text:
|Publication number
|Publication type
|Application number
|Publication date
|May 4, 1993
|Filing date
|Apr 22, 1991
|Priority date
|Apr 22, 1991
|Fee status
|Also published as
|Publication number
|Jeri D. Wright, Brian L. Barclay, David R. Swanson
|Original Assignee
|Alza Corporation
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (17), Referenced by (37), Classifications (8), Legal Events (4)
|External Links: USPTO, USPTO Assignment, Espacenet
The present invention pertains to a dosage form with improved drug delivery capabilities. More particularly, the dosage form comprises a first composition comprising a drug and a carboxymethylcellulose, and a second composition comprising a carboxymethylcellulose comprising a higher molecular weight then the carboxymethylcellulose in the first composition. The first and second compositions cooperate to deliver a maximum dose of drug with a minimum of residual drug left in the dosage form.
Controlled release dosage forms are increasingly important for delivering drugs to an animal for obtaining good therapy. The controlled release of drug by a dosage form indicates control is exercised over both the duration and the profile of a drug release program. Controlled release dosage forms provide many therapeutic advantages over conventional dosage forms. For example, one major and important advantage is the lessening of fluctuation in blood plasma drug concentrations. The pharmacologic basis for minimizing fluctuations in plasma level derives from three therapeutic principles. First, every drug has a therapeutic blood level that must be reached if the desired therapeutic benefit is to be achieved from the administered drug. Second, most drugs have blood plasma levels that define the limits above which side effects may appear, and this can be substantially avoided by the used of controlled release dosage forms. Third, the drug plasma concentration response for most drugs is proportional to the concentration administered, which dictates of the need for controlled release dosage forms. These pharmacologic principles indicate a need for keeping plasma concentrations within a therapeutic level, and accordingly, addresses the need for a controlled release dosage form to achieve the intended results.
The dosage form used for drug administration can influence the course of therapeutic activity by affecting the profile of drug concentration in the blood. For example, the blood level profile of a drug following administration by a prior art conventional dosage form is defined by an initial high peak, followed by a rapid decline, in both the slope and the duration of the drug The initial high peak typically substantially exceeds the therapeutic plasma concentration range and the level fluctuates in peaks and troughs above and below the desired therapeutic level. In contrast, controlled release dosage forms can minimize the fluctuations known to the prior art, minimize or even avoid the peaks in blood level concentration and the following valley in blood level concentrations A controlled dosage form can extend also the duration of therapeutic index levels over time.
In view of the above presentation it is immediately evident a pressing need exists for a controlled release dosage form for administering a therapeutically-important drug, such as a calcium channel blocking drug to a patient in need of calcium channel blocking therapy The expression "calcium channel blocking drugs" also are known as calcium channel blockers, calcium channel antagonist, or calcium antagonists. The calcium channel blockers possess broad pharmacological use and they exhibit pronounced properties such as long-lasting vasodilating effects accompanied by an energy-sparing effect on cardiac metabolism, antiarrhythmic and antianginal action on cardiac muscle, vascular spasmolytic action, antihypertensive action, spasmolytic action on smooth muscle of the gastrointestinal and urogenital tracts and the cerebrovascular and respiratory system, useful for antihypercholesterolemic action, protection of the ischemic myocardium, inhibition of irritable bowel syndrome and esophagal spasm, inhibition of migraine, inhibit vascular calcium contraction, reduce cardiac contractile force, inhibit calcium mediated tracheal contraction, inhibit calcium uptake in primary cells, myocardial ischemia and hypertension. The calcium antagonist drugs that possess these therapeutic properties and can be administered by the dosage form and the method of the invention comprise a member selected from the group consisting of verapamil, nifedipine, diltiazem, bepridil, nicardipine, nitredipine, isradipine, niludepine, nisoldipine, felodipine, cinnarizine, flunarizine, perhexiline, amlodipine, or as their pharmaceutically acceptable salts or as their pharmaceutically acceptable derivatives. The pharmaceutically acceptable salts are acid addition salts of non-toxic pharmaceutically acceptable acids. The acids include inorganic acids and organic acids, and consequently, the salt can be an inorganic or organic salt. The pharmaceutically acceptable salts for the purpose of this invention consist of a member selected from the group consisting of inorganic, hydrochloric, hydrobromic, hydriodic, phosphoric, sulfuric, nitric, and the like, organic, trifluoroacetic, trichloroacetic, acetic, glycolic, pamoic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, mandelic, benzoic, cinnamic, methane sulfonic, ethane sulfonic, salicylic, p-toluenesulfonic or cyclohexanesulfamic. The pharmaceutically acceptable derivatives include alkyl substituted and ester derivatives. The drugs are known to the medical art in USAN and the USP Dictionary of Drug Names, 1961-1990 Cumulative List, published 1990 by United States Pharmacopeial Convention, Inc.; and in Physician's Desk Reference, 45 Ed. 1991, published by Medical Economy Company, Inc.
Dosage forms manufactured as osmotic devices for delivering a drug to an environment of use are known to the prior art in U.S. Pat. No. 3,845,770 issued to Felix Theeuwes and Takeru Higuchi and in U.S. Pat. No. 3,916,899, issued to the same patentees. The osmotic devices disclosed in those patents comprise a semipermeable wall that surrounds a compartment containing a drug. The wall is permeable to the passage of an external fluid, and substantially impermeable to the passage of drug. There is a passageway through the wall for delivering the drug from the device. These devices release drug by fluid being imbibed through the wall into the compartment at a rate determined by the permeability of the wall and the osmotic pressure gradient across the wall to produce an aqueous solution containing drug that is dispensed through the passageway from the device. These devices are effective for delivering a drug in an aqueous solution but often they do not contemplate delivering substantially all of the drug present in a thixotropic pharmaceutically acceptable carrier.
A pioneer advancement in osmotic delivery devices was presented to the art by inventor Felix Theeuwes in U.S. Pat. No. 4,111,202. In this patent, the delivery kinetics of the device are enhanced, for delivering drugs with degrees of solubility in aqueous fluids that are difficult to deliver, such as very soluble or insoluble in the fluid, by manufacturing the device with a drug compartment and an osmagent compartment separated by a film, which film is movable from a rested or essentially straight position to a curved position. The device delivers drugs by fluid being imbibed through the wall into the osmagent compartment producing a solution that causes the compartment to increase in volume and act as a driving force that is applied against the film. This force urges the film to expand against the drug compartment and correspondingly diminish the volume of this compartment, whereby drug is dispensed through the passageway from the device. While this device operates successfully for its intended use, and while it can deliver numerous difficult to deliver drugs, its use can be limited because of the manufacturing steps needed for fabricating and placing the movable film in the device.
In U.S. Pat. No. 4,327,725 patentees Cortese and Theeuwes provided an osmotic dispensing device for delivering beneficial drugs that, because of their solubilities in aqueous and biological fluids, are difficult to deliver in meaningful amounts at controlled rates over time. The osmotic devices of this patent U.S. Pat. No. 4,327,725 comprise a semipermeable wall surrounding a compartment containing a beneficial drug that is insoluble to very soluble in aqueous and biological fluids. The device also contains an expandable hydrogel. In operation, the hydrogel expands in the presence of external fluid that is imbibed into the device and pushes an aqueous drug solution through the passageway from the device. This device operates successfully for its intended use, and it delivers many difficult to deliver beneficial drugs for their intended purpose. However, it has been observed, its use often can be limited because the hydrogel can lack a present ability to imbibe sufficient fluid for the maximum self-expansion needed for pushing all beneficial drugs from the device.
In U.S. Pat. No. 4,765,989 and in U.S. Pat. No. 4,783,337, both patents issued to patentees Wong, Barclay, Deters and Theeuwes, there is provided a novel delivery device for delivering a drug to a patient in need of therapy. The delivery device in these patents comprise a wall permeable to fluid and impermeable to the passage of fluid. An exit port in the wall connects a drug in the compartment with the exterior of the delivery device. The device comprises a first and second composition comprising a mixture of methylcellulose, agar and carboxymethylcellulose or a mixture of hydroxypropylmethylcellulose and sodium carboxymethylcellulose. The patents do not teach regulating and controlling the thixotropic behavior of the composition for delivering substantially all of the drug and concomitantly the release rate behavior characteristics of the delivery device.
The prior art in U.S. Pat. No. 4,816,263 issued to Ayer, Swanson and Kuczynski; in U.S. Pat. No. 4,837,111 issued to Deters, Wong, Barclay, Theeuwes and Swanson; in U.S. Pat. No. 4,859,470 issued to Guittard, Wong, Theeuwes and Cortese; in U.S. Pat. No. 4,863,456 issued to Stephens and Wong; in U.S. Pat. No. 4,902,514 issued to Barclay, Wong, Wright and Childers; in U.S. Pat. No. 4,946,687 issued to Ayer, Swanson and Kuczynski; in U.S. Pat. No. 4,948,593 issued to Wright, Childers, Barclay, Wong and Atkinson; in U.S. Pat. No. 4,950,486 issued to Ayer, Swanson and Kuczynski; and in U.S. Pat. No. 4,966,769 issued to Guittard, Wong, Theeuwes and Cortese, the patentees disclosed delivery devices comprising a composition comprising a drug and a composition comprising a polymer for pushing the drug from the device, however, these patents do not teach two different molecular weight polymers operating together to avoid residual drugs in the device at the end of the drug delivery period. The prior art devices of the above patents are effective for their intended purpose, but they do not teach a unique difference and an accompanying cooperating relationship between two compositions comprising dissimilar polymers for controlled drug delivery over time.
It will be appreciated by those versed in the drug delivery art, that if a delivery device is provided that comprises different internal compositions that exhibit a high level of hydrodynamic and osmotic activity for delivery a drug at a controlled rate for therapy, such a delivery device would have a positive value and represent an advancement in the delivery art. Likewise, it will be immediately appreciated by those versed in the dispensing art that if a delivery device is made available possessing thermodynamic activity for delivering controlled doses of a drug, such a dispensing device would find a practical application in pharmacy and in medicine. Now, it has been found that delivery devices can be enhanced by using different hydrogel polymers for providing maximum self-delivery of drug and maximum self-expansion of the polymer for urging substantially all of the drug from the device.
Accordingly, in view of above presentation, it is an immediate object of this invention to provide a dosage form manufactured as a drug delivery device for providing an advancement over the prior art.
Another object of the invention is to provide a dosage form manufactured as a delivery device comprising a first composition and a different second composition for delivering essentially all of a drug to a patient over time.
Another object of the invention is to provide a dosage form comprising a first composition comprising a drug and a selected cellulose polymer and a second composition comprising a different selected cellulosic polymer from the polymer in the first composition for improving the delivery characteristics of the dosage form.
Another object of the invention is to provide a dosage form comprising two separate compositions with each composition comprising a different molecular weight polymer for delivering a drug at a controlled rate over a prolonged period of time from 30 minutes to 24 hours.
Another object of the invention is to provide a dosage form for delivering in vivo a calcium channel blocking drug that can be delivered from the device by using two different polymers for good therapy.
Another object of the invention is to provide a dosage form that embraces an osmotic structure possessing two compositions that operate as an integrated unit, which dosage form comprises a first osmotic composition comprising a drug and an osmopolymer, and a second composition comprising a different osmopolymer, which first and second compositions act in concert for hydrodynamically and osmotically delivering the drug from the osmotic dosage form.
Another object of the invention is to provide an osmotic dosage form having means for high loading of from 10 nanograms to 750 milligrams of a water soluble or a water insoluble calcium channel blocking drug for delivering the drug by the interaction to two compositions comprising different polymers for delivering the drug at a controlled rate and continuously over time to a drug recipient.
Another object of the invention is to provide an osmotic dosage form comprising a first composition comprising an osmopolymer and a second composition comprising a different osmopolymer which osmopolymers generate distinct osmotic activities independent of the other osmopolymer, but both cooperating to deliver the drug from the device.
Another object of the invention is to provide an osmotic dosage form that can administer a complete pharmaceutical dosage regimen for delivering a calcium channel blocking drug at a controlled rate and continuously for a given time period, the use of which requires intervention only for initiation and possible termination of the therapeutic regimen.
Another object of this invention is to provide an osmotic dosage form which can house a calcium channel blocking drug and dispense the drug in small doses per hour average at a controlled rate to the gastrointestinal tract throughout the length of the gastrointestinal tract following oral administration of the dosage form.
Another object of the invention is to provide an osmotic dosage form manufactured with a compartment comprising a first polymer composition and a second different polymer composition in contacting arrangement that simultaneously maintain their original identity and function as an integrated compositional layers for delivering a drug from the dosage form.
Another object of the invention is to provide a dosage form comprising osmopolymers manufactured free-of-irradiation such as gamma rays, thereby eliminating any potentially dangerous source or irradiation from the dosage form and from a patient.
Another object of the invention is to provide a dosage form free of poly(alkylene oxide) for administering a drug to a recipient in need of controlled drug therapy.
Another object of the invention is to provide an osmotic dosage form comprising osmopolymers made free-of-radiation for enhancing the acceptance of the dosage form by a patient and by a physician.
In the drawing figures, which are not drawn to scale, but are set forth to illustrate various embodiments of the invention, the drawing figures are as follows:
Drawing FIG. 1 is a view of an osmotic dosage form sized, shaped and adapted for oral administration into the gastrointestinal tract of a patient in need of drug therapy;
Drawing FIG. 2 is an opened view of the osmotic dosage form of drawing FIG. 1 with part of the wall of the dosage form removed for illustrating the structure of the dosage form;
Drawing FIG. 3 is a graph that depicts the cumulative amount of drug delivered by the dosage form over time.
In the drawings and in the specification like parts in related figures are identified by like parts. The terms appearing earlier in the specification and in the description of the drawings, as well as embodiments thereof, are further detailed elsewhere in the disclosure.
Turning now to the drawing figures in detail, which drawing figures are an example of the dosage form provided by the invention and which example is not to be considered as limiting, one example of an osmotic dosage form is illustrate in drawing FIG. 1 and in drawing FIG. 2.
In drawing FIG. 1, an osmotic dosage form is seen designated by the numeral 10. Dosage form 10 comprises a body member 11 comprising a wall 12 that surrounds and defines an internal compartment, not visible in drawing FIG. 1. Dosage form 10 comprises at least one passageway 13 that connects the interior of dosage form 10 with the exterior biological environment of use.
In drawing FIG. 2, osmotic dosage form 10 is seen in opened view at 14 for illustrating the internal structure of dosage form 10. In drawing FIG. 2, dosage form 10 comprises a body 11 and wall 12. Wall 12 surrounds, forms and defines an internal compartment 15. Wall 12 comprises one passageway 13, or optionally, more than one exit passageway, for dispensing a drug 16 (represented by dots) from compartment 15 of dosage form 10. Drug 16 is defined herein, comprises any drug that can be delivered from dosage form 10 to produce a therapeutic useful result in a patient. In the present application, the term "drug" includes any physiologically or pharmacologically active substance that produces a local or a systemic effect in animals, including warm-blooded mammals, including humans. The drugs that can be delivered by dosage form 10 comprise drugs that are insoluble to highly soluble in aqueous fluids including biological fluids. In one presently preferred embodiment drug 16 comprises a calcium channel blocking drug.
Wall 12 of dosage form 10 comprises a composition that is permeable to the passage of an exterior fluid present in a biological environment of use, and it is substantially impermeable to the passage of drug 16, its salts or its derivatives, and to other ingredients in compartment 15. Wall 12 is substantially inert, nontoxic and it maintains its physical and chemical integrity during the drug dispensing life of dosage form 10. The phrase, "maintains its physical and chemical integrity" means wall 12 does not lose its physical structure during the dispensing life of dosage form 10. Wall 12, in one presently preferred embodiment, comprises a member selected from the group consisting of a cellulose ester, a cellulose ether, or a cellulose ester-ether. In a more presently preferred embodiment, wall 12 comprises a member selected from the group consisting of a cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, and cellulose triacetate. The cellulose polymeric members comprising wall 12 comprise cellulose acetate having a degree of substitution up to 1 and an acetyl content up to 21%, a cellulose diacetate having a degree of substitution of 1 to 2 and an acetyl content of 21% to 35%, a cellulose triacetate having a degree of substitution of 2 to 3 and an acetyl content of 35% to 44%. The amount of a cellulosic polymer present in wall 12 of dosage form 10 is from 85 weight percent (wt %) to 100 wt %. The cellulosic polymers are known to the art in U.S. Pat. Nos. 3,845,770; 3,816,899; 4,859,470; and 4,863,456; and in Handbook of Common Polymers, by J. R. Scott and W. J. Roff, (1971) published by CRC Press Inc., Cleveland, Ohio. Wall 12 comprises optionally, a flux enhancer, such as a polyethylene glycol that aids in governing fluid flux through semipermeable wall 12. The flux enhancer polyethylene glycol comprises a molecular weight range of 1500 to 7500. The concentration of polyethylene glycol in wall 12, optionally, comprises from 1 wt % to 15 wt %, with the total concentration of the ingredients comprising wall 12 equal to 100 wt %.
Compartment 15, in a drug composition, also identified as a first composition, comprises 20 wt % to 98 wt % of an alkali carboxymethylcellulose ether 17, identified by a wavy line, blended with drug 16. The present invention unexpectedly discovered a carboxymethylcellulose ether 17, or its nontoxic alkali salt, can be used as a thixotropic transport means for drug 16. The amount of drug 16 present in compartment 15 is 2 wt % to 45 wt %. The carboxymethylcellulose ether 17, includes sodium or potassium carboxymethylcellulose, and it possesses an initial gel flow-resistant strength. The carboxymethylcellulose 17 comprising drug 16 on contact by aqueous fluid imbibed into dosage form 10 transforms into a dispensable, thixotropic transport aqueous drug formulation. This dispensable drug formulation, in the presence of a separate osmotic-push force generated in dosage form 10, is subjected to a shear stress applied to the formulation resulting in the formulation being pushed through exit port 13 over 24 hours. The alkali carboxymethylcellulose 17, operable for transporting drug 16 comprises a degree of polymerization of 20 to 1,200, a 10,000 to 300,000 molecular weight and a viscosity of 25 to 1750 cps, centipoises, in a 2% aqueous solution at 25� C. The drug formulation in a preferred manufacture comprises 0 to 40% polyvinylpyrrolidone 18, represented by a vertical line, and comprising a 15,000 to 75,000 molecular weight, from 0 to 40 wt % hydroxypropylcellulose 19, represented by a slant line, comprising a 20,000 to 80,000 molecular weight, and from 0 to 5 wt % of a lubricant such as magnesium stearate, calcium stearate, or stearic acid, with the weight of all ingredients comprising the drug formulation, or the first composition, equal to 100 wt %.
Dosage form 10, in compartment 15, comprises a push formulation 20. Push formulation 20, also identified as a second composition, when dosage form 10 is in operation imbibes a fluid, expands and then pushes the drug composition through exit 13 from dosage form 10. Push composition 20 comprises 6.5 wt % to 100 wt % of a carboxymethylcellulose 21 comprising a greater than 300,000 to 1,200,000 molecular weight and a degree of polymerization of greater than 1,200 to 4,500. Push composition in a preferred manufacture comprises from 0 wt % to 25 wt % of an osmagent 22, represented by circles, selected from the group consisting of an osmotically active salt, an osmotically active carbohydrate, osmotically active polysaccharide, an osmotically active oxide, or an osmotically active acid solute, from 0 wt % to 25 wt % hydroxypropylmethylcellulose 23, represented by a square, comprising a 9,200 to 20,000 molecular weight, from 0 to 5 wt % lubricant comprising magnesium stearate, stearic acid, or calcium stearate, and 0 to 3 wt % ferric oxide, with the weight of all ingredients in push formulation equal to 100 wt %.
The expression, "exit passageway 13," comprises means and methods suitable for dispensing the beneficial drug 16 from dosage form 10. The exit means includes one passageway, or more than one passageway, that passes through wall 12 for communicating drug 16 in compartment 15 with the exterior of dosage form 10. The expression, "one passageway," includes aperture, orifice, bore, pore, porous element through which drug 16 can be dispensed, a hollow fiber, capillary tube, microporous insert, or microporous overlay. Thus, a wall that is in part microporous is optional with the invention. The expression includes a material that erodes or is leached from wall 12 int he fluid environment of use to produce one passageway, or more than one passageway, of controlled exit releasing dimensions. Representative materials suitable for forming at least one passageway, two passageways, or more, include an erodible poly(glycolic) or poly(lactic) acid member in the wall, a gelatinous filament, poly(vinyl alcohol), leachable materials such as fluid removable pore formers providing exit pores of release rate controlling properties. A passageway or a plurality of passageways can be formed by leaching a material such as sorbitol, mannitol or sodium chloride from the wall. The passageway can have any shape such as round, triangular, square, elliptical, or irregular. The dosage form can be constructed with one or more passageways in a spaced apart relation or a single surface or on more than more distant surfaces of a dosage form. Passageways and equipment for forming passageways are disclosed in U.S. Pat. Nos. 3,916,899; 4,063,064 and 4,088,864. Representative passageways formed by governed leaching of a fluid leachable composition to produce a pore of controlled release rate size are disclosed in U.S. Pat. No. 4,200,098.
Dosage form 10 is manufactured by standard techniques. For example, in one manufacture a drug and the other ingredients comprising the drug formulation are homogeneously blended and pressed into a solid formulation. The pressed formulation possesses dimensions that correspond to the internal dimension of the area occupied by the drug formulation in the dosage form 10. The drug formulation also possesses dimensions corresponding to the dimensions of the push formulation for forming a contacting surface arrangement therewith. In this manufacture, the drug and the other ingredients comprising the compositions are blended with a solvent and mixed into a solid or semisolid form by conventional methods such as ballmilling, calendering, stirring or rollmilling and then pressed into a preselected shape. Next, the push composition is placed in contact with the drug composition. The drug composition, push composition can be placed in contacting arrangement by using a conventional two-layered press. The contacting drug composition and push composition are coated with a semipermeable wall. The wall can be applied by compression coating, molding, spraying, dipping, or air suspension procedures. The air suspension and the air tumbling procedures comprise suspending and tumbling the pressed drug composition and the push composition in a current of air containing the wall forming composition. The dosage forms provided by the invention can embrace many shapes for administering a drug. The dosage form, for example, can be round-shaped, square-shaped, oval-shaped, bean-shaped, or caplet-shaped. The dosage form can be manufactured for sublingual administration, buccal administration or gastrointestinal administration.
In another manufacture, dosage form 10 is manufactured by the wet granulation technique. In the wet granulation technique, the drug and the ingredients comprising the drug composition are blended using an organic cosolvent, such as isopropyl alcohol-methylene dichloride 80/20 v/v (volume/volume) as the granulation fluid. The ingredients forming the drug composition are passed through a 40 mesh screen and thoroughly blended in a mixer. Other optional ingredients comprising the drug composition are dissolved in a portion of the granulation fluid and added to the drug blend with continual mixing in the blender. The granulating fluid is added until a blend is produced, which wet blend is then forced through a 20 mesh screen onto oven trays. The blend is dried for 18 to 24 hours at 50� C. in a forced air oven. The dried granules are then sized through a 20 mesh screen. Next, a lubricant such as magnesium stearate, which has been passed through an 80 mesh screen, is added to the drug screened granules and blended in a V-blender for 5 to 10 minutes. The composition is pressed into a layer, for example, in a 3-station Manesty� layer press. The speed of the press is set at 30 rpm and the maximum load set at 2 tons. The drug layer is pressed against the push composition and the bi-layer, drug-push core fed to a coating machine.
Another manufacturing process that can be used for providing the drug composition, push composition comprises blending the powdered ingredients comprising the drug composition, or the push composition separately in a fluid bed granulator. After the powdered ingredients are dry blended in the granulator, a granulating fluid, for example, poly(vinylpyrrolidone) in water, is sprayed onto the powders. The coated powders then are dried in the granulator. This process granulates all the ingredients present therein while adding the granulating fluid. After the granules are dried, a lubricant, such as stearic acid or magnesium stearate, is added to the granules in a V-blender and blended 5 to 10 minutes. The granules then are pressed in the manner described above.
The following examples are merely illustrative of the present invention and they should not be considered as limiting the scope of the invention in any way as these examples and other equivalents thereof will become apparent to those versed in the art in the light of the present disclosure, the drawings and the accompanying claims.
An osmotic dosage form for the controlled and continuous release of the drug nifedipine, and antianginal drug belonging to the pharmacological drugs called the calcium channel blockers, that inhibits the transmembrane influx of calcium ions into cardiac muscles and smooth muscles is made as follows: first, 200 g of nifedipine, 300 g of hydroxypropylcellulose, possessing a 60,000 molecular weight, 295 g of sodium carboxymethylcellulose, possessing a 90,000 molecular weight and 100 g of polyvinylpyrrolidone possessing a 40,000 molecular weight are blended into a mass and then screened through a 40-mesh screen. Then, the screened composition is placed into a Glatt fluid bed granulator, blended and slightly warmed to 35� C. to yield a homogeneous mass. Next, a granulating solution consisting of 100 g of polyvinylpyrrolidone possessing a 40,000 molecular weight in 400 ml of purified water is sprayed onto the fluidized powders.
After initiation of the spraying cycle, the process is monitored to insure formation of acceptable uniformity. The granules are dried in situ and delumped by screening through a 16-mesh screen. Next, 5 g of magnesium stearate is screened through an 80 mesh screen, added to the granules in the blender, and blended to a uniform composition. The composition produced by this process comprised 20 wt % nifedipine, 30 wt % hydroxypropylcellulose, 29.5 wt % of sodium carboxymethylcellulose, 20 wt % of polyvinylpyrrolidone and 0.5 wt % of magnesium stearate. The composition is divided into a drug formulation for making dosage forms wherein the drug formulation comprises 60 mg of nifedipine, 90 mg of hydroxypropylcellulose, 88.5 mg of sodium carboxymethylcellulose, 60 mg of polyvinylpyrrolidone and 1.5 mg of magnesium stearate.
Next, a push formulation is made in an identical manner. First, 788 g of sodium carboxymethylcellulose comprising a 700,000 molecular weight, 10 g of ferric oxide, and 50 g of polyvinylpyrrolidone comprising a 40,000 molecular weight, are screened through a 40-mesh screen, followed by screening 100 g of sodium chloride through a 60 mesh screen. The two screened materials are blended and warmed to 30� C. in a fluid bed granulator. Next, a granulating solution comprising 50 g of polyvinylpyrrolidone comprising a 40,000 molecular weight in 400 ml of distilled water, is sprayed onto the granules. Next, the granules are blended and added to a fluid bed granulator. A granulating solution of 50 g polyvinylpyrrolidone of 40,000 molecular weight in distilled water is coated onto the granules as prepared in the fluidized bed. Then, the granules are dried in situ and delumped by screening through a 16-mesh screen. Then, two grams of magnesium stearate are screened through an 80 mesh screen, and added to the granules in a blender and blended at moderate blending speed for 7 minutes. The composition formed by this process comprises 78.8 wt % sodium carboxymethylcellulose comprising a 700,000 molecular weight, 10 wt % of sodium chloride, 10 wt % of polyvinylpyrrolidone comprising a 40,000 molecular weight, 1.0 wt % ferric oxide, and 0.2 wt % of magnesium stearate. The same composition, divided into a push composition for forming the second composition in a dosage form comprises, expressed in mg as follows: 118.2 mg sodium carboxymethylcellulose comprising a 700,000 molecular weight, 15 mg of sodium chloride, 15 mg of polyvinylpyrrolidone having a 40,000 molecular weight, 1.5 mg of ferric oxide, and 0.3 mg of magnesium stearate.
The drug composition and the push composition, next are fed to a bilayer tablet press and pressed into a bilayer core. Then, a wall forming composition comprising 90 wt % cellulose acetate comprising a 39.8% acetyl content, and 10 wt % polyethylene glycol comprising a 3350 molecular weight, are dissolved in a 90 wt % methylene chloride and 10 wt % methanol cosolvent and is coated around the bilayer cores in a suspension coater. Then, a 25 mil, 0.650 mm, orifice is laser drilled in the center of the wall facing the drug side. Next, the delivery devices are dried in a humidity oven to remove any residual solvent. The devices are overcoated with an inert coat to enhance their appearance.
The delivery system provided by the present invention uses a carboxymethylcellulose in the drug formulation; and a different and higher molecular weight carboxymethylcellulose in the push formulation. The use of two different molecular weight carboxymethylcellulose polymers provides an unexpected result over the prior art. That is, in the prior art U.S. Pat. No. 4,783,337, a composition prepared according to the patent, comprising a drug and a 200,000 molecular weight polymer, resulted in a residual drug concentration in the dosage form in excess of 11.1%; also a dosage form provided by the prior art comprising a drug and a 300,000 molecular weight polymer leaves a residual concentration of 14.7% drug in the dosage form. The present invention unexpectedly found that a dosage form comprising two different molecular weight carboxymethylcellulose with the higher molecular weight carboxymethylcellulose in the push formulation exhibited as little as 3.7% residual drug in the dosage form at the end of the drug delivery period. This invention's improvement in drug delivery is unforseen and it enhances significantly the use of the present dosage form for improved drug therapy. With the present dosage form, both the physician and the patient know the patient is receiving substantially the intended prescribed dose of drug for drug therapy. The accompanying drawing FIG. 3 denotes the total concentration of a drug, exemplified by nifedipine, delivered over time.
A formulation for administering a drug to a patient according to claim 1, wherein the formulation comprises a dose amount of an orally administrable drug, a hydroxypropylcellulose, a polyvinylpyrrolidone and a carboxymethylcellulose of 10,000 to 300,000 molecular weight.
A formulation for administering a drug to a patient according to claim 1, wherein the formulating comprises a dose amount of nifedipine, hydroxypropylcellulose, polyvinylpyrrolidone and carboxymethylcellulose, comprising a 10,000 to 300,000 molecular weight.
A dosage form for orally administering a drug to a patient is provided according to claim 1, wherein the drug nifedipine is replaced by a member selected from the group consisting of verapamil, diltiazem, bepridil, nicardipine, nitredipine, isradipine, niludepine, nisoldipine, felodipine, cinnarizine, flunarizine, perhexiline, and amlodipine, and wherein the patient is in need of a calcium channel blocking therapy.
A dosage form for delivering diltiazem is made as follows: first 9.40 kg of diltiazem hydrochloride, 0.20 kg of sodium carboxymethylcellulose comprising a 200,000 molecular weight, 0.10 kg of hydroxypropylcellulose comprising a 30,000 molecular weight are added to a blender and blended for 15 minutes to produce a uniform blend. Next, 0.20 kg of polyvinylpyrrolidone having a 38,000 molecular weight is mixed with 350 ml of anhydrous ethyl alcohol to form a granulation fluid. Then, the granulation fluid is added slowly to the blended ingredients, and all the ingredients blended to produce a wet mass. The wet mass is dried in a forced air oven for 17 to 23 hours at room temperature, about 25� C., to evaporate the ethyl alcohol. Then, the dry granules are given an additional drying for 2 to 4 hours at 50� C. The dry granules are then passed through a 30 mesh screen. Next, 0.10 kg of the lubricant magnesium stearate is added to the drug blend and blended for 9 minutes to produce a homogeneous composition.
Next, a push composition is made as follows: first, 4.35 kg of sodium carboxymethylcellulose having a 650,000 molecular weight, 0.35 kg of sodium chloride and 0.25 kg of hydroxypropylmethylcellulose having a 11,200 molecular weight are blended for 10 minutes to yield a uniform blend. Next, 350 ml of denatured anhydrous ethyl alcohol is added as a granulating fluid to yield a wet mass. Next, the granulated wet mass is passed through a 30 mesh screen to form wet granules. The wet granules next are spread onto trays, and the wet granules dried at room temperature of 25� C. for 20 to 25 hours. The dry granules then are passed through a 20 mesh screen. The push composition now is ready for manufacturing into the final device.
The granules comprising the diltiazem are transferred to the number one feed inlet of a hopper and the granules comprising the push composition are fed to the number two feed inlet of a hopper. The feed hoppers are placed onto a bi-layer press and the diltiazem composition pressed onto the push composition.
Next, the pressed compositions are surrounded with a semipermeable wall. The wall forming composition is prepared as follows: first, a cosolvent is prepared by mixing 80 parts of methylene chloride with 20 parts of methanol (wt/wt) and cellulose acetate having an acetyl content of 39.8% is slowly added thereto. Then, polyethylene glycol having a 3350 molecular weight is added to the freshly prepared ingredients. Then, the pressed dual compositions are placed in a coating unit, and the pressed dual compositions coated with a semipermeable wall.
Next, the wall coated compositions are removed from the coater and an exit port of 24 mil, 0.609 mm, is drilled through the wall by a laser. The dosage forms are dried in a humidity oven at 50% relative humidity at 50� C. for 48 hours to remove wall traces of residual solvent. The dosage forms are sized and shaped for oral admittance into the gastrointestinal tract of a human. The controlled release dosage forms provided by this manufacture comprises a dose of 360 mg of diltiazem that is delivered for a prolonged period of up to 24 hours.
The above procedures are followed in this example to provide (a) sustained-release, oral osmotic caplets comprising 40 mg, 80 mg, 120 mg, 240 mg or 480 mg of verapamil pharmaceutically acceptable salt; (b) sustained-release, oral osmotic caplets comprising 30 mg, 60 mg, 90 mg, 120 mg, 240 mg or 480 mg of diltiazem pharmaceutically acceptable salt; or (c) extended-release, oral osmotic caplets comprising 20 mg, 30 mg, 45 mg, 60 mg, 90 mg or 120 mg of nifedipine for the relaxation and prevention of coronary artery spasm, for reduction of oxygen requirement and for the reduction of arterial blood pressure.
The above procedures are followed in this example to provide a dosage form wherein the drug composition comprises the drug nitredipine, polyvinylpyrrolidone, sodium carboxymethylcellulose, comprising a 70,000 molecular weight, sodium lauryl sulphate and hydroxypropylcellulose.
The above procedure is followed in this example, with the added H embodiment comprising blending from 0.1 wt % to 15 wt % of vitamin B2, also known as riboflavin, with the drug nifedipine for imparting protection against the adverse effects of light on nifedipine, and also blending a surface active agent with the nifedipine to enhance the fluidic dispensing properties of the drug formulation from the dosage form. The surface active agent, operable for the intended purpose, consists of a member selected from the group consisting of anionic, cationic, and nonionic surface active agents, exemplified by Pluronics, Cremophors, polyoxyalkylene fatty acid esters, polyoxyalkylene fatty acid ethers, and alkoxylated hydrogenated castor oils. The surface active agent is present in a concentration of from 0.01 wt % to 15 wt % with the concentration of all ingredients in the formulation equal to 100 wt %.
This example pertains to a method for delivering a drug to a human patient in need of therapy, which method comprises:
(A) admitting orally into the human a dosage form comprising:
(1) a wall comprising at least in part a semipermeable composition, said wall surrounding, defining and forming a compartment, which compartment comprises:
(a) a drug composition comprising from 10 ng to 750 mg of drug, 20 to 98 wt % of a carboxymethylcellulose comprising a 10,000 to 300,000 molecular weight, 0 to 40 wt % of a hydroxypropylcellulose comprising a 15,000 to 75,000 molecular weight, 0 to 40 wt % of a polyvinylpyrrolidone comprising a 20,000 to 40,000 molecular weight, and 0 to 5 wt % of a lubricant;
(b) a push composition comprising from 65 wt % to 100 wt % of a carboxymethylcellulose comprising a molecular weight greater than 300,000 to 1,200,000, and from 0 to 25 wt % of an osmagent, and from 0 to 25 wt % of a polyvinylpyrrolidone comprising a 20,000 to 40,000 molecular weight;
(2) a passageway in the wall for delivering the drug from the device; and,
(B) delivering the drug from the dosage form by imbibing fluid from the patient into the compartment to form a dispensable drug composition and to form an expanding push composition for pushing the drug through the passageway to the human in need of drug therapy.
In summary, it will be appreciated the present invention contributes to the drug delivery art an unobvious dosage form that possesses practical medical utility. While the invention has been described and pointed out in detail with reference to operative embodiments thereof, it will be understood that those skilled in the art will appreciate that various changes, modifications, substitutions and omissions can be made without departing from the spirit of the invention. It is intended, therefore, that the invention embraces those equivalents within the scope of the claims.
|Cited Patent
|Filing date
|Publication date
|Jun 5, 1972
|Nov 5, 1974
|Alza Corp
|Osmatic dispensing device for releasing beneficial agent
|Feb 7, 1974
|Nov 4, 1975
|Alza Corp
|Osmotic dispensing device with maximum and minimum sizes for the passageway
|Nov 22, 1976
|Sep 5, 1978
|Alza Corporation
|Osmotic system for the controlled and delivery of agent over time
|Nov 25, 1980
|May 4, 1982
|Alza Corporation
|Osmotic device with hydrogel driving member
|Jun 23, 1986
|Jan 5, 1988
|Alza Corporation
|Dosage system and method of using same
|Sep 2, 1986
|Aug 23, 1988
|Alza Corporation
|Osmotic device for administering certain drugs
|Sep 29, 1986
|Nov 8, 1988
|Alza Corporation
|Osmotic system comprising plurality of members for dispensing drug
|Oct 2, 1987
|Mar 28, 1989
|Alza Corporation
|Dosage form for treating cardiovascular diseases comprising isradipine
|Mar 21, 1988
|Jun 6, 1989
|Alza Corporation
|Dosage form for dispensing drug for human therapy
|Jun 2, 1988
|Aug 22, 1989
|Alza Corporation
|Dosage form for delivering diltiazem
|Feb 8, 1988
|Sep 5, 1989
|Alza Corporation
|Dosage form with improved delivery capability
|Jul 21, 1988
|Feb 20, 1990
|Alza Corporation
|Dosage form for administering nilvadipine for treating cardiovascular symptoms
|Jan 25, 1988
|Feb 27, 1990
|Alza Corporation
|Delivery of drug to colon by oral disage form
|Nov 7, 1988
|Aug 7, 1990
|Alza Corporation
|Dosage form for treating cardiovascular diseases
|May 15, 1989
|Aug 14, 1990
|Alza Corporation
|Osmotic dosage form comprising an estrogen and a progestogen
|Nov 7, 1988
|Aug 21, 1990
|Alza Corporation
|Dosage form for treating cardiovascular diseases
|May 11, 1989
|Oct 30, 1990
|Alza Corporation
|Method for delivering dosage form for diltiazem
|Citing Patent
|Filing date
|Publication date
|Jan 31, 1997
|Nov 17, 1998
|Andrx Pharmaceuticals, Inc.
|Once daily pharmaceutical tablet having a unitary core
|Jan 31, 1997
|Jul 13, 1999
|Andrx Pharmaceuticals, Inc.
|Once daily calcium channel blocker tablet having a delayed release core
|Feb 12, 1999
|May 1, 2001
|Alza Corporation
|Anti-asthma therapy
|Dec 12, 1997
|Nov 26, 2002
|Andrx Pharmaceuticals, Inc.
|Once daily pharmaceutical tablet having a unitary core
|Jul 20, 1998
|Feb 25, 2003
|Andrx Pharmaceuticals, Inc.
|Diltiazem controlled release formulation and method of manufacture
|Dec 20, 2000
|May 31, 2005
|Pfizer Inc
|Hydrogel-driven layered drug dosage form
|Jul 6, 2004
|Feb 26, 2008
|Durect Corporation
|Osmotically-driven fluid dispenser
|Aug 5, 2005
|Aug 5, 2008
|Pettegrew Jay W
|Compounds, compositions and methods for treating neuropsychiatric disorders
|Aug 23, 2005
|Apr 20, 2010
|Pettegrew Jay W
|Method and system for diagnosis of neuropsychiatric disorders including chronic alcoholism
|Jan 28, 2003
|Jun 15, 2010
|Janssen Pharmaceutica Nv
|System for delaying drug delivery up to seven hours
|Dec 29, 2005
|Aug 14, 2012
|Osmotica Kereskedelmi �s Szolg�ltat� KFT
|Dual controlled release osmotic device
|Feb 15, 2006
|Dec 11, 2012
|Osmotica Kereskedelmi Es Szolgaltato Kft
|Dual controlled release dosage form
|Sep 24, 2012
|Nov 26, 2013
|Osmotica Kereskedelmi �s Szolg�ltat� KFT
|Dual controlled release dosage form
|Oct 19, 2009
|Jan 14, 2014
|Alza Corporation
|Methods and devices for providing prolonged drug therapy
|Aug 13, 2012
|Nov 25, 2014
|Jay W. Pettegrew
|Method and system for differential diagnosis of chronic schizophrenia and chronic alcoholism
|Feb 8, 2013
|Nov 25, 2014
|Accelerate Diagnostics, Inc.
|Sensitive and rapid determination of antimicrobial susceptibility
|Mar 13, 2013
|Sep 29, 2015
|Alza Corporation
|Methods and devices for providing prolonged drug therapy
|Mar 7, 2012
|Sep 6, 2016
|Accelerate Diagnostics, Inc.
|Rapid cell purification systems
|Mar 15, 2013
|May 23, 2017
|Accelerate Diagnostics, Inc.
|Rapid microbial detection and antimicrobial susceptibility testing
|Mar 13, 2014
|Jun 13, 2017
|Accelerate Diagnostics, Inc.
|Rapid determination of microbial growth and antimicrobial susceptibility
|Jan 21, 2016
|Jul 25, 2017
|Accelerate Diagnostics, Inc.
|Rapid cell purification systems
|Nov 6, 2001
|Oct 2, 2003
|Vergez Juan A.
|Pharmaceutical compositions containing oxybutynin
|Jan 28, 2003
|Nov 20, 2003
|Frank Jao
|System for delaying drug delivery up to seven hours
|Jun 27, 2002
|Jan 8, 2004
|Cheng Xiu Xiu
|Controlled release oral dosage form
|Feb 7, 2003
|Jan 15, 2004
|Sigma-Tau Industrie Farmaceutiche Riunite S.P.A.
|Carnitine in the treatment of depression
|Apr 27, 2005
|Dec 8, 2005
|Pettegrew Jay W
|Methor for use of acetyl-L-carnitine (ALCAR) for treatment of depressive disorders in humans
|Dec 29, 2005
|Aug 10, 2006
|Vergez Juan A
|Dual controlled release osmotic device
|Aug 7, 2006
|Nov 30, 2006
|Jan Buch
|Therapeutic combination
|Nov 13, 2006
|Apr 17, 2008
|Ocean Star International, Inc.
|Controlled release drug compositions and preparation methods
|Dec 5, 2006
|Apr 24, 2008
|Ocean Star International, Inc.
|Nifedipine controlled release compositions and preparation methods therefor
|Oct 10, 2007
|Oct 9, 2008
|Wong Patrick S L
|Osmotically-driven fluid dispenser
|Jul 23, 2009
|Jan 14, 2010
|Pettegrew Jay W
|Method and system for diagnosis of neuropsychiatric disorders including attention deficit hyperactivity disorder (adhd), autism, and schizophrenia
|Oct 19, 2009
|Apr 15, 2010
|Gupta Suneel K
|Methods and devices for providing prolonged drug therapy
|Feb 26, 1999
|Sep 10, 1999
|Alza Corporation
|Anti-asthma therapy
|Nov 15, 2011
|May 31, 2012
|Transcept Pharmaceuticals, Inc.
|Compositions and methods for once-daily administration of a trilayer osmotic tablet
|Mar 7, 2012
|Sep 13, 2012
|Accelr8 Technology Corporation
|Rapid cell purification systems
|Dec 8, 2014
|Jun 11, 2015
|Durect Corporation
|Compositions comprising antioxidant, fluid dispensers, and methods involving the same
|U.S. Classification
|424/473, 424/486, 424/472
|International Classification
|Cooperative Classification
|European Classification
|Apr 22, 1991
Owner name: ALZA CORPORATION
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:WRIGHT, JERI D.;BARCLAY, BRIAN L.;SWANSON, DAVID R.;REEL/FRAME:005708/0487
Effective date: 19910417
|Sep 30, 1996
|Fee payment
Year of fee payment: 4
|Nov 3, 2000
|Fee payment
Year of fee payment: 8
|Oct 26, 2004
|Fee payment
Year of fee payment: 12


text:
Mudslinger stole hearts when he auditioned for "America's Got Talent" back in June. After raising the American flag, sinking a golf putt and dribbling a soccer ball through cones to score a goal, this 7-year-old pot-bellied pig closed out his act with a kiss from Heidi Klum.
Now he's here in Washington with his co-star Digger, a 6-year-old pot-bellied pig, to perform these stunts and more all five days of the Washington Town and Country Fair.
The Top Hogs show will be set up in the Family Fun Center area of the fairgrounds. There will be two 30-minute shows on Wednesday (5 and 7 p.m.), Thursday (2 and 4:30 p.m.) and Friday (3:30 and 6 p.m.), and three 30-minute shows each on Saturday and Sunday (2, 4 and 6 p.m. both days).
Trainer John Vincent, who has spent the last 22 years teaching hogs to perform tricks, said his Top Hogs show is always a crowd-pleaser, in large part because people don't expect pigs to be able to do these kinds of things.
But actually, pot-bellied pigs are quite trainable and very intelligent, he said.
"They are the Einsteins of porcine," Vincent remarked, "the rocket scientists of animals. They are excellent problem solvers, so they're fun to train."
Vincent knows something about rocket scientists — he is one. He may train pot-bellied pigs to do silly tricks for entertainment, but his day job is being an aerospace engineer with Lockheed Martin. He's currently working on the Orion project for NASA that will replace the Space Shuttle program.
Vincent uses positive reinforcement to train his pigs, the same operant conditioning used by B.F. Skinner.
Some of the tricks they can do are sitting up and shaking hands, playing dead, getting mail out of a mailbox, even doing impressions. Their repertoire includes Stevie Wonder, Elvis and Michael Jackson, said Vincent.
Vincent's interest in training pigs goes back to the 1990s, when pot-bellied pigs were becoming popular as pets.
At first it was a curiosity to him, but after meeting one he was won over by its affection and decided to bring it home as a pet. When he noticed how clever the pig was, he thought it would be fun to teach it some tricks.
Now Vincent takes his Top Hogs show on the road year-round, mostly around Colorado, where he lives, but once or twice a year he takes them to fairs.
In addition to "America's Got Talent," Vincent's Top Hogs have been featured on "The Tonight Show" with Jay Leno, "Late Night With David Letterman," several Animal Planet shows and "Pet Star" with Mario Lopez.
He transports them in a van that is equipped with a bed for himself behind the driver's seat.
"They are extremely good travelers," said Vincent, noting he has a USDA license. "They will sleep most of the time."
And while the stereotype is that pigs are messy animals, Vincent said the pot-bellied variety are very clean.
They also don't like mud to get cool. If the fairgrounds get too hot this week, Vincent said he will have a small pool available to keep them comfortable.
In addition to entertaining people, the Top Hogs show also wants to educate people about the animals.
"We like to show how smart these pigs are, what they can do," said Vincent.
"But I also love watching people just enjoy seeing the pigs do their tricks. Our show is a lot of fun.
"We pride ourselves on making it truly family entertainment."
The judges on "America's Got Talent" were impressed by Mudslinger's stunts. All four of them voted to send him on to the next level of competition.
"They get 10,000 people who try to get on the show each year, and 300 people get to audition before the judges," said Vincent. "The judges pick 150 to move on and then they cut it in half again for the next round."
Mudslinger was able to win them over doing just three tricks for his 90 seconds on camera.
Washington Town and Country Fair goers will get to see the full range of stunts over the next five days.
To get a preview of the Top Hogs in action, people can visit www.tophogs.com to see their videos.

subset: commoncrawl


text:
Each month, Rated People connects over 50,000 homeowners with quality tradesmen - simply enter your job details in the form above to get started.
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After the work is complete, return to the site and rate your tradesman based on their quality of work, reliability and value for money.
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"Top Marks To Coronary Care Unit at RCH Treliske"
About: Royal Cornwall Hospital (Treliske) Royal Cornwall Hospital (Treliske) Truro TR1 3LJ
Posted by Robert Toogood
I spent 10 days in the Coronary Care Unit at Royal Cornwall Hospital Treliske from 20th-30 May 2013 prior to heart surgery necessarily conducted elsewhere. I can only echo the comments expressed by Mr Peter Jackson (21st January 2014) concerning his experience of the Coronary Care Unit. In my case all of the doctors, nurses and support staff in the CCU were wonderful, their professionalism, caring and cheerful attitudes were outstanding and made my stay quite memorable. I was treated with dignity and respect at all times and my test results were readily explained to me. The food service was also good and I looked forward to mealtimes. The ward itself was always clean and cheerful and the teamwork particularly amongst the always busy nurses was very evident and a pleasure to see. From a patient perspective the ward appeared to be well managed and I was more than happy with my stay there. I cannot speak highly enough of my experience of this ward. I would have no hesitation in recommending it and would like to say again a big Thank You to all the staff for all they did for me. I would also like to thank the Cardiology team who conducted my stress test for their professionalism and their timely input.
Response from Royal Cornwall Hospital (Treliske) 3 years ago
Many thanks for your comments. It's always a great boost for teams to receive such positive feedback and we'll make sure your thoughts are passed on.
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This step is elective but will dramatically enhance your chances of your profile getting read by other members. Let people know a bit about yourself, your interests and upload any nice photographs of yourself.
Use our website's cutting-edge search to discover members who match your criteria. Or just browse through listings and discover people that take your fancy.
Found someone who could be interesting? Send them a word or two or just a wink and see if anything happens. With a little luck you'll be on your way to an amazing adventure.
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text:
The UK would need almost 50,000 more nurses and 26,500 more doctors to match standards in the rest of the developed world, according to new figures.
Experts said the quality of care in the UK is "poor to mediocre" across several key health areas, while obesity levels are "dire" and the NHS struggles to get even the "basics" right.
A new report from the Organisation for Economic Co-operation and Development (OECD) compared the quality of healthcare across 34 countries.
It found the UK lags behind in key areas, including coming 21st out of 23 countries on cervical cancer survival, 20th out of 23 countries on breast and bowel cancer survival and 19th out of 31 countries on stroke.
On heart attack deaths, the UK is ranked 20th out of 32 countries. While survival after hospital admission for heart attack and stroke is improving, it is "worse than many other OECD countries", including Canada, Italy, the Netherlands and Spain, the study said.
The UK is also a "middling to low performer" on three out of four key health areas, including quality of care and life expectancy, and there is a need for "urgent attention" to tackle the UK's high rates of smoking, harmful alcohol consumption and obesity.
Some 19% of adults in the OECD are obese on average, but the figure in the UK is 25%.
Spending on health is also lower in the UK than the OECD average, with "zero growth in health spending per person in real terms between 2009 and 2013", the report said.
Countries that spend more include France, Canada, Belgium, Germany, New Zealand and Denmark.
The UK also has a lower than average number of doctors and nurses.
Nigel Edwards, chief executive of the think tank the Nuffield Trust, who helped launch the report at a meeting in central London, said thousands more doctors and nurses were needed to even match the OECD average on staffing.
The UK would need 47,700 more nurses and 26,500 more doctors to match the OECD average, he said.
This would cost an extra £5 billion a year.
The OECD average number of nurses is 9.1 per 1,000 population, while the figure in the UK is 8.2.
The UK also lags behind on numbers of doctors, with 2.8 per 1,000 population, compared to the OECD average of 3.3.
Countries with more doctors include Greece, Italy, Germany, Spain, Portugal, Switzerland, the Czech Republic, Israel and Australia.
Mark Pearson, OECD deputy director of employment, labour and social affairs, said the UK was doing "outstandingly poorly" on preventing ill health by tackling issues like obesity.
He added: "While access to care in the UK is good, the quality of care is uneven and continues to lag behind that in many other OECD countries."
He said the UK "often does not do the basic things very well", and said the lower than average levels of public investment in healthcare was mirrored by a "somewhat mediocre performance across the board - from relatively low staffing levels, to high rates of avoidable admissions for asthma and lung disease".
Mr Pearson said the UK "can and must do much better", adding that in healthcare "you get what you pay for".
The UK was spending "considerably less" on health than many of the countries it would like to compare itself to, he added.
Mr Pearson pointed to NHS achievements, including being efficient in some areas, such as lengths of stay in hospital and good performance on avoidable admissions for diabetes.
But while screening rates for NHS cancer screening programmes were high, survival rates from cancer were below average.
Overall, staffing levels were not adequate and there were still too high rates of hospital-acquired infections. Guidelines were also published but not followed, he said.
"These basic sort of things don't seem to be done to the extent in the UK that they are done in other countries," he said.
Mr Pearson said lower levels of spending and lower levels of staffing in the UK meant health workers did not have time to compare their performance with other local hospitals or those on an international level.
He added: "I think it's unrealistic, if you spend less, that you can expect a performance that is as good as these other countries."
Mr Edwards added: "If people are stretched, people don't have the bandwidth to make a change."
He said calculations showed that spending on health was going to remain flat in real terms over the next five years.
And he added that junior doctors were relied upon to provide healthcare.
"What's unusual about British hospitals is that when you see someone, they are quite junior.
"We use juniors to provide the backbone of the workforce in hospitals rather than (more highly qualified) doctors."


text:
College tuition costs are increasing faster than the combined rising prices of gas, milk, postage, rent and other costs of living.
Over a decade, published tuition and fees at public four-year colleges and universities nationally grew nearly 6 percent a year above inflation, as measured by the Consumer Price Index, the College Board recently reported.
"A lot of parents are going to have a rude awakening when it comes to paying the tuition bill," said Niall Bridgeman, a financial adviser and principal of Bridgeman Wealth Management, based in Egg Harbor Township. "I think parents know they need to save for it. A lot of parents aren't in the position to do it because of the economy."
One way for parents and grandparents to save for a child's education is through 529 plans.
In New Jersey, there is no tax deduction for contributing to the plans, although money grows tax-free if used for qualified educational expenses such as tuition, books and required supplies and equipment.
Residents do not have to stick to a New Jersey-based plan and can shop around through other states or investment firms such as Vanguard.
There are benefits and pitfalls to 529s, local financial and accounting professionals say.
Savings in 529 plans tailed off after the start of the recession but have picked up since 2009, according to a May 2011 report by Boston-based Financial Research Corp. Contributions increased more than 35 percent annually in those two years, the company reported.
Bridgeman, who has a 529 set up for his 5-year-old son, said he has seen steady demand for 529s, particularly for their flexibility and control.
Frank Thomas, a professor of accounting and finance at The Richard Stockton College of New Jersey, said funds can be shifted among family members.
"Like a lot of planning tools, it's important and definitely a worthwhile consideration," Thomas said.
Unlike states such as Pennsylvania and Virginia, 529 plans in New Jersey lack a tax deduction, although the issue has been raised. A bill in the Legislature to allow income-tax deductions for the program died by pocket veto in January.
The state Office of Legislative Services in January 2011 estimated allowing income-tax deductions for the NJBEST 529 plan in New Jersey would cost at least $6.3 million in tax revenue in fiscal year 2012 and would increase as the economy improved.
New Jersey plans, however, offer a bonus of as much as $1,500 for those attending a New Jersey institution, Thomas said. That bonus may add a wrinkle to the college selection process.
"It kind of adds an undue influence to the decision on what college to go to. It's a feature that has its benefits but also has its drawbacks," Thomas said.
Those who have 529 plans should consider not only how to contribute to them but when to draw from them.
For example, emptying a 529 account to pay for an entire year of college may disqualify taxpayers from certain credits, including the American Opportunity Tax Credit and the Lifetime Learning Tax Credit, Thomas said.
"What the payer should think about is, if we don't have enough in the 529 for four years, rather than pay 100 percent (one year), it may be better paying some money out of pocket," he said.
"You can shoot yourself in the foot. Let's say you had a child and the first year costs are $30,000 and you take it all out of the 529 plan. That's great, but maybe if you paid some money out of pocket you would have gotten the American Opportunity Credit," Thomas said.
There are other drawbacks.
An unqualified withdrawal will bring taxes and penalties, Bridgeman said.
And a significant amount of money in a 529 plan can affect a child's financial aid opportunities, Bridgeman said.
People should also consider fees associated with 529 plans. High fees can take a chunk out of savings, he said.
Thomas said mutual funds should be more conservative the closer the child gets to college. This was a lesson some learned the hard way several years ago when stock-heavy portfolios tanked shortly before some children neared college age.
"It is very important for the parents to think about how those funds are allocated between safe and unsafe investments," Thomas said. "I see too many contributors to the 529 plan think, 'My child is 5 years old, 100 percent in stocks makes a lot of sense because we won't be using the money for 12 years.' And they forget to change the mix. And then what happens is what happened in 2007, and the value of their portfolio is cut in half."
"The earlier you put the money away the better. It might pay to be a little more aggressive when the child is young, but ease back on that stock throttle as they get older," he said.
Contact Brian Ianieri:


text:
Biomedical engineer Kyle Quinn fends off a frenzied Internet mob after being wrongly identified as a Charlottesville protester.
Speaking of Vision Science
October 1, 2014|
October 2014's selection of notable quotes
October 1, 2014|
October 2014's selection of notable quotes
September 29, 2014|
A campaign to build a direct-to-consumer genome sequencing service pulls the plug after two days of fundraising.
September 1, 2014|
Vein patterns in the wings of developing fruit flies never vary by more than the width of a single cell.
August 13, 2014|
Hemocytes can form neurons in adult crayfish, a study shows.
June 23, 2014|
Starvation suspends cellular activity in C. elegans larvae and extends their lifespan.
June 4, 2014|
A study documents boys with autism who were exposed to elevated levels of testosterone, cortisol, and other hormones in utero.
May 1, 2014|
A symbiotic relationship between squid and bacteria provides an alternative explanation for bacterial sheathed flagella.
April 25, 2014|
Evolution of Y chromosome; delivering gene with "bionic ears"; diversity of an important cyanobacterium; charting genome-sequencing progress; blockbuster pharma deals
April 24, 2014|
Charting the progress of the various large-scale genome-sequencing projects as researchers working separately on their chosen species begin to pool analytical resources
April 14, 2014|
Doctors implant custom-made organs, built from a tissue sample and a biodegradable scaffold, into four female patients born with underdeveloped or missing vaginas.


text:
Trailering and Staying Legal on the Road
- Aug 1, 2008
- Basic
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Photo: Anne M. Eberhardt/The Horse
There's not a cloud in the sky as the sun brightens the horizon, and it appears to be a fine day for a drive. Your truck and trailer stand gleaming in the driveway, hitched and waiting. At your command, your horse clomps into the trailer and busies himself in the hay while you close the doors and secure the latches. You're loaded and ready to hit the road. This scenario occurs countless times throughout the riding season as you venture near and far to places to ride or compete. You have attended to all the recommended maintenance and servicing of both truck and trailer to ensure safety and reliability, but what about the legal aspects of hauling a horse? What must you do to comply with regulations and laws?
Horse Regulations
When traveling between states, there are specific legal documents that should accompany your horse. The first of these is a negative Coggins test, which is a blood test for the presence of equine infectious anemia (EIA). This virus is similar to the human HIV virus and is transmitted mostly by large biting flies, like horse or deerflies. A horse testing positive for EIA might be actively infected or a carrier; in either case, the horse must be quarantined for life away from other horses or euthanized. In attempts to eradicate this disease in the horse population, regulations are enforced for horses crossing state lines.
Rachel Kosmal McCart, JD, senior counsel at Equine Legal Solutions in Beavercreek, Ore., says, "Each state regulates the transport of livestock within that state, including entry requirements, therefore the requirements vary from state to state."
Some states require a negative Coggins test that was performed within the prior 12 months, while others require the test to have been done within the preceding six-month period. Many boarding and show barns often require a negative Coggins test for the horse to enter the premises.
Another required document for interstate travel is a certificate of veterinary inspection (CVI). This health certificate, filled out following a veterinary exam, is meant to ensure that a horse has a clean bill of health and is not infected with a contagious disease--most notably respiratory or skin ailments. Most states require the CVI must be issued within 30 days of transport, but others only honor a CVI that has been done in the last 10 days. Your veterinarian will have up-to-date information regarding timetables for both a Coggins test and health certificate for the state(s) you wish to enter.
Some states (Alabama, Arkansas, Georgia, Kentucky, Louisiana, Mississippi, North Carolina, Tennessee, Oklahoma, South Carolina, Virginia, and West Virginia) are currently honoring an interstate equine passport that serves as shipping papers for a horse for six months following a veterinary health examination or until the expiration date of a Coggins test. Other states (Arizona, Montana, and Oregon) additionally require permits prior to entry; their state regulatory offices must be contacted to issue approvals and permit numbers to include on CVIs.
If you plan to haul into Canada, your horse must be accompanied by a specialized international health certificate filled out by your veterinarian and endorsed by the USDA's Animal Plant and Health Inspection Service (APHIS).
Milton Toby, JD, an attorney, chair of the Equine Division at Midway College in Kentucky, and author of The Complete Equine Legal and Business Handbook, adds, "Each individual Canadian province has its own transportation department, similar to our state agencies, each with their own set of regulations."
Domestically, in some Western states, another document must accompany a horse that travels more than 75 miles from home: a brand inspection. A brand inspection is intended to certify proof of ownership, regardless of whether a horse has a physical brand or tattoo or not. A brand inspector reviews a bill of sale and registration papers when available, compares this information to the horse and its markings, and then either writes up a temporary brand inspection, or, if you desire, he prepares a laminated card that is good for as long as you own that horse.
As your rig crosses the state line, weigh stations often have a sign requesting that all towed vehicles carrying livestock must pull over. McCart advises, "Requirements for private horse owners to stop at state point-of-entry checkpoints vary from state to state. Therefore, drivers would be advised to read the signs and, when in doubt, stop and inquire."
Vehicle and Trailer Compliance
Vehicle and trailer compliance laws are mostly decided at the state level. Toby comments, "If there is a conflict between state and federal law, the federal law controls, unless the state law is more restrictive, in which case the state law will control."
He comments on federal laws that might supersede state regulations: "If you are a 'commercial' interstate horse hauler, there are many federal requirements for recordkeeping and safety equipment, among other things. It is noteworthy that a person may be classified as a 'commercial' shipper, even if not hauling horses for money. As an example, hauling horses in connection with a commercial training stable might classify one as a 'commercial' shipper."
He adds, "For interstate travel, federal regulations require a commercial driver's license (CDL) if the gross vehicle weight (GVW) is more than 26,000 pounds."
Toby suggests that it is best to check with the U.S. Department of Transportation in regard to interstate CDL/ commercial hauler requirements.
McCart similarly recognizes that every state has its own legal requirements when it comes to trailer brakes, safety chains, fire extinguishers, towing speed, size dimensions of truck and trailer, license plate placement and visibility, etc.
Both Toby and McCart strongly urge haulers to monitor each state's current information for up-to-date regulations, and to check with specific state departments of transportation through which one might be hauling a horse.
On occasion, a horse owner might wish to ride in the trailer when hauling a sick horse to an emergency clinic or when transporting a foal. Some states allow a person to travel in the trailer, while others do not; check your state regulations before climbing into the trailer.
There are also times when it is necessary to unload a horse from the trailer while on the side of the road. McCart clarifies some questions that come up about this issue, noting, "Laws regarding livestock on highways vary state by state. However, in general, if a horse you are unloading gets loose on the highway and someone is injured or killed or their vehicle or property is damaged as a result, you will probably be liable. For the safety of other motorists as well as your horses, only unload on the side of a highway if there is an extreme emergency."
She continues, "Because AAA will typically require horses to be unloaded before they will change a trailer tire, haulers should be prepared to change their own trailer tires. With a drive-on ramp product such as a Jiffy Jack, changing a trailer tire on a loaded horse trailer is akin to changing a tire on a truck."
In the event of an accident, McCart stresses, "Your auto insurance will generally not cover damage to your trailer or the contents of your trailer. So, if you get into an accident and your trailer, horses, and show saddle are a total loss, you will probably not receive any compensation from your auto insurance company. For that reason, a horse owner may wish to consider separate coverage, such as horse trailer insurance, equine mortality insurance, and a rider on homeowner's insurance to cover big-ticket items, such as expensive horses, the trailer, or saddles. Fortunately, your auto collision policy usually covers damage to your vehicle and to a vehicle with which you collide, as well as damage to contents. To clarify what is and is not covered by your auto insurance policy, contact your insurance agent."
Authorizing Veterinary Care
Sometimes a horse is hauled by someone other than the owner and the driver must act as a decision-making agent in lieu of an owner. One such occasion involves acquisition of veterinary care for an injury or illness. One means to do this is by a power of attorney (POA), which can be either "general" or "limited." A general POA allows the person with the power of attorney to do anything the grantor could do, while a limited POA authorizes an agent to make legally binding decisions on behalf of an absentee owner for a limited duration of time or for a specific circumstance.
Toby explains the specifics on how a limited POA works: "For example, if you are shipping my horse across the country, I can give you a limited POA authorizing you to obtain medical care for the horse in an emergency. This allows you to call a vet for my horse, and obligates me to pay the bill. A limited POA also gives you the authority to make medical decisions about the horse without having to contact me. This can be important in an emergency."
In addition, Toby notes there are situations where a horse's injuries are sufficient to necessitate euthanasia. He says, "If the horse is insured, the insurance carrier must be notified and authorization given prior to carrying out an owner's or agent's decision for euthanasia."
Insurance policies and contact information should be included with the horse's other travel papers.
McCart discusses a variation on how to obtain medical care for a horse being transported by someone other than the owner: "When a hauler (commercial or private) needs to seek veterinary care for a horse, a horse may be treated as quickly as possible if the hauler is given a document from the horse owner that authorizes the hauler to seek treatment for the horse and promise to pay the veterinarian for such care. For even faster service, a horse owner may want to provide credit card and billing information in the authorization form. Unlike a traditional power of attorney, a veterinary care authorization form need not be notarized to be effective, only requiring a signature by the horse owner."
Safety and Potential Legal Hassles
McCart offers other suggestions for safe hauling, gleaned from personal experience, for avoiding accidents and their potential legal quagmires. She recommends a thorough check of all equipment before hitting the road. "Because trailers are usually stored outside, spare tires mounted on the outside of the trailer and/or regular tires of parked trailers may be ruined by sun and weather. Use tire covers, especially if a trailer is infrequently used," she says. "Remember to rotate the tires on your trailer just like you rotate the tires on your truck. Check your lug nuts after the rotation to ensure that they remain tight."
In addition, she notes, "Not all tire irons fit all lug nuts, so make sure that the tire iron in your rig fits your trailer lug nuts. Don't count on the one for your truck to work on your trailer!"
McCart advises owners to frequently check the hitch, trailer doors, and all connections after parking your rig during a trip, stating, "You never know when some unscrupulous person might tinker with something or when something might come loose."
She urges everyone to carry flares and a powerful flashlight (with charged batteries), since emergencies don't always happen in the daytime. "And," she says, "keep a spare halter and lead with a stud chain in your trailer as an added precaution for control of your horse."
Take-Home Message
Transporting your horse is not just about trailer safety, clean air, and a comfortable environment for your horse to withstand the stress of hauling. It is also important to comply with federal and state laws about specific documents for your horse and state regulations on your vehicle and trailer.
About the Author
Nancy S. Loving, DVM
Nancy S. Loving, DVM, owns Loving Equine Clinic in Boulder, Colorado, and has a special interest in managing the care of sport horses. Her book, All Horse Systems Go, is a comprehensive veterinary care and conditioning resource in full color that covers all facets of horse care. She has also authored the books Go the Distance as a resource for endurance horse owners, Conformation and Performance, and First Aid for Horse and Rider in addition to many veterinary articles for both horse owner and professional audiences.
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