ensure that the hydrolysis of the protector ester group is only partial. Thus for example the starting product to be esterified with the compound XCR.sup.1 R.sup.2 --OCOR will be a copolymer of acid H.sub.2 N--CH[(CH.sub.2).sub.n --COOH]--COOH and of ester NH.sub.2 --CH[(CH.sub.2).sub.n --COO Alk]--COOH. The polymer I and the copolymer II can be used to store drugs in various ways. Thus for example, the present polymers I and copolymers II can be used to produce microcapsules containing a drug. Microcapsules of this type comprise a polymeric membrane and contain an aqueous or oily solution in which the drug is in suspension or in solution. It is also possible to manufacture microspheres, i.e. solid particles or balls containing the drug in a dispersed state or in the form of solid solution in the polymer matrix. It is also possible to produce microporous products called microsponges. In general, it is possible using the present polymers to apply all the methods of manfacturing delayed release drugs, i.e. drugs having the property of releasing (salting out) the drug in a prolonged manner as the carrier degrades. A description of these methods can be found in the following works: "Biodegradables and Delivery Systems for Contraception", Mafez E. S. E., MTP Press Limited (1980); "Controlled Release Technologies=Methods, Theory and Applications" Vol. I and II, A. F. Kydonieus, CRC Press (1980) and "Microencapsulation - New Techniques and Applications" by Tamotsu KONDO, Techno Inc. (1979) Japan. The solubility of the present polymers in numerous solvents, which may or may not be mixable with water, is an advantage for their application according to the methods described in these references. It is also possible to prepare threads comprising these polymers by extruding a solution of the latter in a spinneret and by precipitating the thread either by evaporation or by a bath of non-solvent according to conventional methods of extrusion. Threads prepared in this manner may be knitted, knotted or woven to form stitching, ligatures or tubular structures which can act as artificial arteries, veins, ducts or internal organs for temporary operation. The polymers of the invention can also be used either directly or mixed with a plasticizer in the manufacture of films or surgical prostheses for example for mending fractured bones, such as clips, needles, screws, reinforcement plates, wads etc., these materials can be made by solution casting or moulding, thermoforming or by machining solid polymer blocks. since protheses of this type can be reabsorbed, they are gradually eliminated in the organism and it is therefore not necessary to carry out a new operation, as is currently the case, to remove the reinforcement or consolidation material. Of course, the exact composition of the polymer or copolymer used is to be regulated, as a function of the rates of degradation and the absorbtion characteristics in vivo, according to the type of prosthesis envisaged. The following examples illustrate the invention. Copolymer of benzoyloxymethylene polyglutamate, glutamic acid and methyl glutamate. Partially methylated polyglutamic acid was prepared from methyl γ-glutamate N-carboxyanhydride dissolved in methylene chloride; triethylamine is used as a polymerisation catalyst (A/l=100). The polymer was then precipitated by adding methanol, then vacuum-dried. The solid was redissolved in trifluoroacetic acid (TFA) so as to produce a solution of 5% by weight and a volume of distilled water was added drop by drop whilst stirring vigorously so that the final solution contained equal volumes of water and TFA. This was then agitated for a further 12-15 hrs. at room temperature (viscous solution), after which the entire contents were poured into a large amount of distilled water, which led to the precipitation of a methyl glutamate and polyglutamic acid copolymer, the hydrolysis of the methyl ester having reached approximately 60-70%. This copolymer Was filtered and dried. The relative proportions of the free and esterified COOH groups of the copolymer obtained by NMR analysis in TFA (integration of the methyl ester band --O--CH.sub.3 at 3.95 ppm) were regulated. An analysis of the molecular weight was carried out by GPC (gel permeation chromatography) in DMF on a bimodal DUPONT ZORBAX PSM column (polystyrene calibration); a number average molecular weight Mn of 226.000; and a dispersion (Mw/Mn) of 1.75 were measured. 1.22 g of the copolymer was dissolved in 45 ml of DMF and 3.5 g of tributylamine added. 3.25 g of chloromethyl benzoate prepared according to ULICH, J.A.C.S. 43, 662 (1921) was then added drop by drop and stirring is maintained for 48 hours at room temperature. 50 ml of water was then added, which caused the precipitation of a colourless solid which was filtered, dried and purified by successively dissolving in acetone and precipitating with ether, then dissolving in acetone and precipitation with water. By NMR analysis of the product in TFA, the following resonances were observed: δ=7.8 ppm (4H, aromatic); 8.4 ppm (1H, amido); 6.5 ppm (2H; O--CH.sub.2 --O); 2-3 ppm (complex, 4H, β--CH.sub.2); γ--CH.sub.2) 5 ppm (1H, α--CH); 3.95 ppm (CH.sub.3 ester). The integration of the spectrum showed that the esterification of the free acid functions by chloromethylbenzoate was approximately 60% and that in the formula of the copolymer as shown below: ##STR8## the indices have the following values: y=0.6; z=0.33 and u=0.07. This polymer is insoluble in water, CH.sub.2 Cl.sub.2, CHCl.sub.3 and ether; It expands without dissolving in methanol and ethanol; it dissolves easily in the following solvants: acetone, methylethyl ketone; THF, AcOEt DMF, TFA, dichloracetic acid (DCA). Thin films of the polymer can be prepared by spreading layers of these solution on substrates and allowing them to evaporate. Copolymer of partially methylated glutamic acid and of pivaloyloxyethyl glutamate. Following the process described in the preceding example, a copolymer of glutamic acid and of methyl glutamate was prepared by the gradual hydrolysis of methyl polyglutamate in an aqueous solution of TFA. The copolymer obtained had the formula: Glu (OME).sub.0.25 --Glu(OH).sub.0.75 2 g of this copolymer was dissolved in 50 ml of dry DMF and 5.74 g (0.031 mole) of tributylamine and 5.09 g (0.031 mole) of α-chloroethyl pivalate (prepared according to the reference cited in the above example, by the action of pivaloyl chloride on paraldehyde) was added drop by drop. After 4 days of agitation at normal temperatures, this was diluted by a large amount of water, which precipitated the polymer in the form of a colourless powder which was redissolved, after drying, in acetone and reprecipitated with petroleum ether. Two more stages of purification were then carried out by dissolving in acetone and reprecipitating in petroleum ether, which finally produced 1.8 g of the product. By means of NMR analysis it was established that the copolymer had the following formula: Glu(OMe).sub.0. 25 --Glu(OH).sub.0. 6 --Glu(O--CH(CH.sub.3)--OOCt.Bu).sub.0.15 The results of the analysis were as follows: δ=1.35 ppm (s,ter-butyl);=1.7-1.8 ppm (d, --CH(CH.sub.3)--); δ=6.8 ppm (--CH(CH.sub.3)--) This polymer is soluble in the solvents mentioned in the preceding example with the exception of chloroform. The operations described in the preceeding example were repeated. this time using a copolymer with the formula Glu(OMe).sub.0.5 --Glu (OH).sub.0.5 obtained as described above by the gradual hydrolysis of poly(methyl glutamate), the time of the latter being limited to 6 hrs. It was found that the copolymer corresponded closely to the above-mentioned formula by comparing the integration values of the protons in NMR, the signal at 3.95 ppm (O--CH.sub.3) and that at 5 ppm (α--CH). 1 g of this polymer was reacted with 2 equivalents of α--chloroethyl pivalate for three days, and is then precipitated from solution in DMF with water. After purification as described in the preceding example, it was determined by NMR analysis as described above that the formula of the copolymer was as follows: Glu(OMe).sub.0.5 --Glu(OH).sub.0.33 --Glu(OCH(CH.sub.3)--OCO--t.Bu).sub.0.17 This copolymer is soluble in the above-mentioned solvents and also in CHCl.sub.3. It is insoluble in polyethyleneglycol 400. 3-bromophthalide with the formula ##STR9## by bromination of phthalide was prepared according to document GB-A-1 364 672, p.5. 2 g of polyglutamic acid and 5.74 g (2 equiv.) of tributylamine were dissolved in 35 ml of dry DMF and 16.7 g of the above bromophtalide was added to this mixture. After a few minutes, there was a considerable thickening of the solution (gel) which was redissolved by adding 5 ml of water. After 6 days of agitation at room temperature, 500 ml of ethanol was added, which caused the precipitation of a colourless powdery product, which was filtered, drained rinsed and dried. The product was redissolved in 40 ml of CHCl.sub.3 and purified by precipitating it with ether. Yield 2.77 g (68%). By means of NMR analysis, the following results were obtained: δ=8 ppm (4H, Bz+1H, peptid.); δ=7.7 ppm (CH lactonic); α=5 ppm (α--CH); δ=2-3 ppm (m, --CH.sub.2 --CH.sub.2 --). By comparing after integration the ratio between the 5 proton (α--CH) and the aromatic protons it was found that the esterification was 90%. The formula of the product obtained in this manner is: ##STR10## This product, which is highly soluble in CHCl.sub.3, is insoluble in water, alcohol, glycol polyethylene and pure acetone. It is soluble in a mixture of acetone --CHCl.sub.3. A dry film of several um* of this polymer was prepared by spreading a chloroform solution on a glass plate and evaporating it. This film was placed in a receptacle oontaining a 0.1N solution buffered at pH 9.5 and there was a slow degradation of the polymer which was observed day by day by the increase in the UV absorbtion of the solution (280 mm) owing to the presence of phthalide which gradually formed in the buffer solution. 10 g of a 1/1 copolymer of poly(γ-methyl-L-glutamate) and of poly(pivaloyloxymethyl-L-glutamate) prepared according to example 2 was dissolved in 75 ml of chloroform and 5 g of indomethacin (Sigma) was added. A viscous yellow solution was thereby obtained, which was poured drop by drop whilst agitating vigorously into 1 liter of distilled water containing 0.1% of sodium dodecylsulphate (SDS). This solution was agitated at 40 which led to a dispersion of microspheres. The latter were filtered and separated into batches of different sizes using calibrated sieves. These microspheres dissolve in an isotonic medium (pH 7.5) and, over a long period of time, release the drug which they contain, the rate of release varying according to their average size. When a suspension of this type is injected into a tissue having an inflammatory infection, the action of the drug is much longer than that of a conventional drug with an indomethacin based drug. Polyglutamic acid was prepared from methyl γ-qlutamate N-carboxyanhydride dissolved in methylene chloride; triethylamine was used as a polymerisation catalyst (A/T=100). The polymer was then precipitated by adding methanol, then vacuum dried. The solid was redissolved in trifluoracetic acid (TFA) so as to produce a solution of 5% by weight and a measure of distilled water was added drop by drop whilst stiring vigorously, the measure being sufficient so that the final solution contained equal volumes of water and TFA. Agitation was maintained for a further 24 hrs. at room temperature (viscous solution). after which the entire contents were poured onto a large amount of distilled water, which led to the precipitation of the polyglutamic acid. This acid was filtered and dried. The purity of the acid thus obtained was checked by NMR analysis in TFA (absence of the methyl ester band --O--CH.sub.3 at 4.5 ppm). an analysis of the molecular weight was carried out by GPC (gel permeation chromatography) in DMF on bimodal DUPONT ZORBAX PSM column (polystyrene calibration) and the following values were measured: M.sub.n =226.000; M.sub.w =397.000; M.sub.z =723.000; dispersivity=1.75. The polyacid was dissolved in DMF at a level of 5% by weight and at 50 ml of this solution, 4 ml of water and 4.04 (0.04 mol) of triethylamine was added. Firstly there was a precipitation of triethylamine polyglutamate, the salt then dissolving again by agitation when water was added. When everything was dissolved 6.02 g of chloromethyl pivalate (Fluka Ag) was added drop by drop and agitation was continued for 48 hours at room temperature. 50 ml of water was then added, which caused the precipitation of a colourless solid which was filtered, dried and purified successively by dissolution in acetone and precipitation with water. By means of NMR analysis of the product in TFA, the presence of a tertbutyl peak at 1.35 ppm was observed. Integration of the spectrum revealed that the esterification of the polyglutamic acid was total. The molecular weight was determined as above and provided the following results: M.sub.n =30.480: M.sub.w =708.000; M.sub.z =297.000; dispersivity=3.54 (relative viscosity η=1.57 C=0.2 g/dl in DMF). Final yield 51%. This polymer is insoluble in water, CH.sub.2, CHCl.sub.3 and ether; it expands without dissolving in methanol and ethanol; it dissolves easily in the following solvents: acetone. methylethyl ketone; THF, AcOEt/DMF, TFA dichloracetic acid (DCA). Thin films of polymer can be prepared by spreading layers of these solutions on substrates and allowing them to evaporate. The IR spectrum also confirms the proposed structure (wide band at 1740 cm.sup.-1). A thin film of polymer obtained according to example 6 was prepared by spreading a layer of 10% solution in acetone and allowing it to dry for several hours at ordinary temperature in air. Several samples of the film were then immersed in a solution of 1% pancreatine in 0.1 M phosphate buffer (pH 7.5) and the samples were left at room temperature from 1 to 8 days. After 1 day a noticeable loss of mechanical resistance (approx. 50%) was observed and after 2 days, almost total disappearance of this resistance (the sample broke into pieces). After 8 days, the sample had completely decomposed and was no longer visible. Similar results were observed using esterase or leucinaminopeptidase. The procedure was as in example 6, but starting with an 85/15 copolymer of polyglutamic acid and leucine and an 85/15 copolymer of pivaloyloxymethyl glutamate/leucine was obtained. The NMR spectrum of the polymer in solution in TFA shows that 100% of the lateral carboxylic groups of polyglutamic acid are esterified by chloromethylpivalate. The polymer is also soluble in acetone, MEK, DMF, THF. It expands in alcohol without dissolvinq. NMR spectrum: δ=1.35 ppm, 9 tert-butyle protons; δ=1, 0, 6-isobutyle protons. Integration: ratio of groups 85:15. Synthesis was carried out starting with polyglutamic acid prepared as described in example 6; this polymer was dissolved in DMF previously dried on molecular sieve so as to obtain a 3.2% solution. To 20g of this solution, 1.83g of tributylamine (2 equivalents) was added. In contrast to what was observed with triethylamine, it is not necessary to add water for dissolution. 1.36g of the chloromethyl ester of isobutyric acid (prepared in accordance with ULICH, J.A.C.S. 43, 662, (1921) (b.p. 65 Torr) is then added drop by drop to the solution of tributylamine polyglutamate and is left for 3 days, subject to shaking, at room temperature. The reaction mixture is then precipitated by water, dissolved again in acetone. precipitated aqain with hexane, dissolved again in acetone and precipitated again with water. The RMR analysis of the dried polymer reveals the presence of isobutyl peaks (δ=1.15 ppm, doublet) characteristic of the product researched and, by integration 90% substitution (obtained 1.03 g, 90%). The polymer is also soluble in acetone, MEK, THF, DMF. Both the infrared spectrum of a film cast from a solution of TFA, and the elementary analysis correspond to the proposed structure. 5g of poly(pivaloyloxymethyl glutamate) and 5g of polyethyleneglycol 600 (Fluka, AG) and 2 g of indomethacin (Sigma) are dissolved in 100 ml of acetone. A film is cast from this solution onto a glass plate and the solvent is left to evaporate. The film obtained, heated to 50 melts and can be moulded in to the form of capsules which, once cooled and immersed in an isotonic aqueous solution, allows indomethacin to diffuse into the medium. The synthesis was carried out as in example 9, but starting with chloromethyl acetate. The polymer obtained is also soluble in acetone. Its NMR spectrum shows the presence of a peak at 3.2 ppm, which is characteristic of the acetyl group (3 protons). The polymer dissolves in aqueous caustic soda N/100, being hydrolysed in a few minutes. Poly(pivaloyloxylmethyl glutamate). the methyl group of which is labelled at .sup.14 C, was prepared in accordance with example 6. For this purpose chloromethylpivalate was synthesised by causing pivaloyl chloride to react on paraformaldehyde labelled with .sup.14 C, according to the technique described in J.A.C.S., 89 (21), 5442, (1967). The specific activity of the polymer, measured by combustion, is 3 uCie/g. 3 acetone or in TFA. The films obtained are soaked either in enzymatic solutions of Leucineaminopeptidase from pig kidney (Sigma, 3.7 Units/ml, 0.1 buffer grades, 5 mM MgCl.sub.2, pH 8.4), or esterase from pig liver, (Sigma, 11.6 Units/ml, 0.1M buffer Grades. pH 7.5). The speed of degradation is measured by observing on the one hand the appearance of the polymer, and on the other hand, by counting the degree of radioactivity acquired by the solution. The enzymatic solutions were renewed each day. The following results were obtained. ______________________________________Incuba-tion timefilmdrainedfrom a Esterasesolution (pH 7,5) (pH 8,4) Leucine Aminopeptidaseof: Acetone Acetone TFA______________________________________1 day opaque film, opaque film, opaque film, 3.5% hydrolysis 13.6% hydrolysis 12.6% hydrolysis2 days whitish, blown opaque film film very de- film, 29% hydrolysis formed 9% hydrolysis 46.8% hydrolysis4 days whitish, blown, opaque, blown, film disintegrat- film, film, ed, dissolved, 17% hydrolysis 52% hydrolysis some solid debris 85% hydrolysis5 days expanded film, film begins to 24% hydrolysis to break down, 71% hydrolysis7 days gelatinous film film completely 37% hydrolysis disintegrated 85% hydrolysis______________________________________ Poly(pivaloyloxymethyl glutamate) is dissolved in acetone and 10% by weight of polyethyleneglycol polymer 600 is added. The solution is flowed onto a Teflon plate and a the solvent is left to evaporate. The film obtained is translucent and can be welded thermally at approximately 120 A polymer of aspartic acid and leucine (see Polymer 16, 735 (1975)) was prepared by copolymerising β-benzylaspartate NCA and leucine NCA (N-carboxyanhydrides) in equimolecular proportions. Benzyl ester groups are are transesterified by methanol in order to obtain the copolymer poly-(β-methylaspartate/leucine). The methyl ester groups are then saponified by N/10 soda in methanol to obtain the acid poly-(ASP(OH)/leu). Analysis of the amino acids shows that there is a leucine proportion of 56% and 44% for aspartic acid. The molecular weight M.sub.n is 35,000 (measured by GFC). 1 g of poly-(Asp(OH)/leu) is dissolved in 20 g of dry DMF. 3.25 g of tributylamine (4 equivalents relative to the Asp (OH) groups) and 2.64 g of chloromethylpivalate (4 equivalents). This is left for 3 days, being agitated at room temperature. The polymer is precipitated in distilled H.sub.2 O, is dissolved again in acetone, precipitated in petroleum ether, dissolved again in acetone and preciptated again with H.sub.2 O. It is then dried. NMR analysis shows that poly-(pivaloxymethylaspartate/leucine has indeed been obtained, the esterification rate being approximately 20% (δ=7.5 benzylic protons; δ=8 ppm. NH protons; δ=5.4 and 4.8, alpha-CH protons; δ=3.95, O--CH.sub.3 non-saponified protons: δ=3.3 and 2, --CH.sub.2 -- protons, δ=1.35 ppm. t-butyl protons). Despite the relatively low esterifioation rate, the copolymer is soluble in acetone. For purposes of comparison, there were studied the hydrolysis speeds in an alkaline medium of a copolymer according to the invention, labelled as described in example 7, (pivaloyloxymethyl-leucine glutamate copolymer 85-15 according to example 8) and a methyl leucine glutamate polymer 85-15 of the prior art prepared using the usual known techniques by means of methanol labelled with .sup.14 C The polymer according to the invention (A) was converted into a film of approximately 0.25 mm by placing a layer of acetone solution on a glass plate, which was then subjected to evaporation in air. The same procedure was followed for the control film (B) starting with a solution in TFA acid. This film was washed carefully in water in order to eliminate any traces of TFA. The films (A) and (B) were immersed in pH 9.5 aqueous solutions (phosphate buffer), being slowly agitated, and the radioactivity of the products dissolved in the solutions was measured at intervals, on which basis the hydrolysis rate of the polymers subjected to the test was calculated. The following results were obtained, expressed as a % per weight hydrolysed substance after a given time (hours). ______________________________________Sample (A) Sample (B)time (hrs.) % per weight time (hrs.) % per wt.______________________________________1.5 2.8 18 1.82.5 5.0 42 4.24.5 13.2 64 58 37.25 88 5.98 dissolution 112 6.8______________________________________ It can be seen from the above results that the copolymer (A) decomposes to such an extent in 8-10 hours that the drug which it might have contained would have dissolved completely in such conditions, whereas the prior art copolymer is only slightly decomposed after 112 hours in the same conditions. By varying the leucine rate of the copolymer (A), the hydrolysis time can be varied, for an increase by increasing the said rate and for a decrease by reducing the said rate. Patent Citations
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IES ISS Exam
IES ISS Exam 2012
IES/ ISS Exam, 2011 is carried on through the Union Public Service Commission (UPSC) to recruit Grade IV officers for the Indian Statistical Service (ISS) and Indian Economic Service (IES). Union Public Service Commission (UPSC) has invites application form for following post recruitment on 2011 through IES/ ISS Exam, 2011 and interview Merit List. Interested candidate may also get information about IES/ ISS Exam, 2011 application forms, eligibility, how to apply and selection process related online on Union Public Service Commission official website. Union Public Service Commission is a part of Indian Government.
Date of Notification – 30th July 2011
Post Name –
Indian Economic Service
Indian Statistical Service
Number of Post – Check official website
Age Limit – Minimum 21 Years to Maximum 30 Years as 1st Jan, 2011
Pay Scale – Check official website
Selection Process – Written Examination and Interview Merit List
Application Form – Union Public Service Commission official website
Application Fee – Rs. 20/- (Rupees Twenty only)
Release Date for Receipt of Applications:18th aug 2012
Last date for receipt of applications: Monday, 17th sep, 2012
Date of examination: Saturday, 1st Dec, 2012
Educational Eligibility – For Indian Economic Service: candidate must have Post graduate degree from a recognized university in Economics/Applied Economics/Business Economics/Econometrics.
For Indian Statistical Service: Candidate must have Post grade degree from an Indian university in Statistics/Mathematical Statistics/ Applied Statistics.
Examination Center – Thiruvananthapuram, Mumbai, Delhi, Chennai, Shimla, Shillong, Dispur, Hyderabad, Bangalore, Kolkata, Patna, Cuttack, Ahmedabad, Jaipur, Allahabad, Bhopal, Jammu, Lucknow and Chandigarh
IES/ISS 2012 Paper Pattern:
IES/ISS is divided into 2 sections. In Section one there will be written examination and section two have interview for personality test. Indian Economic Service and Indian Statistical Service examination will have 1000 marks each.
Difference between ISS and IES:
ISS exam is Indian Statistical Service Examination whereas IES based on Engineering Service examination.
The IES exam is conducted for recruiting the qualified engineering graduates and postgraduates in Science from technical backgrounds whereas ISS exam is conducted for the recruitment of Statistical or related fields of Masters' degree holders.
Contact Address
Union Public Service Commission
Dholpur House,
Shahjahan Road,
New Delhi – 110069
Written by StudyChaCha
Discussion related to IES ISS Exam on Forum
Eligible for IES Indian Economic services exam 2011?
Madhya Pradesh Pre Engineering Test (MP PET)
ankita goplani
Posted 1 year ago
I m pursuing msc in statistics..3rd sem..Do i hold the eligibility for appearing in iss 2012 ???
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Get design ideas from fellow DIYers who have constructed these beautiful outdoor rooms.
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St John's RC School
From Wikipedia, the free encyclopedia
Type | Special school |
Religion | Roman Catholic |
Location | Turpins Lane Chigwell/Woodford Green Essex IG8 8AX England Coordinates: 51°36′33″N 0°03′51″E / 51.6091°N 0.0643°E |
DfE number | 881/7050 |
DfE URN | 115466 Tables |
Ofsted | Reports |
Gender | Coeducational |
Ages | 5–19 |
Website | www.stjohnsrcschool.co.uk |
St John's RC School is a Roman Catholic special school located in Essex, England.[1] The school is located south of Chigwell in the Epping Forest District of Essex, but is actually nearer to Woodford Green in the London Borough of Redbridge.
The school educates pupils aged 5 to 19 years old who have moderate to severe learning difficulties, including communication difficulties and autism. According to Ofsted the school has 99 students on roll. [2]
The school is not to be confused with either of the two other secondary schools in Essex also called St Johns:


text:
NiSource Corporate Services Company Jobs in Columbus
2 NiSource Corporate Services Company jobs in Columbus, Ohio found on Monster.
Responsibilities Purpose & Key Results: Business Improvement is an organization within the NiSource Gas Distribution (NGD) Customer Operations business segment that leverages business information to improve and sustain business processes that enable NGD to execute and build for the future. The organization's mission is to leverage our experienced and innovative employees to identify opportunities...
Responsibilities Job Summary: Promote customer growth and retention to meet or exceed sales goals and objectives for the New Business Team and Company by providing a high level of customer service, demonstrating effective sales techniques and collaborating with internal and external business partners. Responsibilities: Educate customers about energy efficiency, features and benefits of natural gas...
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2010 June 25
Burberry's Coming Up Rosie
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Photo of The Daily: Lady Lou
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Coffee Table Book... Or Work of Art?
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Red With Envy
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Fabulous place to stay!
We had a fabulous time in this motel! The manager was really friendly and helpful and the rooms were incredibly clean and so SPACIOUS!
We had a lot of fun in the swimming pool - and the shops and restaurants were just a short walk away.
Highly recommended to allUnique Quality: Great swimming pool
Great staff
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As I was in the shower this morning, I took time to read the label on my shampoo bottle. I am in shock! The shampoo I use in the shower that runs down... Read more
Workout 1 It was hard. I have a really hard time with the pushups and planks, especially having them back to back. I am looking forward to when th... Read more
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Jeremy Piven talks Bears, new Hot Wheels ads
Updated: February 15, 2011, 11:01 PM ET
By Cam Martin
Jeremy Piven has won three Emmy Awards playing confident, can-do agent Ari Gold on HBO's "Entourage," so his turn as the bumbling, sycophantic coffee boy in Funny or Die's new commercial campaign for Hot Wheels is a striking departure from the veteran actor's most recognizable role. But which character does he resemble more?
"This character that I'm playing in this Hot Wheels thing is the antithesis of Ari Gold. Which guy am I more like? Believe it or not, ...
Read full story
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Share: Facebook Twitter Google Plus Sep 6, 2013 6:59 PM Pueblo Co. embraces retail pot shops, proposes sales tax Pueblo County Commissioner Sal Pace is convinced there are enough votes to support the retail sale of recreational marijuana in Pueblo County. This would be, so far, an unprecedented move; virtually all other cities and counties across southern Colorado have voted to opt out, as part of the passage of Amendment 64, legalizing marijuana. Today, commissioners were discussing how to tax it and decided on a November ballot measure that would set a sales tax rate on recreational pot at 3.5 percent. Pace says the revenue will be used to cover the cost of regulation, licensing fees and enforcement. County commissioners believe, if it's approved, it will be used as a model throughout the state. Under the proposal, none of the revenue would go to the state, and it will stay in the county. Pace says that once language is finalized, and public hearings are completed, commissioners will approve retail sales. This would not affect the city of Pueblo, which has imposed a moratorium on retail pot sales until voters decide on a statewide ballot measure on regulating and taxing marijuana.
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1 person found this helpful
I have been working at Cisco Systems full-time for more than 10 years
Pros – Cisco pays well, it's not in the top 10%, but it pays those employees well that it wants to keep. It does give out RSUs and the ESPP has paid well over the past few years. There are four levels of health care benefits, that make it easy to tailor your benefits. Work/like balance is dependent on your individual manager; most are very good. Lots of opportunities to move around. Patent and yearly bonuses are good.
Cons – Depending on the business unit/work group, middle management can place unrealistic demands upon individual contributors. Working outside of San Jose can be a challenge if you want to rise through the ranks; visibility is key. Sick and vacation time is combined into one pool of Paid Time Off (PTO), and the company has a policy of forcing employees to use 3 or 4 days during the year-end "holiday shutdown". Amount of earned PTO does not increase with seniority, but amount one can accumulate and save, does.
Advice to Senior Management – Bring the remote sites into the fold better.
Yes, I would recommend this company to a friend
I have been working at Cisco Systems full-time for less than a year
I have been working at Cisco Systems full-time for more than 3 years
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Big crowd hammers Ferg-Flo. board over superintendent's suspension
Parents, local politicians and other are demanding to know why the Ferguson-Florissant School Board placed Superintendent Art McCoy on administrative leave.
About 1,500 gathered Wednesday night at McCluer North High School to demand answers from their school board. Dozens spoke at the board meeting for more than three hours. Some hurled allegations of racial motivations at the all white board. McCoy is black.
Board President Paul Morris denies race was a factor. He told the crowd that the issues revolved around McCoy's failure to comply with board directives. Morris also told the crowd that he couldn't say more because privacy rules prevent him from being more specific in a personnel matter.
"This would be a whole lot easier if I could say what's going on," Morris told Fox 2 News, "but I can't."
One parent told the board he planned to file a "Sunshine Law request" Thursday morning.
The board took no actions regarding McCoy's status at last night's meeting, but a decision on the superintendent's future is likely in the the next week or so.
Students at two school stage protest in support of superintendent
Ahead of a school board meeting Wednesday, students at a pair of Ferguson-Florissant Schools staged demonstrations in support of their superintendent.
Last week, superintendent Art McCoy was put on paid administrative leave for unspecified reasons. Fox 2 reports that today around 200 students at McCluer North High School jammed the hallways between classes in support of McCoy. At Cross Keys Middle School, 40 students protested in support.
A planned school board meeting Wednesday night has been move to the gym at McCluer North High School because a large crowd is expected.
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Strawberry Balsamic Chutney and Goat Cheese Bruschetta - recipe number one in our 4 course Valentine's Dinner. These delicious nibbles take strawberries to the savory side and combine them beautifully with creamy goat cheese. The three other recipes are coming in the next three days.
Crock Pot Chicken Terriyaki: 1lb chicken (sliced, cubed or however), 1c chicken broth, 1/2c terriyaki or soy sauce, 1/3c brown sugar, 3minced garlic cloves
Our favorite sangria recipes!
11 easy lunches to lose weight - some look really good and some look a little.. Uck... But I'll give the good ones a try!
Strawberry Lemonade Sangria 2 lemons, thinly sliced 2 cups strawberries, sliced 1 bottle white wine 1/2 cup rum 6 oz frozen lemonade concentrate Mix all ingredients in a pitcher and stir. Cover and refrigerate at least 4 hours until ready to serve.
17 Desserts You Can Make On The Grill (click to see them) These look amazing, can't wait to try them all!
"Fried" Honey Banana... only honey, banana and cinnamon
{White Chocolate} Strawberry Cheesecake Bites // Hostess with the ...
{White Chocolate} Strawberry Cheesecake Bites. Looks yummy!
Wine Smoothie! A bag of frozen fruit and blend it with 1 cup of white wine, great for a hot summer day....
Soak strawberries in whipped cream flavored vodka for 24 hours then dip in melted chocolate and let set.Takes Chocolate Covered Strawberries to a whole new level!
Basil, tomato, and mozzarella in wonton wrappers - good finger food appetizer
for new yrs. Fill glass with pink cotton candy and slowly pour champagne over it. Such a beautiful beverage.
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Obama's Pick to Head CIA Called 'War on Terrorism' Over in 2009 Print article Send a Tip by AWR Hawkins 7 Jan 2013 post a comment According to reports, Obama will nominate Counterterrorism and Homeland Security Adviser John Brennan to be Gen. David Petraeus' successor as Director of the CIA. This the same Brennan who, in 2009, told us the "war on terrorism" was over, and that the U.S. is not in the business of chasing down "jihadists" or fighting in a "global war." He has also advised the Obama administration to reach out to the terror group Hezbollah, in much the same way Obama's pending nominee for Sec. of Defense, Chuck Hagel, has advised administrations to reach out to Iran.
Nebraska to pay $2 million to family of woman after prisoner causes fatal crash12 Mar 2014, 5:35 AM PDT
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New Jersey judge blocks dad from delivery room, cites woman's right to privacy12 Mar 2014, 6:21 AM PDT
New Jersey judge bars dad from birth, says mother can decide who will be in delivery room12 Mar 2014, 6:16 AM PDT
UConn temporarily suspends sorority, fraternity while investigating alleged hazing12 Mar 2014, 4:12 AM PDT
Oregon has won 7 straight as the team prepares to defend its Pac-12 tourney title12 Mar 2014, 1:32 AM PDT
Strong finish, Nunn's emergence keeps Illinois' hopes alive, but they have to keep winning12 Mar 2014, 1:28 AM PDT
Marquette's eight-year NCAA tournament streak could be at stake at Big East tourney12 Mar 2014, 1:20 AM PDT
Top-seeded Virginia has history of failure to overcome when ACC tournament gets underway12 Mar 2014, 1:18 AM PDT


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Capital Markets
Company Overview of Rockwood Real Estate Advisors LLC
Executive Profile
Gregory J. McManusFormer Chief Financial Officer, Chairman of Asset/Liability Management Committee, Member of Investment Committee and Member of Management Executive Committee, Capmark Financial Group Inc. |
Age | Total Calculated Compensation | This person is connected to 1 Board Members in 1 different organizations across 5 different industries. See Board Relationships |
49 | -- |
Corporate Headquarters555 Fifth Avenue Phone: 212-286-5800New York, New York 10017-2416 United States Fax: 212-286-5555 Board Members MembershipsFormer Chief Financial Officer and Executive Vice President Chairman Former Principal Executive Officer, President and Director
EducationMBA New York University - Leonard N. Stern School of Business BS Seton Hall University
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I'm proud to be a partner who helped to finance this ? I thought Romney was a bad guy ?
++ PKW tracks the NASDAQ US BuyBack Achievers Index, which "is comprised of US securities issued by corporations that have effected a net reduction in shares outstanding of 5% or more in the trailing 12 months," according to PowerShares. ++
how many div paying funds, own brkb ? how many ETFs that pay divs, own brkb and are buying more ? How many investors seeking YIELD are thinking of buying brkb, this morning ?? I know, I know, I've made the point already BUT knew comers to brkville don't understand the learning curve in brkbs board room, tho I'm certain buffett makes the calls. It takes 5-6 years for buffett to make shareholder friendly moves. Keep LIMITING DEMAND for brkb, read this years letter and he'll splain to us and Lucy why size, global warming, and FOX news caused the underperformance the past 5 years. its very sad.
thanks for the updates z, but NOTHING will EVER compare with smart kids in foolsville making the bullish case for brkb trading up to 1.7 xs book with ZERO div, a 1.2 xs book buyback limit, and buffett constantly touting and promoting stocks OTHER THAN brkb, as buffett and munger get older and closer to the inevitable ?? its so embarrassing the children of the brkville madrassa may have a class action suit, child abuse, investing abuse , who knows what some creative lawyer may come up with but CLEARLY many nice kids who mean well have been damaged ?? sean, still with me bud ?
morning sean, buffett and munger think they can keep LIMITING potential DEMAND for brkb and not hurt the stock price ?? bro, I can cry in my tea every morning or I can make a joke now and then, what do u suggest ? I watched my mom age, I understand what happens to an aging brain, I'm ok with that FACT, but so many brkville madrassa mainliners repeat silly nonsense its heart braking. I cant wait to read this years letter, no doubt FILLED with charts showing brkb results since the 1800s, I'll be very impressed. Have a grand day.
aapl might spike right to 600 ? ucmtsu, no way.
brky, I made the case why buffett is restricting potential DEMAND for brkb. I say non div paying, the 1.2xs book restricted buyback limit, and buffett constantly promoting stocks other than brkb HURTS DEMAND for brkb. so make your case, what do I have wrong , since buffett doesn't take serious questions you are my only hope of understanding the buffett mind? Thank you.
morning brky, u didn't answer the question, will buffett make one of the 2 moves in q-1, 2014 or not ?
u were here in sept 2011 bro, if you can't recall what happened that's fine, lets move on to q-1 , 2014. Does buffett makes moves or not, IF, IF, I was certain he makes no moves I wouldn't be long.
++ He also understands supply and demand. ++
morning bro buffett is learning but IF he understood supply and DEAND he would have done what I suggested in 2006, split the stock, authorize a buyback at a substantial discount to IV, initiate a 1. 5 % div yield and hire a PR kid to make the bull case for brkb at least as well as I do. btw, thanks for being man enough to agree with me BEFORE buffett makes the moves. the other little girls in the brkville madrassa will drop the subject after bashing me and calling me names for years , just like in sept 2011. buffett is stubborn but he isn't stoooooopid !!
Throw in
the fact that buffett is constantly PROMOTING stocks like ibm and byd
battery rather than making the bullish case for BRKB, and you see why I will
never give up on my uncle warren , the guy deserves and has earned my
guidance. SUPPLY and DEMAND matter, even if your two largest shareholders
are buffett and gates, period. I HOPE in this years annual letter read by
10's of millions worldwide , buffett doesn't claim brkb underperformed the
spy so badly the past 5 years because of the big bull market, global
warming,fox news, and other silly nonsense excuses, that would break my
heart. There is still time for buffett to man up and admit he was wrong and
make the right moves, that's my call. PLUS, buffett can still help to
educate his most loyal brkville hopeless devoid of independent thought
followers !! hc , buffett's favorite partner since 2002.
and haven't yet updated their THINKing. Here are my question's for today so
that you have all Sunday for deep critical thinking. In the past buffett has
said he didn't want, inferior investors, owning brkb. If buffett had his way
and ONLY accredited investors could buy brkb would brkb be higher or lower
today ? It took me 5 YEARS to get buffett to split brkb, which added to
liquidity which got brkb added to the spy, Russell index etc. IF buffett
never split the Bs would brkb be higher or lower today ? It took me 5 YEARS
to get buffett to authorize the buyback, without the buyback in place would
brkb be higher or lower TODAY ? More than 50 % of new net dollars being
invested EVERY DAY cant or wont buy brkb because it offers ZERO income. New
money might buy bonds, it might buy msft or appl , maybe funds that pay a
div , BUT, how many dollars invested Monday morning are looking for
investments that pay no income and have a buyback in place with a limit so
low it may never be breached ? IF buffett really wants to limit potential
DEMAND for brkb why doesn't he also say he only wants DEMS to buy brkb, no
republicans ? IF you keep limiting potential BUYERS aka, DEMAND for your
stock to a very limited pool of potential buyers your stock WILL lag spy,
its common sense 101, even if you took finance in the 1800s like munger and
buffett, this is indisputable. buffett and munger worked for brk FREE for 30
, THIRTY YEARS, 30 YEARS, and now they are selling off their life's work at
least 10 % too cheap due to stubbornness and borderline negligence by our
BODs, for not challenging buffett and mungers more goofy theories
buffett cares about the stock price bro, he just doesn't get it. HE is ANAL about NOT paying taxes that's why its so critical to get the H tax on divs passed. If,If, buffett could donate his divs free of tax brkb would yield 3 %, Monday morning and the stock would trade 5-10 % higher, simple .
bro, my main point is amending the buyback to authorize buybacks at a , substantial discount to IV and or with a 1.5 xs book limit. bro i'll lay you 6/5 grandma can get this. tell her you know of a company that doesn't pay a div and has a silly buyback limit. Monday when the market opens what % of money being invested is seeking a yield, either from bonds or stocks ? more than 50 % of money being invested cant or wont buy non div paying brkb and there are 100,000 shs to go every day FOREVER !!! monkeys being fed daily understand supply and demand, many in brkville, don't, it will change sooner than you think OR brkb will continue to lag just like i predicted 6-7 years ago. stay tuned.
admitting u were WRONG in sept 2011. It's your position that brkb will NOT pay a div in 2014 and brk will NOT increase the buyback limit in 2014, do I have that right ? Thank you.
++ We need to be certain he's fully embracing the short-term! ++
mornin brky, I always appreciate it when u share your ignorance so early, it makes my day !! Correct me if I'm mistaken but wasn't it your dad, I mean buffett, who proposed the 5 year test ? r u and daddy changing the rules ?
yahoo limited my post so I wont bother to make the case, we'll see what happens soon enough.
+++ HC, The dividend will come after Buffett's death when all his shares have been gifted to the respective charities. Share buybacks? I doubt he'll raise the buyback limit because why wouldn't he just keep the cash
for investments in companies like IBM and XOM that I know you love and sell at significant discounts to their respective IVs. +++
axp, seriously old bud, how many great capital allocation moves did buffett and munger make prior to sept 2011 and yet brkb was trading at BOOK or below ? How many sweetheart deals did buffett get us during the crash and yet STILL
friends, romans, and brkheads, did the SPLIT INCREASE DEMAND for brk ? man oh man, buffett could tell some of u kids glue is good for your brain just read fools expertville to prove it and many of u would agree. DEMAND for brkb is going to goose the stock to 1.7 xs book with no div and a 1.2 xs book limit, if i read this on expertsville too often, I, may end up doing glue, by the hour ??? very sad.
hi brky you left out the KEY move buffett should make bro, split brkb 100 for 1 to make it a pink sheet er !! i can get blinder, first jersey, and strattan to make a market in it ! brky thanks for posting I hope buffett reads u, THAT alone will guilt trip him into writing an op-ed, the silly things I said over the years that i wish to change so that kids like brky can learn and grow ! stay tuned brky, buffett may shock u again and take my advice, free of course. THINK sept 24th bro u know my post BEFORE he authorized the buyback because he HAD TO, HAD to bro. u know what I'm long lets see how it trades the next 6-8 weeks. thanks for the laughs.


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Mon, 10 Mar 2014
The Lawyer Global Litigation Top 50 report is the only ranking of international law firms by litigation and arbitration revenue and is essential reading for anyone seeking to benchmark their litigation and dispute resolution practices...
Chevalier & Sciales: ESMA publishes opinion on AIFMD rules covering late transposition
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This year, The Lawyer's annual ranking of the largest UK law firms by turnover is available as an interactive, digital benchmarking tool. For the first time this will allow you to manipulate each data set against the metrics of your choice.
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March 8, 2014
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Salem-News.com (Dec-18-2006 15:37)
Victim Identified in Dec 6th Fatal Traffic CrashSalem-News.comFire personnel responded to the scene to put out what was originally reported as a brush fire, when they discovered the car was on fire. (ALBANY) -
The victim of the December 6th single vehicle fatal traffic accident on I-5 south has been identifired as 24-year old Elena Carmen Flores, from McChord AFB in Washington.
Salem-News.com (Dec-11-2006 12:40)
BE AWARE! I-5 Southbound Closed Due to Rollover AccidentSalem-News.comTraffic is in a diversion at mile point 180.5 while construction crews rebuild an I-5 bridge. (CRESWELL) -
A semi truck wreck on Interstate 5 southbound about 1.5 miles south of Creswell will keep the freeway closed until approximately 3:00 PM Monday.
Salem-News.com (Dec-10-2006 13:58)
Two Dead in Fiery Overnight CrashKevin Hays Salem-News.comAn autopsy will be scheduled to determine cause of death and to positively identify the victims. (SALEM) -
Salem Police are investigating a motor vehicle crash that took two lives Saturday night.
Salem-News.com (Dec-04-2006 23:59)
Life Flight Called To Canby Crash for Four VictimsSalem-News.comThere were five people in the car, but the fifth was able to walk away from the scene, getting his own ride to the hospital. (CANBY) -
Four people were taken to area trauma centers by Lifeflight after the car they were in crashed Monday night on Hwy 170 at South Good Lane.
Salem-News.com (Dec-04-2006 10:32)
Truck Transporting Bees Overturns on Oregon HighwaySalem-News.comThere was a whole lot of buzz, but no one was stung by the honeybees. (BEND) -
A truck transporting honeybees overturned Sunday afternoon at the junction of Highway 97 and Highway 197 spilling the load onto the highway.
Salem-News.com (Dec-03-2006 00:33)
Oregon State Police Seeking Witnesses to I-5 CrashSalem-News.comIf you witnessed the crash and/or driving of the involved vehicle, contact OSP Recruit Trooper Jacob Ledbettter at (541) 440-3334 ext. 431 (ROSEBURG) -
Oregon State Police (OSP) troopers are looking for witnesses related to a late Friday night single vehicle traffic crash that critically injured one person on Interstate 5 northbound about three miles south of Roseburg.
Salem-News.com (Nov-24-2006 11:13)
Two Killed, One Critically Injured in Thanksgiving Morning CrashSalem-News.comOSP is requesting anyone who may have witnessed the driving of the Chevrolet Blazer or the crash to contact Trooper Mark Davie at (503) 378-3387 ext. 252. (ALBANY) -
The Oregon State Police is continuing to investigate a Thanksgiving day morning two-vehicle head-on crash on Highway 34 about 1/2 mile west of Interstate 5 in which two people were killed and a third person critically injured.
Salem-News.com (Nov-24-2006 10:58)
Sheriff`s Deputy OK After Thanksgiving Day CrashSalem-News.comThe patrol vehicle, a 2005 Ford Crown Victoria sustained rear end damage. (SALEM) -
A Marion County Sheriff's Deputy was involved Thanksgiving in a single vehicle non-injury accident on Cordon Road, just south of Highway 22.
Salem-News.com (Nov-22-2006 16:19)
Serious Crash Shuts Down I-5 at Ankney HillSalem-News.comEditor Note: Since the filing of this report, the driver of the Camry has unfortunately passed away. (SALEM) -
A 22-year old Grants Pass man was seriously injured Wednesday morning after losing control of his car southbound on Interstate 5 near Ankeny Hill
Salem-News.com (Nov-21-2006 18:57)
Fatal Traffic Crash Tuesday on Hwy 34Salem-News.comBoth vehicles ended up in the ditch on the north side of the roadway (CORVALLIS) -
A 19-year old Newport woman was killed in a two-vehicle crash Tuesday morning on Highway 34 about three miles east of Corvallis. |
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