A drilling tool has a bent sub or a defined xe2x80x9cHigh Sidexe2x80x9d. An instrument housing which includes a magnetometer is secured to the directional drilling tool. The magnetometer measures the magnetic field vector in the plane perpendicular to the tool axis. Prior to running the directional drilling tool and the instrument housing into the well, a magnetic source is positioned next to the instrument housing at a position near the magnetometer. The magnetic source is made and positioned such that its magnetic field at the magnetometer points to the chalk line of the high side of a bent sub. The net magnetic field generated from the source is obtained by the difference in magnetic field measurements before and while the magnetic source is applied The azimuthal angle between the net magnetic field vector and the x-axis of the magnetometer or other direction sensor reference point used for tool face calculation is obtained by a computer. This angle is the angular difference or offset angle between the sensor tool face and the high side of the bent sub (as mimicked by the magnetic source). This offset angle is recorded as a signed (xc2x1) number and is added to the sensor tool face to produce the bent sub""s high side tool face during the drilling operation. No manual measurement of the offset angle and input is required.

This invention relates in general to directional drilling of wells, and in particular to a method and apparatus for more efficient and accurate determination of an angular offset between a directional sensor reference point and the high side of a bent sub.
In one method of directional drilling of wells, the drill string includes a rotary drill bit on the lower end connected to a downhole drill motor. The drill motor operates in response to drilling fluid being pumped down the drill string, causing the drill bit to rotate relative to the drill string. Also, the drill string can be rotated along with the drill bit for conventional drilling.
The drill motor assembly includes a bent sub, which is a tubular housing that positions the bit at a slight angular offset, usually about three degrees, from the longitudinal axis of the drill string. As a result, if the drill string is held stationary while the drill motor rotates the drill bit, the bent sub will cause the well to be drilled in the direction of the inclination of the bent sub.
Accordingly, the operator can steer the drill bit in a desired direction if the operator knows the direction of the tool axis (the axial direction of the sensor frame) and the particular orientation of the bent sub about drillstring axis, namely via three parameters, azimuth, inclination and bent sub tool face. Note, for purposes of this discussion, sensor tool face is the same as directional sensor tool face which can be either gravity tool face (sometimes simply called xe2x80x9ctool facexe2x80x9d) or magnetic tool face. Sensor tool face is a measure of the orientational state of the sensor about the tool axis. The bent sub tool face is a measure of the orientational state of the bent sub about the tool axis.
Downhole directional instruments (or sensors) including magnetometers and accelerometers (inclinometers) provide the azimuth, the inclination and the directional sensor tool face. Typically, three magnetometers and three accelerometers are used to measure the three components of the gravity vector and the Earth magnetic field vector in the sensor frame, respectively. For convenience, the magnetometer and accelerometer axes are aligned. Usually, the angle between the sensor x-axis (x and y are perpendicular to the tool axis and to each other) and a geometrical direction is defined as the sensor tool face. For example, in a horizontal well when the x-axis of the directional sensor frame is vertical, the sensor tool face is defined as an angle of zero. In directional wells, the gravity tool face is defined as the angle between the x-axis and the line intersect between the x-y plane and the vertical plane parallel to the tool axis.
In vertical wells, the gravity tool face is not well defined as the x-axis is approximately in the horizontal plane. In this case, one uses the magnetic tool face to indicate the tool orientation about the tool axis. The magnetic tool face is usually defined as the relative angle between the x-axis and the line intersect between the x-y plane and the vertical plane parallel to the magnetic north vector. Under any situation (vertical, horizontal or deviated well) a tool face measurement is available, indicating the tool""s orientation about the tool axis.
The directional information,, inclination, azimuth, and tool face, sensed by the downhole instruments will be transmitted to the surface, preferably by using a measurement while drilling (xe2x80x9cMWDxe2x80x9d) telemetry system. The system receives the digital signal from the downhole instruments and operates a poppet valve to provide pulses in the drilling fluid inside the drill pipe. These pulses are detected at the surface and decoded into a readout that informs the operator of the tool""s direction.
When the operator is drilling straight, the drill string is rotated along with the drill bit. This makes the borehole slightly larger in diameter than the drill string. When the operator desires to make a turn, he will cease rotating the drill string, and will position it in a desired orientation (e.g. he/she will position the high side of the bent sub in the direction he/she wants to turn). The drilling fluid pumped through the drill string causes the drill bit to rotate. This causes the drill bit to move in the desired direction.
As mentioned, in order to accomplish the directional drilling task, the operator needs to know the orientation of the bent sub. The relationship between the directional sensor sonde and the bent sub is fixed for each bottom hole assembly. From the directional sensor measurement, the directional sensor tool face is known. If the angular difference between the directional sensor reference point and the bent sub is measured on the surface, then the operator can use this measurement and the directional sensor tool face reading to determine the orientation of the bent sub, namely, the bent sub tool face. Such angular difference is sometimes called tool face offset.
In the prior art, the angular difference is determined by the use of a scribe line on the exterior of the instrument housing. The scribe line indicates the direction of the x-axis of the directional sensor frame
At the well site, the downhole assembly is assembled and suspended vertically in the derrick. Next an operator draws a visible indicator or vertical chalk line from the high side of the bent sub, up to the directional sensor housing. The operator then measures the angular difference between the scribe line and the chalk line. The measurement may be made with a protractor. Now, the operator must decide whether to add or subtract this angular difference to the directional sensor tool face for purposes of determining the orientation of the bent sub. Obviously, the decision as to whether to add or subtract the angular difference is critical. Operators are trained to follow a procedure to correctly determine whether the angular difference should be input into the surface computer as a positive or negative number to be added to the tool face reading to obtain the bent sub orientation
The disadvantage of this system is that it is subject to operator error. The operator must measure the angle properly and then properly subtract or add the angular difference. However if a mistake is made in the decision as to whether the angular difference is to be added or subtracted (e.g. the proper correction is xe2x80x9cplusxe2x80x9d sixty degrees and one mistakenly subtracts sixty degrees) serious adverse consequences can result. For example, such a mistake can result in the operator drilling in the wrong direction for a period of time and at a significant expense.
One object of the invention is to eliminate any error which may be made in measuring and applying the angular difference for purposes of determining the orientation of the bent sub. Another object is to implement equipment for achieving same.
In this invention, it is not necessary to form the prior art scribe line on the instrument housing to indicate the internal reference point of the directional sensor. In fact, the magnetometer and inclinometer can be inserted into the instrument housing with a random orientation. However, a locater must be placed on the instrument housing marking the approximate mid-point of the magnetometer between its upper and lower ends. This may be a circumferential locater groove formed in the instrument housing.
At the well site, the tools are assembled and suspended vertically. A technician draws a chalk line from the high side of the bent sub vertically upward onto the directional instrument housing where the chalk line intersects the circumferential locater groove. The operator connects the magnetometer to the surface instrument panel by using a probe and an electrical lead. The magnetic field Bbefore is measured and recorded. The Bbefore is unlikely to be the unperturbed Earth magnetic field due to the amount of steel in the drilling rig and other magnetic fields present on the rig floor. However, measuring the true Earth magnetic field is not relevant at this point.
The operator then takes a magnetic source and places it adjacent the circumferential groove and in alignment with or in a prescribed fixed relationship with the chalk line. The magnetic field Bafter is then measured. The difference between Bafter and Bbefore is Bsource, the magnetic field generated by the source alone. Since the direction of Bsource is that of the chalk line or is in a known relationship with the chalk line, the direction of Bsource in the magnetometer sensor frame relative to directional sensor tool face (usually the x-axis direction) is or gives the angular tool face offset. This information is recorded in the directional sensor and/or in the surface computer. This angular offset is used later for determining the orientation of the high side of the bent sub for directional drilling.
If the magnetometer has a very large dynamic range, the operator can use a very strong magnetic source. Then Bafter is approximately equal to Bsource. The Bbefore measurement is not necessary.

Calculating directional drilling tool face offsets

Precision Drilling Technology Services Group, Inc.


Systems and methods for providing visual feedback to aid in the proper placement and location of a fetal sensor during a fetal oximetry monitoring procedure. An imaging device, such as an optical fiber can be used to image and illuminate the same or nearby region of tissue which the fetal sensor contacts. The image from the illuminated portion of tissue is transmitted along the optical fiber to an optical viewing device such as a hand-held image viewing instrument, camera, or an image processor/video display.

The present invention relates generally to fetal probes for monitoring the condition of a fetus in utero and more specifically to a fetal probe having an optical imaging device.
During in utero labor and delivery of a fetus, fetal probes are used to monitor the health of the fetus. Fetal probes having pulse oximeters are typically used to measure various blood characteristics including arterial blood oxygen saturation and pulse rate. Pulse oximetry sensors pass light through a portion of the fetus"" skin and photo-electrically detect pulsatile changes in the absorption of the light by the tissue. The detected light is then used to determine the characteristic of interest.
In order to achieve accurate measurements, the aforementioned sensing devices must maintain contact with the fetus at an appropriate part of the fetus"" body. The quality of the optical signal generated by the pulse oximeter sensor depends, in part, on the placement of the sensors on the fetus"" body and on the quality of optical coupling between the sensor and the patient. The quality of optical coupling is related to the amount of light emitted by the sensor that actually enters the fetus"" tissue and to the portion of the light received by the sensor that actually passes through the fetus"" blood-perfused tissue.
Tissue characteristics at the sensor site can affect the quality of the optical coupling between the sensor and the patient. The presence of hair or vernix on the skin will attenuate the light transmitted into the tissue by the sensor. For example, if the sensor is placed on a part of the fetus"" scalp the system may not be able to appropriately process the signal. Consequently, it is important that the physician position and orient the fetal probe at a proper place on the fetus.
One method of placing the fetal probe adjacent the fetus is through manual assessment of the womb to determine the orientation of the head of the fetus and depth of the fetus within the womb. Once the physician has determined the position of the fetus, the physician picks a line of entry and introduces the fetal probe along the line to try to place the fetal sensors on the fetus"" cheek. Unfortunately, the physician will only have tactile feedback in regards to the positioning of the sensors and will have no visual indication of the position of the fetal sensors relative to the fetus. If the physician has misassessed the position of the fetus and has not placed the fetal probe adjacent the fetus"" cheek, the physician will have a difficult time in correctly positioning the fetal probe.
Accordingly, what is needed are systems and methods that provide visual feedback to the physician as to the orientation and position of the fetal probe sensors within the womb.
The present invention provides devices, systems and methods for providing visual feedback to aid in the proper placement of a fetal sensor during a fetal oximetry monitoring procedure. An imaging device, such as an optical fiber or fiber bundle, optical conduits, CCD camera, or the like can be coupled to a distal portion of the fetal probe to visually image and/or illuminate the same or nearby region of tissue which the fetal sensor contacts. The images from the illuminated portion of tissue are transmitted through the imaging device to an optical viewing device such as a hand-held image viewing instrument, camera, or a video monitor.
In exemplary embodiments, the fetal probe will include fetal oximetry sensors that have a light emitter (e.g., an LED) and a light detecting sensor. The light emitter can emit an infrared light, a visible light, or the like. In exemplary configurations, the imaging device can be positioned adjacent the fetal oximetry sensors so as to provide a visual indication of the position of the fetal sensors relative to the fetus"" tissue.
In some arrangements, the LED can be used for emitting light for spectral pulse oximetry and for illuminating the fetus"" tissue for visual examination. In other configurations, a separate illumination source (e.g., such as an optical fiber coupled to a broad spectrum light source) can be used to provide illumination for the visualization of the region of the fetus.
The light detecting sensors of the present invention will typically be configured to sense the light emitted from the light emitter for pulse oximetry purposes. In most arrangements the imaging device will be a separate component coupled to the distal portion of the probe. However, in some arrangements, the light detecting sensors can be configured to detect the light for visualization purposes. For example, a light sensor can vary its mode of operation to be able to both detect pulse oximetry data and to provide visual images of the fetus. In such embodiments, the pulse oximetry light detecting sensor will have a dual function and the separate imaging device will not be needed.
In a first aspect, the present invention provides a fetal probe. The fetal probe comprises a body. A fetal sensor is coupled to the body. An imaging assembly is positioned on the body to provide visual feedback of the position of the fetal sensor.
In one embodiment, focusing optics are coupled to the fetal sensor so as to provide a field of view and depth of field for the imaging device. In an exemplary embodiment, the imaging device includes a bundle of optical fibers. The optical fiber bundle may work in close proximity to the tissue being viewed so that no focusing element at the distal end is necessary. In most embodiments, the optical fiber bundle comprises a coherent arrangement of fibers (plastic or glass) to provide an image with the necessary resolution. Typically, the fiber bundle has a flexibility and diameter (approximately 1 mm to 3 mm) such that the fiber bundle can follow the turns and bends of the fetal sensor cable. Consequently, the flexible fiber bundle provides minimal discomfort to the patient during insertion. The proximal ends of the fiber bundle are typically attached to an eye piece, CCD camera with a video display, or other viewing devices. In most configurations, the viewing device can be adapted to alter the image orientation and/or provide magnification.
Appropriate attachments could be provided to permit easy removal of the optical fiber from the fetal sensor after completion of placement in utero. In alternative embodiments, the fiber bundle can be left attached to the fetal sensor and the viewing device can be disconnected from the proximal end of the fiber bundle. Such an arrangement would be particularly helpful if the optical fiber bundle is used to verify continued good placement of the fetal probe during the progress of labor.
In a particular embodiment, the present invention provides a fetal probe having a light emitter and a dual mode light detector. The light detector can function in at least two modes. In a first mode the light detector can detect light from the light emitter to provide a visualization of a fetus. In the second mode the light detector processes spectral oximetry data.
In another aspect, the present invention provides a method for positioning a fetal probe adjacent a fetus. The method comprises placing a fetal probe having a fetal sensor in close proximity to the fetus. A portion of at least one of the fetus and in utero environment is imaged with an imaging device that is coupled to the fetal probe. The image(s) are transmitted to a viewing device so as to provide a visual indication of the position of the fetal sensor.
In yet another aspect, the present invention provides a method for positioning a fetal probe adjacent a fetus. The method comprises advancing a fetal probe having a fetal sensor into contact with the fetus. The position of the fetal sensor is monitored with an imaging device that is attached to the fetal probe. The position of the fetal probe is adjusted if it is determined that the position of the fetal sensor is not adequate for monitoring the fetus.
For a further understanding of the nature and advantages of the invention, reference should be made to the following description taken in conjunction with the accompanying drawings.

Fetal probe having an optical imaging device


A method of manufacturing a label assembly including a plurality of individual label flaps each including a separate coupon includes the steps of imprinting a coupon graphic on a first release liner and printing a label graphic on a continuous strip of label material. The coupon shape is die-cut into the first release liner in a position aligned with the label flap to be subsequently formed. Once the coupon has been die-cut from the first release liner, the first release liner is separated from the label material. As the first release liner separates from the label material, the die-cut coupon remains in contact with the pressure-sensitive adhesive formed on the back surface of the label material. A second release liner is brought into contact with the continuous strip of label material including the coupons. The label shape is then die-cut and the portions of the label material not forming the label flap are removed to leave a series of spaced labels each including a coupon mounted onto the continuous strip of the second release liner.

The present invention relates to a resealable label flap that is positionable to cover an opening in a product package containing removable articles such that the label flap can be repeatedly removed and reapplied to access the articles contained within the package. More specifically, the present invention relates to a label flap that includes a separate coupon that is hidden beneath the label flap and is revealed the first time the label flap is removed from the product package.
Resealable label flaps are commonly used with product packages that include packaged sheet-like removable articles that have been thoroughly wetted with a liquid prior to packaging. The product package is generally constructed from a thin, liquid impervious material that has an opening over which the label flap is removably adhered. Typically, the label flap is a strip of flexible or semi-rigid thermoplastic material having a pressure-sensitive removable adhesive applied to one surface of the label. The removable adhesive creates a generally air-tight seal around the package opening to prevent the packaged removable articles from drying out during storage.
In the retail industry, a common marketing practice is to include a coupon within or on the packaging for a product such that the purchaser of the product can receive a discount on subsequently purchased merchandise. A key feature of this type of marketing is the concealment of the coupon until the product package has been purchased and opened such that the purchaser is required to purchase another product to redeem the coupon.
In some types of packaging, it is undesirable to place the coupon within the product package since the packaged product may damage the coupon. To solve this problem, various systems have been developed to secure the coupon to the exterior of the product package while at the same time preventing the easy pilfering of the coupon from the package prior to the purchase of the package.
The Buske U.S. Pat. Nos. 3,524,271 and 3,524,782 each disclose a combination label and coupon in which the coupon graphics are printed on the back surface of the label liner. The shape of the coupon is then scored or cut into the label liner around the coupon graphics. As the printed labels are separated from the liner, the coupon remains in contact with the label such that when the label is applied to the package, the label covers the coupon and prevents its removal from the package. Although this combination of label and coupon has proved to be somewhat successful, the manufacturing process for the label has limited the size and position of the coupon with respect to the overlaying label. Specifically, the size and position of the coupon are limited due to the strength of the label liner, since the label liner has a tendency to tear when the label is removed if only a small amount of material remains between the coupon and the edge of the label liner.
The Romengali U.S. Pat. No. 4,060,168 discloses a similar label assembly in which a series of printed labels are arranged in serial order and a die-cut portion of the label liner in contact with the printed labels remains adhered to the label upon application of the label to a container. As illustrated in the patent, when the label is removed from the label liner, the coupon is torn from the liner. A limitation of the system disclosed in this patent is that the liner must be of sufficiently light weight to permit the label to be torn from the liner as the label itself is removed. Therefore, because of the limitation in the strength of the label liner, high speed removal and application of the combined label and coupon is not possible or practical.
Therefore, it is an object of the present invention to provide a method of manufacturing a plurality of removable label flaps that each include a separate coupon and are contained on a label liner of sufficient strength. Further, it is an object of the present invention to provide a label flap that includes a separate coupon adhesively attached to the label flap such that the coupon is invisible upon initial removal of the label flap from a product package. Further, it is an object of the present invention to provide a method of manufacturing such label flaps in which the coupon is printed and removed from a first liner prior to the label material being placed in contact with a second liner of increased strength.
The present invention is a method of manufacturing a continuous label assembly that includes a plurality of removable label flaps that each include a separate coupon. The label assembly of the present invention can be wound around a supply roll and shipped to an off-site location for application of the individual label flaps, including the coupons, to a product package.
Initially, a continuous supply of material including a continuous strip of label material adhered to a first release liner by a pressure-sensitive adhesive is received by the processing machinery. After receipt, a series of coupon graphics are imprinted on the back surface of the first release liner in positions that generally correspond to the shape of the label flap to be subsequently formed. After the coupon graphics have been printed, a series of spaced label graphics are imprinted on the front surface of the label material in locations that also generally correspond to the position of the individual label flaps to be subsequently formed.
After the label graphics and the coupon graphics have been printed on the supply material, the first release liner is die-cut around each of the coupon graphics to form the plurality of individually spaced coupons. The size and shape of the coupon can vary greatly depending upon the customer requirements.
Once the coupons have been die-cut in the first release liner, the portions of the first release liner that do not form the coupon are removed from contact with the label material and discarded as waste. Since the label material includes the pressure-sensitive adhesive on its back surface, as the waste portions of the first release liner are removed, each of the die-cut coupons remain in contact with the label material.
Once the excess portions of the first release liner are removed, a second release liner is brought into contact with the label material including the plurality of spaced coupons. The second release liner is formed from a material more durable than the first release liner to aid in the subsequent removal and application of the label flaps to desired product packaging. The second release liner is preferably formed from plastic and provides the required stability and strength for the label assembly being formed.
After the label material including the spaced coupons is applied to the second release liner, the perimeter of the label flap is die-cut into the desired shape. The perimeter of the label flap is die-cut around the label graphic previously printed as well as the coupon attached to the back surface of the label material.
After the label flap has been die-cut, the excess portions of the label material are removed and the plurality of individual label flaps remain mounted on the second release liner. The label assembly including the plurality of individual label flaps and associated coupons mounted to the strip of the second release liner, is wound onto a supply roll. The supply roll including the continuous strip of the second release liner with the plurality of label flaps mounted thereto can be shipped to another location and the individual label flaps applied to product packaging.
Various other features, objects and advantages of the invention will be made apparent from the following description taken together with the drawings.

Removable label flap including hidden coupon


A method of treating an individual to increase the individual""s bone mineral density (BMD) is disclosed. The method includes co-administering a calcitonin-like agent and a DHEA-like agent. Also disclosed are methods for potentiating the effect of treatment with a calcitonin-like agent on BMD and for increasing BMD in an individual being treated with DHEA, e.g., for treatment of systemic lupus erythematosus (SLE).

The present invention relates generally to the treatment of bone loss by administering dehydroepiandrosterone (DHEA) and calcitonin.
The following references are cited as pertinent to the background of the invention, or as providing guidance in practicing the invention.
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Osteoporosis is a xe2x80x9csystemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase of bone fragility and susceptibility to fracture.xe2x80x9d It is the consequence of imbalance between bone formation (anabolic) and resorption of bone, with the latter predominating.
Following the first trimester of fetal development, bone growth is rapid. Multiple factors may regulate in utero transplacental calcium transport and in utero bone formation, including but not limited to vitamin D, calcitonin, parathyroid hormone, and miscellaneous growth factors. In humans, bone mass peaks at approximately the end of the second decade of life and declines thereafter. The cause of the shift from predominantly bone formation in early life to bone resorption in later life is unknown.
The NIH has stated that xe2x80x9costeoporosis is an important and potentially growing public health problem in which weakened bones are easily fractured. More than 1.3 million hip, spine and wrist fractures each year are attributable to osteoporosis. Low bone density is a major cause of fractures. Data from the National Health and Nutrition Examination Survey, using a definition of osteoporosis developed by the World Health Organization, determined that up to 20% of white women over 50 have osteoporosis and up to 50% have low bone mass. Non-white women and men have lower rates of osteoporosis but contribute up to 25% of the fractures annually (Looker). Low trauma fractures at any site in the elderly are largely due to low bone mass. Hip fractures are the most devastating and costly osteoporotic fractures.xe2x80x9d (NIH press release, 1998)
While osteopenia and osteoporosis are most often associated with aging, they can also be secondary to numerous diseases and/or therapies associated with these diseases. Aside from postmenopausal and age-related osteoporosis, osteoporosis can be heritable, endocrine-mediated, diet-related, drug-induced, disuse- or disease-related, or idiopathic (no identifiable cause). No class of drugs has been more often associated with osteoporosis than treatment with exogenous glucocorticoids, which are notorious for causing rapid onset of bone loss with ultimate osteopenia/osteoporosis, even at low doses.
Almost all currently available treatments for preventing progression of osteopenia/osteoporosis include drugs which are primarily antiresorptive including estrogens, bisphosphonates, and calcitonin (salmon or human). Additional therapies include calcium supplements, progesterone or progesterone analogs, and vitamin D and its analogs.
Calcitonin and calcitonin-gene related peptide have been of particular interest. Both are proteins secreted in abundance in the fetal circulation and are thought to be essential for bone growth in the fetus. Concentrations of both decline shortly after birth and remain low thereafter. While the physiologic role of each in adulthood is unclear, salmon and human calcitonin are known to inhibit resorption of bone and have found application as therapies for osteoporosis, Paget""s disease of bone, hypercalcemia, and other diseases.
Although calcitonin has been available as a treatment for osteoporosis for a number of years, reports on its efficacy in prospective bone density studies have been variable, with many studies demonstrating either no or little improvement in bone density during chronic treatment with this drug. In an analysis of 16 studies, mean increase in spine bone mineral density (BMD) was reported to be 1.97% (Cardona).
Alendronate, a bisphosphonate, is perhaps the most commonly prescribed treatment for the treatment of bone loss diseases today. In the largest study conducted to date assessing efficacy of calcitonin vs. alendronate, only modest increases in BMD were observed in the total femur and lumbar spine during up to 1 year of therapy with calcitonin in postmenopausal women (Rosen). This study was designed to compare efficacy of alendronate to calcitonin when used for treatment of osteoporosis in postmenopausal women.
In the study, two-hundred and seventy-five postmenopausal women with low bone mass (low BMD), xe2x88x922.0 standard deviations (SD) at lumbar spine (LS) or femoral neck (FN) and xe2x88x921.0 SD at the other site) were randomized at 9 US sites to either blinded alendronate at 10 mg or matching placebo or open-label calcitonin at 200 IU daily. All patients received vitamin D at 400 IU daily and calcium at 1000 mg daily including diet and supplements. LS, FN and hip trochanter (HT) BMD were measured at baseline, 6 and 12 months.
The authors found calcitonin did not improve bone mineral density in long-term use and concluded as follows: xe2x80x9cTreatment with alendronate produced significantly greater increases in BMD than did calcitonin at both LS and HT at 6 and 12 months (p less than 0.001) and at FN at 12 months (p=0.003). BMD changes with calcitonin were not statistically different from placebo at LS, HT or FN at either 6 or 12 months. Adverse experiences similar between alendronate and calcitonin were difficult to interpret for calcitonin due to open-label drug. In postmenopausal women with low bone mass, alendronate produced significantly greater increases in BMD than nasal calcitonin at one year at both lumbar spine and hip.xe2x80x9d
In a second large multicenter study, it was observed that bone mass increases with calcitonin were short-lived (Downs). The Downs study compared the efficacy of alendronate and calcitonin at doses currently prescribed in the U.S. Postmenopausal women with osteoporosis (n=299) were randomized at 24 US sites to either blinded alendronate 10 mg or matching placebo or open-label calcitonin 200 IU daily. All patients received calcium at 1000 mg daily including diet and supplements and vitamin D at 400 IU daily. Lumbar spine (LS), femoral neck (FN) and hip trochanter (HT) BMD were measured at baseline, 6 and 12 months.
Treatment with alendronate produced significantly greater increases in BMD than did calcitonin at both LS and HT at 6 and 12 months (p less than 0.001) and at FN at 12 months (p=0.001). BMD changes with calcitonin were statistically different from placebo at FN at 6 (p=0.003) and 12 months (p=0.008) but were not significantly different at either LS or HT at 6 or 12 months. Again, it can be seen that the effects of calcitonin on bone density were only modest compared to placebo.
DHEA (dehydroepiandrosterone) is the principal steroid secreted by the fetal adrenal gland, with concentrations significantly higher than other circulating steroids. Its role in fetal physiology is poorly understood, but it is thought to serve as a precursor for other steroids, leading to androgen and estrogenic steroids. It has been reported that DHEA may be useful in the treatment of osteoporosis/osteopenia. U.S. Pat. No. 5,776,923 indicates that administration of DHEA to ovarectomized rats results in increased bone density. However, the administration of DHEA to humans to prevent bone loss or increase bone density is not a recognized treatment for osteoporosis/osteopenia by the medical community. Extensive clinical trial data from systemic lupus erythematous (SLE) patients being treated with DHEA, 200 mg administered daily, showed only slight improvement of BMD, both in patients receiving DHEA alone, or in combination with prednisone.
Thus, there continues to be a need for more effective treatments for subnormal BMD in diseases such as osteoporosis, steroid induced osteoporosis, immunosuppressant induced osteoporosis, osteopenia, Paget""s disease, periodontal disease and hypercalcemia.
The invention includes, in one aspect, a method of treating an individual to increase the individual""s bone mineral density (BMD). The individual is preferably a human patient having a subnormal BMD. The method includes administering a calcitonin-like agent to the individual and administering a dehydroepiandrosterone (DHEA)-like agent during the period of calcitonin-like agent administration. The amounts of calcitonin- and DHEA-like agents administered are, in combination, effective to increase BMD, and wherein the co-administration of calcitonin- and DHEA-like agents potentiates any increase in BMD achievable by administration of that amount of calcitonin-like agent alone. Preferred treatment doses are an average daily dose of about 50-200 IU calcitonin, administered parenterally or orally, and about 50-200 mg DHEA per day, administered orally. Treatment is preferably continued for at least about 25 weeks.
Where the individual is being treated an immunosuppressant, e.g., one that tends to reduce BMD, such as a corticosteroid or methotrexate, the immunosuppressant treatment can be continued during administration of the calcitonin-like and DHEA-like agents. In particular, where the individual has systemic lupus erythematosus (SLE), which is being treated with a corticosteroid, such as prednisone, the corticosteroid treatment is preferably continued during administration of the calcitonin-like and DHEA-like agents.
In a second aspect, the invention includes a method of potentiating the effect of treatment with a calcitonin-like agent on BMD in an individual, preferably a human patient with subnormal BMD. The method involves administering a DHEA-like agent to the individual, in an amount of at least about 50 mg/day, during the period of calcitonin treatment. In a preferred embodiment, the individual is being treated with an average daily dose of about 50-200 IU calcitonin, administered parenterally or orally, and DHEA is administered orally, in an amount between about 50-200 mg/day, preferably for at least about 25 weeks.
As in the first aspect of the invention, where the individual is being treated an immunosuppressant, e.g., one that tends to reduce BMD, such as a corticosteroid or methotrexate, the immunosuppressant treatment can be continued during administration of the calcitonin-like and DHEA-like agents. In particular, where the individual has systemic lupus erythematosus (SLE), which is being treated with a corticosteroid, such as prednisone, the corticosteroid treatment is preferably continued during administration of the calcitonin-like and DHEA-like agents.
In a third aspect, the invention includes a method of increasing BND in an individual undergoing treatment for systemic lupus erythematosus (SLE) by daily administration of a DHEA-like agent. The method includes administering a calcitonin-like agent to the patient, in an average daily amount of at least about 50 IU per day. The individual is preferably a human patient having a subnormal BMD. In a preferred embodiment, the individual is being treated with a daily dose of about 50-200 mg/day DHEA, administered orally, and calcitonin is administered parenterally or orally in an average daily dose of about 50-200 IU calcitonin, preferably for at least about 25 weeks.
In a fourth aspect, the invention includes a method for inhibiting bone loss in an individual in need of such treatment, by administering a therapeutically effective amount of a DHEA-like agent and an antiresorptive agent, such as a calcitonin-like agent or a bisphosphonate, to the individual.
The invention additionally provides a pharmaceutical formulation for inhibiting bone loss in an individual comprising a therapeutically effective amount of a dehydroepiandrosterone (DHEA)-like agent and a therapeutically effective amount of an antiresorptive agent selected from the group consisting of a calcitonin-like agent and a bisphosphonate.
The methods and formulations of the invention preferably employ DHEA compositions having desirable bioavailability. In particular, at least about 85%, and more preferably at least about 95%, of the DHEA is present in such compositions as the form I polymorph, the form II polymorph, or a combination thereof.
Loss of bone mineral density (BMD) is common in post-menopausal women, people who are severely inactive, e.g., bedridden, and in patients undergoing a variety of immuosuppressive or anti-inflammatory therapies with compounds such as corticosteroids and methotrexate. In all of these cases, it is important to restore BMD to a level that does not leave the patient exposed to low-stress bone fractures or other bone pathologies associated with low BMD. In particular, in patients undergoing therapy by a compound that leads to bone density loss, it is important to restore bone density without having to cut back or discontinue the therapy.
The present invention provides novel methods and formulations for increasing, maintaining, and/or inhibiting loss of BMD that offer the following advantages over prior-art approaches: (i) these novel methods and formulations can lead to dramatic increases, on the order of 15-30%, in BMD over a treatment period of 1-2 years; (ii) the two preferred treatment compoundsxe2x80x94calcitonin and DHEAxe2x80x94are both natural human hormones, and therefore, well-tolerated by human patients, and (iii) treatment can be carried out successfully even in patients undergoing concomitant drug therapy that would otherwise tend to reduce bone mass.
Unless otherwise indicated, the terms below have the following meaning herein.
xe2x80x9cSubnormal bone mineral density (BMD)xe2x80x9d in a patient means a level that would classify the patient as having osteopenia, osteoporosis, or established osteoporosis as defined by the following World Health Organization categories based on T-score values:
Normal: a value of BMD not more than 1 standard deviation (SD) below the young adult mean value (T greater than xe2x88x921.0);
Osteopenia: a BMD that is between 1 and 2.5 SD below the young adult mean (xe2x88x921.0 greater than T greater than xe2x88x922.5);
Osteoporosis: a BMD value more than 2.5 SD below the young adult mean value (T less than xe2x88x922.5);
Established osteoporosis: a BMD value more than 2.5 SD below the young adult mean value (T less than xe2x88x922.5) in the presence of one or more fragility fractures.
BMD standard deviations are generally calculated from population standards that have been derived for normal age-related bone density of the femur and spine as measured by dual x-ray absorptiometry (DEXA). BMD results on an individual patient are compared to values obtained for a healthy reference population (usually healthy subjects aged 25-35 years, and matched for sex and race as measured on any particular manufacturer""s machine). The T-score is calculated a measured BMD minus young adult mean BMD/young adult standard deviation (SD).
The term xe2x80x9ctreatmentxe2x80x9d refers to therapy, which ameliorates a symptom of an existing disorder (by affecting the symptom and/or by affecting a cause of the disorder) or which prevents or reduces the progression of the disorder. As used herein, the term xe2x80x9ctreatmentxe2x80x9d also encompasses prophylaxis, i.e., reducing the risk that a disorder will develop.
A drug effect of one drug, e.g., calcitonin, is xe2x80x9cpotentiatedxe2x80x9d by another drug, e.g., DHEA, if the combined therapeutic effect of the two drugs is greater than the sum of the individual effects of the drugs, when each is drug administered alone.
The term xe2x80x9cDHEAxe2x80x9d or xe2x80x9cdehydroepiandrosteronexe2x80x9d includes pharmaceutically active acid, salt, and ester forms of DHEA, such as DHEA sulfate (e.g., Heinz).
xe2x80x9cDHEA metabolitesxe2x80x9d include steroids for which DHEA is a normal body precursor, including the immediate metabolic products of DHEA, 7-alpha-hydroxy-DHEA, 5-androstene-3 beta, 17beta-diol (Morfin), and 4-androstene diol (Bird), and further conversion to several other C19-steroids, including C19-steroid sulfates (Bird), including various androgenic or estrogenic steroids (Labrie, 1991, 1995, 1997; Young).
xe2x80x9cDHEA-like agentsxe2x80x9d include xe2x80x9cDHEAxe2x80x9d and xe2x80x9cDHEA metabolites.xe2x80x9d
xe2x80x9cCalcitoninxe2x80x9d refers to a 32-amino-acid residue peptide hormone which plays an important role in maintaining serum calcium levels (Epand). The term encompasses calcitonin from salmon (Epand) or from a variety of mammalian sources, such as human. (Katahara), porcine, murine, or rat. The term xe2x80x9ccalcitoninxe2x80x9d also encompasses active peptide analogs (e.g., Uda, Suva, Stroop, Cerovsky, Pozvek, and Jablonski), and mimetics, such as described for example, in U.S. Pat. Nos. 5,719,122, 5,175,146, and 5,698,6721.
The xe2x80x9ccalcitonin superfamilyxe2x80x9d consists of calcitonin, calcitonin gene-related peptide (CGRP), and amylin (Wimalawansa). Calcitonin and CGRP derive from the CT/CGRP gene, in humans. Alternative splicing of the primary RNA transcript leads to the translation of CGRP and CT peptides in a tissue-specific manner. CGRP (a 37-amino-acid neuropeptide) and its receptors are widely distributed in the body. Amylin (a 37-amino-acid peptide) is generated from a gene located on chromosome 12 (thought to be an evolutionary duplication of chromosome 11) and shares 46% amino acid sequence homology with CGRP and 20% with human calcitonin.
The term xe2x80x9ccalcitonin gene-related peptidexe2x80x9d or xe2x80x9cCGRPxe2x80x9d includes native CGRP, preferably human CGRP, and its active analogs (e.g., Boulanger, Hakala). CGRP is known to have a variety of roles in bone formation (Ballica, Wimalawansa, Vignery).
The term xe2x80x9camylinxe2x80x9d includes native amylin, typically from a human source, and its pharmaceutically active analogs (Borm). The hormone is known to induce bone-mass formation through a variety of mechanisms (Romero, Cornish, 1995, 1998).
xe2x80x9cCalcitonin-like agentsxe2x80x9d include xe2x80x9ccalcitonin,xe2x80x9d xe2x80x9cCGRP,xe2x80x9d and xe2x80x9camylin.xe2x80x9d
An xe2x80x9caverage amountxe2x80x9d, referring to a daily average dose of drug refers to the amount of drug administered over a given number of days, divided by that number of days. Thus, calcitonin administered in a total dose of 1,000 IU over a 5-day period, e.g., from a depot-release device, represents an average daily dose of the compound of 200 IU/day.
A xe2x80x9ctherapeutically effectivexe2x80x9d amount is an amount sufficient to treat (as defined above) a disorder.
Female patients with systemic lupus erythematosus (SLE) were treated with DHEA (dehydroepiandrosterone, prasterone) 200 mg/day for up to 2 years. Patients who had been treated with prednisone (or other glucocorticoids) for at least 6 months prior to entry into the study underwent DEXA evaluation of the lumbar vertebrae (L1-L4) and the nondominant proximal femur (neck, Ward""s triangle, trochanter, and intertrochanteric region) of baseline (prior to treatment with DHEA) and at 1 year. A few patients were also studied out to 2 years. Scans at baseline, 1 and 2 years were conducted on the same machines. Centers were required to conduct quality control including scanning of phantoms for determination of precision. All DEXA scans and precision data were monitored at a central facility for quality control.
Two patients treated with salmon calcitonin and DHEA had clinically meaningful increases in bone density as measured by DEXA. These findings were unexpected in view of the variable response to calcitonin reported in the literature and the fact that both of these patients were cotreated with prednisone, a potent steroid known to cause bone loss, for control of their lupus disease activity. One patient also was treated with high doses of methotrexate, 15 mg/week, for control of her lupus disease activity. Methotrexate in conjunction with prednisone has been reported to promote osteoporosis (Buckley 1997).
Specifically: Patient A was treated with DHEA 200 mg/day for 2 years and also received prednisone at 5 mg/day at entry into the study. During the study, she was able to reduce her prednisone dose to 0 mg/day. Patient B was treated with high-dose methotrexate, 15 mg/week, and prednisone at 10 mg/day, during one year of treatment with DHEA at 200 mg/day. She received 200 IU daily of calcitonin and calcium supplements. The results are shown in Table 1 below.
As seen, both patients A and B demonstrated clinically meaningful improvements in bone density while receiving treatment with DHEA, calcitonin and various other therapies including calcium supplements and vitamin D. The improvement in Patient A for both hip-bone density and spinal-bone density was in the 15%-30% range, a remarkable improvement over the very small percentage changes normally seen in BMD under calcitonin treatment alone, or DHEA treatment alone.
While the improvement in patient B was not as great as that in patient A, the fact that Patient B was able to improve her bone density is remarkable in view of the fact that she was receiving high-dose steroids and high-dose methotrexate while participating in the 2 years of the study. The combination of steroids and methotrexate has been found to be particularly damaging to bone (Buckley 1997), and any degree of improvement in this setting is highly meaningful.
The clinical trial data show that the effect on BMD of calcitonin treatment in a patient with subnormal BMD can be potentiated by administering DHEA to the patient while calcitonin treatment is continued. In particular, the use of DHEA in combination with calcitonin produces an increase in BMD that is greater than the expected sum of increases in BMD, were the patient to be treated individually with either drug alone.
A. In General
The invention provides treatment methods that exploit the ability of co-administration of a calcitonin-like agent and a dehydoepiandrosterone (DHEA)-like agent to potentiate any increase in bone mineral density (BMD) achievable by administration of the calcitonin-like agent alone. In one method, a calcitonin-like agent is administered to an individual and a dehydroepiandrosterone (DHEA)-like agent is also administered to the individual during the period of calcitonin-like agent administration. The amounts of calcitonin- and DHEA-like agents administered are, in combination, effective to increase BMD, and the co-administration of calcitonin- and DHEA-like agents potentiates any increase in BMD achievable by administration of that amount of calcitonin-like agent alone.
A second treatment method is directed to potentiating the effect of treatment with a calcitonin-like agent on an individual""s BMD. In this method, DHEA is administered to the individual during the period of calcitonin-like agent treatment. In a preferred embodiment of this method, the DHEA dose is at least about 50 mg per day.
A third treatment method is directed to increasing BMD in an individual undergoing treatment for systemic lupus erythematosus (SLE). This method entails administering a calcitonin-like agent to an individual receiving a daily dose of a DHEA-like agent. In a preferred embodiment, the calcitonin-like agent is administered at a dose designed to provide an average daily dose of at least about 50 IU per day.
In a fourth treatment method, a therapeutically effective amount of a dehydroepiandrosterone (DHEA)-like agent and an antiresorptive agent selected from the group consisting of a calcitonin-like agent and bisphosphonate is administered to an individual to inhibit bone loss (i.e., to help maintain or increase BMD).
Those of skill in the art readily appreciate that the periods of administration of calcitonin-like agent and DHEA-like agent need not be exactly coextensive in the treatment methods of the invention. The treatment methods encompass any period of co-administration of these agents sufficient to potentiate increases in BMD. Generally, the period of co-administration is at least about 4 weeks, preferably at least about 25 weeks, more preferably at least about 1 or 2 years or longer. Co-administration is usually continued for as long as improvement in BMD is being observed.
The individual treated can be any animal, but is usually a mammal, and preferably a human patient. In preferred embodiments, the individual has a subnormal BMD.
B. Calcitonin-like Agents
The treatment method of invention can employ any calcitonin-like agent, typically in combination with a physiologically acceptable carrier, excipient, or stabilizer that is non-toxic to recipients at the dosages employed.
Calcitonin, or a peptide analog or thereof, is available from a variety of sources. One preferred compound is recombinant salmon calcitonin, available, for example, from Novartis. Human calcitonin is also suitable, as are a variety of synthetic analogs (see references above in definition of xe2x80x9ccalcitonin,xe2x80x9d including U.S. Pat. No. 5,175,146).
Calcitonin may be administered parenterally, e.g., by intravenous, intramuscular, or subcutaneous injection; transmucosally, transdermally, intranasally, or by lung inhalation. Oral forms of calcitonin are also available, e.g., U.S. Pat. Nos. 5,912,014, 5,726,154, and 5,441,933.
U.S. Pat. No. 5,912,014, for example, describes an oral calcitonin formulation-designed to reduce proteolytic degradation of the calcitonin by stomach proteases and intestinal or pancreatic proteases. Briefly, calcitonin is transported through the stomach under the protection of an enteric coating or other appropriate vehicle for substantially preventing contact between the calcitonin and stomach proteases capable of degrading it. When the formulation reaches the intestinal region, where basic to neutral pH predominates, and where proteases tend to have basic to neutral pH optima, the enteric coating or other vehicle releases the calcitonin and a pH-lowering agent (in close proximity to each other). The resultant decrease in pH reduces the proteolytic activity of the intestinal proteases, thus protecting the calcitonin from degradation. The formulation also contains an absorption enhancer that speeds the transport of calcitonin from the intestine to the blood, so that substantial absorption occurs while conditions of reduced proteolytic activity prevail.
Bioavailability of such oral calcitonin formulations is enhanced when the active components of the formulation are released together. To this end, the volume of enteric coating is preferably as low as possible, consistent with providing protection from stomach proteases. In general, enteric coatings that add less than 20% to the weight of the remainder of pharmaceutical formulation (i.e., before enteric coating) are preferred.
Calcitonin is preferably administered in an amount providing an average daily dose of between 50-200 IU/per day, meaning that the patient is receiving an average of between 50-200 IU day. This can be achieved either by daily administration or through the use of an extended-delivery device, such as a transdermal patch or an implantable delivery device.
Other calcitonin-like agents, such as CGRP and amylin, can be obtained or synthesized by known methods and delivered as described for calcitonin.
Treatment with calcitonin may be supplemented with oral delivery of calcium and/or vitamin D.
C. DHEA-like Agents
The treatment methods of the invention can employ any DHEA-like agent, typically in combination with a physiologically acceptable carrier, excipient, or stabilizer that is non-toxic to recipients at the dosages employed. DHEA can be isolated in at least 6 different polymorphic forms, as described in detail in co-owned PCT Application No. PCT/US/00/06987 (International Publication No. WO 00/54763). DHEA was previously known, via analytical techniques such as x-ray diffraction, infrared (IR) spectroscopy, and differential scanning calorimetry (DSC), to occur in several different hydrate and anhydrate crystal forms. The anhydrate forms include forms I, II, III, IV and V, although the latter two forms have been observed only transiently by DSC. The hydrates (solvates) include forms S1 (1/4 hydrate), S2 (monohydrate), S3 (monohydrate), and S4 (1/2 methanolate). PCT Application No. PCT/US/00/06987 describes an additional form, form VI, which is detectable only by solid state NMR.
In preferred embodiments of the present invention, the DHEA employed has defined bioavailabilities and pharmacokinetic properties, which can be achieved by using preparations containing polymorphs that provide the desired properties.
In one aspect, the treatment methods of the invention employ a DHEA preparation that is at least about 85%, preferably at least about 90%, more preferably at least about 95%, and most preferably at least about 99%, form I. The form I polymorph has the following characteristics:
(1) X-Ray Powder Diffraction unique peaks at 15.0 (s), 16.8 (w), 18.0 (m), 18.7 (m), 19.1 (w), 19.3 (w), 20.2 (w), 24.8 (w) 25.0 (w), 25.2 (w) (peak positions are given in degrees 2xcex8; s=strong, m=medium, w=weak); and
(2) Solid State 13C-NMR peaks: 14.8, 14.1 ppm carbon no. 18, 120.4, 118.9 ppm carbon no. 6, where these characteristics are measured as described in PCT Application No. PCT/US/00/06987.
DHEA form I-containing preparations exhibit good uptake by the GI tract upon oral administration, show good therapeutic activity, and are highly stable under ambient conditions.
In another aspect, the DHEA preparation is at least about 85%, preferably at least about 90%, more preferably at least about 95%, and most preferably at least about 99% form II. The form II polymorph has the following characteristics:
(1) X-Ray Powder Diffraction unique peaks at 8.6 (w), 17.3 (w), 20.9 (m), 22.0 (w), 22.2 (w), 27.1 (w) (peak positions are given in degrees 2xcex8; s=strong, m=medium, w=weak); and
(2) Solid State 13C-NMR peaks: 13.1 ppm carbon no. 18, 119.9 ppm carbon no. 6, where these characteristics are measured as described in PCT Application No. PCT/US/00/06987.
DHEA form II-containing preparations exhibit good uptake by the GI tract upon oral administration, a rapid rate of absorption (greater than the form I polymorph) and good therapeutic activity, and are also stable under ambient conditions.
Additionally, DHEA preparations useful in the treatment methods can contain mixtures of the form I and II polymorphs. Generally, the combined form I and II polymorphs account for at least about 85%, preferably at least about 90%, more preferably at least about 95%, and most preferably at least about 99% of the DHEA in such preparations. Preparations enriched in form I and/or form II, as described herein, provide more predictable pharmnacokinetic profiles than are provided by formulations having random polymorphic compositions.
Such formulations, including DHEA and precursors such as DHEA acetate, are commercially available from various sources (e.g., Sigma Chemical Co., St. Louis, Mo.; Aldrich Chemical Company, Inc.; Diosynth, Inc.; Pfaltz and Bauer, Inc.; Schering AG). DHEA formulations enriched for selected polymorphs can be prepared by crystallization of commercial DHEA in selected solvents under appropriate cooling or evaporation conditions.
In one preferred method, pure form I is prepared by (a) crystallizing DHEA from anhydrous 2-propanol (or, alternatively, acetone or acetonitrile) under a nitrogen stream at room temperature over about 2 days, producing a crystalline precipitate that contains predominantly form I and some amount of form VI, followed by (b) suspending the precipitate in ethyl acetate (about 100 ml/30 g of DHEA) and stirring the resulting slurry at room temperature for about one week, followed by filtration. The filter cake is allowed to dry at room temperature overnight. 13C-SSNMR analysis (discussed below) showed that product prepared by this method consisted of pure or nearly pure ( greater than 99%) form I; no other forms were detected by 13C-SSNMR.
DHEA highly enriched for form II can be obtained by rapid crystallization from tetrahydrofuran (THF), dioxane, chloroform or mixtures of chloroform and THF. Example 1 of PCT Application No. PCT/US/00/06987 provides a specific procedure for crystallization from THF, which produced a product shown by X-ray powder diffraction to be pure form II.
DHEA may be administered in a variety of ways, including parenterally, e.g., by intravenous, intramuscular, or subcutaneous injection; transmucosally, transdermally, intranasally, or by lung inhalation, although oral administration is generally preferred.
Depending upon the manner of introduction, the DHEA may be formulated in a variety of ways. DHEA formulations can be prepared in various pharmaceutical forms, such as granules, tablets, capsules, suppositories, powders, controlled release formulations, suspensions, emulsions, creams, ointments, salves, lotions, or aeresols and the like.
Preferably, DHEA formulations are employed in solid dosage forms suitable for simple, and preferably oral, administration of precise dosages. Solid dosage forms for oral administration are preferably tablets, capsules, or the like.
DHEA formulations useful in the invention can include one or more pharmaceutical grade organic or inorganic carriers, excipients, and/or diluents, especially those suitable for oral or topical use. Such carriers include tocopherol, dimethyl sulfoxide, and the like. For oral administration, suitable excipients include lactose, mannitol, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
To prepare orally deliverable tablets, DHEA is mixed with at least one pharmaceutical excipient, and the solid formulation is compressed to form a tablet according to known methods, for delivery to the gastrointestinal tract. The tablet composition is typically formulated with additives, e.g. a saccharide or cellulose carrier, a binder such as starch paste or methyl cellulose, a filler, a disintegrator, or other additives typically usually used in the manufacture of medical preparations. To prepare orally deliverable capsules, DHEA is mixed with at least one pharmaceutical excipient, and the solid formulation is placed in a capsular container suitable for delivery to the gastrointestinal tract.
Diluents known in the art include, for example, vegetable and animal oils and fats. Stabilizing agents, wetting and emulsifying agents, salts for varying the osmotic pressure, buffers for securing an adequate pH value, and/or skin penetration enhancers can be used as auxiliary agents in the DHEA formulations. Methods for preparing various conventional dosage forms are known or will be apparent to those skilled in the art; for example, see Remington""s Pharmaceutical Sciences (19th Ed., Williams and Wilkins, 1995).
The proportion of pharmaceutically active DHEA to carrier and/or other substances may vary from about 0.5 to about 100 wt. % (weight percent). For oral use, the pharmaceutical formulation will generally contain from about 5 to about 100% by weight of the active material. For other uses, the formulation will generally have from about 0.5 to about 50 wt. % of the active material.
DHEA formulations employed in the invention provide an effective amount of DHEA upon administration to an individual. As used in this context, an xe2x80x9ceffective amountxe2x80x9d of DHEA is an amount that is effective to ameliorate a symptom of SLE. Such an effect is generally observed within about 4 to about 6 weeks of initiating administration of an effective amount of DHEA.
The subject formulations are preferably, though not necessarily administered daily, in an amount to provide at least about a 10%, and more usually at least about 25%, increase in the blood level of DHEA. Generally, the total daily dosage will be at least about 50 mg, preferably at least about 100 mg, and more preferably at least about 200 mg, and preferably not more than 500 mg per day, administered orally, e.g., in 4 capsules or tablets, each containing 50 mg DHEA. Capsules or tablets for oral delivery can conveniently contain up to a full daily oral dose, e.g., 200 mg or more. When administered by other than an oral route, the DHEA may be delivered over an extended period, e.g., 3-10 days, in an amount effective to produce at least an average daily dose of, e.g., 50 mg.
D. Co-administration of Calcitonin and DHEA
In preferred embodiments of the treatment methods of the invention, calcitonin is co-administered with DHEA. Generally, calcitonin is administered in an average amount of at least about 50 IU per day, and DHEA is administered orally in an amount of at least about 50 mg per day. Preferably, calcitonin is administered in an average amount of at least about 100 IU per day, and DHEA is administered orally in an amount of at least about 100 mg per day. More preferably, calcitonin is administered in an average amount of at least about 200 IU per day, and DHEA is administered orally in an amount of at least about 200 mg per day.
E. Administration of Other Drugs
The methods of the invention are particularly beneficial where the individual is being treated with a drug or drugs that cause a loss of BMD. For example, the use of corticosteroids (usually glucocorticoids), ubiquitously used as treatment for many autoimmune diseases and to inhibit rejection following transplantation, is associated with significantly increased rates of bone loss and bone fracture. Longitudinal studies have shown rapid early bone loss during steroid use. One study reported an 8% loss of trabecular bone mass in the lumbar spine in patients with rheumatoid arthritis treated for 6 months with steroids (Laan). Recently, even small doses of corticosteroids, thought to be xe2x80x9cphysiologic replacement dosesxe2x80x9d were reported to be associated with significantly increased rates of fracture. Doses as low as prednisone 2.5 to 7.5 mg/day were found to be associated with a relative risk of hip fracture of 1.77 (95% confidence interval 1.55-2.02) and over 7.5 mg 2.27 (1.94-2.66) (van Staa). Immunosuppressants, such as methotrexate used in treatment of leukemia, rheumatoid arthritis, SLE, and many other diseases, have been reported to increase bone loss.
Thus, for individuals receiving prednisone, methotrexate or other immunosuppressants or anti-inflammatory agents, that are known to cause or contribute to loss of BMD, the combined treatment with a calcitonin-like agent and a DHEA-like agent may be carried out as immunosuppressant or antisense-inflammatory treatment is continued. Where the patient is undergoing treatment with DHEA, for example, in the treatment of systemic lupus erythematous (SLE), particularly in combination with an immunosuppressant or an anti-inflammatory agent, like a corticosteroid (e.g., prednisone), that is known to cause or contribute to bone resorption, calcitonin may added to the SLE treatment regimen.
In a preferred embodiment, an SLE patient receiving at least about 7.5 mg of a corticosteroid per day, for treatment of SLE, is also treated with calcitonin and DHEA to increase BMD.
The invention also provides a pharmaceutical formulation for inhibiting bone loss in an individual comprising a therapeutically effective amount of a dehydroepiandrosterone (DHEA)-like agent and a therapeutically effective amount of an antiresorptive agent selected from the group consisting of a calcitonin-like agent and a bisphosphonate. These agents are referred to herein as xe2x80x9cactive agents.xe2x80x9d The DHEA-like agent is preferably DHEA, 7-alpha-hydroxy-DHEA, 5-androstene-3-beta, 17-beta-diol, or 4 androstene diol. The calcitonin-like agent is preferably calcitonin, calcitonin gene-related peptide (CGRP), and/or amylin. Any bisphosphonate useful for inhibiting bone loss, such as alendronate, can be empolyed in such formulations. In particularly preferred embodiments, the formulation includes calcitionin in combination with DHEA.
As discussed above, the DHEA form I and II polymorphs are preferred for use in the invention. Accordingly, preferred formulations are those in which at least about 85%, and more preferably, at least about 95%, of the DHEA is present as the form I polymorph, the form II polymorph, or a combination thereof.
Pharmaceutical formulations containing a calcitonin-like agent and a DHEA-like agent that are suitable for administration through a variety of routes, such as orally, parenterally, e.g., by intravenous, intramuscular, or subcutaneous injection; transmucosally, transdermally, intranasally, or by lung inhalation can be designed in accordance with standard formulation techniques and the guidance herein. Oral formulations are preferred for their ease of administration.
Generally, pharmaceutical formulations of the invention provide a daily dose of DHEA-like agent of at least about 50 mg, preferably at least about 100 mg, and more preferably at least about 200 mg. Such formulations typically provide a calcitonin-like agent in an average amount of at least about 50 IU per day, preferably at least about 100 IU per day, and more preferably at least about 200 IU per day.
As described above, formulations of calcitonin-like agents and/or DHEA-like agents can include a physiologically acceptable carrier, excipient, or stabilizer. Examples of such components include, in addition to those discussed above, a buffer (such as a phosphate buffer, citrate buffer, and buffers made from other organic acids), an antioxidant (e.g., ascorbic acid), low-molecular weight (less than about 10 residues) polypeptide, a protein (such as serum albumin, gelatin, and an immunoglobulin), a hydrophilic polymer (such as polyvinylpyrrolidone), an amino acid (such as glycine, glutamine, asparagine, arginine, and lysine), a monosaccharide, a disaccharide, and other carbohydrates (including glucose, mannose, and dextrins), a chelating agent (e.g., ethylenediaminetetratacetic acid [EDTA]),a sugar alcohol (such as mannitol and sorbitol), a salt-forming counterion (e.g., sodium), and/or an anionic surfactant (such as Tween(trademark), Pluronics(trademark), and PEG).
In one embodiment, the invention provides sustained-release pharmaceutical formulations. An exemplary sustained-release formulation has a semipermeable matrix of a solid hydrophobic polymer to which the active agents of the invention are attached or in which the active agents are encapsulated. Examples of suitable polymers include a polyester, a hydrogel, a polylactide, a copolymer of L-glutamic acid and T-ethyl-L-glutamase, non-degradable ethylene-vinylacetate, a degradable lactic acid-glycolic acid copolymer, and poly-D-(xe2x88x92)-3-hydroxybutyric acid. Such matrices are in the form of shaped articles, such as films, or microcapsules.
Exemplary sustained release formulations include an active agent attached to a polyalkylene glycol (e.g., polyethylene glycol [PEG]). Attachment of PEG to proteins is a well-known means of reducing immunogenicity and extending in vivo half-life of polypeptides (see, e.g., Abuchowski, J., et al. (1977) J. Biol. Chem. 252:3582-86). Any conventional xe2x80x9cpegylationxe2x80x9d method can be employed, provided the xe2x80x9cpegylatedxe2x80x9d agent retains its pharmaceutical activity.
In another embodiment, a sustained-release formulation includes a liposomally entrapped active agents. Liposomes are small vesicles composed of various types of lipids, phospholipids, and/or surfactants. These components are typically arranged in a bilayer formation, similar to the lipid arrangement of biological membranes. Liposomes containing active agents are prepared by known methods, such as, for example, those described in Epstein, et al. (1985) PNAS USA 82:3688-92, and Hwang, et al., (1980) PNAS USA, 77:4030-34. Ordinarily the liposomes in such preparations are of the small (about 200-800 Angstroms) unilamellar type in which the lipid content is greater than about 30 mol. percent cholesterol, the specific percentage being adjusted to provide the optimal therapy. Useful liposomes can be generated by the reverse-phase evaporation method, using a lipid formulation including, for example, phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). If desired, liposomes are extruded through filters of defined pore size to yield liposomes of a particular diameter.
Pharmaceutical formulations can also include an active agent adsorbed onto a membrane, such as a silastic membrane, which can be implanted, as described in International Publication No. WO 91/04014.
Pharmaceutical formulations of the invention can be stored in any standard form, including, e.g., an aqueous solution or a lyophilized cake. Such formulations are typically sterile when administered to recipients. Sterilization of an aqueous solution is readily accomplished by filtration through a sterile filtration membrane. If the formulation is stored in lyophilized form, the formulation can be filtered before or after lyophilization and reconstitution.
The invention also provides articles of manufacture including such formulations and related kits. The invention encompasses any type of article including a formulation of the invention, but the article of manufacture is typically a container, preferably bearing a label identifying the formulation contained therein. The container can be formed from any material that does not react with the contained formulation and can have, any shape or other feature that facilitates use of the formulation for the intended application.
Kits of the invention generally include one or more such articles of manufacture and preferably include instructions for use. The instructions can be affixed to the packaging material or can be included as a package insert. While the instructions typically comprise written or printed materials they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this invention. Such media include, but are not limited to, electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. As used herein, the term xe2x80x9cinstructionsxe2x80x9d can include the address of an internet site that provides the instructions.
All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.

Treatment of subnormal bone mineral density


A two-component concentrate which includes an aqueous dispersion of a cathodically depositable binder having groups comprising active hydrogen that are cross-linkable using blocked polyisocyanate, as the binder component, and an anhydrous, organic solution of an oxime-blocked isocyanate-functional adduct of aromatic polyisocyanate and at least one compound comprising at least one group capable of addition towards isocyanate and at least one tertiary amino group, as the cross-linking component is used for the preparation of cathodic electrodeposition coating compositions.

The invention relates to a concentrate suitable for the preparation of cathodically depositable coating compositions (i.e., cathodic electrodeposition coating compositions) and to the use thereof for the preparation of cathodic electrodeposition (xe2x80x9cCEDxe2x80x9d) coating compositions.
The majority of the CED coating compositions currently employed contain cathodically depositable binders having functional groups comprising active hydrogen, for example hydroxyl groups, primary and/or secondary amino groups, and blocked polyisocyanates as the cross-linking agents. The CED coating compositions are provided as one- or two-component materials, from which cathodic electrodeposition-baths can either be prepared afresh or a compensation of the solids of cathodic electrodeposition-baths in use can be carried out. The one-component materials are water-containing concentrates containing binders and cross-linking agents and, in general, pigments, whereas two-component materials include an aqueous dispersion containing binders and cross-linking agents and a separate aqueous pigment paste.
For reasons of conserving energy, there has been a desire, in particular in the automotive industry, to obtain CED coating compositions that can be stoved at low temperatures.
CED coating compositions that are curable at a low stoving temperature, which contain cathodically depositable binders that are curable with blocked polyisocyanates, and blocked polyisocyanates having isocyanate groups which are bonded to aromatic rings and are blocked with oximes, as the curing agents, are for example known from EP-A-0 199 663, U.S. Pat. Nos. 4,596,744, 4,872,961, 5,096,555 and 5,461,091. The CED materials disclosed therein are chemically unstable. They undergo to a certain extent a decomposition that surprisingly creates no adverse effects in CED coating, but creates problems during transport and storage of the CED materials. During the decomposition, a pressure build-up occurs within the containers containing the CED coating compositions. The speed of the decomposition process depends in particular on the temperature and may lead to an accelerated pressure build-up at high temperatures. The handling of these CED coating compositions in open containers is not allowed under applicable legal restrictions and also for practical reasons. Although the use of pressure containers or pressure compensation containers could be a possible solution for the problem, these CED coating compositions have not been successful, however, in practice because of the requirements involved.
The object of the invention is to provide CED coating compositions which are curable at a low stoving temperature, and which overcome the aforementioned problems.
The present invention provides a two-component concentrate suitable for the preparation of cathodic electrodeposition coating compositions, comprising, in combination, (a) a binder component comprising an aqueous dispersion of a CED binder having groups comprising active hydrogen that are cross-linkable using blocked polyisocyanate; and (b) a cross-linking component comprising an anhydrous, organic solution of an oxime-blocked isocyanate-functional adduct of an aromatic polyisocyanate and at least one compound comprising at least one group capable of addition towards isocyanate and at least one tertiary amino group.
The concentrate according to the invention contains a binder component and a cross-linking component. The binder component is an aqueous dispersion of a CED binder having functional groups comprising active hydrogen that can be chemically cross-linked by using the oxime-blocked isocyanate groups of the cross-linking component.
CED binders carry cationic groups or groups able to be converted into cationic groups, e.g. alkaline groups, e.g. amino groups, ammonium groups, for example quaternary ammonium, phosphonium and/or sulphonium groups. Preferred are alkaline groups, in particular preferred are nitrogen-containing alkaline groups, such as amino groups. These groups may be present in quaternised form, or they are converted into cationic groups with a conventional neutralising agent, for example lactic acid, formic acid, acetic acid, methanesulfonic acid. The groups able to be converted into cationic groups may be present in completely or partially neutralised form. They are preferably resins containing amino groups, preferably tertiary amino groups, the total amine value of which is 20 to 150, preferably 50 to 100 mg KOH/g. The total amine value consists in this case of 50 to 100, preferably 80 to 100, in particular preferably 100% of tertiary amino groups. The weight average molecular mass (Mw) of these binders is preferably about 300 to 10000.
The CED binders contain functional groups comprising active hydrogen that can be cross-linked with the oxime-blocked polyisocyanate. Examples of such functional groups are primary amino groups, secondary amino groups and in particular hydroxyl groups. Combinations of these groups may be present in the same CED binder, but preferably there are no primary or secondary amino groups apart from the hydroxyl groups. The proportion of the groups comprising active hydrogen in the CED binders corresponds to an active hydrogen value of 50 to 300 mg KOH/g, corresponding to a sum of primary amine value, secondary amine value and hydroxyl value. The hydroxyl value is generally in the range of 50 to 250 mg KOH/g.
CED binders suitable for use in the present invention are known to the person skilled in the art and are conventional amino(meth)acrylic resins, aminopolyurethane resins, amino group-containing polybutadiene resins, epoxy resin-carbon dioxydeamine-reaction products and in particular aminoepoxy resins, for example aminoepoxy resins having primary OH-groups.
An aqueous dispersion of the CED binders is prepared according to methods known to those skilled in the art. For example, the CED binders may be neutralised with acid and diluted with water. Organic solvents that may be present can be removed (or eliminated) by vacuum distillation or other known method. It is also possible to prepare the CED binder in a way to minimize the presence of organic solvents, such as neutralising with acid in the low-solvent state or as a solvent-free melt and then diluting with water to make the dispersion. In addition, the CED binders can also be neutralised with acid as a solution in an olefinically unsaturated monomer capable of radical polymerisation, and then be converted into an aqueous dispersion by diluting with water, followed by a subsequent total polymerisation of the monomer capable of radical polymerisation.
The cross-linking component of the concentrate according to the invention is an anhydrous, organic solution of an oxime-blocked isocyanate-functional reaction product of aromatic polyisocyanate and at least one compound comprising at least one group capable of addition towards isocyanate and at least one tertiary amino group. The reaction products blocked with oxime are designated in short as xe2x80x9ccross-linking agentsxe2x80x9d herein.
The cross-linking agents are prepared by reacting one or more aromatic polyisocyanates with at least one compound comprising at least one group capable of addition towards isocyanate and at least one tertiary amino group and one or more oximes (as the blocking agents). The reaction can take place at temperatures of 20 to 75xc2x0 C. as a one-step process or in general as a multi-step process. In a multi-step process, for example, at first an isocyanate-functional reaction product is prepared, the free isocyanate groups of which are blocked with oxime in a subsequent step. Alternatively, at first the aromatic polyisocyanate is partially blocked with oxime prior to the reaction with the further components.
Examples of aromatic polyisocyanates suitable for preparing the cross-linking agents are aromatic diisocyanates (diisocyanates having at least one isocyanate group bonded to an aromatic ring) such as phenylene, toluylene, xylylene or naphthylene diisocyanate and in particular diphenylmethane diisocyanate, each being either in the form of the isomeric mixture or of pure isomers. Further examples are polyisocyanates derived from the aromatic diisocyanates, for example oligomers of the aromatic diisocyanates or isocyanurate or uretdione derivatives of the aromatic diisocyanates or isocyanate-functional adducts of aromatic diisocyanates and polyols or polyamines, such as, for example, trimethylolpropane, 1:1-adducts of dialkanolamines and cyclic carbonate and diethylene triamine.
Examples of compounds comprising at least one group capable of addition towards isocyanate and at least one tertiary amino group are corresponding aminoalcohols, such as dimethyl ethanolamine, dimethyl isopropanolamine, methyl diethanolamine or triethanolamine. Also suitable (and preferred) are polyamines having at least one tertiary amino group and at least one non-tertiary (i.e., primary or secondary) amino group, such as dialkyl aminoalkylamnine, for example diethyl aminopropylamine, dimethyl aminopropylamine and diethyl aminoethylamine.
Examples of oximes suited as the blocking agents are aldoximes or in particular ketoximes such as acetonoxime, cyclohexanonoxime and in particular butanonoxime.
Compounds having at least two groups containing active hydrogen per molecule can optionally be used to prepare the cross-linking agents. Such compounds include polyols, polyamines that contain no tertiary amino groups or aminoalcohols that contain no tertiary amino groups such as ethylene glycol, trimethylolpropane, glycerin, neopentyl glycol, hexanediol, ethylene diamine, diethylene triamine, ethanolamine and methyl ethanolamine.
In a preferred manner, the cross-linking agents comprise 8 to 20 wt-% of isocyanate groups blocked with oxime, calculated as NCO (molecular mass NCO=42), for example corresponding to a number of average 2 to 6 isocyanate groups blocked with oxime per molecule and an amine value of 10 to 50 mg KOH/g. The amine value results in this case from the tertiary amino groups. Hence, the aromatic polyisocyanates, the compounds comprising at least one group capable of addition towards isocyanate and at least one tertiary amino group, the oximes and optionally the compounds having at least two groups containing active hydrogen per molecule are preferably reacted together in such quantity proportions that the cross-linking agents have the aforementioned preferred content of isocyanate groups blocked with oxime and the aforementioned preferred amine value.
The preparation of the cross-linking agents can be carried out without solvents or in the presence of solvent(s) inert towards isocyanate, as the reaction medium. Preferably solvents that are not disturbing or that are even desired in the CED coating compositions, are used. Should an organic solution of the cross-linking agents be prepared which contains solvents that are reactive towards isocyanate, the latter can be added once the synthesis is complete, and any solvents optionally used before as the reaction medium can be removed as carefully as possible, for example by vacuum distillation, until the desired content is achieved.
It is essential to the invention that the cross-linking component is present as an anhydrous organic solution of the cross-linking agents, for example with a solids content of the solution of 50 to 90 wt-%. Examples of suitable organic solvents are solvents conventionally used in CED coating compositions, for example glycol ethers, such as butyl glycol, ethyl glycol, hexyl glycol, methoxypropanol and ethoxypropanol; alcohols, such as butanol and 2-ethylhexanol; ketones, such as methyl isobutylketone, cyclohexanone and methyl ethylketone; propylene carbonate. The cross-linking component is preferably present as a solution in an organic solvent or in a mixture of organic solvents, wherein the solvent (mixture) has a solubility in water of less than 250 g/l water at 20xc2x0 C.
The cross-linking component can contain the cross-linking agents in a non-neutralised form or preferably in a form neutralised with acid, for example corresponding to a neutralisation degree of 50 to 100%. For this purpose, suitable anhydrous acids can be added to the cross-linking agents in corresponding quantities. Examples of anhydrous acids suitable as neutralising agents are the acids conventionally used in CED coating compositions, for example formic acid, acetic acid and methanesulfonic acid.
The concentrate may also contain pigments, fillers and/or additives (collectively xe2x80x9cadditivesxe2x80x9d) that are essential to the preparation of CED coating compositions. These additives may be incorporated into the binder and/or isocyanate components of the concentrate, or may be added to the concentrate as separate components. Such separate components may include, for example, pigment pastes and/or filler pastes. The separate components may be added to the concentrate in any suitable water soluble or water-dilutable form known to those skilled in the art (e.g., as such, as an aqueous or organic solution or as an emulsion, for example).
Examples of pigments and fillers are the conventional inorganic and/or organic coloured pigments and/or effect pigments and/or pigments imparting electrical conductivity and/or fillers. These include, for example, titanium dioxide, iron oxide pigments, carbon black, graphite, phthalocyanine pigments, quinacridone pigments, metallic pigments, interferential pigments, kaolin, talcum, silicon dioxide or corrosion protective pigments. Pigment pastes and/or filler pastes can be prepared by dispersing the pigments and/or fillers in the CED binder or preferably in a paste resin and then ground and then mixed to completion with the outstanding portion of the CED binder or paste resin.
Examples of additives are wetting agents, neutralising agents, levelling agents, catalysts, corrosion inhibitors, defoamers, light protecting agents, antioxidants, radical scavengers and conventional anticratering additives.
The components of the concentrate according to the invention are components which are stable when stored, and which are to be stored separately. They can be stored in conventional, closed containers, such as normal barrels or containers. There is no decomposition with gas generation while the components are stored, and hence, no measures against any pressure build-up are required to be taken in the closed containers.
By mixing the binder component, the cross-linking component and optionally further components of the concentrate according to the invention and by diluting with water, CED coating compositions can be prepared that are curable at a low stoving temperature and that have the desired bath-solids content. The preferred proportion between the binder component and the cross-linking component is in this case 60 to 90 solids parts by weight of CED coating binder: 40 to 10 solids parts by weight cross-linking agent.
The components of the concentrate according to the invention can also be used as refill-materials in the course of a compensation of the solids of CED coating-baths which is required on a regular basis. For this purpose the components are mixed with CED coating-bath material which is poor in solids due to a deposit of CED coating and are then added again to the CED coating-bath.
The CED coating compositions to be prepared by using the concentrate according to the invention are conventional aqueous CED coating compositions having a solids content of for example 10 to 30 wt-%. The solids content consists of the resin solid and any pigments, fillers and non-volatile additives that are present. The resin solids include binders and cross-linking agents of the aforementioned binder and cross-linking component, and optionally paste resins. Apart from water and a content of organic solvents of for example 1.5 to 20 wt-%, based on the resin solids content, the CED coating compositions can also contain volatile additives. The ratio by weight of pigment plus filler/resin solids of the CED coating compositions is for example 0:1 to 0.8:1, preferably between 0.05:1 and 0.4:1 for pigmented CED coating compositions. The content of additives in the CED coating compositions is for example 0.1 to 5 wt-%, based on the resin solids content.
CED coating layers can be deposited from the CED coating compositions in conventional manner on electrically conductive substrates, such as, in particular, automotive bodies, and can be stoved at low stoving temperatures of for example 100 to 150xc2x0 C. object temperature. Higher stoving temperatures of for example up to 200xc2x0 C. object temperature are of course possible.
The CED coating layers can be deposited as an electrically isolating or electrically conductive primer, in the stoved state, on metallic substrates or as an intermediate or top layer on substrates that have been provided with an electrically conductive precoating, for example with an electrically conductive electro-dip primer. The CED coating layers can be stoved separately or together with one or more coating layers that are applied subsequently. Examples of subsequently applied coating layers are coating layers that are applied by spraying, for example primer surfacer, base coat or top coat layers. A subsequently applied coating layer can also be a coating layer that is applied by electrodeposition, if the CED coating layer applied and stoved beforehand has a sufficient electrical conductivity.

Concentrate suitable for the preparation of cathodic electrodeposition coating compositions