text:
|Publication number
|Publication type
|Application number
|Publication date
|Dec 25, 1990
|Filing date
|Jun 1, 1988
|Priority date
|Jun 1, 1988
|Fee status
|Publication number
|Ooi Wong, Toshiaki Nishiahta, Joseph H. Rytting
|Original Assignee
|Odontex, Inc.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (10), Referenced by (67), Classifications (19), Legal Events (6)
|External Links: USPTO, USPTO Assignment, Espacenet
The invention relates to the development of safe and effective agents which improve the rate of percutaneous and oral mucosal transport of physiologically active agents. More particularly, the present invention relates to an improved topical penetration enhancer for use in the topical delivery of a local or systemic physiologically active agent to a mammalian organism.
Dermal drug formulations may represent the oldest drug dosage form in human history. It is highly probable that even ancient people used resins and animal fats to treat damage to the skin resulting from injuries and burns. The use of such dermal formulations for local effect remained largely unchanged until the middle of this century. The concept of administering drugs through the skin to achieve a local or systemic effect was first seriously advocated by Dr. Alejandro Zaffaroni in the early 1970's. Since that time extensive research has been undertaken in this field.
The transdermal route of drug administration offers a number of advantages over the more conventional routes of drug administration. For instance, a drug may be delivered to targeted tissues from adjacent skin areas. The transdermal route of drug administration also allows for a gradual, controlled release of drug into the systemic circulation. Since many drugs are poorly absorbed or delivered through the traditional routes of administration, the transdermal route provides an effective method of achieving improved bioavailability for those drugs. The transdermal route of drug administration is also advantageous since the administration of dermally administered drugs may be easily stopped should an undesirable side effect occur during therapy.
In spite of the foregoing advantages, transdermal formulations are limited. They cannot be used with most polar drugs since they tend to penetrate the skin too slowly. This characteristic is particularly crucial since most drugs are of a polar character. In addition, many drugs elicit a reaction and/or irritation at the site of topical application.
Two methods are known for improving the rate of penetration of polar drugs across the skin. The first method is to make a better formulation of the drug to increase its thermodynamic activity. The thermodynamic activity of a drug in a dermal formulation is dependent on the concentration of the drug and the choice of the vehicle. According to the laws of thermodynamics, the maximum activity of the drug is usually fixed by that of the pure state, i.e., the drug crystal. The second method involves the use of compounds or penetration enhancers to increase the permeability of the barrier membrane. The latter method is generally more practical because of its convenience and effectiveness.
Thus, in the last two decades, a wide variety of compounds have been evaluated as to their effectiveness in enhancing the rate of penetration of drugs through the skin. The classically recognized strong enhancers tend to be proton accepting solvents, e.g., dimethyl sulfoxide (DMSO) and dimethyl acetamide (DMA). Recently, 2-pyrrolidone, N,N-diethyl-m-toluamide (Deet), 1-dodecylazacycloheptane-2-one (Azone, a registered trademark of Nelson Research), N,N-dimethylformamide, N-methyl-2-pyrrolidone and calcium thioglycolate have been reported as effective enhancers. The structures of these compounds are set forth in Table I.
TABLE I______________________________________Dimethyl Sulfoxide (DMSO) ##STR2##N,N-Dimethyl Acetamide (DMA) ##STR3##N,N-Diethyl-m-Toluamide (Deet) ##STR4##1-Dodecylazacycloheptane-2-One (Azone or laurocapram) ##STR5##2-Pyrrolidone- 5-Carboxylic Acid ##STR6##2-Pyrrolidone ##STR7##N,N-Dimethylformamide ##STR8##N-methyl-2-pyrrolidone ##STR9##calcium thioglycolate CaCH2 COOS.3H2 O______________________________________
See, for example, the review article by Kenneth A. Walters entitled "Percutaneous absorption and transdermal therapy," Pharmaceutical Technology, March 1986, pp. 30-46, which discusses the use of surfactants and penetration enhancers to improve skin transport and their possible mechanisms of action.
Several problems have been associated with these prior art dermal enhancers. They cannot be applied to most polar drugs because they tend to penetrate the skin too slowly. And many of these prior art dermal enhancers produce reactions and/or irritation at the site of application.
In the search for new dermal penetration enhancers, Rinta Iubuki, in his Ph.D. Thesis in 1985 at the University of Kansas entitled "Use of Snake Skin as a Model Membrane for Percutaneous Absorption Studies," investigated the use of six compounds for transdermal penetration enhancement of indomethacin in a dosage form of a petrolatum ointment. The compounds disclosed in his thesis are presented below: ##STR10##
The primary problem with these compounds is their toxicity. Obviously, if a compound when used as a dermal enhancer is either toxic, irritating or allergic, then that compound is unsuitable for application to the human body. DMSO and DMA are also not clinically acceptable for those reasons. Deet and Azone have lower reported toxicities yet their toxicity is high enough such that they are not widely used.
In developing effective dermal enhancers, it would be advantageous to evaluate the potential enhancers by in vivo determination of the rate of human skin penetration of a drug administered along with the enhancer. The amount of drug could be measured in the host's circulation or in the target tissue. Unfortunately, due to the risks involved and the cost of such an evaluation, human in vivo determination is not practical. Thus, researchers have used a variety of mammals for in vivo study. Typical mammals include mice, rats, rabbits, pigs and dogs. However, significant differences have been found in the pattern of drug penetration among these mammals and humans. Although the reason for this species variation has not been well-established, the difference in the density of hair follicles is considered to be a factor.
Thus, the disadvantage of in vivo methods has encouraged wide use of various in vitro methods. Copending application U.S. Ser. No. 901,732, filed Aug. 29, 1986, now U.S. Pat. No. 4,771,044, incorporated by reference herein, discloses a novel method for in vitro determination of transdermal absorption. The method involves the use of shed snake skin.
In spite of the numerous attempts in the art to prepare a method for enhancing the absorption of drugs, especially polar drugs, through the skin, there still exists a clear and present need in the art for a method to enhance the absorption of drugs through the skin. This need has been addressed by co-pending application U.S. Ser. No. 096,092, filed Sept. 11, 1987, now U.S. Pat. No. 4,845,233, which describes a novel group of cyclic urea compounds which enhance the absorption of active substances through the skin while avoiding the significant pharmacological activities and toxicities of the prior art enhancers. The soft penetration enhancers of Ser. No. 096,092, now U.S. Pat. No. 4,845,233, have the formula ##STR11## wherein R, R1 and R2 are independently selected from hydrogen; hydroxy; fluorine; bromine; chlorine; C1 -C20 alkyl; C2 -C20 alkenyl; C2 -C20 alkynyl; C3 -C10 cycloalkyl; C2 -C20 (monohydroxy or polyhydroxy)alkyl; C1 -C20 (monohalo or polyhalo)alkyl; carboxy; C1 -C20 alkylcarboxy; C1 -C20 alkenylcarboxy; C1 -C20 carboxyalkyl; C1 -C20 alkanoyl; C1 -C20 alkanoyloxy; C1 -C20 alkoxycarbonyl; carbamoyl; carbamyl; C1 -C20 alkylcarbamyl; sulfo; C1 -C20 alkylsulfonyl; C1 -C20 alkylsulfinyl; C1 -C20 alkylsulfoxide; C1 -C20 alkylsulfone; thio; C1 -C20 alkylthio; amino; nitro; C1 -C20 alkylamino; C1 -C20 aminoalkyl; substituted or unsubstituted phenyl or benzyl, the substituents being selected from hydroxy, fluorine, bromine, chlorine, C1 -C20 alkyl, C2 -C20 alkenyl, C2 -C20 (monohydroxy or polyhydroxy)alkyl; X is methylene or oxygen and n is 0 to 20.
Improvement of transdermal drug delivery has thus been a focus of pharmaceutical research for many years. However, the stratum corneum presents a formidable barrier to percutaneous drug absorption. This barrier function is believed to be due to the ordered matrix of intercellular lipids and to the low water content in the stratum corneum. Since human gingivae also have stratum corneum, the problems besetting development of gingival formulations are much the same. There is clearly a need for additional novel compounds which enhance the absorption of active substances through the skin and mucous membranes such as the gingivae, but which are designed to have greatly reduced toxicity.
Surprisingly, the present inventors now find that a novel group of long chain alkyl (N,N-disubstituted amino)acetates and related compounds enhance the absorption of active substances through the skin and mucous membranes while avoiding the significant pharmacological activities and toxicities of the classical prior art enhancers. The present invention thus provides a new class of biodegradable soft penetration enhancers which because of their structure have less adverse or toxic effects but which are nevertheless excellent promoters of percutaneous and oral mucosal (especially gingival) absorption.
The soft penetration enhancers of the present invention have the structural formula ##STR12## wherein R is hydrogen, C1 -C7 alkyl, benzyl or 4-hydroxybenzyl; n is a whole number from 4 to 18 inclusive; R1 and R2 are independently selected from hydrogen and C1 -C7 alkyl, or R1 and R2 together with the nitrogen atom to which they are attached are combined to form a substituted or unsubstituted heterocycloalkyl radical having a total of 5 to 7 ring atoms, optionally including a hetero ring atom selected from oxygen, sulfur and nitrogen in addition to the indicated nitrogen atom, the substituents when present being one to three C1 -C7 alkyl radicals, which may be the same or different; and R3 and R4 are independently selected from hydrogen, methyl and ethyl.
The present invention also provides a method for carrying physiologically active agents through body surfaces such as skin and mucous membranes and to compositions for use in that method. More specifically, the invention relates to a method for increasing the penetration of a physiologically active agent across the skin or mucous membrane of a mammalian organism comprising topically applying a physiologically active agent in an amount sufficient to achieve the desired local or systemic effect and the soft penetration enhancing compound described above in an amount sufficient to effectively increase penetration of the physiologically active agent. The invention further provides a pharmaceutical composition comprising same along with a pharmaceutically acceptable carrier therefor.
FIG. 1 is a plot of the amount of indomethacin, in μg, detected in the donor cell of a vertical diffusion cell apparatus, versus time, in hours, for an ointment composition containing the prior art enhancer Azone (Δ) or one of three representative enhancers of the invention, CH3 (CH2)9 OCOCH2 N(CH3)2 (O), CH3 (CH2)13 OCOCH2 N(CH3)2 and ##STR13## (□).
FIG. 2 is a plot as described with reference to FIG. 1 for an ointment composition containing the prior art enhancer Azone (X) or one of three representative enhancers of the invention, CH3 (CH2)7 OCOCH2 N(CH3)2 (O), CH3 (CH2)9 OCOCH2 N(CH3)2 ( ) and CH3 (CH2)11 OCOCH2 N(C2 H5)2 (□).
FIG. 3 is a plot as described with reference to FIG. 1 for an ointment composition containing the prior art enhancer Azone (X) or a representative enhancer of the invention, CH3 (CH2)11 OCOCH2 N(CH3)2 (O).
FIG. 4 is a plot as described with reference to FIG. 1 for a patch containing 542�31 mg indomethacin together with a representative enhancer of the invention, CH3 (CH2)11 OCOCH2 N(CH3)2 (O), and for a patch containing 582�24 mg indomethacin together with dodecyl alcohol ( ).
The long chain alkyl (N,N-disubstituted amino)acetates of the present invention may be described as "soft" dermal penetration enhancers since subsequent to exerting their desired effect, they "cleave" via chemical and/or enzymatic hydrolysis to release nontoxic by-products. Without being bound by any particular theory, it is believed that an active ingredient and a soft penetration enhancer are released from a topical formulation and the soft enhancer would then exert its penetration enhancing effect. The soft or biodegradable penetration enhancer, either during or after penetration, would be broken down by skin enzymes, e.g. esterases, into a long chain alkanol and a substituted amino acid. In this way, the toxicity of the soft penetration enhancer would be greatly reduced. The possible cleavage of the soft penetration enhancer is set forth below: ##STR14## Subcutaneous tissues also contain esterases, so the esters break down during and after incorporation, but before reaching the systemic circulation. The penetration enhancers of the invention may act like biodegradable surfactants in that, after they exert their penetration enhancing effects on drug transport from the topical dosage form, they will be fragmented into smaller compounds, thus reducing toxicity.
The alkanols and amino acids to which the present enhancers are initially converted by esterases may themselves act as strong enhancers. Alkanols are widely used moisturizers in the cosmetic field and are known to increase transport across the stratum corneum. However, they are weak in practical use, due to their slow incorporation into the stratum corneum. On the other hand, compounds with amino groups are rapidly incorporated into skin.
As noted earlier, the prior art absorption enhancers have significant pharmacological activities and toxicities. The compounds of the present invention, on the other hand, are a new class of enhancers which, because of their structure, do not demonstrate a significant adverse effect on the skin or mucous membranes and yet are excellent promoters of percutaneous absorption. The toxicity of known enhancers is generally due to the fact that they are not metabolized by pathways which would diminish their toxicity. To minimize toxicity, the basic structure of the synthesized enhancer should be selected to resemble those biological substances which are well-known metabolites. The enhancers of the present invention were specifically designed to be metabolized in a non-toxic fashion. Moreover, the present compounds are liquid so they can be readily incorporated into the skin.
The long chain alkyl (N,N-disubstituted amino)acetates and related compounds of the present invention have the formula: ##STR15## wherein R is hydrogen; C1 -C7 alkyl, benzyl or 4-hydroxybenzyl; n is a whole number from 4 to 19 inclusive, and R1 and R2 are independently selected from hydrogen and C1 -C7 alkyl, or R1 and R2 together with the nitrogen atom to which they are attached are combined to form a substituted or unsubstituted heterocycloalkyl radical having a total of 5 to 7 ring atoms, optionally including a hetero ring atom selected from oxygen, sulfur and nitrogen in addition to the indicated nitrogen atom, the substituents when present being one to three C1 -C7 alkyl radicals, which may be the same or different; and R3 and R4 are independently selected from hydrogen, methyl and ethyl.
The alkyl radicals may be straight or branched, i.e. methyl, ethyl, propyl, butyl, pentyl, hexyl and heptyl, and the branched chain groups isomeric therewith.
When R1 and R2 are combined with the adjacent nitrogen atom such that ##STR16## represents a heterocycloalkyl radical, illustrative such heterocycloalkyl radicals include morpholino, 1-pyrrolidinyl, perhydro-1,2,4-oxathiazin-4-yl, 1- or 4-piperazinyl, 4-methyl-l-piperazinyl, piperidino, hexamethyleneimino, 2-methyl-1-pyrazolidinyl, 1- or 2-pyrazolidinyl, 3-methyl-1-imidazolidinyl and 1- or 3-imidazolidinyl.
In preferred embodiments of the invention, the substituents in formula (I) have one or more of the following values:
(1) R is hydrogen:
(2) n is 6, 8, 10 or 12; and
(3) R1 and R2 are both methyl or both ethyl, or together with the adjacent nitrogen atom represent a 4-methyl-1-piperazinyl radical, i.e. a radical of the formula ##STR17##
(4) R3 and R4 are both hydrogen.
Particularly preferred compounds of the present invention include dodecyl (N,N-dimethylamino)acetate, decyl (N,N-dimethylamino)acetate and octyl (N,N-dimethylamino)acetate.
The compounds of formula (I) are readily prepared via a two-step synthesis. In the first step, long chain alkyl chloroacetates are prepared by reaction of the corresponding long chain alkanols with chloromethyl chloroformate or the like in the presence of an appropriate base such as triethylamine, typically in a suitable solvent such as chloroform. The reaction can be depicted as follows: ##STR18## wherein R, R3, R4 and n are as defined as above. The reaction temperature may be selected from about 10� C. to about 200� C. or reflux; however, room temperature is preferred. The use of a solvent is optional. If a solvent is used, a wide variety of organic solvents may be selected. Choice of a base likewise is not critical. Preferred bases include tertiary amines such as triethylamine, pyridine and the like. Reaction time generally extends from about one hour to three days.
In the second step, the long chain alkyl chloroacetate is condensed with an appropriate amine according to the scheme: ##STR19## wherein n, R, R1, R2, R3 and R4 are defined as before. Excess amine reactant is typically used as the base and the reaction is conveniently conducted in a suitable solvent such as ether. The reaction is preferably run at room temperature; however, other temperatures may be selected above or below room temperature, as in the first synthetic step. Again, reaction time usually varies from about one hour to several days.
The amount of the penetration enhancer of formula (I) which may be used in the present invention is an effective, non-toxic amount for enhancing absorption either through the skin or mucous membranes. Generally, this amount ranges from about 1 to about 95 weight percent of the topical composition. Preferably, about 0.5 to about 40 weight percent of the penetration enhancer is used in the composition.
The compounds described herein are useful in improving percutaneous or mucous membrane absorption of physiologically active agents. The term "percutaneous" means transdermal or transcutaneous; it denotes the passage of substances through unbroken skin. While the term "mucous membrane absorption" refers generally to any of the mucous membranes in the body, absorption through the mucous membranes of the oral cavity is of particular interest. Thus, buccal, sublingual, gingival and palatal absorption are specifically contemplated by the present invention. In a preferred embodiment, the instant penetration enhancers are used to improve absorption through those oral tissues which most resemble the skin in their cellular structure, i.e. the gingivae and palate. The term "physiologically active agent" is used herein to refer to a broad class of useful chemical and therapeutic agents including physiologically active steroids, antibiotics, antifungal agents, antibacterial agents, antineoplastic agents, analgesics and analgesic combinations, anorexics, anthelmintics, antiarthritics, antiasthia agents, anticonvulsants, antidepressants, antidiabetic agents, antidiarrheals, antihistamines, anti-inflammatory agents, antimigraine preparations, antimotion sickness preparations, antinauseants, antiparkinsonism drugs, antipruritics, antipsychotics, antipyretics, antispasmodics, including gastrointestinal and urinary; anticholinergics, sympathomimetics, xanthine derivatives, cardiovascular preparations including calcium channel blockers, betablockers, antiarrhythmics, antihypertensives, diuretics, vasodilators including general, coronary, peripheral and cerebral; central nervous system stimulants, cough and cold preparations, decongestants, hormones, hypnotics, immunosuppressives, muscle relaxants, parasympatholytics, parasympathomimetics, psychostimulants, sedatives, tranquilizers, allergens, antihistaminic agents, anti-inflammatory agents, physiologically active peptides and proteins, ultraviolet screening agents, perfumes, insect repellents, hair dyes, and the like. The term "physiologically active" in describing the agents contemplated herein is used in a broad sense to comprehend not only agents having a direct pharmacological effect on the host but also those having an indirect or observable effect which is useful in the medical arts, e.g. the coloring or opacifying of tissue for diagnostic purposes, the screening of U.V. radiation from the tissues and the like.
For instance, typical fungistatic and fungicidal agents include thiabendazole, chloroxine, amphotericin, candicidin, fungimycin, nystatin, chlordantoin, clotrimazole, ethonam nitrate, miconazole nitrate, pyrrolnitrin, salicylic acid, fezatione, ticlatone, tolnaftate, triacetin, zinc, pyrithione and sodium pyrithione.
Steroids include cortisone, cortodoxone, fluoracetonide, fludrocortisone, difluorsone diacetate, flurandrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and its esters, chloroprednisone, clorcortelone, descinolone, desonide, dexamethasone, dichlorisone, difluprednate, flucloronide, flumethasone, flunisolide, fluocinonide, flucortolone, fluoromethalone, fluperolone, fluprednisolone, meprednisone, methylmeprednisolone, paramethasone, prednisolone and prednisone.
Antibacterial agents include sulfonamides, penicillins, cephalosporins, penicillinase, erythromycins, lincomycins, vancomycins, tetracyclines, chloramphenicols, streptomycins, and the like. Specific examples of antibacterials include erythromycin, erythromycin ethyl carbonate, erythromycin estolate, erythromycin glucepate, erythromycin ethylsuccinate, erythromycin lactobionate, lincomycin, clindamycin, tetracycline, chlortetracycline, demeclocycline, doxycycline, methacycline, oxytetracycline, minocycline, and the like.
Peptides and proteins include, in particular, small to medium-sized peptides, e.g., insulin, vasopressin, oxytocin and human growth hormone.
Other agents include iododeoxyuridine, podophylline, theophylline, isoproterenol, triamicinolone acetonide, hydrocortisone, indomethacin, phenylbutazone paraaminobenzoic acid, aminoprionitrile and penicillamine.
The foregoing list is by no means intended to be exhaustive and any physiologically active agent may be applied by the method of the present invention.
An important advantage of the present invention is that absorption of polar bioactive agents as well as nonpolar drugs is also improved. The polar bioactive agents encompass a variety of therapeutic agents such as the xanthines, triamterene and theophylline, the antitumor agents, 5-fluorouridinedeoxyriboside, 6-mercaptopurinedeoxyriboside, vidarabine, the narcotic analgesics, hydromorphone, cyclazine, pentazocine, bupomorphine, the compounds containing organic anions, heparin, prostaglandins and prostaglandin-like compounds, cromolyn sodium, carbenoxolone, the polyhydroxylic compounds, dopamine, dobutamine, 1-dopa, α-methyldopa, the polypeptides, angiotensin antagonists, bradykinin, insulin, ACTH, enkaphaline, endorphin, somatostatin, secretin and miscellaneous compounds such as tetracyclines, tromocriptine, lidocaine, cimetidine or any related compounds. The quantity of these polar bioactive agents necessary for preparing the drug form could vary over a wide range, but would normally be regulated by that quantity necessary to comprise the therapeutically effective dosage form.
Agents normally applied as eye drops, ear drops or nose drops or into the membranes of the oral cavity are also more effective when applied along with the penetration enhancers of the present invention.
As indicated earlier, agents used in diagnosis may be used more effectively when applied dissolved in one of the vehicles of this invention. Patch tests to diagnose allergies may be effected promptly without scratching the skin or covering the area subjected to an allergen when the allergens are applied along with the enhancers of this invention.
This invention is also useful in topical application of cosmetic or esthetic agents. For example, compounds such as melanin-stimulating hormone (MSH) or dihydroxy acetone and the like are more effectively applied to skin to simulate a suntan when they are applied along with the enhancers of this invention. The agent is carried into the skin more quickly and in greater quantity when applied in accordance with this invention. Hair dyes also penetrate more completely and effectively when dissolved in one of the vehicles of this invention.
While the foregoing discussion describes the simultaneous administration of the physiologically active agent along with the penetration enhancer, the penetration enhancer may be applied before or after to the application of the physiologically active agent, if desired.
The physiologically active agents intended for use in the practice of the present invention are intended for either their systemic effect or for their local effect.
Dosage forms for topical application to the skin or mucous membranes of humans and animals include creams, lotions, gels, ointments, suppositories, sprays, for example nasal sprays, aerosols, buccal and sub-lingual tablets, gingival and buccal patches or any one of a variety of transdermal devices for use in the continuous administration of systemically active drugs by absorption through the skin, oral mucosa or other membranes, see for example, one or more of U.S. Pat. Nos. 3,598,122, 3,598,123, 3,731,683, 3,742,951, 3,814,097, 3,921,636, 3,971,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084, 4,069,307, 4,201,211, 4,230,105, 4,292,299 and 4,292,303 and U.S. Pat. No. 4,077,407. The foregoing patents also disclose a variety of specific systemically active agents which may also be useful in transdermal delivery, which disclosures are hereby incorporated herein by reference.
The usual pharmaceutical compounding agents, diluents or carriers may be included in these compositions as desirable for the particular route of administration and dosage form. The amount and type of diluent or carrier used should, of course, be consistent with the compatibility of the agent with the compound of this invention. For instance, a cosolvent or other standard adjuvant, such as a surfactant, may be necessary to maintain the agent in solution or suspension at the desired concentration.
For nasal sprays and other mucous membrane applications isotonic saline may be preferable as a diluent. The instant enhancer may be present in these forms in various concentrations, for example, from about 2% to about 75% by weight or higher.
Lotions and gels, ointments or creams, may contain the usual ingredients to provide a base, as for example cetyl alcohol, an emulsifier such as lauryl sulfate and water. Another base may be formulated by combining equal weight amounts of stearic acid, cetyl alcohol, triethanolamine and glycerol monostearate with water. Still other bases may utilize polyethylene glycols of different viscosities, depending upon the desired consistency.
A suppository form may be made from a high viscosity polyethylene glycol 4000, water and the penetration enhancer.
Typical inert carriers which may be included in the foregoing dosage forms include conventional formulating materials, such as, for example, water, acetone, isopropyl alcohol, freons, ethyl alcohol, polyvinyl pyrrolidone, propylene glycol, fragrances, gel-producing materials such as "Carbopol", mineral oil, stearyl alcohol, stearic acid, spermaceti, sorbitan monooleate, "Polysorbates", "Tweens", sorbital, methylcellulose, and the like. The compositions of the present invention are formulated with any suitable nontoxic pharmaceutically acceptable inert carrier material. Such carrier materials are well known to those skilled in the art of pharmaceutical formulations. For those not skill in the art, reference is made to the text entitled, "REMINGTON'S PHARMACEUTICAL SCIENCES," 17th edition, 1985, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton, Pa. 18042.
Any type of transdermal drug delivery system is also suitable in the practice of the present invention, for instance, the transdermal patch. A variety of transdermal drug delivery systems are disclosed and described in U.S. Pat. No. 4,624,665, herein incorporated by reference.
The amount of the composition, and thus of the physiologically active agent therein, to be administered will obviously be an effective amount for the desired result expected therefrom. This, of course, will be ascertained by the ordinary skill of the practitioner. Due to enhanced activity which is achieved, the dosage of the physiologically active agent may often be decreased from that generally applicable. In accordance with the usual prudent formulating practices, a dosage near the lower end of the useful range of the particular agent may be employed initially and the dosage increased as indicated from the observed response, as in the routine procedure of the physician.
The concentration of physiologically active agent in the various dosage forms is, of course, commensurate with that normally utilized for the particular agent in conventional formulations for effective results for the intended route. Both the amount of physiologically active agent and the amount of penetration enhancer will be influenced by the type of effect desired. To a certain degree, if a more localized effect is required, as for example, in treating a superficial infection with an antibacterial agent, lower amounts of physiologically active agents and lower concentrations of enhancer may be called for. Where deeper penetration is desired, as in the case of local anaesthesia, a higher concentration of enhancer may be desirable to promote adequate penetration. Where general systemic concentration of an agent is desired for a topical preparation, generally higher concentrations of enhancer are desirable and the amount of agent as, for example, a steroid, may be included in the composition sufficient to provide the blood level desired.
In order to further illustrate the present invention and the advantages thereof, the following specific examples are given, it being understood that same are intended only as illustrative and in nowise limitative.
A mixture of dodecanol (10 g, 0.054 mol), chloromethyl chloroformate (6 g, 0.05 mol) and triethylamine (5.5 g) in 40 ml of dry chloroform was stirred at room temperature for 16 hours. The reaction mixture was then washed twice with water (50 ml per washing) and the organic phase was dried over anhydrous magnesium sulfate. Removal of the solvent gave 13.3 g (94% yield) of liquid product, which was chromatographed through a column of Florisil using chloroform as the eluent. 1 HNMR(CCl4) δ0.90(3H, t, CH3); 1.28[20 H, s, broad, --(CH2)10 --]; 3.93(2H, s, --CH2 Cl); 4.11 (2H, t, J=6Hz, --CH2 --O). νmax (film): 2940, 2880(CH); 1765, 1745(C═O); 1180 (--C--O--C--)cm-1.
Dodecyl chloroacetate (5.5 g, 0.021 mol) was dissolved in 20 ml of ether and the resultant solution was cooled in an ice-bath. Dimethylamine (40 ml, 0.1 M in ether) was added to the cooled solution of dodecyl chloroacetate. The reaction mixture was stirred at room temperature for two hours, then filtered through a filter paper to remove the white solid which formed. The filtrate was concentrated to give a liquid product which was chromatographed through a column of silica gel (60-200 mesh) using ethyl acetate as the eluent. The purity of the fractions was checked by thin layer chromatography. The pure fractions were combined and the solvent was removed by a rotary evaporator under reduced pressure to afford 5.8 g (100% yield) of dodecyl (N,N-dimethylamino)acetate. 1 HNMR(CCl4) δ0.83(3H, t, CH3); 1.20[20 H, s, broad, --(CH2)10 ]; 2.23[6H, s, (CH3)2 N--]; 3.0 (2H, s, --CH2 --N); 3.93 (2H, t, J=6 Hz, --OCH2 --) νmax (film): 2940,2870,2790 (CH); 1760, 1740(C═O); 1200, 1170 (--C--O--C) cm-1. m/e 271; C16 H33 NO2 requires 271.
Following the general procedure of Example 2, a mixture of decyl chloroacetate (5 g, 0.021 mol) and 1-methylpiperazine (2 equivalents) in 20 ml of ether was stirred for one and one-half days. Work-up as in Example 2 gave 6 g of a liquid product (92% yield), which was chromatographed through a column of silica gel using ethyl acetate as the eluent. 1 HNMR(CCl4): 0.73(3H, t, CH3); 1.13[16H, s, broad, --(CH2)8 --]; 2.03 (3H, s, CH3 N--); 2.27(8H, multiplets, --NCH2 CH2 --); 2.91 (2H, s, --CH2 N--); 3.87(2H, t, J=6 Hz, OCH2). νmax (film): 2940, 2870, 2800, 2700 (CH); 1755 (C═O); 1170 (--C--O--C)cm-1. m/e 298; C17 H34 N2 O2 requires 298.
Alkyl chloroacetates were prepared in almost quantitative yields by reaction of chloromethyl chloroformate with n-alkanols in the presence of triethylamine, as in Example 1. The purification of these compounds is straight-forward, by column chromatography using silica gel as the supporting material and chloroform as the eluent. Yields are summarized in TABLE 1 below.
TABLE 1______________________________________ ##STR20## (II)Name of Compound R n R3 R4 Yield (%)______________________________________tetradecyl H 12 H H 85chloroacetatedodecyl chloroacetate H 10 H H 94decyl chloroacetate H 8 H H 100octyl chloroacetate H 6 H H 100______________________________________
The penetration enhancers of formula (I) were also prepared in high yield, as in Example 2, by condensation of the alkyl chloroacetates with excess amine. Purification is also simple due to the high yields and high Rf values on thin layer chromatography using ethyl acetate as the developing solvent. Because of their low ultraviolet absorption, the purity of the products was checked by thin layer chromatography, using Analtech HPTLC-GHLF tlc plates, ethyl acetate as the developing system and iodine vapor as the visualizing agent. Nuclear magnetic resonance, infrared and mass spectra were consistent with the assigned structures. Yields are summarized in Table 2 below:
TABLE 2__________________________________________________________________________ ##STR21## (I)Name of Compound R n NR1 R2 R3 R4 Yield (%)__________________________________________________________________________tetradecyl (N,N- H 12 N(CH3)2 H H 90dimethylamino)-acetatedodecyl (N,N- H 10 N(CH3)2 H H 100dimethylamino)-acetatedecyl (N,N- H 8 N(CH3)2 H H 91dimethylamino)-acetateoctyl (N,N- H 6 N(CH3)2 H H 72dimethylamino)-acetatedodecyl (N,N- H 10 N(C2 H5)2 H H 95diethylamino)-acetatedecyl (4-methyl- 1-piperazinyl)- acetate H 8 ##STR22## H H 96__________________________________________________________________________
Ointments were prepared by mixing 100 mg (1%) indomethancin, 500 mg (5%) penetration enhancer and 9400 mg (94%) petrolatum at 55�-60� C. to give a homogenous dispersion of indomethacin. In each transport study, 30 mg of ointment containing 300 g of indomethacin was applied.
Patches were prepared by first dissolving 300 mg indomethacin, 400 mg penetration enhancer, 300 mg polyethylene glycol 400 and 800 mg hydroxypropyl cellulose in 20 ml of ethanol. That viscous solution was spread on a backing layer, which was a film of ethoxycellulose, with 0.9 mm of thickness. After drying at 40� C. for one hour, two layer film patches were obtained. Circles with a diameter of 12 mm were used for the transport studies.
A whole shed snake skin from the molt of adult Elahe obsoleta (black rat snake) was obtained from the Animal Care Unit of the University of Kansas. Only the dorsal side of the shed snake skin was used for in vitro penetration studies. The head and tail sections of the snake skin was removed and the remainder of the skin was cut randomly into sections of approximately 2 inches by 2 inches. Each piece of snake skin was hydrated overnight by first soaking the skin in water (about 5 to 10 minutes) until it could be stretched and then placing it on a plastic pan which held some water. The pan was floated on a water-bath at 32� C. overnight.
For the transport studies using ointments, approximately 30 mg of ointment prepared as described in Example 5 was smeared evenly on an area of the 2"�2" snake skin. The ointment was smeared into an essentially circular area approximately 1.77 cm2 and having a diameter of approximately 15 mm. The snake skin was then mounted on top of the receptor cell of a vertical diffusion cell assembly in which a small magnetic bar was inserted and filled with an isotonic buffer. A rubber o-ring was placed on top of the skin followed by the placement of the donor cell. The two cells were clamped together and transferred to a water-bath (32� C.) which had several magnetic stirrers placed underneath to stir the contents of the diffusion cells. Samples from the cells were withdrawn periodically by gravity by inputting fresh isotonic buffer into the cell inlets. The first five drops were discarded and the following four drops were collected for analysis. These nine drops of sample solution were approximately equivalent to about 0.20 ml.
The samples were analyzed for the concentration of indomethacin using a Perkin-Elmer ISS-100 HPLC apparatus with a Perkin-Elmer LC90 UV spectrophotometric detector and a Perkin-Elmer ISS-100 automatic sampler with the detection wavelength set at 260 nm. The peak heights of the chromatograms were recorded on a Perkin-Elmer LCI-100 Laboratory Computing Integrator. A reverse phase column, RP-8 Spheri-5, 4.6�100 mm and a guard column OD-GU, purchased from Brownlee Labs, were used in conjunction with the HPLC system. The flow rate was 1.0 ml/min and the solvent system was a mixture of acetonitrile (50%) and a 0.01 M phosphate buffer (pH 3.0) (50%).
The concentration in each sample was interpreted from a standard curve which was obtained by plotting the peak areas obtained from HPL chromatograms versus four different standard solutions of indomethacin. The standard curves were linear over a range of concentrations from 2.5 to 10 g/ml. The receptor cell volume was calibrated by weighing the amount of water in the cell. The first sample needs no concentration correction. However, the concentration in the subsequent samples can be corrected by the following equation: ##EQU1## where Xi is number of microgram of indomethacin in the ith sample. Yi is the concentration correction for i-l sample. The volume withdrawn for each sampling is about 0.20 ml.
For the transport studies using patches, the same procedures were used as described above for the ointments, except that patches were prepared as described in Example 6 and the studies were performed using a new diffusion cell in which receptor medium was recirculated through the spectrophotometer to assay automatically at 265 nm.
Statistical analyses were performed using the Student's t-test.
Table 3 below summarizes the transdermal penetration results for representative enhancers of the invention in the ointment studies.
TABLE 3__________________________________________________________________________ ##STR23## (I) RelativeCompound Name of EnhancementNo. Compound R n NR1 R2 R3 R4 %__________________________________________________________________________1 tetradecyl H 12 N(CH3)2 H H 100 (N,N-dimethyl- amino)acetate2 dodecyl (N,N- H 10 N(CH3)2 H H 200 dimethyl- amino)acetate3 decyl (N,N- H 8 N(CH3)2 H H 380 dimethyl- amino)acetate4 octyl (N,N- H 6 N(CH3)2 H H 250 dimethyl- amino)acetate5 dodecyl (N,N- H 10 N(C2 H5)2 H H 70 diethyl- amino)acetate6 decyl (4- methyl-1- piperazinyl)- acetate H 8 ##STR24## H H 40__________________________________________________________________________
Relative penetration enhancements (%) were calculated by ##EQU2##
Azone was selected as the for comparison since it is claimed to excellent enhancer although it is too toxic; was assigned a value of 100% enhancement. It has reported by that the LD50 of Azone by intraperitoneal administration is approximately 232 mg/kg.
Penetration that was equal the penetration of Azone was reported as 100% rela penetration. All of the relative enhancements in Table 3 are based on the early stage or hours o penetration studies.
Results of the ointment studies are shown in FIGS. 1, 2 and 3. At least 3 or 4 cells were used for each enhancer and mean val (μg) of indomethacin in the receptor cells are plotted versus time in hours.
In FIG. 1, results are depicted for tests of ointments containing Azone () or one of three enhancers of the invention, namely compound No. 3 (O), Compound No. 1 (), and Compound No. 6(□). In FIG. 2, results are depicted for tests of ointments containing Azone (X) or one of three enhancers the invention, namely Compound No. 4 (O), Compound 3 () and Compound No. 5 (□). In FIG. 3, results are depicted for tests of ointments containing Azine (X) or a preferred enhancer of the inven Compound No. 2 (O), also referred to hereinbelo NDMA.
As can be seen from FIGS to 3, the new enhancers of the present invention show quick action and exhibit a leveling profile after 24 hours. The fact that the instant enhancers are several times better than Azone at the early time points suggests that the onset of these compounds is short, i.e. they exhibit quick action. This is particularly important in the preparation of topical formulations since one of the most important criteria for enhancers is to have quick action. In receptor cells in which ointments containing enhancers of the present invention were tested, as much as 25 μg of indomethacin were detected in the early stage of less than 12 hours. However, at the same stage, only a few μg of indomethacin were detected in the cells for which Azone was used as the enhancer. The final amounts of indomethacin which penetrated the snake skin in the presence of these enhancers was also high. As high as 117 μg of indomethacin was detected after 72 hours, representing about 40% of the total indomethacin incorporated into the petrolatum ointment.
The effect of Compound No. 2, or NDMA, in ointment on the transport of indomethacin compared with that of Azone is depicted in FIG. 3. The transport of indomethacin accelerated by NDMA was twice that accelerated by Azone during the first 24 hours. The percent of indomethacin across the membrane was 18.2�0.9% (n =4, p <0.01 versus Azone) for 24 hours and 34.1�2.1% (n=4, p<0.01 versus Azone) for 72 hours when NDMA was present in the ointment, while the values were 8.3�0.9% (n =4) for 24 hours and 26.4�1.8% (n =4) for 72 hours when Azone was present. The effect of NDMA appeared to be faster than that of Azone. In the absence of either adjuvant, the percent of indomethacin transported was less than 1% for 72 hours (n=4).
The effect of dodecyl (N,N-dimethylamino)-acetate (NDMA) on the transport of indomethacin from a film patch compared to the effect of dodecyl alcohol is shown in FIG. 4. The NDMA (o) patch contained 542�31 mg indomethacin, while the dodecyl alcohol patch contained 582�24 mg indomethacin. The transport of indomethacin enhanced by the presence of NDMA reached steady state flux at about 2 hours, while transport enhanced by dodecyl alcohol reached steady state at about 5 hours. The steady state flux for indomethacin was 3.84�0.57 μg/hour (n =4, p<0.01 versus dodecyl alcohol) in the presence of NDMA, which was 2.5 times greater than that in the presence of dodecyl alcohol (1.49�0.21 μg/hour, n =4).
Dodecyl (N,N-dimethylamino)acetate or NDMA (10% w/w) was dispersed in saline (0.85% NaCl in deionized boiled water) with 2% Tween 80. Seven male CF-1 white mice were injected subcutaneously (dorsal site) with the NDMA dispersion at a dose of 1 g/kg daily for seven days. Six control mice were injected with an equivalent volume of 2% Tween 80 saline solution daily for seven days. All mice survived after 14 days.
While the invention has been described in terms of various preferred embodiments, the skilled artisan will appreciate that various modifications, substitutions, omissions and changes may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the present invention be limited solely by the scope of the following claims.
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|U.S. Classification
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|International Classification
|Cooperative Classification
|European Classification
|Jul 20, 1988
Owner name: ODONTEX, INC., 2605 CONSTANT AVENUE, LAWRENCE, KAN
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|Jun 24, 1994
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text:
Omg i need help!!
by, August 11th, 2012 at 12:31 AM (651 Views)
My worst fears have came true. I am a week into phase 3 and I have gained 7 pounds. I am eating what I have been told to eat. I don't know what to do. I did a steak day and I still gained weight. I didn't cheat in P2....please I need help. I don't want to gain all this weight that I just worked really hard to lose. I am really sad and disappointed.

subset: commoncrawl


text:
The Lyptus test - TTJ magazine
How to install a deck
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What are the benefits of
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As well as the plus points of
using wood generally, sustainable timber has other benefits:
Wood is considered as carbon neutral because trees absorb carbon dioxide
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UK & Co. Limited,
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text:
United Plankton Pictures, Inc.
Motion picture films featuring comedy, motion picture films featuring drama; motion picture films featuring animation; pre-recorded videodiscs, pre-recorded audio tapes, and pre-recorded audio compact discs in the nature of a motion picture film featuring comedy, drama and animation; pre-recorded videodiscs and DVDs, pre-recorded video cassettes, pre-recorded audio tapes, and pre-recorded audio compact discs in the nature of a television serie...
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Entertainment services in the nature of an on-going television series featuring comedy; entertainment services in the nature of an animated television series; entertainment services in the nature of an on-going television series featuring drama; entertainment services in the nature of a series of motion picture films for theatrical release, television distribution and distribution to video rental outlets featuring comedy, animation and drama; ...
Perfect for these industries
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General News of Saturday, 25 January 2014
Source: XYZ
The Presidency has denied claims that former National Youth Employment Programme (NYEP) Coordinator, Abuga Pele, is being used as a scapegoat in the corruption controversy that has bedeviled the programme.
Mr Pele and the Chief Executive Officer of Goodwill International Group Philip Akpeena Assibit are standing trial at the fast track high court on 19 criminal charges related to fraudulent contracts awarded to some private firms by the programme.
Now christened Ghana Youth Employment and Entrepreneurial Development Agency (GYEEDA), the NYEP, which was designed to absorb teeming unemployment youth with temporary jobs, has been fraught with unbridled corruption.
Most of the contracts signed between GYEEDA and some private firms were recently cancelled by the Government.
Some of the firms have also been ordered to refund Ghc55 million to the state.
The Chairman of the main opposition New Patriotic Party, Jake Obetsebi-Lamptey has applauded the move to prosecute the former NYEP Coordinator but said Mr Pele must not be used as a scapegoat.
Presidential Staffer Dr Clement Apaak told Strict Proof on Radio XYZ that: "…To say that Abuga Pele and co are being used as sacrificial lambs quite clearly can't be given any authenticity until they come forward with information to suggest and support why such claims are being made".
He said: "Quite clearly the Criminal Investigations Department (CID), Economic and Organised Crimes Office (EOCO) and the Attorney General's Department have together looked at this and identified the individuals that they feel and believe that based on the evidence, should be brought forward for querying including prosecution; and Abuga Pele and others who are now before court, quite clearly will have the opportunity to present their side of the story".


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In this release…
The Trans-Pacific Partnership: Free Trade at What Costs?
The United States and eight other Asia-Pacific nations are engaged in top secret negotiations for the Trans-Pacific Partnership (TPP), hailed by the White House as a 21st century trade agreement. Although the pact will significantly benefit regional economic integration, the TPP will encompass far more than trade. Additional provisions address investment, intellectual property rights, and environmental protection among other topics. Beyond the leaked texts and vague statements, which makes it apparent that the TPP will rewrite domestic laws and uphold investor-to-state relations, few outside the negotiating room know any details of the agreement. Thus, the TPP presents a troubling case of free trade being purchased at too great a price.
This analysis was prepared by Eric Stadius and Elizabeth Briggs, Research Associates at the Council on Hemispheric Affairs.
To read full article, click


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Riverton spikers get Gillette to open state 4-A volleyball tourneyOct 30, 2013 By Craig Blumenshine, Staff Writer
The Riverton Lady Wolverines took last Sunday to put their two weekend regional tournament losses behind them and came to practice Monday ready to work. Now it's on the the state high school volleyball tournament in Casper with a Thursday first-round match against Gillette, the top seed from the Class 4-A East.
Game time is set for 2 p.m. at the Casper Events Center.
"By the time Monday came around, they were ready to go. They were hashing out game plans on what they need to do. It was fun to watch," RHS head coach Adrian McNamee said.
Riverton enters the tournament as the fourth seed from the Class 4-A West. Their first-round match is the first match of the tournament.
After the Riverton/Gillette match, Cheyenne Central (3E) plays Casper Kelly Walsh (2W), Evanston (3W) takes on Cheyenne East (2E), and Laramie (4E) will match up against Casper Natrona (1W).
If the Wolverines advance in the championship bracket, they will play the winner of the Cheyenne Central/Kelly Walsh match Friday at 4:30 p.m. A first-round loss will pit Riverton against the loser of the Central/KW match at 1 p.m. Friday.
"Number one, we have to serve them out of system. We have to make the move on serve-receive. We have to be able to block well and we can't give them free balls. We have to make them move defensively," McNamee said of her team's first-round match against the Lady Camels.
Gillette, the regular season Class 4-A East champion, won a thrilling five-set match against Cheyenne East after dominating Laramie 3-0 to claim the Class 4-A East tournament championship.
The Lady Wolverines finished second in the Class 4-A West regular season, but slipped to fourth place in their tournament with a 3-1 loss to Casper Natrona and a 3-1 loss to Evanston.
"There is more of a tendency at state to do more than you need to. I think everybody at state goes like, 'we want to go big and hard' and get everything. We'll see how our team does," McNamee said.


text: Has changed hands all the last 3 titles defenses and 4 of the last 5. Was thinking about it this AM --I initially thought it went back 4 fights but I momentarily forgot that Rampage did defend against Hendo. So then, Rampage loses to Forrest. Forrest's first title defense he loses to Rashad. Rashad's first title defense he loses to Machida. Has this ever happened before in the UFC? Or any of the other big orgs?


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Auburn's Malzahn set to face former team, Arkansas State
AUBURN, Ala. (AP) Gus Malzahn didn't spend much time at Arkansas State, just enough to win a quick Sun Belt Conference title and land a bigger job in the SEC.
The first-year Auburn coach and much of his staff will have a reunion with their old team Saturday night at Jordan-Hare Stadium, nine months after leaving Jonesboro. Malzahn is businesslike more than sentimental, but speaks fondly of a Red Wolves group he describes as "a lot of winners."
"Personally, I care greatly for a lot of their players," he said Tuesday. "Their administration was great to me while I was there. It was a very good experience, and I'm very grateful for the opportunity they gave me. Professionally, you've got to flip the switch and once the game starts, you do everything in your power to help your team win. And we'll definitely do that."
Maybe Arkansas State will have a little extra motivation. The Red Wolves have won two straight league titles only to lose their coach to the SEC West. First, Hugh Freeze, who stayed one year and was hired at Mississippi. Then, Malzahn, who returned to the school where he spent three seasons as offensive coordinator before taking his first college head coaching job with the Red Wolves.
His Arkansas State successor, Bryan Harsin, figures the relationship between his players and Malzahn and facing a Southeastern Conference team "are very hard to not think about."
"I think our guys will handle that," Harsin said. "They've been in some of those games, but I know that will be an emotional game."
Malzahn took offensive coordinator Rhett Lashlee, offensive line coach J.B. Grimes and most of his support staff with him to Auburn.
That familiarity means the offensive-minded Malzahn spent a little extra time with the defensive staff discussing Arkansas State's personnel.
Lashlee said he recruited a "handful" of players on Arkansas State's offense and one or two on defense. Now, they'll try to beat each other.
"I thought last year that we brought in a pretty good class at Arkansas State," Lashlee said. "Those guys are winners. They've won nine straight. They're going to come in here with the expectation of winning and we'll have to play a really good football game to beat them."
They're certainly familiar with Arkansas State tailback David Oku, who rushed for 16 touchdowns last season after transferring from Tennessee. Oku was one of four Arkansas State players to rush for 100-plus yards in the opener against Arkansas-Pine Bluff.
He's now on his fourth head coach in as many years, going back to Lane Kiffin and Derek Dooley at Tennessee. Oku said he signed with the Red Devils largely because he wanted to play in Malzahn's offense.
He said his initial reaction to the coach's departure was, "Oh no, not again."
"Who could possibly dream that up or even think that could happen to them?" said Oku, who was recruited by Auburn. "To me, it was crazy, and I wondered if I made the wrong decision.
"Coaches are going to do what's best for them, but It's helped me become a lot stronger today."
AP Sports Writer Kurt Voigt in Jonesboro, Ark., contributed to this report.


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can u tell me wer to download this map?
DuelTerror is right, but he did mod his recon is modded.
that guy works for bungie anyway, so i dont think he can get banned
Fallen Shadovv
I need to know where to get this! too ban its kinda bannable
Did you see the size of his nipples?
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Velour dash cover
Reviewed By Mike B (Ponchatoula, LA) Reviewed for a 2015 GMC Sierra —4/22/2017 5:23 AM
The velour dash cover,is flimsy. It fits ok, but you must secure tightly with the Velcro fasteners. If you don't want to use the Velcro,fasteners, then this is not the cover for,you.


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"Enjoy the win, but keep it in perspective," said Bronson basketball head coach Aaron Haldeman after his team after beating Newberry 50-34 this past Monday.
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Mace Windu's Attack Battallion Battle 5-PackSKU: 653569160854 Price: $79.99 Write a review | No reviews for this product.
In a stunning move, the Separatist droid army has descended upon Coruscant! Mace Windu leads a battalion of fearless clone troopers to battle the droids. Mace makes short work of the super battle droids as his battalion takes care of the leftovers with their powerful blaster rifles. Includes 3 Clone Troopers (with blaster rifles), Clone Commander (with removable helmet, blaster rifle and 2 pistols) and Mace Windu (with slashing lightsaber action).
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1 Person Hospitalized In Shooting, Arson Detectives Called
COLUMBUS, Ohio
One person was injured in a shooting on the west side of Columbus Thursday morning.
The shooting was reported around 9 a.m. on a home at the corner of Hayden and Cable avenues.
The female victim was transported from the scene with injuries. She did speak with detectives.
According to police, a fight broke out between two people and a man living in the home. One of the men fired a weapon which injured the female.
The two suspects also spread an accelerant in the home but did not try to set in on fire. Arson investigators were called to the scene.
The suspects then fled the scene.
The name of the victim has not been released.
Police did not say if a suspect was still at large.
©2017 by 10TV.com. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.


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Research Topics
Richard J Shaw
Affiliation: University of York
Country: UK
Detail Information
- Ethnic density effects on birth outcomes and maternal smoking during pregnancy in the US linked birth and infant death data setRichard J Shaw
Department of Health Sciences, University of York, Heslington, York, YO10 5DD, UK
Am J Public Health 100:707-13. 2010....
- The health benefits of Hispanic communities for non-Hispanic mothers and infants: another Hispanic paradoxRichard J Shaw
Department of Health Sciences, University of York, York, UK
Am J Public Health 103:1052-7. 2013..The contextual effects of Hispanic neighborhoods may partially explain this "Hispanic paradox." We investigated whether this benefit extends to other ethnic groups...
- Ethnic density effects on maternal and infant health in the Millennium Cohort StudyKate E Pickett
University of York, York, North Yorkshire, UK
Soc Sci Med 69:1476-83. 2009..For some measures of maternal health, in some ethnic groups, the psychosocial advantages of shared culture, social networks and social capital may override the adverse effects of material deprivation...


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Apparently one major construction project on campus wasn't enough to handle St. Ambrose's growth.
In late November, the university broke ground on a new residence hall, the third to be constructed or renovated in the past five years, that will be move-in ready at the start of the fall 2004 semester. The 140-bed facility will go a long way toward easing the strain on at-capacity residence halls and providing the upscale accommodations that attract and retain students.
With a nine-month construction period, "It will take a tremendous effort by the contractors and our university staff to get the building ready for students," says Stan Kabat, dean of students.
The additional residence hall will help enhance St. Ambrose's excellent reputation for the kind of high-quality student housing that had more than 88 percent of first-year students in 2003 requesting on-campus accommodations. Considering the increased competition for traditional-age students and the need to access those markets where the number of high school graduates is on the rise, particularly the Chicago area, "we have to have spaces for these students," says Jamie Loftus, vice president of enrollment management and student services.
At a cost of $5 million, the new co-ed hall will have double, suite-style rooms, with some single rooms for men, an option not currently available in existing halls. Bathrooms with showers will also be installed in each floor's lounge to accommodate short-term overflow housing as the need arises.
"The growth we're experiencing is a by-product of excellent recruiting and high student retention rates," says Loftus. "The faculty and staff who work so diligently on behalf of our students are the reason for our success."


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Qatar Airways increases frequency to newly launched Istanbul Sabiha Gökçen flights
- Published by Ozgur Tore
It has been three months Qatar Airways has launched flights to Istanbul Sabiha Gökçen Airport and now the carrier is responding to the increased demand for its services by increasing frequency.
Qatar Airways announced an addition of three weekly flights to Istanbul Sabiha Gökçen Airport making the route daily, commencing October 26, 2014. The non-stop four-flights-a-week service from Doha to Istanbul Sabiha Gökçen Airport was initially launched on May 22nd this year, marking Qatar Airways' expansion to its third route in Turkey.
The airline currently operates to three destinations in Turkey - Istanbul Sabiha Gökçen Airport (four-weekly-flights), Istanbul Ataturk Airport (10-flights-a-week) and Ankara (four-weekly-flights).
With the additional flights from Doha to Istanbul Sabiha Gökçen Airport on October 26, the number of flights to Istanbul rises from 14 to 17 frequencies each week.
Qatar Airways Group Chief Executive Officer, His Excellency Mr. Akbar Al Baker said: "Qatar Airways passengers looking to travel to Istanbul will have even more choice with further convenience and flexibility to their travel plans.
"The extra flights will also be a great boost for the travelling public from Istanbul to cities around the world."
Turkey's tourism industry has experienced a recent upward surge and Istanbul is growing commercially serving as a vital connecting hub between Asia and Europe.
Now, passengers to and from Istanbul will have better connections across a number of routes in the airline's extensive network of global destinations including popular destinations such as the UAE, Saudi Arabia, Bangkok, the Maldives, Bali, Singapore, Melbourne and Hong Kong.


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As millions of gallons of crude oil continue to flow into the Gulf of Mexico from the Deepwater Horizon catastrophe, the National Park Foundation is mounting a campaign to raise money to help national park units affected by the disaster.
So far the only impact the parks along the Gulf Coast -- Padre Island National Seashore, Gulf Islands National Seashore, Everglades National Park, Dry Tortugas National Park, De Soto National Memorial, Big Cypress National Preserve, and Biscayne National Park -- have reported are some tar balls coming ashore at one of the islands that make up Gulf Islands.
Still, with no end in sight to this disaster, the parks will truly be fortunate if no other impacts are reported. With that in mind, the National Park Foundation has launched a drive for its National Parks Disaster Recovery Fund.
The oil disaster in the Gulf of Mexico is affecting and threatening some of our most precious eco-systems, wildlife and landscapes – including our national parks. From Gulf Islands National Seashore to the Everglades, some of our beloved national parks are at risk.
You can help. Give to the "National Parks Disaster Recovery Fund" online or by texting "PARKS" to 90999 on your mobile phone by July 1st. Your money will go DIRECTLY to the parks impacted by the Gulf oil spill.*
Each year our national parks suffer devastating events. From floods to fires, hurricanes to tornadoes, earthquakes to oil spills, our national parks are vulnerable from catastrophes both natural and man-made. By giving to the National Park Foundation's "National Parks Disaster Recovery Fund" you can now support our parks when they need it most – providing immediate assistance, as well as helping in sustained recovery efforts.
This is your land. Help our national parks of the Gulf region, and all of our parks, in their moments of need.
* Funds raised between now and July 1st will go to National Park Service efforts in the Gulf Coast region including park enhancements, education and environmental monitoring. No funds will go towards mitigating BP's responsibilities.


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Friday night had been billed up to be one of the better games between two of the better teams, Pearl City, Hawaii and Manhattan Beach, CA in the 2013 Little League Western Regional Baseball Tournament, but Hawaii had other ideas to prove its worth as the best team in the tournament.
Hawaii demolished Manhattan Beach 14-4 in six innings at Jay Littleton Ballpark in Ontario behind a contagious offensive force and a fabulous pitching effort by Hawaii's starting pitcher Trestan Nakamura.
"The boys just believe in themselves and they trust in each other as they enjoy playing baseball," said Hawaii manager Alex Takemura. "We have a lot of depth, experience, and the kids really enjoy each other and bring out the best in each other."
Seven of the starting nine players in Hawaii's batting lineup produced RBI hits. Hawaii's big explosion was in the second when it batted around while scoring seven runs.
Chevy Sumile had an RBI triple to put Hawaii up 4-0 two batters into the second inning. The contagious hitting never seemed to halt. Following two walks, Matt Tsutomi hit a two-run single to bring in two runs to lead 6-0. Sanyo Lo helped out with an RBI double to knock out Manhattan Beach starter Adam Reinart.
Shaye Higa got into the hit parade as well with a deep two-run drive to make it 9-0. A couple of batters later a wild pitch brought in Hawaii's last run of the inning, making it 10-0.
Reinart lasted only one inning, allowing seven runs on four hits with five walks.
Just before Tsutomi's at-bat in the second inning, Manhattan Beach's manager Carlos Rojas was ejected from the game for arguing balls and strikes as he was coming off a mound visit to his pitcher.
"We all came together as a team and just stuck as one and just do what we do," said Tsutomi. "We just stay focused all game."


text: By GREGG BELL, AP Sports Writer September 26, 2006 KIRKLAND, Wash. (AP) -- Last month, Shaun Alexander sat in a golf cart, surveyed the empty field of Seahawks training camp and mused about his goals for this season. "How about we get 40 touchdowns?" the NFL record holder with 28 last season said with a straight face. "That'd be cool." Now, that'd be miraculous. Last year's league MVP has a broken left foot, and is out for at least a couple of weeks, perhaps more. He was on crutches Monday at team headquarters -- instead of the center of the Seahawks' game plan for Sunday night's showdown at fellow unbeaten Chicago. Seattle coach Mike Holmgren said Monday that a bone scan revealed Alexander sustained a "small crack" and "displaced fracture" on a non-weight-bearing foot bone sometime during the Seahawks' 42-30 win over the New York Giants on Sunday...(cont)


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VietNamNet Bridge – Many retail markets in HCM City are facing a sharp decrease in stall occupancy rates, causing financial problems for market managers.
Citizens shop at Binh Tay Market in HCM City's District 6. The number of vendors at HCM City's big traditional markets has decreased sharply. (Photo: VNS)
At Pham Van Hai Retail Market in Tan Binh District, for example, most stalls selling fresh food closed by 10am the other day, far earlier than normal. Market vendor Huynh Thanh Hai said she had sold only VND100,000 worth of vegetables.
The number of stalls in the market has fallen significantly, according to Nguyen Xuan Truong, head of the Pham Van Hai Market Managing Board.
In the market section C alone, the number has dropped from 200 to 20, Truong said.
The scenario is the same in Go Vap market in Go Vap District, Ba Chieu market in Binh Thanh District, Hoang Hoa Tham market in Tan Binh District and Binh Tay market in District 6.
At Go Vap Market, Nguyen Thi Huong was putting bunches of unsold vegetables in a bag, saying that she was going to give them to a nearby pagoda and charity house.
"There are very few customers coming into the market these days," Huong said. "Many stalls around me have been left empty since owners of these stalls stopped selling or shifted to selling other kinds of items because of few customers and high taxation."
According to figures from the Ba Chieu Market Management Board, the number of stalls that sell fresh food had fallen to 15 per cent of capacity, with the remaining 70 per cent unoccupied, since the beginning of the year. Owners of some of these stalls moved their businesses to areas outside of the market.
The Go Vap Market Managing Board also revealed that the purchasing power at the market fell by 40 per cent compared with last year.
Market management boards say more stalls are closing because of a rapid increase in wet markets (illegal street-based markets) outside the main markets, high taxation, and deterioriating facilities at traditional markets.
Tran Minh Phuong of the Ba Chieu Market Management Board said the wet market nearly encircles the main market because the former was favoured by many housekeepers as they did not have to leave their motorbikes while buying food.
"We have done many things to settle this wet market problem; however, it has not been very effective since streets around the market are under the control of people's committees of different wards," Phuong said.
"The market management board has many times worked with the district's examination teams and construction inspectors as well as the city's market management board to clear wet markets around Pham Van Hai Market," Xuan said.
However, violations continue even though the department has spent a great deal of money to carry out numerous inspections.
Currently, traders' selling power has fallen significantly in the main market because goods sold there are available at the outside markets.
"Sellers outside the main market are required to pay a small fee to the ward management board, which is much lower than the tax level being paid by traders in the main market," he said.
Many small traders as well as consumers are turning their face away from traditional markets also because of poor infrastructure. Many of the markets are dirty with old waste water drainage systems that cannot be used.
Other problems included unstable prices of goods and competition from an increasing number of supermarkets with modern equipment, which offered prices cheaper than in the traditional markets, market managers said.
According to the city's market development scheme, by 2015 authorised agencies plan to either relocate or clear at least 48 traditional markets. Those that are not on the list of relocation will be upgraded. The function of some ineffective markets will be changed, also.
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Inseparable Father and Son, 4, Die After Plunging Through Ice Into Frozen Lake
A father and young son who relatives call inseparable died on Monday after plunging through the ice of a frigid Michigan lake.
David Lyons, 30, and four-year-old Jackson Lyons were pulled from Alderman Lake in Highland Township after ice broke up beneath them while they were ice fishing, authorities say.
The father and son were rushed to a hospital while paramedics attempted to resuscitate them, but they were both soon pronounced dead.
Conflicting accounts put the time the two were in the frigid water from 3 or 4 minutes to as long as 35 minutes, reports CBS Detroit.
Highland Township Fire Chief Richard Cole said both father and son were wearing snow suits but not life jackets.
"Alderman Lake is a very deep lake, but they weren't far from shore, but when they went through they went through to about five or six feet of water — and the bottom of the lake in that area is nothing but muck," Cole said.
The problem, authorities say, is the wave of warmer temperatures that has affected much of the Midwest and East in recent days.
In a statement, Oakland County Sheriff Michael J. Bouchard called the tragedy a "horrific reminder that we should always hold safety first when we undertake water-related activities."
"No ice is safe ice especially due to the mild weather we have experienced this winter. Our thoughts are with the family during this unthinkable time," Bouchard said.
Lyons was reportedly engaged to Jackson's mother, who's now lost a son and a fiance.
A man who identified himself to the Detroit News as Jackson's grandfather said the father and son were joined at the hip.
"They liked to do things together," said the man. "Ice fishing, riding four wheelers. Anything together."
A friend of Lyons' who visited the lake to say his "goodbyes," also remembered them as close.
"He was actually a great father, he cut hair for a living and really looked out for his son…His kid meant the world to him. It's just heartbreaking," the friend told WWJ.


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BASEBALL: LaFayette rallies for first subregion win
The LaFayette Ramblers finally broke through with their first subregion victory of the season on Tuesday night and did so in dramatic fashion.
Down five runs headed into the bottom of the seventh inning, the Ramblers rallied to tie visiting Southeast Whitfield and force extras. The Raiders regained the lead with a run in the top of the eighth, but LaFayette pushed home two in the bottom of the frame for a 9-8 win.
LaFayette improved to 4-7 overall and 1-3 in subregion play, while Southeast fell to 3-9 and 0-4.
No other details on the game were available as of press time.
The two teams will battle in Game 2 of the series on Thursday in Dalton before the final game of the series Friday night back in LaFayette.
First pitch of both games is slated for 5:55 p.m.


text: Search Results Studies Variables Publications (1) Your query returned 1 citations. Sort by: Pub Date (newest) Title Recent Additions Author Clear All Pub. Year Citation 1. 2006 Joyner, K., Campa, M. How do adolescent relationships influence the quality of romantic and sexual relationships in young adulthood. Romance and Sex in Adolescence and Emerging Adulthood: Risks and Opportunities. Mahwah, NJ: Lawrence Erlbaum and Associates. Export Options: RIS EndNote XML Results 1 - 1


text: By MEGAN EDWARDST-G Staff WriterBlushing brides-to-be and their entourages armed themselves with a barrage of pamphlets, samples and information necessary to plan the perfect wedding at the fourth annual Ashland Bridal Expo Sunday.To a backdrop of a sunny autumn day, girls and their mothers, grandmothers, best friends, fiancs and even fathers walked throughout the Country Club of Ashland to see what local vendors have to offer for wedding planning.Some future brides chose to undergo free makeup applications, while others sampled food and sipped wine. A harpist, donned in a tuxedo, accompanied a flautist dressed in a ruffled purple gown, both providing background music to the event.Area resident Kendall Workman viewed a display for rental equipment, while her mother, Audrey Workman, and her future mother-in-law, Sarah Spray, stood close by. Workman, who got engaged to Dustin Spray over the Fourth of July weekend this year, is planning an outdoor wedding for October 2008 on Sprays farm in Mount Vernon, she said.Though the big day is in a couple years, Workman wanted to get a head start and knows some of the details already.Shes a girly-girl, said her mother, laughing.Some brides-to-be opt to take care of arrangements themselves. But Workman wanted to involve her mother and future mother-in-law.I figured theyve been through it before, she said.For the future brides who hadnt picked out what some consider the most important piece of a wedding the gown several fashion shows took place. From dresses with accessories such as fur wraps and traditional gowns to modern gowns with vibrant color accents and even shorter gowns, the fashion shows gave a wide range of options from which to choose. Brides-to-be whispered to their counterparts when a particular dress that caught their eye came on stage. A young girl modeling a flower girl dress strutted out on stage, turned and strutted back into place, as the audience laughed and clapped.Ashley Long, her fianc Ryan Echelberger and her friend, Nicole Smith, walked around the tent after having just arrived. The event gave Long a chance to see available services, though she said her upcoming wedding is pretty much planned.She already had it planned before we met, Echelberger said with a grin.She could get married tomorrow, added Smith. All I have to do is pick out my dress.Paul Martin stood back while his fiancee, Christina Berry, and her friend looked at flowers. The two Wooster residents, who were engaged one month ago, plan to get married in August or September 2007.I came out to give my opinions on dresses and flowers and to get acquainted with the whole situation, Martin said, watching his fiancee.While some brides would rather their grooms take a back seat to wedding planning, Berry wants her fianc to be involved, Martin said.I even asked if theres something I can do 100 percent, and she suggested centerpieces, Martin said, adding he also will have input on tuxedos.So far, the wedding planning process has gone smoothly, Martin said. It has been a telling experience of the cooperation between the bride-to-be and groom-to-be.Well be talking about something we like, and one will look at the other and say, I was thinking that exact same thing, Martin said.n Megan Edwards can be reached at 419-281-0581, ext. 239, or email@example.com.


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A Phone That Can't Be Hacked? Devices Keep Eyes Out4:46
So-called secure smartphones are touting their ability to keep out the prying eyes of governments and corporations. WSJ's Elizabeth Dwoskin discusses on digits. Photo: Boeing.
THOUSANDS of people are being left distraught, frightened and confused after receiving emails as part of a sick scam informing them they have been diagnosed with cancer.
The horrible hoax claims to be from the National Institute for Health and Care Excellence (NICE) — a real organisation that acts as an advisory service to the UK's National Health Service — with the subject line: "IMPORTANT: Blood analysis result".
Upon opening the email, which looks quite genuine, it states "we have revealed that white blood cells is very low and unfortunately we have a suspicion of cancer". It then advises you print off an attached document to take to your doctor, which is almost certainly a virus or Trojan intended to steal your personal data as soon as you open it.
While many easily identified the email as suspicious and chose not to open it, some who received the email actually went for tests. They used Twitter to describe the emotionally-wrenching event.
@NICEcomms Sitting here in tears. Waiting real cancer results and this email floored me. Please find out who is responsible and stop them.
— Frances Taylor (@Thordale) March 13, 2014
@NICEcomms just had blood test 2 hours ago and got the email. Thought this was the results, still shaking!!!
— John Walter (@Bigghit) March 13, 2014
@latentexistence Yep. I've had about 15 of these this morning. All with varying subject lines. And Tax requests. pic.twitter.com/Kz0uEMhEJ8
— Christine ⚧ Anderson (@TheBinaryGirl) March 13, 2014
NICE has denied any involvement in sending the emails and described the hoax as "sickening". It has been fielding concerns on Twitter and warned people of the false messages on its website.
It has also stated that the emails received by people awaiting blood results were a coincidence but some believe this could be a targeted email and highlights the possibility of a major security breach.
@emma_stimson Pure coincidence. The spammers seem to have sent thousands of these emails.
— NICE (@NICEcomms) March 13, 2014
As to who could be held responsible, it is still a mystery with the IP addresses linking to several cities all over the world, which indicates the culprit is using a proxy to hide their location.
Like parasites, computer hackers are constantly evolving ways to infect your system. This is just another in a line of disgusting attempts to manipulate you to fall into their trap.
Remember, always remain vigilant when it comes to online security and never open an email that looks suspicious.