text:
|Publication number
|Publication type
|Application number
|Publication date
|May 31, 1994
|Filing date
|Mar 25, 1993
|Priority date
|Jan 31, 1990
|Fee status
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|Publication number
|Volker Krone, Axel Walch
|Original Assignee
|Hoechst Aktiengesellschaft
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|Patent Citations (12), Non-Patent Citations (18), Referenced by (2), Classifications (19), Legal Events (7)
|External Links: USPTO, USPTO Assignment, Espacenet
This is a division of application Ser. No. 07/651,295, filed Jan. 29, 1991, U.S. Pat. No. 5,229,469.
The invention relates to biologically degradable polymers, in particular polyaminodicarboxylic acid-co-anhydroaminodicarboxylic acid derivatives, a process for their preparation and the use thereof for depot preparations having controlled delivery of active compound. The active compounds are embedded in a matrix consisting of the polymers according to the invention and released in a controlled manner in vivo by bioerosion of the matrix. During the degradation of the products according to the invention, fragments which are endogenous or known in their biotolerability are predominantly formed and are metabolized by natural metabolic means or excreted by the kidneys as a result of their water solubility.
A modern drug treatment requires, in particular for the administration of active compounds, novel administration forms which combine a controlled delivery rate of the active compounds with high biocompatibility of the depot. A long-lasting controlled delivery of active compound is of great relevance because of the increasing importance of chronic diseases and long term-orientated treatment concepts in human and veterinary medicine. Biodegradable polymers are particularly advantageous as matrix materials for depot systems of this type, as the bioerosion controls the release of active compound and makes the surgical removal of a depot of this type unnecessary.
Drug delivery systems in which the active compound is dispersed in a non-degradable polymer matrix and released by diffusion are described in American Patent 4,069,307. However, after exhaustion of the active compound reservoir such implants have to be removed from the organism surgically.
In biologically degradable drug delivery systems, as indicated in U.S. Pat. No. 4,093,709, the active compound is dispersed in a biodegradable polymer which releases the active compound on degradation. Typical biologically degradable polymers investigated by the prior art are homo- and copolyesters, in particular of lactic and glycolic acid, such as are described in U.S. Pat. Nos. 3,773,919 and 3,297,033. A disadvantage is, inter alia, the low or poorly controllable swellability of the polyesters in physiological medium, which prevents the transport of the active compounds incorporated in the implant through the polymer matrix to the surface and effects only a slow release rate after an initial "burst effect".
More recently, polyacetals and polyketals (U.S. Pat. No. 4,304,767) or polyanhydrides (H. G. Rosen et al., Biomaterials 4, 131 (1983) and polyorthoesters (U.S. Pat. No. 4,180,646) have been described, which were developed as biologically degradable polymers for use as implant materials.
As a further class of polymers, polyamides, in particular poly-α-L-amino acids, have been described in U.S. Pat. No. 3,371,069 as bioabsorbable implant materials. However, the industrial production of polyamino acids requires the use of expensive protected amino acids, relatively large amounts of highly toxic phosgene, the removal of the protecting groups and the subsequent derivatization of the polymers obtained.
A further disadvantage of polyamides of this type is the presence of charged groups as a result of incomplete derivatization during the synthesis of the implant material. The pure poly-L-glutamic acid and pure poly-L-lysine mentioned in the patents are toxicologically extremely hazardous (A. D. Kenny, Proc. Soc. Exp. Biol. Med. 100, 778 (1959)) and their copolymers formed by biodegradation of hydrophobic derivatives must therefore also be very critically evaluated.
U.S. Pat. No. 4,356,166 describes biodegradable implant materials which release a bioactive compound in vivo. Progestins which are first chloroformylated and then covalently bonded to the polymer are described as bioactive compounds in U.S. Pat. No. 4,356,166. Poly(hydroxyalkyl)-L-glutamine or poly(hydroxyalkyl)-L-aspartamide are employed here as polymers. The bioactive compounds are either bonded via a so-called "spacer group" or else directly via the reactive component of the polymer. The release rate of the bioactive compound is controlled by means of the molecular weight of the polymer or by means of the length and the character of the "spacer group".
A disadvantage of the substances according to U.S. Pat. No. 4,356,166 is that they are already pharmaceuticals with high pharmacological activity themselves. In such polymer/active compound conjugates (polymeric drugs), biocompatible polymer and active compound form a unit whose properties are determined in a complex manner by both components. The release rate of the polymer-immobilized bioactive molecule is variable in the context of the abovementioned parameters, but crucially dependent on the nature of the active compound. Hydrophobic bioactive substances such as, for example, steroid hormones, can only be cleaved from the polymer backbone very slowly in aqueous biological medium and are therefore suitable exclusively for extreme long-term depot forms. Novel polymer/active compounds conjugates must be synthesized for each active compound, which extremely restricts the utility of the concept of polymer-immobilized pharmaceuticals described in U.S. Pat. No. 4,356,166.
For these reasons, these substances are not suitable for use as polymers which are degradable in a controlled manner and which release an active compound as a result of their own biodegradation, the active compound being embedded in the inert polymer matrix without being bonded chemically to the polymer.
A substantial improvement has already been achieved by the biodegradable poly(hydroxyalkyl)-aminodicarboxylic acid derivatives which are described in EP 0,274,127. However, even these biodegradable polymers still have the following disadvantages:
a) The microparticles prepared using these substances are only suspensible in water using auxiliaries. The use of auxiliaries such as �Pluronic or dextrans, however, is not unproblematic as these auxiliaries pass into the organism during the implantation of the active compound depot.
b) In aqueous medium, microparticles of this type have a tacky, oily consistency which leads to an agglomeration of the individual particles.
c) The release profile of the active compound from these microparticles--using some poly(hydroxyalkyl)-aminodicarboxylic acids according to EP 0,274,127--still always shows a considerable "initial burst", i.e. an initially very high release rate of active compound, which then very rapidly decreases.
d) The degradation times determined in vitro for microparticles according to EP 0,274,127 (phosphate buffer, 37� C.) are too long--in particular for use as an active compound depot for peptide active compounds.
The object of the present invention was to develop polymers which have the advantages described in EP 0,274,127, but without having to accept the abovementioned disadvantages.
Polyaminodicarboxylic acid-co-anhydroaminodicarboxylic acid derivatives (polyaminodicarboxylic acid-co-AHADA derivatives) have now been synthesized which are surprisingly outstandingly suitable for use as degradable drug implants having controlled active compound delivery. The active compounds are in this case not bonded chemically to the polymer, but only embedded in this polymer matrix. The degradation rate of the polymer in vivo and thus, at the same time, the release rate of the active compound can be controlled in the desired manner by incorporation of suitable biologically inactive groups. In particular, the suspensibility in water of the microparticles prepared using the polymers according to the invention and their consistency can be improved by the incorporation of unopened anhydroaminodicarboxylic acid rings (AHADA rings). Additionally, the release profile and the degradation time is further improved. The advantage of this procedure is that now those active compounds can also be administered over a relatively long period at a relatively constant dose which can either be not bonded chemically to a polymer at all or else are too sensitive to survive the very drastic conditions during the chemical coupling to the polymer. Moreover, the polymers can fundamentally be employed universally as a pharmacologically inert matrix for all relevant pharmaceuticals, independently of the molecular size and other physicochemical parameters. The fact that it was possible to further improve the properties of the polymer according to EP 0,274,127 by the incorporation of unopened AHADA rings is therefore particularly surprising, as the tackiness of the polymers and the poor suspensibility of the microparticles according to EP 0,274,127 is obviously based on the hydrophilicity and the manifestation of hydrogen bridges in the main polyamide chains or in the amide-containing side groups. However, the AHADA units remaining in the copolymers according to the invention are at least just as capable of the manifestation of hydrogen bridges as the main polyamide chain or the amide-containing side group. However, the "rigid" character of the AHADA units unexpectedly predominates, which led to solid products which were also non-oiling in water. The particles also hardly agglomerate in water, so that suspending auxiliaries can be entirely dispensed with. The outstanding consistency of the copolymers according to the invention is also shown in the relatively problem-free spraying to give microparticles.
Active compound-containing microparticles composed of these copolymers also show a further substantial advantage in release measurements: there is nearly no "initial burst", i.e. no strongly increased release of active compound in contact with water in the first hours.
The more rapid "degradation times", which can be put down to a more rapid reaction or dissolution in water (<4 weeks in phosphate buffer at 37� C.), also fits in well with use as an active compound depot for peptide active compounds which are intended to be largely released within 4 weeks.
The copolymeric products according to the invention are additionally economical, as the first stage of the synthesis only has to be partially further reacted. These biologically degradable polymers are obtained by polycondensation of aminodicarboxylic acids, which are then partially reacted with water, amino alcohols, ammonia or alcohols to give polyaminodicarboxylic acid-co-AHADA derivatives and are then reacted, if desired, with carboxylic acids, carbonyl halides or haloformic acid esters in a polymer-analogous acylation to give further polyaminodicarboxylic-co-AHADA derivatives according to the invention. In vivo, these polymers are metabolized to give non-toxic, non-allergenic and non-immunogenic compounds and excreted.
The invention thus relates to: polyaminodicarboxylic acid-co-anhydroaminodicarboxylic acid derivatives of the formula I ##STR1## in which n is 1 or 2,
x is 1 to 500,
y is 1 to 500, where
x+y is 2 to 1000 and
R is O--R1 or NH--R2, in which
R2 is H, (CH2)m --OR1, (CH2)m --O--C(O)--R1 or (CH2)m --O--C(O)--OR1 and
m is 2 to 6 and
R1 is H, aryl, aralkyl, arylalkenyl, alkyl or C3 -C8 -cycloalkyl or a biologically inactive steroid alcohol or an amino acid, where aryl is unsubstituted or substituted by C1 -C4 -alkyl, C2 -C4 -alkenyl, C1 -C4 -alkylcarbonyloxy, C1 -C4 -alkoxycarbonyl, C1 -C4 -alkoxy or hydroxyl,
where said alkyl radicals for R1 have 1-22 carbon atoms and the alkenyl radicals have 2-22 carbon atoms,
which are uninterrupted or interrupted by a carbonyloxy or oxycarbonyl group, where the repeating units in square brackets are distributed randomly and/or in blocks in the polymers and where both the repeating units indicated by x and y are identical or different and where the amino acids are α- and/or β-linked.
Aryl is understood as meaning aromatic hydrocarbons such as phenyl and naphthyl, in particular phenyl. In the substituted aryl radicals indicated, 1 to all replaceable hydrogen atoms are replaced by identical or different substituents. The aryl radicals are preferably mono- or disubstituted. Said alkyl and alkenyl radicals can be either straight-chain or branched. The biologically inactive steroid alcohols are preferably bonded via their OH group. A preferred steroid alcohol is cholesterol. Said amino acids for R1 are preferably naturally occurring amino acids such as Tyr, Ala, Ser or Cys, particularly preferably Tyr and Ala. They can be bonded either via their NH2 or via their COOH function.
The invention also relates to the process for the preparation of the abovementioned polyamides and also their use in a mixture with other biotolerable polyamides, particularly in combination with biologically active substances, as a degradable active compound depot preparation having controlled delivery of active compound.
The invention is described in detail in the following.
Aspartic acid and/or glutamic acid, which can be reacted to the corresponding polyanhydroaminodicarboxylic acids II in a polycondensation reaction, are employed as aminodicarboxylic acids. As a result of partial reaction with one or more compounds of the formulae III and/or IV and/or NH3
H2 N--(CH2)m --OH (IV),
in which m and R1 are defined as above for formula I, an α,β-poly-D,L-amino acid ester or an α,β-poly-D,L-amino acid amide of the formula VIII ##STR2## is obtained.
It is essential to the invention in this reaction that the polyanhydroaminodicarboxylic acid (II) is only partially converted into the open-chain derivatives. The proportion of unopened anhydroaminodicarboxylic acid units is 0.1 to 99.9%, preferably 10 to 90%, particularly preferably 60 to 80% (the percentage data relate to the total number of repeating units in the entire polymer). Depending on which side the anhydroaminodicarboxylic acid ring is opened in the reaction described above, α- or β-linked amino acids are obtained. Preferably employed compounds of the formulae III and IV are: 2-aminoethanol, 3-aminopropanol, 2-aminopropanol, alcohols having 1-18 carbon atoms, in particular methanol, ethanol, isoamyl alcohol, tertiary butyl alcohol and isopropyl alcohol.
A process for the preparation of α,β-poly-(2-hydroxyethyl)-DL-aspartamide (PHEA) (formula I; y=0; R=NH--CH2 --CH2 --OH) is described by P. Neri, G. Antoni, F. Benvenuti, F. Cocola, G. Gazzei, in J. Med. Chem. Vol. 16, 893 (1973). A general procedure for the preparation of PHEA can be found in P. Neri, G. Antoni, Macromol. Synth. Vol. 8, 25. Reference is expressly made here to this literature reference. The reaction takes place in high yield to give a product having a high degree of purity. The analogous poly-aspartic acid derivative-co-succinimide compounds of the formula VIII (n=1) can be prepared in the same way by sub-stoichiometric use of NH3 and/or compounds of the formulae III and/or IV.
Another, more involved process, as is described in U.S. Pat. No. 4,356,166, has to be used for the preparation of pure poly-(hydroxyalkyl)-L-glutamine. In this process, the COOH group in the γ-position of L-glutamic acid is first protected by esterification with benzyl alcohol. This γ-benzyl glutamate is then reacted with phosgene to give an N-carboxyanhydride, which is polymerized in an inert solvent after adding triethylamine, poly-γ-(benzyl) L-glutamate being obtained. The protecting group is removed either by adding an HCl/HBr mixture to the free poly-α-L-glutamic acid or else in the presence of hydroxyalkylamines to give the analogous poly-α-(hydroxyalkyl)-L-glutamines. A general procedure for the preparation of poly-α-(hydroxypropyl)-L-glutamine is found in U.S. Pat. No. 4,356,166, to which reference is expressly made here. In the same manner, the analogous compounds of the formula VIII (n=2) can also be prepared by use of NH3 and/or compounds of the formulae III and/or IV.
Compared to the complicated preparation of pure polyglutamic acid and its derivatives, glutamic acid can additionally be incorporated up to high proportions in the simple condensation of aspartic acid by means of phosphoric acid to give polyanhydroaspartic acid-co-glutamic acid.
The polyamino acid amide-co-anhydrodicarboxylic acids of the formula VIII (R'=HN--(CH2)m --OH) can then be reacted, if necessary, in the following reaction step with one or more different, biologically inactive compounds of the formulae V and/or VI and/or VII ##STR3## to give further polyaminodicarboxylic acid-co-AHADA derivatives according to the invention. In this connection, X is a leaving group which enables a mild esterification of the polymer alcohol group. Chlorine, bromine, iodine, imidazolides, anhydrides or hydroxyl are preferred, in particular chlorine.
The reaction with the compounds of the formula type V, VI or VII can be carried out either using a single compound of this type or using any desired combinations of these compounds or, alternatively, using compounds which have different R1 radicals, for example in the manner of their branching, in particular differing in their chain length. The last-mentioned polymer-analogous alkylation or acylation is carried out by known methods of organic chemistry. It proceeds selectively at the hydroxyl function (formula VIII, R'=HN--(CH2)m --OH) to give ethers, esters or carbonates, without attacking other functions in the starting polymer. The Einhorn variant of the Schotten-Baumann acylation in the presence of pyridine is particularly suitable. In this acylation, very high degrees of derivatization (greater than 70%) are achieved under mild conditions.
The molecular weight of the polymers according to the invention is 200 to 100,000, preferably 3,000 to 70,000.
Compounds of the formula type V are commercially available or, if not commercially available, can be synthesized in a simple manner by methods known from the literature.
The chloroformic acid esters (formula VII) are obtained by reaction of phosgene with the appropriate biologically inactive, physiologically acceptable aromatic, araliphatic, aliphatic or cycloaliphatic alcohols, in particular unbranched alcohols. Those alcohols are particularly preferably employed which have an even number of carbon atoms. The chloroformylated steroids are also obtained in this manner. Thus, in principle, all biologically inactive steroids which have reactive hydroxyl groups are accessible. Examples which may be mentioned here are: cholesterol, cholestanol, coprostanol, ergosterol, sitosterol or stigmasterol.
The acid chlorides (formula VI) which can also be employed are obtained, for example, from the corresponding carboxylic acids by reaction with phosphorus trichloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride.
Compounds of the formula type V, VI or VII in which an alkyl chain is interrupted by an oxycarbonyl or carbonyloxy group are prepared, for example, by reaction of cyclic dicarboxylic acid anhydrides with alcohols. The dicarboxylic acid monoesters obtained in this manner are then reacted to give the corresponding acid chlorides analogously to the carboxylic acids described above, for example using oxalyl chloride.
The hydrophobicity of the polyaminodicarboxylic acid-co-AHADA derivatives--and thus the residence time of an implant prepared from these in the organism--can be adjusted within wide limits both via the number of carbon atoms in the alkylation or acylation agent and via the degree of substitution and the content of unopened AHADA.
However, an exact indication of the relation chain length/AHADA content/degradation time in vitro/vivo is only possible with difficulty, as apart from the chain length and the AHADA content, the degradation time is still dependent on a large number of other parameters; for example on the particle size and distribution, the preparation method, for example, for microspheres, the porosity of the microspheres, the temperature or the degradation medium. However, by means of simple routine tests within the bounds of the disclosure, it is possible for the person skilled in the art to achieve the desired degradation time.
The degree of substitution in the compounds VIII (R'=HN--(CH2)m --OH) can be modified via the stoichiometry of the substances employed in the alkylation or acylation reaction, but should preferably be kept within the bounds of the maximum yield (greater than 70%), i.e. an as large as possible percentage of the substitutable OH groups in the polymer structure (formula VIII; R'=HN--(CH2)m --OH) should be esterified. If a lower degree of substitution is desired, the concentration of the alkylation or acylation agent is correspondingly reduced with respect to the polymer.
During the degradation of these polyamides in vivo, a) the imide rings in the main polymer chain are cleaved and b) the reactive side groups in the polyamides are hydrolyzed again and the corresponding biologically inactive carboxylic acids or alcohols and poly-(hydroxyalkyl) aminodicarboxylic acid and, if provided for the purpose of better water-solubility, to a small extent oligoaminodicarboxylic acid sequences are formed. Ideally, this degradation under physiological conditions should exclusively produce endogenous fragments known in their high biotolerability and which are metabolized by natural metabolic means or excreted by the kidneys owing to their water-solubility. The biotolerable carboxylic acids and alcohols include those having 6-22 carbon atoms in the alkyl moiety, in particular those having an even number of carbon atoms.
The presence of α- and β-peptide bonds in the D- and L-form in the α,β-poly-DL-aminodicarboxylic acid amide-co-AHADA derivatives employed prevents the formation of organized structures (for example folded sheet or helix areas) in the polymer, which influence the biodegradation in an unforeseeable manner.
Some of the polyamides according to the invention are thermoplastic and are therefore suitable for the preparation of active compound depot forms by various methods, such as, for example, by compression, extrusion, precipitation, spraying, etc.
Implantable particles, in particular microcapsules and microspheres and also macroscopic shaped articles formed by compaction, of any desired geometry, in particular tablets and rods, can be prepared from the polyamides according to the invention by known methods.
The excellent solubility of the polymers according to the invention in many organic solvents also enables the formation of microspheres by dripping from a solvent having a high melting point into a condensed cold gas, for example liquid nitrogen, absolutely round particles being formed by the Leidenfrost's phenomenon. The high-melting and water-miscible solvent is dissolved out by transfer of the microspheres to water and the polymer is precipitated at the same time, the spherical shape of the polyamide microspheres being retained.
If, in addition to a high melting point, the organic solvent used at the same time has a low boiling point, this drop formation process is further simplified in that the solvent, for example tert. butanol, can be directly removed in a mild manner and without active compound losses by means of freeze-drying of the microspheres obtained by dropwise addition to liquid nitrogen.
The solubility of the polyamides according to the invention has a particularly advantageous effect in many solvents which are also physiologically tolerable, for example alcohols, in the processing to give microspheres by means of spray-drying. Thus, the use of toxicologically hazardous halogenated hydrocarbons, such as are necessary for the spray-drying of biodegradable polyesters, can be dispensed with in the case of the polyamides according to the invention. Moreover, their solubility also permits the preparation in alcohol/water mixtures of monolithic, active compound-containing microspheres, as in this case polymer and active compound can be sprayed from a molecularly disperse form.
The polyamides according to the invention can also be employed as mixtures and in mixtures with other biodegradable and/or biotolerable polymers (for example �Pluronic F68, PHEA, dextrans, polyethylene glycols, hydroxyethylstarch and other degradable or excretable polysaccharides) or physiologically acceptable auxiliaries (for example polymer plasticizers).
Degradation tests in vitro using the polyamides according to the invention have shown that the degradation rate can be controlled both by means of the functional side groups and by means of the number of AHADA units.
The invention is described in detail in the following examples. Percentage data relate to the weight, unless stated otherwise.
10 g (103 mmol) of polyanhydroaspartic acid are dissolved in about 40 ml of DMF, if necessary with gentle warming. 1.83 ml (30 mmol) of freshly distilled 2-aminoethanol are added dropwise to this solution and it is stirred overnight at room temperature. The reaction mixture is precipitated in butanol and the precipitate is washed several times with dry acetone. Drying is carried out in vacuo at elevated temperature. The white, water-soluble product is formed to approximately 100% and is tested for residues of DMF and butanol by NMR spectroscopy. The molar ratio of polyanhydroaspartic acid to aminoethanol employed corresponds approximately to the copolymer composition.
Excess thionyl chloride and a few drops of DMF are added to monobutyl succinate. The reaction starts with evolution of gas. The mixture is stirred overnight with the exclusion of moisture and the excess thionyl chloride is then removed by distillation at normal pressure. The crude product which remains is fractionally distilled at 0.05 mbar and the pure product is obtained at about 70� C. In the IR-spectroscopic characterization, the product has bands at 1,800 cm-1 (acid chloride) and 1,740 cm-1 (ester) of equal intensity.
6 g of polyanhydroaspartic acid-co-α,β-(hydroxyethyl)-D,L-aspartamide ( 16 mmol of hydroxyethyl groups), prepared as described in Example 1, are dissolved in 100 ml of dry N,N-dimethylformamide (DMF). After adding 4 g (50 mmol) of pyridine, the mixture is cooled to 0� C. and 4.8 g (25 mmol) of n-butyl 4-chloro-4-oxobutyrate (preparation Ex. 2) are added with stirring in the course of 15 minutes. The mixture is stirred overnight and precipitated in 0.5 l of ether. The precipitated product is filtered off with suction, washed with ether, acetone, water, acetone and ether. About 8 g of a white polymer having a degree of substitution of approximately 100% (checkable by NMR spectroscopy) are obtained. The resulting polymer is soluble, for example, in acetonitrile containing a trace of DMSO, and in DMSO or DMF.
6 g of a polyanhydroaspartic acid-co-α,β-(hydroxyethyl)-D,L-aspartamide (50:50) ( 24 mmol of hydroxyethyl groups), which was prepared from polyanhydroaspartic acid (MW=14,000) and 2-aminoethanol (molar ratio 2:1) analogously to Example 1, are dissolved in 100 ml of dry DMF, 8 g (100 mmol) of dry pyridine are added and the mixture is cooled to 0� C. 9.6 g of distilled decanoyl chloride are slowly added dropwise and the mixture is further processed analogously to Example 3. About 8 g of a white, completely substituted polymer (NMR checking) are obtained, which is soluble, for example, in dichloromethane and THF each containing a trace of DMSO or in methanol/dichloromethane mixtures.
Differing polyanhydroaspartic acid-co-α,β-(hydroxyethyl)-D,L-aspartamides, inter alia of the composition 70:30, 50:50 and 30:70, were prepared from polyanhydroaspartic acids of different molecular weights (MW=7,000; about 13,000; 30,000) analogously to Example 1 and reacted with decanoyl chloride, as described in Example 4, to give the corresponding polyanhydroaspartic acid-co-α,β-(nonylcarbonyloxyethyl)-D,L-aspartamides.
a) Polyanhydroaspartic acid-co-α,β-(nonylcarbonyloxyethyl)-D,L-aspartamide (70:30) from polyanhydroaspartic acid (MW=7,000); characterized by NMR
b) Polyanhydroaspartic acid-co-α,β-(nonylcarbonyloxyethyl)-D,L-aspartamide (70:30) from polyanhydroaspartic acid (MW=14,000); characterized by NMR
c) Polyanhydroaspartic acid-co-α,β-(nonylcarbonyloxyethyl)-D,L-aspartamide (70:30) from polyanhydroaspartic acid (MW=30,000); characterized by NMR
d) Polyanhydroaspartic acid-co-α,β-(nonylcarbonyloxyethyl)-D,L-aspartamide (30:70) from polyanhydroaspartic acid (MW=12,000); characterized by NMR
Microparticles of these products differ distinctly in solubility, consistency, degradation behavior and active compound release (Examples 12 and 13)
6 g of polyanhydroaspartic acid-co-α,β-(hydroxyethyl)-D,L-aspartamide (70:30) (16 mmol of hydroxyethyl groups), prepared as described in Example 1 from polyanhydroaspartic acid (MW=37,000) and aminoethanol, are reacted with 4.8 g (25 mmol) of octyl chloroformate analogously to Example 3 and also worked up correspondingly. About 8 g of a white, completely substituted polymer are obtained, which is soluble in THF or methanol/dichloromethane mixtures.
6 g of polyanhydroaspartic acid-co-α,β-(hydroxyethyl)-D,L-aspartamide (60:40) (20 mmol of hydroxyethyl groups), which was prepared from polyanhydroaspartic acid and 2-aminoethanol (molar ratio 6:4) analogously to Example 1, are reacted with 2.3 g of decanoyl chloride (12 mmol) analogously to Example 3. As a result of the incomplete conversion (comparatively small excess of acid chloride), only half of the free OH groups are esterified. About 7 g of a white polymer are formed. Despite the rapid solubilization and the rapid degradation associated therewith in comparison to the microparticles of polymers of Examples 3-6, microparticles of this substance have a similar solid consistency in water and are easily suspensible.
6 g of polyanhydroaspartic acid-co-α,β-(hydroxyethyl)-D,L-aspartamide (10:90) (40 mmol of hydroxyethyl groups), prepared analogously to Example 1 using a molar ratio of polyanhydroaspartic acid to 2-aminoethanol such as 1:9, are reacted with 20 g of distilled oleyol chloride analogously to Example 3. The heterogeneous reaction mixture becomes homogeneous as a result of the addition of dichloromethane. It is precipitated twice in methanol cooled to -20� C. The yellowish-colored polymer is thermoplastic.
An intimate mixture of pulverulent, thermoplastically processable polymers (substance from Example 8), additives and active compound(s) is heated to above the softening point in a suitable device, for example an extruder for thermoplastics, a plastic material being formed. Additives and active compound(s) are homogeneously dispersed in the softened polymer by kneading and the polymer/active compound suspension obtained is forced through a nozzle of suitable diameter (>0.5 mm). On cooling, the strand of the extruded polymer/active compound suspension solidifies to give a solid rod-shaped aggregate whose active compound content is determined by its length and its diameter.
40 mg of polyanhydroaspartic acid-co-α,β-(nonylcarbonyloxyethyl)-D,L-aspartamide (50:50) from Example 4 are dissolved in 1 ml of methylene chloride/methanol (volume ratio 50:1). 10 mg of buserelin are added to the solution and dispersed using ultrasound. The dispersion is introduced with stirring (800 rpm) into a beaker containing 60 ml of 0.1% strength aqueous polyvinyl alcohol solution (�Mowiol 28-99) which is saturated with 0.3 ml of methylene chloride/methanol (50:1).
After 5 minutes, the contents are added to a beaker containing 200 ml of water and stirred for 30 minutes (200 rpm). The supernatant water is decanted off and the microspheres are lyophilized (diameter after lyophilization: 20-90 μm)
80 mg of polyanhydroaspartic acid-co-α,β-(octylcarbonyloxyethyl)-D,L-aspartamide (70:30) from Example 6 are dissolved in 1 ml of dimethyl sulfoxide at 50� C. and 20 mg of hydroxypropylcellulose (�Klucel M.) are added. The solution of the two polymers is added dropwise using a needle (disposable syringe, external needle diameter 0.6 mm) to a receiver of liquid nitrogen (100 ml).
The resulting microspheres are transferred to 200 ml of water and residual solvent is extracted for 2 hours. Excess water is removed by decantation and the microspheres are lyophilized (diameter after lyophilization: 1-2 μm).
c) 3.76 g of polyamide according to Example 5 c) are dissolved in 195 ml of dichloromethane (0.25% DMSO) with warming and the mixture is combined with a solution of 240 mg of buserelin in 5 ml of water. The mixture is sprayed into a spray-drier to give microspheres.
d) 3.76 g of polyamide according to Example 5 d) are dissolved in 195 ml of dichloromethane (0.25% DMSO) with warming and the mixture is combined with a solution of 240 mg of buserelin in 5 ml of water. The mixture is sprayed into a spray-drier to give microspheres.
e) 3.76 g of polyamide according to Example 6 are dissolved in 195 ml of dichloromethane (0.25% DMSO) with warming and the mixture is combined with a solution of 240 mg of buserelin in 5 ml of water. The mixture is sprayed into a spray-drier to give microspheres.
f) 3.76 g of polyamide according to Example 4 are dissolved in 195 ml of dichloromethane (0.25% DMSO) with warming and the mixture is combined with a solution of 240 mg of buserelin in 5 ml of water. The mixture is sprayed into a spray-drier to give microspheres.
g) 3.76 g of polylactide glycolide (50:50) (PLGA 50:50) (Boehringer Ingelheim) are dissolved in 195 ml of dichloromethane (0.25% DMSO) with warming and the mixture is combined with a solution of 240 mg of buserelin in 5 ml of water. The mixture is sprayed into a spray-drier to give microspheres.
h) 3.76 g of polyamide according to Example 5 d) are dissolved in 195 ml of tetrahydrofuran (0.25% DMSO) with warming and the mixture is combined with a solution of 240 mg of buserelin in 5 ml of water. The solution is sprayed into a spray-drier to give microspheres.
The water absorption of the polyamides after storage at 92% relative atmospheric humidity for 74 h is 8-10% by weight for polyanhydroaspartic acid-co-α,β-(nonylcarbonyloxyethyl)-D,L-aspartamide (70:30) from polyanhydroaspartic acid (MW=30,000) according to Example 5 c) and for polyanhydroaspartic acid-co-α,β-(octyloxycarbonyloxyethyl)-D,L-aspartamide (70:30) from polyanhydroaspartic acid (MW=37,000) according to Example 6.
4 samples of 120 mg of polymer each are incubated at 37� C. in 30 ml each of a phosphate buffer solution composed of 2.05 mmol of Na2 HPO4, 4.5 mmol of NaH2 PO4 and 7.8 mmol of NaN3 (pH 7.4) in closed glass flasks (50 ml). The decrease in weight of the polymer samples was measured by filtering the buffer solution containing incubated polymer through a tared glass frit, drying the residue in vacuo over phosphorus pentoxide for 24 h and determining the decrease in weight.
Series of examples with polyanhydroaspartic acid-co-α,β-(nonylcarbonyloxyethyl)-D,L-aspartamides of differing copolymer composition (x:y) and different molecular weights (from Examples 4 and 5).
______________________________________from Ex. Weight decrease (%) afterNo. X : Y MW* 2 5 10 20 days______________________________________5c 70 30 30,000 6 20 45 705b 70 30 14,000 15 40 65 954 50 50 14,000 10 35 58 885d 30 70 12,000 8 15 30 50______________________________________ *value for the polyanhydroaspartic acid employed determined by viscometry
20 mg of microparticles having a 6% loading of buserelin were weighed into 10 ml glass flasks and 5 ml of lecithin-containing buffer solution (2.91 g of Na2 HPO4, 0.54 g of NaH2 PO4, 0.1 g of NaN3, 6.33 g of NaCl, 2.52 g of NaHCO3 and 10 g of egg lecithin made up to 1 l H2 O) were added. The samples were stirred using magnetic stirrer bars in such a way that the microparticles were kept in suspension and no particles were able to collect on the surface or the vessel walls and larger aggregates were unable to be formed with microparticles of tacky consistency. After 24 hours, the samples were filtered and the buserelin content in the filtrate was determined by means of HPLC.
______________________________________ Micro- Buserelin spheres MW of the PSI releasePolymer from Ex. employed after 24 h______________________________________*PLGA (50:50) 10 g) 50-60%PSI-co-HEA C10 (70:30) 10 c) 30,000 10-15%PSI-co-HEA-C1C8 10 e) 37,000 10-15%PSI-co-HEA C10 (50:50) 10 f) 14,000 40%PSI-co-HEA C10 (30:70) 10 d) 12,000 60-70%______________________________________ *Comparison example PSI = polyanhydroaspartic acid HEA = hydroxyethylamide
|Cited Patent
|Filing date
|Publication date
|Oct 31, 1963
|Jan 10, 1967
|American Cyanamid Co
|Surgical sutures
|Mar 17, 1964
|Feb 27, 1968
|Ajinomoto Kk
|Filaments and surgical sutures of polyl-glutamic acid partly esterified with lower alkanols and process therefor
|Oct 8, 1970
|Nov 20, 1973
|Du Pont
|Polylactide-drug mixtures
|Aug 21, 1974
|Dec 16, 1975
|Sclavo Inst Sieroterapeut
|Use of {60 ,{62 -poly-(aspartic acid)-hydroxyalkylamides as a plasma expander
|May 30, 1975
|Jan 17, 1978
|Alza Corporation
|Drug-delivery device comprising certain polymeric materials for controlled release of drug
|Jan 28, 1975
|Jun 6, 1978
|Alza Corporation
|Drug delivery devices manufactured from poly(orthoesters) and poly(orthocarbonates)
|Mar 3, 1978
|Dec 25, 1979
|Alza Corporation
|Novel orthoester polymers and orthocarbonate polymers
|May 15, 1980
|Dec 8, 1981
|Sri International
|Polymers of di- (and higher functionality) ketene acetals and polyols
|Dec 8, 1978
|Oct 26, 1982
|University Of Utah
|Time-release chemical delivery system
|Dec 31, 1987
|Mar 6, 1990
|Hoechst Aktiengesellschaft
|Biodegradable poly(hydroxyalkyl)amino dicarboxylic acid) derivatives, a process for their preparation, and the use thereof for depot formulations with controlled delivery of active ingredient
|Jan 29, 1991
|Jul 20, 1993
|Hoechst Aktiengesellschaft
|Biologically degradable polyamino dicarboxylic acid--CO--anhydro amino dicarboxylic acid derivative
|Title not available
|, Poly(2 Hydroxyethyl) DL Aspartamide, P. Neri et al., Macro molecular Synthesis , vol. 8, pp. 25 28.
|Bioerodible Polyanhydrides for Controlled Drug Deliver, H. B. Rosen et al., Biomaterials 1983, vol. 4 Apr.
|Evaluation of Sodium Poly , L glutamate as a Plasma Expander, Alexander D. Kenny, Children s Cancer Research Fn., Children s Medical Center and Dept. of Pharmacology, Harvard Medical School, Boston, Mass.
|Evaluation of Sodium Poly-α, L-glutamate as a Plasma Expander, Alexander D. Kenny, Children's Cancer Research Fn., Children's Medical Center and Dept. of Pharmacology, Harvard Medical School, Boston, Mass.
|Excerpt, Repair of cranial defects, J. M. Vaahorager et al., Biomaterials 1983, vol. 4, Apr.
|Kenny, "Evaluation of Sodium Poly-α, L-glutamate as a Plasma Expander," Proc. Soc. Exp. Biol. Med. 100, Jun. 1969, pp. 778-780.
|Kenny, Evaluation of Sodium Poly , L glutamate as a Plasma Expander, Proc. Soc. Exp. Biol. Med. 100, Jun. 1969, pp. 778 780.
|Neri et al. "Synthesis of α,β-Poly[(2-hydroxylethyl-)-DL-aspartamide]a New Plasma Expander," J. of Med. Chem., 1973, vol. 16, No. 8, pp. 893-897.
|Neri et al. Synthesis of , Poly (2 hydroxylethyl ) DL aspartamide a New Plasma Expander, J. of Med. Chem., 1973, vol. 16, No. 8, pp. 893 897.
|Neri et al., "α,β-Poly(2-Hydroxyethyl)-DL-Aspartamide," Macromolecular Syntheses, vol. 8, pp. 25-28, Nov., 1982.
|Neri et al., , Poly(2 Hydroxyethyl) DL Aspartamide, Macromolecular Syntheses, vol. 8, pp. 25 28, Nov., 1982.
|Rosen et al., "Bioerodible Polyanhydrides for Controlled Drug Delivery," Biomaterials, 1983, vol. 4, Apr., pp. 131-133.
|Rosen et al., Bioerodible Polyanhydrides for Controlled Drug Delivery, Biomaterials, 1983, vol. 4, Apr., pp. 131 133.
|Synthesis of , Poly 2 hydroxyethyl) DL aspartamide , a New Plasma Expander, Paolo Neri et al., Research Centre, I.S.V.T. Sclavo, Siena, Italy.
|Synthesis of α, β-Poly[2-hydroxyethyl)-DL-aspartamide], a New Plasma Expander, Paolo Neri et al., Research Centre, I.S.V.T. Sclavo, Siena, Italy.
|Vaahorager et al., "Repair of cranial defects", Biomaterials Apr. 1983, vol. 4, Apr. 1983.
|Vaahorager et al., Repair of cranial defects , Biomaterials Apr. 1983, vol. 4, Apr. 1983.
|α,β-Poly(2-Hydroxyethyl)-DL-Aspartamide, P. Neri et al., "Macro molecular Synthesis", vol. 8, pp. 25-28.
|Citing Patent
|Filing date
|Publication date
|Jun 21, 2000
|Apr 2, 2002
|Mississippi Chemical Corporation
|Process for production of polyasparagine and the high nitrogen content polymer formed thereby
|Aug 14, 2001
|May 13, 2003
|Mississippi Chemical Corporation
|Process for production of polyasparagine and the high nitrogen content polymer formed thereby
|U.S. Classification
|525/420, 525/419, 528/328
|International Classification
|Cooperative Classification
|European Classification
|Dec 20, 1994
|Certificate of correction
|Dec 8, 1997
|Fee payment
Year of fee payment: 4
|Dec 8, 1997
|Surcharge for late payment
|Oct 7, 2001
|Fee payment
Year of fee payment: 8
|Dec 14, 2005
|Maintenance fee reminder mailed
|May 31, 2006
|Lapse for failure to pay maintenance fees
|Jul 25, 2006
|Expired due to failure to pay maintenance fee
Effective date: 20060531


text:
What's Going On?
County Council Meetings
Cardston County's Council Meetings are held on the 2nd Monday of each month and occasionally we require a second meeting during the month which will be held after the MPC meeting on the 4th Monday.
The next Council meeting will be held on July 25th, 2016. The agenda can be viewed here. There next Municipal Planning Commission meeting wil be held on July 25th, 2016. The agenda can be viewed here.
As always, anyone is welcome to attend our meetings and recordings of the meetings are available on our Youtube page.
Chautauqua 2016
The Mormon Trail Canada's Chautauqua 2016 will be touring Stirling, Magrath, Raymond, and Cardston this summer, with each community hosting a full-day event between August 10th and 13th.
Check out the handbill and check out the Mormon Trail website to learn more about this educational, cultural arts, religious, and recreational event that is coming back to southern Alberta!
Final Property Tax Reminder
Just a reminder that property taxes are due by June 30th, 2016 and that late penalties will be applied on outstanding accounts beginning July 1st, 2016. You can pay your property taxes through the mail, in-person at our office, or through your online banking service.
Our late penalty structure is as follows:
- Starting July 1st, 2016, a 5% penalty will be applied to the original property tax levy on outstanding accounts.
- On January 1st, 2017, another 5% penalty will be applied to the original property tax levy on outstanding accounts.
- On March 1st, 2017 a final penalty of 12% will be applied to the total remaining balance (including the previous penalties) on outstanding accounts.
We are also reminding you that with the possibility of a Canada Post strike or lockout, you may have to make alternate arrangements if you were planning on paying your property taxes by mail. Property taxes will still be due on June 30th regardless of the Canada Post strike or lockout situation and penalties will still be applied beginning July 1st.
If you have questions about your property tax notice or payment options, please call us at (403) 653-4977 or email at email@example.com
An online version of the Cardston County publication can be found here.
Assessments are available for review. If you feel that your property has been improperly assessed, you have until July 30th, 2016 to make an appeal. If you are looking to make an appeal, you can contact our office for more information on the process.
Alberta Century Farm and Family Award
We would like to congratulate the Jorgensen Family from Del Bonita for being awarded the Alberta Century Farm and Family Award! We are proud to be home to such committed and determined farmers and ranchers.
Keeping the farm or ranch from generation to generation and actively operating is an impressive achievement for any Alberta family.
The Alberta Century Farm & Ranch Award salutes those families who have continuously owned and actively operated the same land for 100 years.
You can read more from the official press release here.
The Real Dirt on Farming
Hopefully you have had a chance to browse through the Farm & Food Care magazine that we provided to you with our property tax notices this year.
The Real Dirt on Farming magazine is also available online without charge. Help us spread the word about our agricultural industry, which is vital for our region and for anyone who eats food.
Weed Spraying Program & Equipment Rentals
Weed Spraying
Cardston County provides a weed spraying program for residents to help combat the spread of damaging weeds throughout our region.
We provide this service on a cost-recovery basis, with our rates begin at $55/hour, with a $50 startup fee and a minimum total charge of $100. Take a look at the attached brochure for more information.
Equipment Rentals
We provide a rental equipment service to assist our local agricultural producers with soil conservation, pest control, and weed control. Take a look at our brochure for more information. A full list of rental equipment and rates are available by clicking the link on the sidebar to the right.
Fire Bans
Cardston County is no longer under a provincial fire ban, so we are now able to issue fire permits as usual. You can obtain a fire permit by calling (403) 653-3712.
During 2015 alone, nearly 5,500 square kilometers of land was lost in Alberta in 1,786 wildfires. These wildfires affect Albertans' homes and livelihoods and our province's land and wildlife.
Approximately 35% of wildfires are caused by lightning, with the remaining 65% being caused by humans. The Alberta Fire Bans app will hopefully help decrease the amount of human-caused wildfires in Alberta by making it easier for Albertans to access information on fire notices.
You can find more information on provincial fire bans here or by using the provincial fire ban app available on your smartphone.
Gravel Days
Gravel will be available for purchase from the County again this year during the following weeks:
- May 24th to 27th
- August 15th to 19th
If you are interested in purchasing gravel this year, you will need to come to the County Office and pick up a purchase order prior to receiving any gravel. You will need to produce your purchase order to the truck driver when you arrive to pick up your gravel.
If you have received a purchase order, we will be calling you at a later time to let you know the available dates and times for loading at specific gravel pits.
Please be aware that if you are planning on picking up gravel, you must be wearing appropriate safety vests and equipment.
Information on Accessing Pole Haven
Cardston County has been receiving a number of inquiries on changes to the accessibility of the Pole Haven Community Pasture. The County does not manage Pole Haven nor does the County have any influence on how the Community Pasture is managed, but we can provide the following information to residents from the Provincial Department of Environment and Parks and the Pole Haven Grazing Association:
- "Effective immediately, the Pole Haven Grazing Association will restrict recreational access to foot access."
- "Motorized access, camping, campfires, mountain biking, horse use, snowmobiling, and wood cutting for personal use will not be permitted at this time."
- "The intent is not to restrict reasonable foot access, but to manage the rangeland resources under best management practices and the Rangeland Stewardship Code of Practice to maintain a healthy rangeland status."
- "Currently, the best way to achieve a healthy range status is to restrict recreational access on the lease due to the increase in recreational use and the resulting undesirable impacts to rangelands and wildlife habitat."
If you have any concerns about the changes to Pole Haven Community Pasture, please contact the Provincial Department of Environment and Parks or the Pole Haven Grazing Association directly.Social Media
We are now on Facebook and Youtube. Follow our pages for the latest updates and information from Cardston County.

subset: commoncrawl


text:
The Green News Report is also available via... ...
If you take Gandhi's statement, "You must be the change you wish to see in the world," and blend it with Mother Theresa's "If you want to change the world, pick up a broom." you will have Rachel Carbary's formula for creating a successful grassroots effort for change.
As humans, we're shaped by the experiences that get us outside our comfort zone. The rush of adrenaline that comes from a scare, a laugh, or pure repulsion causes our brains to record things more clearly than normal.
Michael's jump into the Sea of Cortez to save Valentina was symbolic of his frustration at the current situation that these majestic animals face, his way of appealing to all of us to do our bit and speak up for the whales to our appropriate agencies and governments.
The new moon of March 31, 2014 ushered in a long overdue win for the whales of the Great Southern Ocean and Sea Shepherd Conservation Society. An ex...
Given Russia's use of natural gas exports to bully Ukraine and Western Europe in the current crisis, sanctions should be expanded to include companies working in Russia's oil and gas export sector.
Following a winter that was exceptionally harsh for much of the United States, spring has finally returned. Milder weather, longer days, and the re-emergence of flowers and creatures should remind us of the wonders of nature that are just outside our doors. Help your kids to appreciate and understand the eco-world around us.
After decades of lethal target practice against whales and dolphins by the U.S. Navy's sonar programs, our marine life is so threatened that they may not survive the navy's request for renewed permits for their bombing and sonar exercises from northern California to the Canadian border.
Must whales and dolphins be subjected to deafening noise that will cause more than 3.5 million instances of temporary and/or permanent hearing loss?
The constant whine from fleets of motorized vessels crisscrossing the global seas, sonar blasts created by military exercises, and deafening booms from air guns used in oil and gas exploration have created a frightening environment for many marine species.
There's an old adage that the environment is never saved -- just continually being saved. And the U.S. Navy's testing and training with high-intensity active sonar is a perfect example.
We would like to introduce you to several people who made such an impressive impact with their grant that we've awarded them another grant to continue seeding the change.
Even though I am a teenager in Chicago, I believe I can make a difference. And that's to stop feeding into this multi-billion dollar industry.
When fishing gear scoops up, hooks, entangles, or otherwise harms another creature not destined for market, it's called bycatch: an innocuous term for a senseless waste of marine life. Bycatch occurs all over the world's oceans on a massive scale.
For the past year I have extensively covered the 'Global War Against Nature.' Without question the relentless massacring of whales has been the most g...
What Hermanus is most famous for is its giant guests who stop by once a year to frolic in the waters of Walker Bay.


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Central Oregon Articles
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Sunriver Resort
Bring your central Oregon wedding to Sunriver Resort with lawns, courtyards and the stunning Great Hall to name a few – an unforgettable Northwest backdrop. The breathtaking Cascade Mountains will create a truly inspiring setting, while the resort's professional staff will assist you in planning all the details. Choose from a variety of onsite... more
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text:
Separate names with a comma.
Here's mine for today.
My Galaxy Nexus.
LOVE the phone. I also enjoy how you can disable any app from your app drawer which is a big plus. Only pet peeve that I have so far is that the...
I'm not sure how Verizon's 4G LTE sim cards work. When I sell it to the person, should I just leave the sim card in? Or should I just keep it?
Late to the party I am then. Oh well.
Sweet. Just got Fruit Ninja & Age of Zombies for free!
Did some adjustments to my previous screen shot. :)
ADW Launcher Ex - My choice of home replacement. Customizable to make your Bionic your own.
WidgetLocker - Customize your lockscreen with widgets...
It's all Minimalistic Text. Well, besides the photo frame anyways which is from the 3D Gallery.
Can't wait til were actually able to theme the status bar.
This is what I miss the most from the Droid. Any possible port to the X?


text:
Little Worlds
By Pixels By Paul / Paul L. Richman
Open iTunes to buy and download apps.
Over a thousand high resolution photographs are presented here in 63 little world images, each giving an artful 360⁰ treatment of a special subject. Aside from being beautiful, these images have unique properties. They can be viewed and enjoyed from any angle. There is no hard and fast "up" or "down", and each angle of view gives a fresh look. The images demand attention, a casual glance challenging and drawing in the viewer to understand the breadth of all that is presented. Being quite malleable, these images can be stretched to fill the screen in both landscape and portrait orientation, without detraction.
This app takes full advantage of these special image properties by offering unique features that exploit them. The images are automatically expanded (stretched) to precisely fill the screen in any orientation, for full screen enjoyment/ There are no black bands at the edges on any device.
This app is fully optimized for Retina iPad All photographs and graphical elements are at full Retina iPad resolution.
This app is also fully optimized for the new iPhone 5. The app takes full advantage of the enlarged iPhone 5 screen size, and takes into account the new safe areas of this device when making wallpaper.
In full screen (1-up) viewing, a button is provided to lock screen rotation, so that you can easily view each image from all angles. Without locking the screen, you would only be able to view the image in one orientation, as the image would rotate as the device rotates. Try it!
NEW: You can now send physical postcards from within this app to anyone anywhere in the world*. The picture you choose (from this app or from your own Photos library) will be on the front of the postcard. You enter a message and recipient address, and the postcard is printed and mailed.
Best of all, gorgeous "safe area" wallpaper for any orientation can be made from each image. (The "safe areas" are the central regions not obscured by the lock screen's unlock slider and date-time bar, nor by the home screen's icon dock and status bar.) The full image is stretched to precisely fill the home and lock screen safe areas, for unobstructed viewing. Home screen wallpaper is reflected behind the dock area, to avoid an ugly black band at the bottom.
You can also create safe area wallpaper from your own pictures with this app.
Detailed information is available for each photo.
A pictorial help file is included, with usage tips and disclosure of hidden features.
This app requires no internet* connection to run. Everything you need is included inside this application. And it's a universal app! Run it on your iPad, iPhone and iPod Touch, all for one low price.
Order large prints of these photos, unmounted or mounted, at discounted prices.
This app requires iOS 4.3 or higher.
* An internet connection is needed only to send postcards.
What's New in Version 5.0.0
+ This app is now fully optimized for Retina iPad All graphical elements are at full Retina iPad resolution.
+ This app is also fully optimized for the new iPhone 5. The app takes full advantage of the enlarged iPhone 5 screen size, and takes into account the new safe areas of this device when making wallpaper.
+ When making safe area wallpaper from your own photos, you can now wrap and stretch them.
+ iOS 6 introduced new auto-rotation behavior, which broke the auto-rotation lock in this apps full screen (1-up) mode. This is now fixed.
+ The Help file has been updated and improved.
+ Minor bug fixes.
- $1.99
- Category: Photo & Video
- Updated: Nov 14, 2012
- Version: 5.0.0
- Size: 154 MB
- Language: English
- Seller: Paul L. Richman
- © 2011 by Pixels By Paul - all rights reserved
Compatibility: Requires iOS 4.3 or later. Compatible with iPhone, iPad, and iPod touch.


text:
A water conservation symposium will be held Feb. 8 in Amarillo.
Indeed, water conservation is a necessary and major component of any water preservation and availability discussion, but as Vice President Dick Cheney said in a speech in Toronto in April 2001, "Now, conservation is an important part of the total effort. But to speak exclusively of conservation is to duck the tough issues. Conservation may be a sign of personal virtue, but it is not a sufficient basis all by itself for sound, comprehensive energy policy." The vice president's message also applies to water policy. For several years I have been raising the issue of water shortages in the Panhandle; I have also proposed a viable solution to the water shortage but sadly almost no one, including some of our politicians, seems interested.
I am gratified to read in the December issue of Discover magazine: "The engineering firm Black & Veatch has developed a plan that would siphon of 1,000 cubic feet of water per second from the Mississippi and move it across the Great Plains and over the Rockies to southwestern Colorado."
Roberto Pacheco


text:
A mother's forceful determination more than a half-century ago has led an Amarillo woman to share her love for music with hundreds over the years.
Nellie James, who teaches piano from her home on South Crockett Street, said she remembers the exact moment when she first sat before a piano.
"I was 8, in the third grade, when I started taking lessons," she said. "My mother was so determined to have a piano player in the family, I had no option.
"I'm glad, now."
The 60-ish James said back then she took two half-hour lessons a week, "at $1.50 per lesson." She said 30-minute piano lessons are custom.
"Little kids can't stand an hour," she said.
Her love of music, begun as a young child, continued to grow as her proficiency with the piano keys increased.
"I took lessons through college and after," said James, who attended Nazarene College in Pasadena, Calif., and later Ohio State University.
"I was going to be a musician in college," she said. "I was very short-sighted.
"I thought I could teach music so I could stay at home with my kids but I didn't know how short a time that would be."
James, who grew up in Roswell, N.M., married an airman and followed him from duty station to duty station. She took on her first piano student in 1959 while living in Newfoundland.
"I didn't know I could make a living at teaching piano, but when I married in the late 1950s, women had a profession as a backup," she said.
That backup proved to be a wise decision. When her marriage ended, James found herself in Columbus, Ohio. Her background in piano instruction helped land her a job in Nashville, Tenn.
"I worked for a gospel publishing company and helped put out piano books," she said, but even though she held a full-time job, she still made time to teach piano.
"In Nashville, I had 60 to 80 students," James said. "I'll never do that again."
Family obligations drew her back west in the middle 1970s.
Two years later, she married Ron James, an employee at the Pantex Plant.
Now, she teaches piano to between 25 and 30 students.
"My youngest is 4; the oldest in her 60s," Nellie James said.
The main difference between teaching students at either end of the age spectrum is that "the kids think they have a lifetime; they don't care," she said. "The adults think they have to learn right now and if they can't play like they want to, they quit after a couple of months."
James and her husband Ron celebrated their 26th wedding anniversary on July 10. They received congratulations from her sons Terry Barker, 45, and Paul 40, and Ron's son, Lynn James, 30.
Amarillo Globe-News © 2016. All Rights Reserved. Terms of Service | Privacy Policy / About Our Ads


text: Posted January 16, 2014 So if a team has already traded their first round pick we would get the pick from the following two seasons, yes? So far as I can tell, it absolutely has to be the two drafts following the trade. The rules aren't very clear on whether or not a team without a first round pick in the next draft would be barred from entering negotiations. It could be that the team only has to give up the next two first rounders it has original rights to, or it could be that if a team does not have original rights to its next two consecutive first round picks at the time of the deal then they can't deal. So, this could mean that Washington and Indy can't talk to Hardy until after this year's draft, or it means those teams have to be willing to give up an even greater piece of their future than they already have in order to do so. 1 person likes this Share this post Link to post Share on other sites


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I pulled the wires off the old board and put them on the new board, I just read the instructions and caught that the Black 110 volt wire should go to the L1 on the new board, not to the ACC. I had...
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Deep Blue Apps develop games, templates and tools for various SDK's. In no way are Deep Blue Apps affiliated with any of the companies or SDK's used. We develop templates and tools independently. Templates available within the site are made for GameSalad Creator and the Corona SDK.


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Join the 'Feraheme' group to help and get support from people like you.
Feraheme Support Group
Our support group for Feraheme has 3 questions and 7 members. Updated 7 Dec 2012.
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Feraheme (ferumoxytol): Drug Safety Communication – Warnings Strengthened and Prescribing Instructions Changed
ISSUE: FDA is strengthening an existing warning that serious, potentially fatal allergic reactions can occur with the anemia drug Feraheme (ferumoxytol). FDA changed the prescribing instructions and ...
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text:
Novartis's Alcon Offer More Attractive, Jimenez Says
Novartis AG indicated Alcon Inc. shareholders should take another look at its $11.5 billion buyout offer now that an increase in the Swiss drugmaker's share price and a rally in the franc have lifted the value of the bid.
Novartis, which owns 77 percent of the eye-care company, isn't waiting to buy the remaining shares and instead is starting to work with Alcon at "arm's length," Novartis Chief Executive Officer Joe Jimenez said on a conference call after reporting an 8.4 percent increase in third-quarter profit. Novartis is willing to pay a fair price and no more, and the deal must benefit both companies, he said.
"We will see how things play out," Jimenez said. "This has to be a fair offer for Novartis and Alcon. The attractiveness of that offer has gone up."
The rise in Basel, Switzerland-based Novartis's stock eases pressure on Jimenez to sweeten the terms, said Andrew Weiss, an analyst at Bank Vontobel AG in Zurich. The independent directors committee of Alcon's board has demanded a higher price since Novartis offered Alcon's public shareholders less than Nestle SA received this year for its 52 percent stake.
Novartis finished unchanged at 30 Swiss francs in Zurich. The shares have risen 13 percent since touching their low for the year on July 30, while the Swiss franc has gained 7 percent against the dollar.
In announcing the purchase of Nestle's stake on Jan. 4 for $28.3 billion, or $180 a share, in cash, Novartis also said it would exchange 2.8 of its shares for each of Alcon's. That valued the publicly traded stock at about $153 a share that day. The offer is now worth about $165.80, based on today's closing price for Novartis and the franc's exchange rate with the dollar.
Higher Price
Nestle deserved a higher price than Alcon's public shareholders because the Nestle stake gave Novartis control of Alcon, Novartis has said. Alcon, the world's largest eye-care company, is based in Huenenberg, Switzerland, and its shares trade on the New York Stock Exchange. Alcon has traded at a premium to the Novartis bid as investors speculated on a higher offer.
Novartis bought 25 percent of Alcon from Nestle in 2008 for $143 a share. Combined with what it paid Nestle this year, the average price was $168.
"The offer is just short of $168, and at $168 it will be difficult for the IDC to block a merger," Weiss said in a telephone interview today, referring to the independent directors. "The terms are good, the price is in line. The ice under the IDC's feet is getting thin."
Alcon fell $1.06, or 0.6 percent, to close at $167.70.
Rising Profit
Novartis's net income rose to $2.28 billion in the third quarter from $2.1 billion a year earlier, the company said in a statement today. Analysts predicted $2.22 billion, according to the average of 15 estimates compiled by Bloomberg over the past month. Sales increased 13 percent to $12.6 billion. Demand for drugs to treat eye disease and high blood pressure and a new generic blood thinner helped lift earnings.
Novartis is rebuilding its stable of products to help replace revenue it will lose when its best-seller, Diovan for hypertension, starts to lose U.S. patent protection in 2012. Regulators approved Lucentis, an eye medicine, and Exforge, a blood-pressure drug, in the past four years. Novartis began selling a copy of Sanofi-Aventis SA's Lovenox blood thinner this year.
Sales growth this year will be in the mid teens on a percentage basis because of the inclusion of four months of revenue of Alcon, the company said. Excluding Alcon, Novartis maintained its forecast from July for growth at a mid-to-high single-digit pace on a constant currency basis.
Diovan, Gleevec
Prescription drug sales climbed 5 percent to $7.6 billion. Lucentis sales climbed 19 percent to $398 million, while Exforge increased 30 percent to $222 million.
Diovan generated $1.5 billion in revenue, a gain of 1 percent, and sales of Gleevec for leukemia rose 4 percent to $1 billion. Diovan faces competition from Teva Pharmaceutical Industries Ltd.'s generic version of Merck & Co.'s Cozaar hypertension pill, which won U.S. regulatory approval in April.
Revenue from the Sandoz generic-drug business gained 18 percent to $2.2 billion. Enoxaparin, the generic of Lovenox, had $292 million of sales. Novartis won U.S. regulatory approval in July to sell the drug, which uses technology from Momenta Pharmaceuticals Inc.
Momenta shares rose 85 cents, or 5.8 percent, to close at $15.57 on the Nasdaq Stock Market.
Alcon yesterday raised its profit forecast for the year and reported a 13 percent drop in third-quarter earnings on costs linked to the Novartis offer.


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Community action against Monsanto
On March 26, President Obama signed H.R. 933 with a provision called the Monsanto Protection Act. Monsanto is a large agricultural corporation focused on providing genetically modified seeds to farmers. They have created revenue by applying biotechnology techniques to the farming industry that include modifying DNA of seeds such as the "terminator seed" which will produce plants that will never yield fertile seeds. Monsanto has also created seeds that could endure pesticides and herbicides.
There are many concerns about Monsanto, search and learn. Knowledge is power or atleast choice. Food justice activists are furious with the backdoor signing of the Monsanto Protection Act for a number of reasons. The act would protect Monsanto from being sued for health damages caused by the use of their genetically modified crops. Additionally, if health damages were discovered by the use of GMO foods, then the United States government would not be able to ban them from consumption.
May 24, 2013
Photos: 56
Get out of that tree, koala...
This action was directed by Mark Selmes of Mt Rae NSW
Cranky koala was high up in a tree out the front of State parliament on Wednesday 8th May. There are two keystone cops ordering him down. He has refused. State police have attended but we told them we have it covered. The issue being highlighted is
The declining forests and woodlands of the Southern Tablelands , which have been saved for the very reason that they exist as remnants in highly modified agricultural landscapes, not containing millable timbers or many quality saw logs, are now at risk of being cleared anew for firewood or biomass .
May 7, 2013
Photos: 19
No amateur shooters in National Parks
Over three thousand concerned citizens and members of The Wilderness Society attended the rally to hold Barry O'Farrell accountable for allowing amateur shooters into National parks with rifles, muskets, bows and arrows and knife hunting. Bush walkers and those outside parks life's are in danger from stray shots. Photo Daryl Morris
Apr 17, 2013
Photos: 34
TWS verses Greenpeace pics by Daryl and Anne Claire
Feb 7, 2013
Photos: 58
TWS team soccer (Just some of the team) You will be there in the next lot of pics, of the Event.
Jan 30, 2013
Photos: 17
Jan 26, 2013
Photos: 1
Support Broome
Dec 3, 2012
Photos: 2
Bad Jane farewell
Nov 29, 2012
Photos: 42
Human sign Sydney Park
Oct 12, 2012
Photos: 18
Profile Photos
Album for profile photos
Oct 8, 2012
Sea Shepherd vessel Steve Irwin
Action to Protect the Kimberley of Western Australia from a proposed worlds largest liquid natural gas plant (LNG) at James Price Point. WA Premier Collin Barnett and woodside want it built at JPP.
Sep 1, 2012
Photos: 52
Bushland not Gasland anti CSG action
Coal Seam Gas is emerging as a massive public issue. Farmers, locals and conservationists standing up to multi-national corporations, community blockades in Queensland, and growing problems in New South Wales have captured the public's imagination. But just what are the environmental impacts of this massive new industry? And what is the Wilderness Society in NSW doing about it? Save the Pilliga!. Lock the gate
Apr 30, 2012
Photos: 41
NSW Marine sancturies Action Coogee beach
Feb 17, 2012
Photos: 43
Global 24 hours Tasmania's Ancient Forest day of action
Feb 13, 2012
Photos: 82
Brookfield Read all about it
Jan 12, 2012
Photos: 16
Forest Forum Canberra 2011
Aug 17, 2011
Photos: 13
Miserable Clowns action Ethical Paper Campaign
Jun 9, 2011
Photos: 10
Ulan Coal protest
Jun 4, 2011
Photos: 20
WildEndurance 2011 vollies
Apr 29, 2011
Photos: 30
Mar 23, 2011
Photos: 5
World Forest Day Action in Sydney
Forest workers day of acknowledging their world wide destruction.
Mar 21, 2011
Palm Oil
Mar 20, 2011
Photos: 24
No Coal Seam Gas action Sydney
Taking a stand against the onslaught of Coal and Coal Seam Gas. Community members from many different groups including "Lock the Gate" from Queensland and N.S.W. Also volunteers from The Wilderness Society. Samba Band conducted by "Tom the Pom" Of SAMBA NINJA http://www.thesambaexperience.com.au/index.html
Mar 19, 2011
Photos: 40
eight pics
Can you name these people
Nov 22, 2010
Photos: 8
Coal Seam Gas action State Library
People getting together to stop coal seam gas extraction in N.S.W. Australia. Gas extraction methods used are some of the most dangerous practices used in any industrial activity. Refer to the documentary "Gasland" Also look up information on fracking. Join us in our fight to protect our food bowl and environment. http://riverssos.com/
Nov 10, 2010
Photos: 46
TWS EDO Soccer
Aug 20, 2010
Walk against warming Sydney Samba 2010
Aug 14, 2010
Photos: 86
You have to get your FOOT in door
Aug 4, 2010
Photos: 35
Kristina koala killer
May 31, 2010
Photos: 63
no coal
Apr 21, 2010
Photos: 3
Mumbula marin place
Apr 19, 2010
Red Gum arrest
Botanical Gardens action to protect River Red Gums
Mumbula comes to martin pl
Apr 18, 2010
Mumbula Martin Place
South east Koalas
Mar 27, 2010
Photos: 15
Mar 23, 2010
Newcastle meets Clancy
Mar 15, 2010
Mar 9, 2010
The Three Stooges
Jan 13, 2010
Photos: 6
Walk Against Warming. The Wildeness Soc & Samba Ninja
Dec 11, 2009
Photos: 25
Dec 9, 2009
Canberra STOP Forest Green Wash
Nov 30, 2009
Canberra Stop Forest Conference
Nov 23, 2009
Photos: 60
ALP Sydney Action
Nov 13, 2009
Photos: 53
Bill goes to Town
Nov 11, 2009
Photos: 31
soccer TWS versus DECC 10-09
Oct 29, 2009
Photos: 11
350 Salsa Samba Sydney
Oct 23, 2009
350 Samba extras
Photos: 122
Peter is glad to see us. Randwick Enviro fair
Sep 26, 2009
Toongabbie electorate photo petition
May 27, 2009
Photos: 57
Koala Pub Krawl to Toongabbie
The Wilderness Society took a bus of volunteers to pubs in the Toongabbie Electorate to gauge how the community felt about protect the River Red Gum Forests along the Murray. As you can see some Koala's accompanied them on the journey!! Staff and patrons in the Toongabbie Hotel and the Pendle in sent a strong message to Nathan Rees, the Premier of NSW that these forests should be protected.
Koala Pub Crawl to Toongabbie 2
This is a small selection of images from The Wilderness Society Koala Pub Crawl to Toongabbie featuring photographs taken of volunteers, staff and patrons at The Pendle Inn


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|Clemson supercomputers ranked in top 5 fastest at public universities
|Tuesday, July 8, 2014 7:36 PM-
CLEMSON — Clemson University's Palmetto Cluster once again ranked among the top five fastest supercomputers at public universities in the United States in the latest Top500 list released this week at the annual International Supercomputing Conference in Leipzig, Germany.
The biannual Top500 list is a ranking of the top 500 fastest supercomputers across the globe, including those from national laboratories, corporations, universities and government agencies. Globally, Clemson's Palmetto cluster ranks as the 66th fastest supercomputer, its third-highest ranking in six years.
In this year's Top500 list, the Palmetto Cluster's performance achieved a benchmark of 551 teraflops. In context, one teraflop is equal to one trillion mathematical operations per second.
"The Top500 ranking for the Palmetto Cluster is an indication of the sustained growth of the Clemson computational community," said Jim Bottum, vice provost for information technology and chief information officer at Clemson. "A significant portion of the cluster is funded by federal grants and this is indicative of the central importance of computing to research and a measure of Clemson's growth in this area."
Clemson students, faculty and staff from all across campus take advantage of the world-class computing resources offered in the Palmetto Cluster, and an estimated 88 percent of departments have had one or more faculty or students receive training on how to use the cluster for their research and education activities.
"Almost 75 percent of our users are students and use of these resources adds value to their education and research experiences at Clemson," Bottum said.
The Palmetto Cluster also couples with Clemson's National Science Foundation-funded Advanced Cyberinfrastructure Research and Educational Facilitation program (NSF ACI-1341935) designed to extend the reach and impact of campus and national research computing infrastructure on the science conducted by students and faculty.
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- WATCH: Mike Williams Returns From Neck Injury To Be Difference Maker
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Associate Professor of BiologyTel: 301-696-3648
Email: firstname.lastname@example.com: Hodson Science & Technology Center, Room 148
Sue Carney, associate professor of biology, teaches courses in genetics, evolution, introductory and graduate biology, and environmental science. Her background is in ecological genetics, and she has published several research papers describing various uses of genetics for investigating individual and population level variation related to different environments.
I am interested in using genetics as a tool to investigate questions related to conservation, evolution, and the adaptation of individuals and populations in ecological systems. At Penn State, I studied genetics and gene expression analysis of deep-sea hydrothermal vent tubeworms and hydrocarbon seep mussels. As a postdoctoral scientist at Mote Marine Laboratory, I worked on projects involving conservation genetics of the Florida manatee. Here at Hood, undergraduate and graduate students and I continue to work on a diversity of projects involving manatees, stingrays, crayfish, and other invertebrates within local freshwater, estuarine, and marine systems, all with the goal of understanding how individuals and populations adapt to their environments at the genetic level.
Through an integration of the liberal arts and the professions, Hood College provides an education that empowers students to use their hearts, minds and hands to meet personal, professional and global challenges and to lead purposeful lives of responsibility, leadership, service and civic engagement.
401 Rosemont Ave.
Frederick, MD 21701


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George Groves / James DeGale... Who will have done more?
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knockout artist
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Re: George Groves / James DeGale... Who will have done more?
Originally Posted by
I think to be fair to them both, for the respective amount of fights each has had, they are doing very well in terms of their competition, if we're looking at it from the perspective of the normal British prospect. It's good beign tested regulalrly as early as they have been and will only stand them in good stead for the future.
Agree with this, both have taken on tough fights considering how early on they are in their respective careers. I think both will make it to world level within the next three years, I agree with those who say DeGale should consider a new trainer, could Enzo Calzaghe be a good fit for him?
Look forward to Groves-Johnson, I can see that being a real barnburner, if Glen has anything left in the tank, Groves is in for a war, and we'll find out if he's future world champion material (which I think he is)
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Atlas robot tries to do the Karate Kid "Crane" stance
If robots of the future start trying to become our new overlords, we could probably trace it back to this day. Well, sort of. Florida Institute for Human and Machine Cognition (IMHC) is teaching its Atlas robot a few kickass moves. Or at least is trying to. The latest stunt this humanoid contraption is trying to pull off is that iconic stance from 1984's Karate Kid, popularly known as "The Crane". But while it seems to have its arm movements down to a T, it still needs a lot of work on its legs.


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This is a follow up on my previous question, here:
Windows modified memory without a pagefile - Super User
I have no pagefile and a lot of modified memory according to resource monitor (Win 7 x64). The answerer to my original question said that the modified memory must be written to the "backing store" and when I asked if he meant files on the disk he said yes. So I have Sysinternals' RamMap program and I've tried the option 'Empty Modified Page List' but nothing changes.
Right now I'm using gigabytes of modified memory and it seems it's always that way with VMWare Workstation (several VMs open) and Firefox (ton of tabs open). How can I flush the modified memory, and is there any way to make Windows do that more often short of enabling a pagefile?
EDIT - I've since discovered the source of several gigs of modified memory came from running Sysinternals' Process Monitor. When I closed Process Monitor I got back a few gigs. That modified memory does not show in the process list in RAMMap.


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Visual Studio 2015
Provides a default message loop.
An int value that is returned by WinMain.
Run acquires and dispatches Windows messages until the application receives a WM_QUIT message. If the application's message queue currently contains no messages, Run calls OnIdle to perform idle-time processing. Incoming messages go to the PreTranslateMessage member function for special processing and then to the Windows function TranslateMessage for standard keyboard translation; finally, the DispatchMessage Windows function is called.
Run is rarely overridden, but you can override it to provide special behavior.
Header: afxwin.h


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Would be nice to see that added.
Even though it is not rated for 4.0, I really like this plugin. Simple to use, no conflicts, wish they would update just to have all my plugins at 4.01 but so far have had no problems with it as is.
There is one thing I would like to do to match my theme better and that is to enlarge the boxes a bit and flush left instead of right. I know this is probably an easy fix in the code but I'm not real code savvy.
Have been using for awhile on several installations, including MU. Works great. Idiot proof usage ;-}}}
I wish it had the ability to make sizable "thumb" previews since Pin boards are such random and varied sizes, just to even up the look on the page.
Cool plugin, its the only one that works with WordPress 4.0 . If it only had a way to change the thumbnail size it would be awesome.
Works perfectly for me.
Easy to configure, looks nice
Tried other plugins and they couldn't display - something about Pinterest stopping feeds. Yet jowkli seems to not have that problem! Yayyy! Thanks for a top little plugin.
Feature request to more easily configure display (side by side) if you have time and inclination. But it's great that it works out of the box - champion!
Easy to customize. Thank you!!
Love this plugin. Works great and easy to configure.
Definitely lives up to the name and it's easy to configure.
You must log in to submit a review. You can also log in or register using the form near the top of this page.


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Niranjan Kala
I love writing code and I am really passionate about it.
I have accumulated experience in various programming languages such as C# and VB.Net through years. I enjoy programming in .net environment using C#, ASP.NET MVC, ORM and other cutting edge technologies producing Windows desktop, web.
I am currently work with MothersonSumi Infotech & Designs Ltd as a Senior Software Engineer specialized in .net area. I have Bachelor degree in Computer Science & Engineering. I have worked at Lio Technologies as Software Engineer, as consultant at AGCSS.
I like to share with my two blogs:
Development Solutions - .Net Technology
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