Methods, systems, devices and kits for performing lung volume reduction in patients suffering from chronic obstructive pulmonary disease or other conditions using and comprising minimally invasive instruments introduced through the mouth (endotracheally) to isolate a target lung tissue segment from other regions of the lung and reduce lung volume. Isolation is achieved by deploying an obstructive device in a lung passageway leading to the target lung tissue segment. Once the obstructive device is anchored in place, the segment can be aspirated through the device. This may be achieved by a number of methods, including coupling an aspiration catheter to an inlet port on the obstruction device and aspirating through the port. Or, providing the port with a valve which allows outflow of gas from the isolated lung tissue segment during expiration of the respiratory cycle but prevents inflow of air during inspiration. In addition, a number of other methods may be used. The obstructive device may remain as an implant, to maintain isolation and optionally allow subsequent aspiration, or the device maybe removed at any time.

1. Field of the Invention
The present invention relates generally to medical methods, systems, and kits. More particularly, the present invention relates to methods and apparatus for effecting lung volume reduction by aspirating isolated segments of lung tissue.
Chronic obstructive pulmonary disease is a significant medical problem affecting 16 million people or about 6% of the U.S. population. Specific diseases in this group include chronic bronchitis, asthmatic bronchitis, and emphysema. While a number of therapeutic interventions are used and have been proposed, none are completely effective, and chronic obstructive pulmonary disease remains the fourth most common cause of death in the United States. Thus, improved and alternative treatments and therapies would be of significant benefit.
Of particular interest to the present invention, lung function in patients suffering from some forms of chronic obstructive pulmonary disease can be improved by reducing the effective lung volume, typically by resecting diseased portions of the lung. Resection of diseased portions of the lungs both promotes expansion of the non-diseased regions of the lung and decreases the portion of inhaled air which goes into the lungs but is unable to transfer oxygen to the blood. Lung reduction is conventionally performed in open chest or thoracoscopic procedures where the lung is resected, typically using stapling devices having integral cutting blades.
While effective in many cases, conventional lung reduction surgery is significantly traumatic to the patient, even when thoracoscopic procedures are employed. Such procedures often result in the unintentional removal of healthy lung tissue, and frequently leave perforations or other discontinuities in the lung which result in air leakage from the remaining lung. Even technically successful procedures can cause respiratory failure, pneumonia, and death. In addition, many older or compromised patients are not able to be candidates for these procedures. For these reasons, it would be desirable to provide improved methods, systems, and kits for performing lung volume reduction which overcome at least some of the shortcomings noted above.
2. Description of the Background Art
WO 99/01076 and corresponding U.S. Pat. No. 5,957,919 describes devices and methods for reducing the size of lung tissue by applying heat energy to shrink collagen in the tissue. In one embodiment, air may be removed from a bleb in the lung to reduce its size. Air passages to the bleb may then be sealed, e.g., by heating, to fix the size of the bleb. WO 98/48706 describes a plug-like device for placement in a lung air passage to isolate a region of lung tissue, where air is not removed from the tissue prior to plugging. WO 98/49191 describes the use of surfactants in lung lavage for treating respiratory distress syndrome. U.S. Pat. No. 5,925,060 may also be of interest.
Patents and applications relating to lung access, diagnosis, and treatment include U.S. Pat. Nos. 5,957,949; 5,840,064; 5,830,222; 5,752,921; 5,707,352; 5,682,880; 5,660,175; 5,653,231; 5,645,519; 5,642,730; 5,598,840; 5,499,625; 5,477,851; 5,361,753; 5,331,947; 5,309,903; 5,285,778; 5,146,916; 5,143,062; 5,056,529; 4,976,710; 4,955,375; 4,961,738; 4,958,932; 4,949,716; 4,896,941; 4,862,874; 4,850,371; 4,846,153; 4,819,664; 4,784,133; 4,742,819; 4,716,896; 4,567,882; 4,453,545; 4,468,216; 4,327,721; 4,327,720; 4,041,936; 3,913,568 3,866,599; 3,776,222; 3,677,262; 3,669,098; 3,542,026; 3,498,286; 3,322,126; WO 95/33506, and WO 92/10971.
Lung volume reduction surgery is described in many publications, including Becker et al. (1998) Am. J. Respir. Crit. Care Med. 157:1593-1599; Criner et al. (1998) Am. S. Respir. Crit. Care Med. 157:1578-1585; Kotloff et al. (1998) Chest 113:890-895; and Ojo et al. (1997) Chest 112:1494-1500.
The use of mucolytic agents for clearing lung obstructions is described in Sclafani (1999) AARC Times, January, 69-97. Use of a balloon-cuffed bronchofiberscope to reinflate a lung segment suffering from refractory atelectasis is described in Harada et al. (1983) Chest 84:725-728.
The present invention provides improved methods, systems, devices and kits for performing lung volume reduction in patients suffering from chronic obstructive pulmonary disease or other conditions where isolation of a lung segment or reduction of lung volume is desired. The present invention is likewise suitable for the treatment of bronchopleural fistula. The methods are minimally invasive with instruments being introduced through the mouth (endotracheally) and rely on isolating the target lung tissue segment from other regions of the lung. Isolation is achieved by deploying an obstructive device in a lung passageway leading to the target lung tissue segment. Once the obstructive device is anchored in place, the segment can be aspirated through the device. This may be achieved by a number of methods, including coupling an aspiration catheter to an inlet port on the obstruction device and aspirating through the port. Or, providing the port with a valve which allows outflow of gas from the isolated lung tissue segment during expiration of the respiratory cycle but prevents inflow of air during inspiration. In addition, a number of other methods may be used. The obstructive device may remain as an implant, to maintain isolation and optionally allow subsequent aspiration, or the device may be removed at any time. Likewise, the device may biodegrade over a period of time.
The obstruction device may take a variety of forms to allow delivery, deployment and anchoring in a lung passageway. Delivery is commonly performed with the use of a minimally invasive device, such as a flexible bronchoscope or an access catheter. The flexible bronchoscope may be utilized with a sheath having an inflatable cuff disposed near its distal end, a full description of which is provided in co-pending application Ser. No. 09/699,313, assigned to the assignee of the present invention and incorporated by reference for all purposes. When using such a sheath, the scope is introduced into a lumen in the sheath to form an assembly which is then introduced to the lung passageway. The cuff may then be inflated to occlude the passageway. Similarly, an access catheter may be used which may be steerable or articulating, may include an inflatable balloon cuff near its distal end and may include a number of lumens for balloon inflation, tracking over a guidewire, and optical imaging, to name a few. The obstruction device is typically housed within a lumen of the access catheter, bronchoscope, sheath or suitable device, mounted near the distal tip of the catheter or carried by any method to the desired lung passageway leading to the target lung tissue segment. Therefore, the obstruction device must be sized appropriately for such delivery and is typically designed to expand upon deployment to anchor within the lung passageway. Hereinafter the present invention is depicted in relation to use with an access catheter, however it may be appreciated that any suitable device may be used.
In a first aspect of the present invention, the obstruction device comprises a structural support which expands and thereby anchors the device in the lung passageway. Such supports may comprise a number of configurations for a variety of expansion techniques. For example, the structural supports may allow the obstruction device to coil, roll, bend, straighten or fold in a cone, rod, cylinder or other shape for delivery. Then, once positioned in a desired location, the obstruction device may be released and expanded to anchor the device in the passageway. Such expansion may be unaided, such as in the release of a compressed structure to a pre-formed expanded position. Or, such expansion may be aided, such as with the use of an inflatable balloon or cuff. In some cases, a balloon or inflatable member may be incorporated into the obstruction device and may remain inflated to occlude the passageway. This may be provided in combination with structural supports or an inflatable balloon or similar device may be used without such support.
The structural supports may be comprised of any type of wire, particularly superelastic, shape-memory or spring tempered wire, or any type of polymer or a suitable material. The balloon or inflatable member may be comprised of any flexible, polymeric material suitable for such a purpose. The member may be inflated with gas or liquid as desired, or it may be inflated with an expanding foam or similar material. Likewise, it may be inflated or injected with an adhesive. Such an adhesive may expand the member and/or rigidify the member to reduce the likelihood of collapse. Further, the adhesive may additionally serve to bond the device to the walls of the lung passageway to increase anchorage. In addition, the device may be impregnated or coated with an antibiotic agent, such as silver nitrate, or similar agent for delivery of the agent to the lung passageway. Such delivery may occur by any applicable means.
When structural supports are present, such supports may comprise a variety of designs. In a first embodiment, the structural supports comprise radial segments which expand to fill the passageway and longitudinal segments which rest against the walls of the passageway to help anchor the device. In a second embodiment, the structural supports comprise a mesh which expands to fill the passageway. In a third embodiment, the structural supports comprise a helically or spirally wound wire which also expands to contact the walls of the passageway and anchor the device. In each of these embodiments, the structural support may be connected with or encapsulated in a sack comprised of a thin polymeric film, open or closed cell foam or other suitable material to provide a seal against walls of the lung passageway and obstruct airflow through the device. The sack material may also be infused with an adhesive, sealant or other material to improve obstruction of the airway and possibly improve adhesion to the airway walls.
In a second aspect of the present invention, the obstruction device may further comprise ports for aspiration through the device. This may allow access to the collapsed lung segment at a later time, for example, in the case of an infection. Typically, the obstruction device will have an inlet port located near the proximal end of the device, away from the isolated lung tissue segment. Such a port is thus accessible by minimally invasive devices, such as an aspiration catheter, which may be advanced through the bronchial passageways. Optionally, an outlet port may be located near the distal end of the obstruction device. The ports may comprise a variety of designs for a number of purposes.
In a first embodiment, the port comprises a self-sealing septum. Such a septum may comprise a solid membrane or a pre-cut membrane. Aspiration through the port may be achieved with the use of an aspiration catheter having an access tube or penetrating element at its distal end. Such a catheter may be advanced to the site of the obstruction device itself or with the use of an access catheter. The septum may be penetrated, either pierced through a solid membrane or passed through the cuts of a pre-cut membrane, by the access tube. Depending on the design of the obstruction device, the inlet port and optionally the outlet port may be penetrated in this fashion. Aspiration may be achieved through the access tube and aspiration catheter to withdraw gases and/or liquids from the isolated lung tissue segment and passageway. Optionally, prior to aspiration, a 100% oxygen, Helium-Oxygen mixture or low molecular weight gas washout of the lung segment may be performed by introducing such gas through the access tube, such as by a high frequency jet ventilation process. In this case, aspiration would remove both the introduced gas and any remaining gas. Similarly, liquid perfluorocarbon or certain drugs, such as antibiotics, retinoic acid and hyaluronic acid, may be introduced prior to aspiration. In most cases, aspiration will at least partially collapse the lung segment. Upon removal of the aspiration catheter from the port, the septum may self-seal or it may be further sealed with a sealant or other sealing means for later access or permanent closure.
When the self-sealing septum comprises a pre-cut membrane, aspiration through the port may alternatively be achieved by coupling an aspiration catheter to the obstructive device. Coupling may comprise engaging the aspiration catheter to the port or sliding a coupling member or the aspiration catheter over the port to form a seal. In either case, suction through the aspiration catheter may allow gases and/or liquids to pass through the cuts in the membrane to be withdrawn from the isolated lung tissue segment and passageway. Again, this will at least partially collapse the lung segment. Likewise, upon removal of the aspiration catheter from the port, the septum may self-seal or it may be further sealed with a sealant or other sealing means for later access or permanent closure.
In a second embodiment, the port comprises a unidirectional valve. Such a valve may comprise a port covered by a flexible layer which is attached to the port by at least one point of connection. Movement of the layer away from the port opens the valve and movement against the port closes the valve. Wherein the flexible layer is solid, movement of the layer away from the port allows gas to flow between the points of connection and around the edges of the flexible layer. Alternatively, the flexible layer may have holes therethrough. In this case, the port may also comprise a partition having holes which are not aligned with the holes in the flexible layer. Movement of the layer away from the port allows gas to flow through the holes in the partition and out through the holes in the flexible layer. When the layer moves against the partition, the holes will be covered closing the valve. Other valve designs include a spring-loaded ball valve or a biased pre-loaded diaphragm valve.
Aspiration through a unidirectional valve may be achieved by a number of methods. Again, the port may be accessed by advancing an aspiration catheter or similar device through the bronchial passageways to the site of the obstruction device. This may optionally be achieved with the use of an access catheter. The aspiration catheter may be placed near the valve or engaged to the valve, wherein suction or vacuum applied through the catheter opens the valve. If the aspiration catheter is not engaged to the valve, adequate suction to open the valve may be achieved by occluding the passageway proximal to the point of suction which is typically the distal end of the aspiration catheter. Such occlusion may be achieved by inflating a balloon or occlusion device mounted on the distal end of the aspiration catheter or mounted on an access catheter. In either case, the vacuum may draw the flexible layer away from the port, allowing gases and/or liquids to flow out from the isolated lung segment, through the valve and into the aspiration catheter. Alternatively, aspiration through a unidirectional valve may be achieved naturally during respiration. Pressure changes may open the valve during expiration as gases flow out from the isolated lung segment. Reverse pressure changes, during inspiration, may close the valve preventing gases from flowing into the isolated segment. This may reduce the amount of gas trapped in the terminal segment over time and thus at least partially collapse the lung segment. Similarly, aspiration through the unidirectional valve may be achieved by external mechanical pressure on the lung to force out of the lung segment and through the valve. Again, reverse pressure changes upon recoil of the lung would close the valve preventing gases from flowing into the isolated segment.
In a third aspect of the present invention, the obstruction device may comprise a blockage device which is deployed in a lung passageway to close the airway. Such a blockage device may be of similar design as previously described obstruction devices as it may be similarly delivered, deployed and anchored within a lung passageway. Thus, embodiments of the blockage device typically comprise expandable support structures. For example, in one embodiment the support structure comprises a coil. And, in a second embodiment, the support structure comprises a mesh. Again, the support structures may be connected to or encased in a polymer film or sack to provide a seal against the walls of the lung passageway and obstruct airflow through the device. Typically the blockage device will be placed in the passageway after the terminal lung segment has been aspirated by other methods. This will seal off the lung segment and maintain lung volume reduction. Alternatively, the blockage device may be placed in the passageway before the terminal lung segment has been aspirated. In this case, air trapped in the lung segment may be absorbed over time and would eventually collapse, a process known as absorption atelectasis. This process may be enhanced by insufflating the lung segment with 100% oxygen, a Helium-Oxygen mixture or low molecular weight gas prior to placing the blockage device. Such enhancement may promote complete collapse of the lung segment. In any case, the blockage device may optionally be later removed if it is so desired.
Methods of the present invention include the utilization of an obstruction device to achieve lung volume reduction. As described above, methods include delivery, deployment and anchoring of an obstruction device in a lung passageway leading to a target lung tissue segment. At least partial collapse of the terminal lung tissue segment may be achieved by aspirating the segment through the obstruction device deployed in the passageway. Aspiration may be accomplished with the use of an aspiration catheter or similar device through a port on the obstruction device. Also described above, when the port comprises a unidirectional valve, aspiration and eventual lung volume reduction may be accomplished by the opening and closing of the valve in response the respiratory cycle. In addition, methods of the present invention include deployment of a blockage device in a lung passageway leading to a terminal lung tissue segment, as previously described.
Systems of the present invention may include any of the components described in relation to the present invention. A particular embodiment of a system of the present invention comprises an access catheter and an obstruction device, as described above, wherein the obstruction device is introduceable by the access catheter. For example, the obstruction device may be houseable within a lumen of the access catheter for deployment out the distal end of the catheter, or the obstruction device may be mountable on the access catheter near its distal end. In either case, the obstruction device may be deployed and anchored within a lung passageway.
The methods and apparatuses of the present invention may be provided in one or more kits for such use. The kits may comprise an obstruction device deployable within a lung passageway and instructions for use. Optionally, such kits may further include any of the other system components described in relation to the present invention and any other materials or items relevant to the present invention.
Other objects and advantages of the present invention will become apparent from the detailed description to follow, together with the accompanying drawings.

Methods and devices for obstructing and aspirating lung tissue segments


A C-clamp capo comprises a string press for clamping down on the strings of a string-instrument against a front side of a fretboard. An extension arm curves behind and has an idler clamp with a first pivot attachment. Such enables a clamping action against a backside of the fretboard. A continuous insert having a positioning bumper that ensures consistent positioning against the fretboard is disposed all along an inside surface of the string press from a distal end across the first pivot attachment bridging over to an inside surface of the idler clamp and out to its distal end. A locking lever has a second pivot attachment to the extension arm behind the first pivot attachment, and provides a locking action against a backside of the idler clamp. A setscrew disposed in the locking lever provides an adjustable locking action between the idler clamp and the locking lever, e.g., for a range of thicknesses of the fretboard to be accommodated. A plastic, pointed tip on a distal end of the setscrew helps for a smooth engagement along a backside of the idler clamp. A grooved slot in the backside of the idler clamp provides a track in which the plastic, pointed tip of the setscrew is smoothly guided into a locking position. A depression located at a locking end of the grooved slot provides for a detent in the locking position.

The present invention relates to stringed-instrument fretboard capos, and more specifically to guitar and banjo capos that are easy to clip-on and remove, and that protect the instrument fretboard from being damaged during its installation and removal.
Capotastos are used by musicians who play guitars and banjos to make it easier to change music keys. In effect, a xe2x80x9ccapoxe2x80x9d will simultaneously finger all the strings at a single fret as long as the capo is secured in place. This therefore sets the half-notes sounded when the open strings are strummed. Playing the guitar, banjo, or lute, is therefore highly simplified without compromising the original composition. Capos are in widespread use as a result, and there are many screw-down and clamp-down versions being sold commercially.
One particular type of capo is a levered clamp with separate rubber linings on the inside of the two jaws, commonly called a xe2x80x9cC-clampxe2x80x9d capo. Richard Shubb describes such a capo in U.S. Pat. No. 4,250,790, issued Feb. 17, 1981, (Shubb ""790). A frame with a straight rubber facing is clamped down tight over the strings of a guitar and pulls them against the fretboard. An idler clamp with a concave curve and a short rubber facing presses from behind the fretbbard. A locking lever with a setscrew rides over a hump on the back of the idler clamp and is able to lock the idler clamp tight. The setscrew allows for some adjustment of the pressure and allows a range of fretboard thicknesses to be accommodated. The placement of the rubber linings allows the fretboard to be marred by exposed metal in the capo. And the setscrew tends to gouge the backside of the idler clamp such that the action is no longer very smooth. Experience has shown that the commercial units sold like this also tend to pull away from the strings. Such capo was improved by Richard Shubb, and is described by him in U.S. Pat. No. 5,792,969, issued Aug. 11, 1998, (Shubb ""969). The basic form is maintained from Shubb ""790, but an idler wheel is provided between the setscrew end and the backside of the idler clamp to relieve friction and gouging when the clamp is locked. A large knurled head is shown on the outside end of the setscrew to make it easier for the user to adjust the clamping range. Shubb ""969 shows the rubber facing on the xe2x80x9ctop arm 7xe2x80x9d as fully wrapping around the distal end. There is still a large exposed metal area inside the jaws, e.g., around the xe2x80x9croll pin 39xe2x80x9d, that can contact and mar the users"" fretboards.
A different approach to locking a capo down on a fretboard is described by Richard Steinberger in U.S. Pat. No. 6,008,441, issued Dec. 28, 1999. The idler clamp is fitted with a spring that presses the jaws closed around the fretboard. A release lever is linked to force the idler clamp jaws open when it is squeezed together by hand with a stationary lever on the frame. A problem with prior art xe2x80x9cC-clampxe2x80x9d type capos is that they tend to move across the strings and pull them out of tune, especially when being clamped on. There is a slight decrease in the applied pressure when the adjustment tip rotates past its top-dead-center and comes back in a bit. Such xe2x80x9coverstretched knee effectxe2x80x9d seems to be inherent in conventional capos.
An object of the present invention is to provide a capo that grips the fretboard and strings firmly.
Another object of the present invention is to provide a capo that will not mar a fretboard.
A further object of the present invention is to provide a capo with a positioning bumper that ensures consistent positioning against the fretboard.
Briefly, a capo embodiment of the present invention comprises a string press for clamping down on the strings of a string-instrument against a front side of a fretboard. An extension arm curves behind and has an idler clamp with a first pivot attachment. Such enables a clamping action against a backside of the fretboard. A continuous insert having a positioning bumper maybe disposed all along an inside surface of the string press from a distal end across the first pivot attachment bridging over to an inside surface of the idler clamp and out to its distal end. The positioning bumper may also be on an insert disposed on the inside surface of the string press or on the inside surface of the idler clamp. A locking lever has a second pivot attachment to the extension arm behind the first pivot attachment. It provides a locking action against a backside of the idler clamp. A setscrew disposed in the locking lever provides an adjustable locking action between the idler clamp and the locking lever, e.g., for a range of thicknesses of the fretboard to be accommodated. A plastic, pointed tip on a distal end of the setscrew helps for a smooth engagement along a backside of the idler clamp. A grooved slot in the backside of the idler clamp provides a track in which the plastic, pointed tip of the setscrew is smoothly guided into a locking position. A depression located at a locking end of the grooved slot provides for a detent in the locking position.
An advantage of the present invention is that a capo is provided that grips the fretboard and strings firmly without detuning the instrument.
Another advantage of the present invention is that a capo is provided that will ensure consistent positioning against the fretboard.
A further advantage of the present invention is that a capo is provided that is simple to use.
These and other objects and advantages of the present invention will no doubt become obvious to those of ordinary skill in the art after having read the following detailed description of the preferred embodiment as illustrated in the drawing figures.


An assembly for effecting the condition of a mitral valve of a heart includes a mitral valve therapy device, a guide wire, and a guide tube. The mitral valve therapy device is configured to reshape the mitral valve annulus of the heart when placed within the coronary sinus adjacent the mitral valve annulus. The guide wire is configured to be fed into the coronary sinus of the heart adjacent the mitral valve annulus. The guide tube has a distal end, a proximal end, and a lumen extending between the distal end and the proximal end. The guide tube further includes a side port, intermediate the distal and proximal ends which communicates with the lumen. This permits the guide tube to be slidingly received on the guide wire with the guide wire extending from the distal end, through the lumen, and out the side port. In use, the guide tube is slid along the guide wire into the coronary sinus. The mitral valve therapy device is then delivered by the guide tube into the coronary sinus adjacent the mitral valve annulus.

The present invention generally relates to a system and method for treating a deformed heart valve. The present invention more particularly relates to a system and method for delivering a mitral valve therapy device into the coronary sinus of a heart to treat mitral valve dilation.
The human heart generally includes four valves. Of these valves, a most critical one is known as the mitral valve. The mitral valve is located in the left atrial ventricular opening between the left atrium and left ventricle. The mitral valve is intended to prevent regurgitation of blood from the left ventricle into the left atrium when the left ventricle contracts. In preventing blood regurgitation the mitral valve must be able to withstand considerable back pressure as the left ventricle contracts.
The valve cusps of the mitral valve are anchored to muscular wall of the heart by delicate but strong fibrous cords in order to support the cusps during left ventricular contraction. In a healthy mitral valve, the geometry of the mitral valve ensures that the cusps overlie each other to preclude regurgitation of the blood during left ventricular contraction.
The normal functioning of the mitral valve in preventing regurgitation can be impaired by dilated cardiomyopathy caused by disease or certain natural defects. For example, certain diseases may cause dilation of the mitral valve annulus. This can result in deformation of the mitral valve geometry to cause ineffective closure of the mitral valve during left ventricular contraction. Such ineffective closure results in leakage through the mitral valve and regurgitation. Diseases such as bacterial inflammations of the heart or heart failure can cause the aforementioned distortion or dilation of the mitral valve annulus. Needless to say, mitral valve regurgitation must not go uncorrected.
One method of repairing a mitral valve having impaired function is to completely replace the valve. This method has been found to be particularly suitable for replacing a mitral valve when one of the cusps has been severely damaged or deformed. While the replacement of the entire valve eliminates the immediate problem associated with a dilated mitral valve annulus, presently available prosthetic heart valves do not possess the same durability as natural heart valves.
Various other surgical procedures have been developed to correct the deformation of the mitral valve annulus and thus retain the intact natural heart valve function. These surgical techniques involve repairing the shape of the dilated or deformed valve annulus. Such techniques, generally known as annuloplasty, require surgically restricting the valve annulus to minimize dilation. Here, a prosthesis is typically sutured about the base of the valve leaflets to reshape the valve annulus and restrict the movement of the valve annulus during the opening and closing of the mitral valve.
Many different types of prostheses have been developed for use in such surgery. In general, prostheses are annular or partially annular shaped members which fit about the base of the valve annulus. The annular or partially annular shaped members may be formed from a rigid material, such as a metal, or from a flexible material.
While the prior art methods mentioned above have been able to achieve some success in treating mitral regurgitation, they have not been without problems and potential adverse consequences. For example, these procedures require open heart surgery. Such procedures are expensive, are extremely invasive requiring considerable recovery time, and pose the concomitant mortality risks associated with such procedures. Moreover, such open heart procedures are particularly stressful on patients with a comprised cardiac condition. Given these factors, such procedures are often reserved as a last resort and hence are employed late in the mitral regurgitation progression. Further, the effectiveness of such procedures is difficult to assess during the procedure and may not be known until a much later time. Hence, the ability to make adjustments to or changes in the prostheses to obtain optimum effectiveness is extremely limited. Later corrections, if made at all, require still another open heart surgery.
An improved therapy to treat mitral regurgitation without resorting to open heart surgery has recently been proposed. This is rendered possible by the realization that the coronary sinus of a heart is near to and at least partially encircles the mitral valve annulus and then extends into a venous system including the great cardiac vein. As used herein, the term xe2x80x9ccoronary sinusxe2x80x9d is meant to refer to not only the coronary sinus itself but in addition, the venous system associated with the coronary sinus including the great cardiac vein. The therapy contemplates the use of a device introduced into the coronary sinus to reshape and advantageously effect the geometry of the mitral valve annulus.
The device includes a resilient member having a cross sectional dimension for being received within the coronary sinus of the heart and a longitudinal dimension having an unstressed arched configuration when placed in the coronary sinus. The device partially encircles and exerts an inward pressure on the mitral valve. The inward pressure constricts the mitral valve annulus, or at least a portion of it, to essentially restore the mitral valve geometry. This promotes effective valve sealing action and eliminates mitral regurgitation.
The device may be implanted in the coronary sinus using only percutaneous techniques similar to the techniques used to implant cardiac leads such as pacemaker leads. One proposed system for implanting the device includes an elongated introducer configured for being releasably coupled to the device. The introducer is preferably flexible to permit it to advance the device into the heart and into the coronary sinus through the coronary sinus ostium. To promote guidance, an elongated sheath is first advanced into the coronary sinus. Then, the device and introducer are moved through a lumen of the sheath until the device is in position within the coronary sinus. Because the device is formed of resilient material, it conforms to the curvatures of the lumen as it is advanced through the sheath. The sheath is then partially retracted to permit the device to assume its unstressed arched configuration. Once the device is properly positioned, the introducer is then decoupled from the device and retracted through the sheath. The procedure is then completed by the retraction of the sheath. As a result, the device is left within the coronary sinus to exert the inward pressure on the mitral valve to restore mitral valve geometry.
The foregoing therapy has many advantages over the traditional open heart surgery approach. Since the device, system and method may be employed in a comparatively noninvasive procedure, mitral valve regurgitation may be treated at an early stage in the mitral regurgitation progression. Further, the device may be placed with relative ease by any minimally invasive cardiologist. Still further, since the heart remains completely intact throughout the procedure, the effectiveness of the procedure may be readily determined. Moreover, should adjustments be deemed desirable, such adjustments may be made during the procedure and before the patient is sent to recovery.
Unfortunately, the human anatomy does impose some obstacles to this recently proposed procedure for treating mitral regurgitation. More specifically, the human heart includes a coronary artery which descends from the aorta. One branch of the coronary artery is the circumflex artery which, in turn, includes the left marginal branch of the circumflex artery. As used herein, the term xe2x80x9ccircumflex arteryxe2x80x9d is taken to include the circumflex artery itself or any branch therefrom. The circumflex artery extends distally generally along the coronary sinus but at a point proximal to the coronary artery, it passes under the coronary sinus. The circumflex artery supports blood flow important to the viability of the heart. Hence, reduction in this blood flow must be avoided. As a result, a device placed in the coronary sinus must not be permitted to extend within the coronary sinus beyond the crossover point of the circumflex artery and the coronary sinus to avoid constriction of the circumflex artery. This contemplates the need to know the location of the circumflex artery and coronary sinus crossover point. It also contemplates accurate positioning of the device within the coronary sinus to assure that the device does not extend over the circumflex artery.
The present invention addresses these issues. The present invention provides a therapy system and procedure which enables accurate positioning of the therapy device. This enables effective treatment while also avoiding the crossover of the circumflex artery with the coronary sinus. Further, the present invention enables the positioning of the device with relative ease.
The present invention provides an assembly for effecting the condition of a mitral valve of a heart. The assembly includes a mitral valve therapy device configured to reshape the mitral valve annulus of the heart when placed within the coronary sinus adjacent the mitral valve annulus, a guide wire configured to be fed into the coronary sinus of the heart adjacent the mitral valve annulus, and a guide tube having a distal end, a proximal end, and a lumen extending between the distal end and the proximal end, the guide tube further including a side port, intermediate the distal end and the proximal end and communicating with the lumen, to permit the guide tube to be slidingly received on the guide wire with the guide wire extending from the distal end, through the lumen, and out the side port. As a result, the guide tube is slidable along the guide wire to a position adjacent the mitral valve annulus within the coronary sinus and the mitral valve therapy device is guidable within the guide tube for placement in the coronary sinus adjacent the mitral valve annulus.
The present invention further provides a method of deploying a mitral valve therapy device within the coronary sinus of a heart adjacent the mitral valve annulus. The method includes the steps of providing an elongated flexible guide wire having a cross sectional dimension, feeding the guide wire into the coronary sinus of the heart, providing an elongated flexible guide tube having a proximal end, a distal end, a lumen, and a side port communicating with the lumen, and feeding the guide tube into the coronary sinus of the heart with the guide wire extending through the lumen from the distal end to and through the side port. The method further includes the steps of providing a mitral valve therapy device configured to be slidingly received within the lumen of the guide tube, the device including a proximal end, providing a flexible elongated introducer configured to be slidingly received within the lumen of the guide tube, the introducer having a distal end, placing the device into the guide tube lumen, placing the introducer into the guide tube lumen, engaging the distal end of the introducer with the proximal end of the device, pushing the device with the introducer in a distal direction within the guide tube lumen until the device is at least partially encircling the mitral valve within the coronary sinus of the heart, and releasing the device from the guide tube into the coronary sinus of the heart adjacent to the mitral valve annulus.
The guide wire may be visible under X ray fluoroscopy and the method may include the further steps of inserting a second wire into the circumflex artery of the heart, the second wire being visible under X ray fluoroscopy, subjecting the heart to X ray fluoroscopic examination to visualize the crossover point of the guide wire and the second wire, and releasing the mitral valve annulus therapy device within the coronary sinus in a position such that the device is proximal to the crossover point of the guide wire and the second wire.

Mitral valve therapy assembly and method


Fibers for diamond-impregnated cutting tools and their associated methods for manufacture and use are described. A matrix is formed that contains fibers made from carbon, glass, ceramic, polymer, and the like. The matrix is then sintered to form a cutting portion of a drill bit. The type and concentration of the fibers can be modified to control the tensile strength and the erosion rate of the matrix to optimize the cutting performance of the tools. Additionally, the fibers may be added to the cutting section to weaken the structure and allow higher modulus binders to be used for the cutting tools at a lower cost, allowing the amount of fibers to be tailored to retain the diamonds in the cutting portion for the desired amount. As the cutting portion erodes, the fibers may also increase the lubricity at the face of the cutting portion.

1. The Field of the Invention
This application relates generally to cutting tools and their methods of use. In particular, this application relates to diamond-impregnated cutting tools that may contain fibers.
2. Discussion of the Relevant Art
Cutting tools can be impregnated with diamonds so that they can be used to grind, polish, or otherwise cut a variety of materials that normal cutting tools cannot. The part of these tools that performs the cutting action (or the cutting portion of the tool) is generally formed of a matrix that contains a powdered metal or a hard particulate material, such as tungsten carbide. This material is sometimes infiltrated with a binder, such as a copper alloy. Finally, the cutting portion of these tools is impregnated with diamond crystals or some other form of abrasive cutting media. As the tool grinds and cuts the desired materials, the cutting portion of the tool erodes and exposes new layers of the diamond crystal (or other cutting media) so that a sharp surface is always available for the cutting process. Any diamond-impregnated cutting tool may continue to cut efficiently until the diamond impregnated portion of the tool is completely consumed. At that point, the tool becomes dull and must be replaced with another one.
In some cases, diamond-impregnated cutting tools may be expensive and their replacement may be time consuming, costly, as well as dangerous. For example, the replacement of a diamond-impregnated core sampling drill bit requires removing (or tripping out) the entire drill string out of the hole that has been drilled (the borehole). Each section of the drill rod must be sequentially removed from the borehole. Once the drill bit is replaced, the entire drill string must be assembled section by section and then tripped back into the borehole. Depending on the depth of the hole and the characteristics of the materials being drilled, this process may need to be repeated multiple times for a single borehole.
As well, conventional diamond-impregnated cutting tools often have several characteristics that can add to the consumption rate of the cutting portion and, therefore, increase the operating costs associated with those cutting tools. First, the binder materials in the tools may be relatively soft in comparison to the cutting media. Accordingly, the cutting portion may erode and allow diamonds or other abrasive cutting materials to slough off prematurely. Second, the erosion rate of the cutting portion can be increased by insufficient lubrication to and around the cutting face of the tool, or the interface between the cutting portion of the tool and the material being cut. Third, conventional impregnated cutting tools may also be too wear resistant to expose and renew layers of the cutting portion.

This patent is subject to a terminal disclaimer.


A cosmetic composition which can be used for caring for and/or for making up the human face, in particular, the skin, eyelids, or lips, comprising at least one wax, at least one ester, and at least one long chain alcohol.

The present invention relates to a cosmetic composition which can be used for caring for and/or for making up the human face, in particular, the skin, eyelids, or lips.
Cosmetic compositions such as lipsticks and foundations generally comprise fatty substances, such as oils, pasty compounds and waxes, as well as a particulate phase generally composed of fillers and of pigments. These compositions can also contain cosmetic or dermatological active principles (vitamins, screening agents, moisturizers). However, when applied on the skin, eyelids, or lips, these compositions exhibit the disadvantage of transferring. In other words, the composition is deposited, at least in part, on certain substrates with which it is brought into contact, such as, for example, a glass or cup, an item of clothing, or the skin. On being deposited, the composition leaves a mark on the substrate. The result is thus a mediocre persistence of the composition on the skin, eyelids, or lips, requiring it to be reapplied regularly. Moreover, the appearance of unacceptable marks on certain items of clothing and in particular on the collars of shirts or blouses might dissuade some consumers from using this type of makeup.
Another disadvantage of these compositions lies in the problem of migration. It has been found that certain cosmetic compositions have a tendency to spread into the fine lines and/or wrinkles of the skin, in the case of foundations; into the fine lines which surround the lips, in the case of lipsticks; and into the folds of the eyelid, in the case of eyeshadows. Streaks in the makeup may also occur, particularly in the case of eyeshadows due to the movements of the eyelids.
All these phenomena produce an unsightly effect which it is very clearly desirable to avoid.
For a number of years, cosmetic scientists have been interested in long-wearing cosmetic compositions, in particular lipstick or foundation compositions. Some of these compositions contained silicone derivatives which, when combined with other ingredients, resulted in a lipstick which, although longer-wearing than previous lipsticks, left an uncomfortable dry, tight feeling on the lips. Additionally the long-wearing cosmetic compositions generally had a matte finish rather than the more desirable shiny finish. The art has continued to search for a composition combining moisturizing and long-wearing attributes.
Now, the inventors have discovered, unexpectedly and surprisingly, a long-wearing cosmetic composition which provides a film which substantially does not transfer or migrate and which additionally exhibits improved properties with respect to those of the long-wearing products of the prior art, in particular moisturizing, softening, and shine.
In order to achieve these and other advantages, the present invention is drawn to a cosmetic compositions comprising at least one wax, at least one ester, and at least one long chain alcohol. The composition may further comprise at least one film-forming agent and at least one volatile silicone derivative. In addition, the composition of the invention contains substantially no fluorinated oils.
Waxes
The waxes that may be used in the present invention include, but are not limited to, waxes of animal, vegetable, mineral and synthetic origin, such as ozokerite, candelilla, and carnauba waxes, polyethylene waxes, microcrystalline waxes, silicone waxes, paraffin, petrolatum, montan wax, beeswax, Japan wax, ouricury wax, lanolin and its derivatives, cocoa butter, sugarcane or cork fiber waxes, hydrogenated oils which are solid at 25xc2x0 C., waxes obtained by the Fisher-Tropsch synthesis, and mixtures thereof. Preferably, the waxes used in the present invention have a melting point greater than 45xc2x0 C. and are selected from ozokerite, available as, for example, OZOKERITE 170 from Strahl and Pitsch, microcrystalline wax, available as, for example, MULTIWAX W-445 from Witco, and polyethylene, available as, for example, PERFORMALENE 400 from New Phase Technologies. The at least one wax of the invention is preferably present in an amount of from about 1% to about 35%, including about 1% to about 30%, about 1% to about 25%, or about 3% to about 20%.
An ethylene homopolymer or ethylene copolymer having a melting point of 30 to 135xc2x0 C. may be used. Such ethylene homopolymer or ethylene copolymer will have a molecular weight ranging from about 100 to about 2,000. Preferably the ethylene copolymers are comprised of ethylene monomer units of the following formula:
CH2xe2x95x90CHxe2x80x94R1
wherein R1 is a C1-30 straight or branched chain saturated or unsaturated alkyl, aryl, or aralkyl, preferably a C1-10 straight or branched chain alkyl. Examples of ethylene homo- and copolymers which may be used in the invention are set forth in U.S. Pat. No. 5,556,613, which is hereby incorporated by reference.
Esters
The esters that are useful in the presently claimed composition are esters obtained from acids having at least 4 carbon atoms such as, but not limited to, citric acid, octanoic acid, palmitic acid, hydroxystearic acid, stearic acid, oleic acid, arachidonic acid, myristic acid, and isostearic acid. These esters include C12-22 fatty esters of citric acid. Preferred esters include, but are not limited to, citrate esters, dipentaerythrityl esters, and dilinoleate esters. Particularly preferred esters are dipentaerythrityl tetrahydroxystearate/isostearate, triisostearyl citrate and mixtures thereof. Dipentaerythrityl tetrahydroxystearate/isostearate is available, for example, from Nisshin Oil Mill under the trade name COSMOL 168E. The at least one ester of the invention is preferably present in an amount ranging from about 5% to about 40%. Where two esters are used, the combined amount may range from about 10% to about 60%. In a preferred embodiment, triisostearyl citrate is used in an amount of 5% to about 19% by weight, and optionally dipentaerythrityl tetrahydroxystearate/isostearate in an amount of 10% to about 20% by weight.
Long Chain Alcohols
The long chain alcohols useful in the presently claimed invention preferably have at least 8 carbon atoms in a linear or branched chain. Preferably, the long chain alcohols useful in the claimed invention contain from 12 to 48 carbon atoms. Such long-chain alcohols include, but are limited to, octyldodecanol, octyltetradecanol, octahexadecanol, oleyl alcohol, linoleyl alcohol, linolenyl alcohol, cetyl alcohol, lauric alcohol, lauryl glycol, hexadecylic alcohol, and isostearyl alcohol. Octyldodecanol, available from Henkel as EUTANOL G, is particularly preferred. The at least one long chain alcohol of the invention is preferably present in an amount ranging from 1 to 40%. The straight or branched chain fatty alcohols may also be used in amounts of from about 1% to about 35%.
Film-forming Agents
Film-forming agents which can be used in the inventive composition may be selected from any film-forming agents commonly known in the art. Among the film-forming polymers which may be used, mention may be made of synthetic polymers, polymers of natural origin and mixtures thereof. Preferably, the film-forming agent is a polyvinyl pyrrolidone (PVP) copolymer such as GANEX V216 (PVP/hexadecene), GANEX V220 (PVP/eicosene), or GANEX WP 660 (PVP/tricontanyl), available from ISP, or a polypropylene glycol/sodium maleic acid diisobutylene copolymer such as POLYOLPREPOLYMER-2 (PPG-12/SMDI) and POLYOLPREPOLYMER-14 (PPG-51/SMDI), available from Penederm Inc. It has been found that the combination of the film-forming agent with the long chain alcohol, esters and wax results in a long-wearing lipstick which is moisturizing, softening, and has shine.
Evaporative Solvents
Although not necessary to achieve long-wearing properties, the composition may also include evaporative silicone solvents to further improve the long-wear properties of the cosmetic. Evaporative solvents are solvents which have a vapor pressure of at least 0.01 mm of Hg at 20xc2x0 C. and a viscosity of between 0.5 and 10 centipoise at 25xc2x0 C. The evaporative solvents may be further classified as volatile solvents and near volatile solvents.
Volatile Solvents
The volatile solvents include low viscosity silicone fluids having a viscosity between 0.5 and 5.0 centipoise at 25xc2x0 C., and a vapor pressure of at least 0.8 mm Hg and more preferably at least 2 mm Hg at 25xc2x0 C., including cyclic silicones of the formula:
wherein n=3-7. Volatile linear polydimethyl siloxanes may also be used. These generally have about 2 to 9 silicon atoms and are of the formula:
(CH3)3Sixe2x80x94Oxe2x80x94[xe2x80x94Sixe2x80x94(CH3)2xe2x80x94Oxe2x80x94]nxe2x80x94Si(CH3)3
where n=0-7. Volatile silicone derivatives useful in the present invention include those known in the art. For example, one can use cyclomethicones such as DC 244, DC 245, DC 344, DC 345, 200 Fluid(copyright) 0.65 cs., and 200 Fluid(copyright) 1.0 cs., available from Dow Corning. It may be necessary to use mixtures of the fluids to achieve the minimum vapor pressure. For example, the vapor pressure of DC 245 is only about 0.1 mm Hg at 25xc2x0 C., thus it would be necessary to blend DC 245 with a more volatile solvent, such as Dow Corning 200(copyright) Fluid, 0.65 cs. to achieve the necessary volatility. The use of these highly volatile silicone derivatives is not preferred since they tend to evaporate too quickly from the surface of the skin, resulting in drying of the skin. It is believed that the combination of the volatile solvent with the long chain fatty alcohol will result in the volatile solvent not evaporating as quickly as it otherwise would, thereby reducing its drying effect on the skin as the volatile solvent evaporates.
xe2x80x9cNear Volatilexe2x80x9d Solvent
It has been found that silicone solvents having a vapor pressure of between 0.01 and about 0.14 mm Hg, more preferably between 0.01 and 0.10 mm Hg, and most preferably between about 0.01 and 0.05 mm Hg, a viscosity of greater than 4 centipoise, but less than 10 centipoise, preferably between 6 and 8 centipoise and most preferably from about 6 to about 7 centipoise, provide surprisingly beneficial results of improving the wear of the lipstick without excessive drying of the skin. Suitable near volatile silicone solvents include DC 245, DC 246, DC 345, and Dow Corning 200(copyright) Fluid, 1.5 cs., Dow Corning 200(copyright) Fluid, 2.0 cs., Dow Corning 200(copyright) Fluid, 5.0 cs., and mixtures. The most preferred of these silicone solvents, for convenience termed xe2x80x9cnear volatile solvent,xe2x80x9d is the DC 246 sold by Dow Corning. DC 246 contains 92% of cyclohexane siloxane, often termed a xe2x80x9chexamerxe2x80x9d or xe2x80x9cD6 cyclomethicone.xe2x80x9d The chemical name is dodecamethylcyclohexasiloxane. DC 246 fluid also contains a small percentage (2%) of the pentomer, i.e., D5 and about 5% of the D7 cyclomethicone. The DC 246 has a viscosity of about 6.5 to about 7.3 centipoise at 25xc2x0 C. and a vapor pressure of about 0.002 mm Hg at 20xc2x0 C.
It is believed that the combination of this near volatile solvent with the long chain fatty alcohol results in the near volatile solvent not evaporating as quickly as it otherwise would, thereby still further reducing the possibility of drying of the skin as the near volatile solvent evaporates.
A cross-linked polymer may be included in the composition. Suitable cross-linked polymers include porous microspheres which are capable of adsorbing components from the cosmetic composition. Microspheres are sold by Advanced Polymer System, Inc. under the trade name Microsponge(copyright). Similar to the Microsponge(copyright) are cross-linked polymethacrylate copolymers sold generally under the name Polytrap(copyright), which are available from Dow Corning. Particularly preferred is the highly cross-linked polymethacrylate copolymer available as Polytrap(copyright) 6603, from Advanced Polymers System, Inc. and as Polytrap Q5 6603 from Dow Corning. Polytrap(copyright) Q5 6603 (and Polytrap(copyright) 6603) has a unique morphology consisting of unit particles less than one micron in size which are associated into agglomerates of 20 to 80 microns in size. These agglomerates are electrostatically aggregated into macro-particles 20 to 1200 microns in size. Since these aggregates are weakly structured, the material breaks apart upon rubbing on the skin, conveying a lubricious skin feel and allowing the particles to disappear on the skin. The Polytrap(copyright) Q5 6603 is capable of containing as much as 4 times its weight of the liquid components in the cosmetic. The adsorption activity is a physical phenomenon controlled by the surface tension of the fluids on the polymer powder surface and the filling of interstitial voids by capillary action. Since the material is strongly oleophilic, but hydrophobic, it controls oils and lipids on the skin, without overdrying. The following table summarizes the Polytrap Q5 6603 properties:
The composition of the invention may also include any additive conventionally used in the cosmetics or dermatological filed, such as, but not limited to antioxidant, fragrances, essential oils, preservatives, thickeners, cosmetic active principles, moisturizers, botanical extracts, vitamins, dyes, pigments, essential fatty acids, C8-C18 isoparaffin, volatile oils such as isodecane, isododecane, and isohexadecane, or sunscreens.
The composition may contain a particulate phase generally composed of fillers and pigments. This particulate matter may be present in the composition in an amount ranging form 0.1 to 25%, including 0.5 to 20% as well as 1 to 18% by weight of the total composition. The particulate matter has a particle size of 0.5 to 200 microns, including 1 to 100 microns, preferably below about 4 microns. The particulate matter may be colored or non-colored (e.g., white). Suitable powders include bismuth oxychloride, titanated mica, fumed silica, spherical silica, polymethylmethacrylate, micronized teflon, boron nitride, acrylate copolymers, aluminum silicate, aluminum starch, octenylsuccinate, bentonite, calcium silicate, cellulose, chalk, corn starch, diatomaceous earth, fuller""s earth, glyceryl starch, hectorite, hydrated silica, magnesium aluminum silicate, magnesium trisilicate, maltodextrin, montmorillonite, microcrystalline cellulose, rice starch, silica, talc, mica, titanium dioxide, zinc laurate, zinc myristate, zinc rosinate, alumina, attapulgite, calcium carbonate, calcium silicate, dextran, kaolin, nylon, silica silylate, silk powder, sericite, soy flour, tin oxide, titanium hydroxide, trimagnesium phosphate, walnut shell powder, or mixture thereof. The above mentioned powders may be surface treated with lecithin, amino acids, mineral oil, silicone oil or various other agents either alone or in combination, which coat the powder surface and render the particles more lipophilic in nature.
The particulate matter component also may comprise various organic and inorganic pigments. The organic pigments are generally various aromatic types including azo, indigoid, triphenylmethane, anthraquinone, and xanthine dyes which are designated as DandC and FDandC blues, browns, greens, oranges, reds, yellows, etc. Organic pigments generally consist of insoluble metallic salts of certified color additives, referred to as the Lakes. Inorganic pigments include iron oxides, ultramarines, chromium, chromium hydroxide colors, and mixtures thereof.
The composition may contain a mixture of both pigmented and non-pigmented powders. The percentage of pigments used in the powder component will depend on the type of cosmetic being formulated.
In one embodiment, the composition of the invention may be an anhydrous cosmetic composition in the form of a continuous fatty phase containing at least one wax, at least one ester, and at least one long chain alcohol. The composition may additionally contain at least one volatile silicone derivative. Further, the composition does not contain any fluorinated oils. Specifically, in a particularly preferred embodiment, the composition may comprise ozokerite, polyethylene, and microcrystalline wax; dipentaerythrityl tetrahydroxystearate/isostearate and triisostearyl citrate; octyldodecanol; and cyclomethicone. Preferably the composition also includes a film-forming agent such as polyvinyl pyrrolidone/hexadecene copolymer and a moisturizing agent such as LIPODERMOL LS 8656, available from Laboratoires Sxc3xa9robiologiques.
In a still further preferred embodiment, the cosmetic will include silica. The silica in combination with the LIPODERMOL LS 8656 and the triisostearyl citrate and a dipentaerythrityl tetrahydroxystearate/isostearate improves the mass release of the mixture.
In a particularly preferred embodiment, one combines the LIPODERMOL LS 8656 with the triisostearyl citrate, the dipentaerythrityl tetrahydroxystearate/isostearate, silica, long-chain fatty alcohol, high melting point cosmetic waxes such as polyethylene, ozokerite and microcrystalline wax, polyglyceryl-2 triisostearate, and the Polytrap(copyright) 6603 result in a cosmetic having excellent adhesive properties, moisturizing effects, long-wear, shine and, when formulated into a lipstick, increased stick stability in high temperature and high humidity conditions without the need to change the texture of the product. In addition, the use of the polyglyceryl-2 triisostearate results in improved pigment dispersion in the lipstick. The combination of these properties results in a superior product.
The composition of the invention may be in the form of, for example, a make-up foundation, an eyeshadow, an eyeliner, a blush, a concealer, a mascara, a lipstick or a lip composition. The composition may be in the form of a stick, a cream or a soft paste. The composition may be in stick form, poured into a pan or other types of cake or cream forms.
The cosmetic composition of the invention can provide good adhesion to the skin, have good film-forming properties, be long-wearing, have shine, and additionally can provide moisturizing and softening. The invention will be further clarified by the following examples, which are intended to be illustrative of the invention but not limiting thereof.

Moisturizing and long-wearing make-up composition


A transdermal therapeutic system for transcutaneous administration of sexual steroid hormones over long time periods, and a solvent-free method for the production thereof, is disclosed. The steroid hormones are subjected to as little thermal exposure as possible, thereby avoiding decomposition of the steroid hormones.

The present invention concerns a Transdermal Therapeutic System (TTS) for the administration of steroid sex hormones alone or with other steroid sex hormones through the skin over a long period of time, as well as a method for its production without the use of solvents, the method being especially protective for the active ingredient.
The bioavailability of orally administered active ingredients is frequently unsatisfactory. Metabolization of many active ingredients in the liver can lead during the first passage through the liver to undesirable concentration relationships, toxic by-products and to the reduction of the activity and even to loss of activity. In comparison to oral administration, transdermal administration of active ingredients has various advantages. The introduction of the active ingredient can be controlled better over a longer period of time as a result of which high fluctuations in blood level are avoided. In addition, the required therapeutically effective dose can mostly be reduced significantly. In addition, patients frequently prefer a plaster to tablets, which must be taken once or several times daily.
In the past, in order to overcome the disadvantages of nontransdermal administration of active ingredients mentioned above, a number of transdermal therapeutic systems (TTS) with different structure were proposed for various active ingredients for the therapy of different diseases.
Thus, the technical documents given below describe a broad variety of systemically or locally reacting active ingredients, the parenteral administration of which is either based on dose-controlled or generally releasing systems.
For example, these are: U.S. Pat. Nos. 3,598,122; 3,598,123; 3,731,683; 3,797,494; 4,031,894; 4,201,211; 4,286,592; 4,314,557; 4,379,454; 4,435,180; 4,559,222; 4,568,343; 4,573,995; 4,588,580; 4,645,502; 4,702,282; 4,788,062; 4,816,258; 4,849,226; 4,908,027; 4,943,435 and 5,004,610.
In the late sixties of this century, it was assumed originally theoretically that all active ingredients with short half-life but high activity and good penetration through the skin would be suitable for safe and effective administration via a TTS. These early expectations regarding the possibilities of transdermal administration of active ingredients by TTS could, however, not be fulfilled. The reason for this is mainly that the skin is equipped naturally with an unassessable variety of properties in order to maintain its function as an intact barrier to the penetration of substances that are foreign to the body. (See in this regard: Transdermal Drug Delivery: Problems and Possibilities, B. M. Knepp et al., CRC Critical Review and Therapeutic Drug Carrier Systems, Vol. 4, Issue 1 (1987).)
Therefore, transdermal administration is available only for those few active ingredients which have a suitable combination of many favorable characteristics. For a given active ingredient, all the required characteristics that permit safe and effective transdermal administration cannot be predicted, either theoretically or practically.
The requirements for an active ingredient suitable for transdermal administration are the following:
permeability through the skin,
no adverse influence on the adhesiveness of the plaster by the active ingredient,
avoidance of skin irritations,
avoidance of allergic reactions,
favorable pharmacokinetic properties,
favorable pharmacodynamic properties,
relatively broad therapeutic window,
metabolic properties which are consistent with therapeutic application with continuous administration.
Undoubtedly, the above list of requirements is not exhaustive. In order to have an active ingredient available for transdermal application, the xe2x80x9ccorrectxe2x80x9d combination of all these requirements is desirable.
What was said above for the active ingredient applies similarly to the TTS composition containing the particular ingredient and to its structure.
Usually, transdermal therapeutic systems (TTS) are plasters which are equipped with an impermeable cover layer, a removable protective layer and a matrix which contains the active ingredient or a reservoir with semipermeable membrane, which contains the active ingredient. In the first case, they are called matrix plasters and, in the second case, they are called membrane systems.
For the cover layer, usually films made of polyester, polypropylene, polyethylene, polyurethane, etc., are used which can also be metallized or pigmented. For the removable protective layer, among others, films made of polyester, polypropylene or even paper with silicone and/or polyethylene coating come into consideration.
For the active-ingredient-containing matrices which are usually used pharmaceutically or medically, polymer materials based on polyacrylate, silicone, polyisobutylene, butyl rubber, styrene/butadiene copolymer or styrene/isoprene copolymer are used.
The membranes used in the membrane systems can be microporous or semipermeable and are usually based on an inert polymer, especially polypropylene, polyvinyl acetate or silicone.
While the active-ingredient matrix compositions can be self-adhesive, depending on the active ingredient used, one can also have active-ingredient containing matrices, which are not self-adhesive, so that, as a consequence of this, the plaster or TTS must have an overtape in its structure.
In order to ensure the required flux rate of the active ingredient, frequently skin penetration enhancers are necessary as additives, such as aliphatic, cycloaliphatic and/or aromatic-aliphatic alcohols, which can be monovalent or polyvalent and may have up to 8 C-atoms, including an alcohol/water mixture, a saturated and/or unsaturated fatty alcohol with 8 to 18 carbon atoms, a saturated and/or unsaturated fatty acid with 8 to 18 carbon atoms and/or their esters, as well as vitamins.
Furthermore, frequently stabilizers such as polyvinylpyrrolidone, xcex1-tocopherol succinate, propyl gallate, methionine, cysteine and/or cysteine hydrochloride are added to the active-ingredient-containing matrix.
As the above discussion shows, numerous TTS structures and materials used for them are known. In any case, there are many interacting requirements to be considered when a drug is to satisfy medical requirements in the form of a TTS.
The following problems are to be considered fundamentally in the development of active-ingredient-containing TTS:
1. In order to achieve the therapeutically necessary penetration rates of the active ingredient through the skin, mostly a high load of active ingredient is required in the polymer matrix. After the end of application, the active ingredient remaining in the TTS is not used therapeutically and is disposed with the plaster. However, this is undesirable, especially in the case of highly active and expensive active ingredients for reasons of environmental protection and costs.
2. The polymer matrix which is loaded with the active ingredient and optionally additionally with skin penetration enhancers is not stable physically upon long storage. Especially, recrystallization of the active ingredient may occur, which leads to an uncontrollable decrease of the active-ingredient release capacity of the TTS.
3. High load of the polymer carrier with active ingredient and/or skin penetration enhancers makes the adjustment of optimum adhesive properties of the transdermal system difficult in the case of self-adhesive polymer films.
4. The resorption rate of the active ingredient decreases during application over several days in an unacceptable manner, so that additional control layers and/or control components are necessary.
5. If the active-ingredient-loaded layers are made from organic solutions, the problem arises that solvent residues remain in the active-ingredient-containing layer after the drying process. Additionally, there is a danger of undesirable evaporation of volatile additives during manufacture. Since, for reasons of physical stability and skin compatibility of the system, as a rule, an attempt must be made to have a system completely free from solvent, the reservoir therefore must be built up in several layers, as the case may be. This again leads to an increase of manufacturing costs.
Therefore, the problems described above require a large number of embodiments of Transdermal Therapeutic Systems, which are reflected in the state of the art in this field.
A more recent review on this is given, for example, in U.S. Pat. No. 5,662,926 (Wick et al., 1997). This document describes transdermal systems which contain a monolithic thermo plastic polymer film in which an active ingredient, preferably nicotine, is distributed homogeneously, as well as a method for solvent-free production of this active-ingredient-containing layer by mixing the active ingredient with the polymeric carrier material in the polymer melt, at temperatures from 170xc2x0 C. to 200xc2x0 C. In order to attach the active-ingredient-containing matrix film on the skin, there is an additional contact adhesive film which is applied onto the active ingredient matrix, and, if necessary, there is an additional plaster which has a larger area, and which is applied onto the active-ingredient-containing polymer film on the side of the matrix away from the skin.
Special pharmaceutical technical problems are to be solved in the development of estrogen plasters which must be applied for the treatment of climacteric complaints. The application should occur only once or twice per week. Increasing attention was received in this connection by the so-called 7-day plasters for reasons of cost and patient compliance in this indication. Cost aspects are of special importance here because many steroid sex hormones are highly costly drugs which are provided for continued therapy. In addition, when hormones are administered, for medical reasons, frequently a combination therapy is desired.
Thus, the natural estrogenxe2x80x9417xcex2-estradiolxe2x80x94is usually administered for the treatment of climacteric complaints, either continuously or sequentially together with a gestagen.
An adequately known embodiment of such TTS is represented by monolithic active ingredient plasters, which make controlled release of the active components possible from a thin adhesive layer. However, in practice, the development of such active ingredient plasters with steroid sex hormones, especially when used over several days, encounters one or several of the difficulties outlined below, which frequently can be solved only by expensive measures and which increase the development and/or manufacturing costs. These are essentially the following problems:
1. The steroid sex hormone is released from the adhesive films at a relatively low rate per unit time through the skin, with the consequence that relatively large plasters must be applied in order to build up the therapeutically necessary hormone level in the blood over a long period of time and/or the so-called penetration accelerators must be administered together with the active ingredient(s) in order to achieve the required transepidermal transport rate.
2. The steroid sex hormone is physically unstable in the self-adhesive film, depending on the storage conditions, that is, there is especially the danger of recrystallization of an active ingredient during storage, which is related to uncontrollable decrease of the active ingredient release capacity.
3. The active ingredient resorption rate drops during use over several days in an unacceptable manner, so that additional control layers or control components are necessary.
4. High loading with active ingredient and penetration accelerators makes the optimum adjustment of the adhesive properties of the TTS difficult during development.
For example, cold flow of the self-adhesive reservoir layer represents special problems which, in human application, can lead to leakage of the active-ingredient-containing mass beyond the edge of the plaster and thus to the formation of dirty edges. Furthermore, partial or complete separation of the TTS, caused by the action of moisture (for example, during taking a shower, swimming, heavy sweating) and/or due to strong shear stresses as a result of muscular or skin movements, can be observed at the skin/plaster boundary.
5. Reservoir layers for the transdermal application are frequently prepared from solutions, so that the problem of remaining solvent residues in the active-ingredient-containing layer after the drying process and optionally the related evaporation and/or undesirable evaporation of volatile additives during manufacture occurs. In order to achieve complete absence of solvent, which should be strived for as a rule for reasons of physical stability and skin compatibility of the system, the reservoir should optionally be built from several layers, but this would lead to making the manufacturing process more expensive.
Regarding the transdermal application of estrogens and/or gestagens and/or androgens with the aid of monolithic systems, in which the active ingredient or ingredients are incorporated into a self-adhesive matrix, according to the state of the artxe2x80x94among others, because of their relatively good solvent properties for this group of active ingredientsxe2x80x94preferably adhesives based on acrylate copolymers are used without (EP 0 416 8412, WO 93/10772) or with (WO 96/08255, DE 44 05 898) the addition of penetration-promoting, crystallization-inhibiting (WO 95/09618, WO 93/08795), active-ingredient solubility-enhancing (DE OS 44 05 898) and water-binding (DE 39 33 460) substances.
As a rule, the described formulations require the use of organic solvents, which must be removed again quantitatively during manufacture. Also, in spite of the relatively simple structure of monolithic TTS, the usual pharmaceutical quality requirements regarding adhesive properties, reproducibility of the active ingredient release and storage stability can only be provided with high technical expenditure for development and production because of the difficulties described above. Frequently, large-area plasters must be applied, especially for the administration of gestagens, in order to maintain the required active ingredient level in the blood over several days of application, as a result of which, first of all, the use properties and the related patient compliance become worse and, on the other hand, the cost of the preparation is increased further.
Furthermore, monolithic systems with sex steroids based on polystyrene block copolymers as carrier materials are known from the literature, the use of which permits in principle the production of self-adhesive active ingredient reservoirs from the melt without the use of organic solvents. Thus, in WO 94/26257, steroid-containing adhesives are described, which contain esters of colophonium and for which the manufacture of estradiol- and/or levonorgestrel-containing adhesive matrix can be done by melting and intensive kneading at high temperature over a long period of time. Transdermal Therapeutic Systems which are produced in this way have the disadvantage that the active ingredient(s) and/or pharmaceutical additives partially decompose under the conditions of the manufacturing process, that the adhesive properties and/or skin compatibility of the plaster over several days are insufficient andxe2x80x94especially for the gestagen componentxe2x80x94the attainable plasma concentrations are therapeutically insufficient.
Furthermore, active ingredient plasters are known from EP 0 186 019 in which swellable polymers are added to a rubber adhesive mass in water and from which estradiol can be liberated, and, for which, in some individual cases, manufacture according to the hot-melt method is possible. With these formulations, it is still difficult to keep sufficient amounts of steroid sex hormones in the plaster matrix in solution and to release these over a long period of time at an approximately constant rate through the skin.
Furthermore, formulations are known from DE 44 29 667 for the transepidermal release of estradiol, which are produced without the use of organic solvents by melting the components of the formulation, with glycerol being added as protection against the precipitation of the estradiol hemihydrate during storage. The adhesive formulations, named in the Description and in the Examples, based on polystyrene block copolymers, correspond to the state of the art, that is, the active ingredient uptake and release capacity of TTS of this type are generally too low for application of the hormone plaster over several days, especially in the case of gestagens and androgens.
In addition to the monolithic system, multilayer matrix and reservoir systems are also adequately known from the literature, in which the active ingredient reservoir layer, adhesive layer and/or release-control layers are separated from one another functionally and/or spatially. EP 0 285 563 describes a TTS for the combined application of estrogens and gestagens. Here, the active ingredient reservoir contains ethanol as solvent and release-control agent for the active components. Furthermore, a membrane also participates in the control of the release of the steroidal hormones, being located between the reservoir and the separately arranged adhesive layer. The possible duration of application of such TTS depends, among others, greatly on the ethanol content in the reservoir (J. A. Simon et al. (1991), Fertility and Sterility, 56: 1029-1033), which, during application in humans, decreases continuously during resorption and thus limits the functional lifetime of the system. Since, in addition to the active ingredient, another component, which increases resorption, is also released at a relatively high rate, depending on the environmental, storage and application conditions, there is a risk of physical instability, decreasing adhesive force and/or local skin irritations.
A so-called xe2x80x9cenhancedxe2x80x9d system, in which, besides the active ingredient penetration accelerators are released on the skin and which contains separate reservoir, control and adhesive layers, is known and from the state of the art, again for the transepidermal application of testosterone (U.S. Pat. No. 5,152,997).
This TTS has the advantage for the patient that it does not have to be adhered to the relatively permeable scrotal skin, which is the case otherwise, due to the low absorption of the active ingredient in the case of testosterone plasters without penetration aid (for example, according to DE OS 35 23 065). However, application of such xe2x80x9cenhancedxe2x80x9d systems when used for more than 24 hours, is involves increased risk of local skin irritation, caused by the additives that control the skin permeation of testosterone. Especially in the case of unfavorable application conditions (perspiring, strong skin movements, showers), problems occur relating to the adhesion properties.
Finally, in the development of transdermal systems, polymers based on acrylic acid esters and methacrylic acid esters are of special interest because of their relatively good ability to take up and release a number of active ingredients. In order to avoid the use of solvents in the manufacture of matrix systems based on poly(meth)acrylate, DE 4310012 describes a dermal therapeutic system in which one or several layers are made of mixtures of poly(meth)acrylates and are produced from the melt, and the first mixing component consists of (meth)acrylate polymers which contain functional groups, the second mixing component controls the flow behavior and contains only insignificant amounts of functional groups. The composite systems with poly(meth)acrylates with functional groups are supposed to make it possible to have controlled release of the active ingredient(s) on or through the skin and facilitate simple manufacture. However, while there are advantages in the manufacture in comparison to solvent-based methods, according to experience, these systems exhibit a number of disadvantages and these are caused by the following:
1. Longer thermal exposure of all TTS components during (1) manufacture of the polymer melt, (2) homogeneous incorporation of the active ingredient or ingredients and/or (3) coating of the hot active-ingredient-containing mass onto suitable carrier materials, with an increased risk of degradation or decomposition reactions in the polymer melt and/or during storage of the active-ingredient-containing polymer films.
2. Difficulties in the optimization of the cohesion/adhesion balance of the poly(meth)acrylate-containing layer, since crosslinking of the acrylate copolymer with covalent bonds during manufacture of the active-ingredient-containing polymer matrix in the melt is not possible, in combination with problems that can arise because of cold flow of the polymer mass during application on the skin and/or during storage.
Strong bonding of the active ingredient/steroid hormones, especially of 17xcex2-estradiol, in the polymer matrix by poly(meth)acrylates with a high content of free amino groups, as a result of which the flux rates of the sex steroid are reduced in comparison to poly(meth)acrylate matrices without free amino groupsxe2x80x94at the same loading with active ingredientxe2x80x94(see FIG. 1, Comparison Example).
As the above list shows, many plaster constructions and materials used for these are known. Similarly, today there is still a great demand for many active ingredients that are incorporated into Transdermal Therapeutic Systems to have a TTS available, which makes it possible to provide the therapeutically required release of the active ingredient, without the construction being expensive and in which, overall, the components are in an optimal relationship.
This also applies to the active ingredient of the type of sex steroids when they are to be administered transcutaneously, especially to estrogens, gestagens and androgens.
Therefore, the task of the invention is to avoid the disadvantages of TTS with sex steroids described above and to provide a TTS for transepidermal administration of sex steroids alone or with other sex steroids with good adhesive properties, which is simple to construct, is compatible with the skin and is physically and chemically stable over a long duration of storage and application, and
a) releases on and through the skin as much active ingredient as possible per unit area,
b) is free from solvent and
c) in which the active ingredient or ingredients used undergo as little thermal exposure as possible.
To solve this task, a steroid-hormone-containing TTS and a method for its preparation without the use of solvents is made available, the special composition of which surprisingly fulfills the tasks given above.
The Transdermal Therapeutic System (TTS) according to the invention contains a steroid-hormone-containing matrix mass in the form of a layer, in which the matrix mass has ammonium-group-containing (meth)acrylate copolymers, melt-extruded at 200xc2x0 C. and also contains at least one plasticizer alone or in a mixture with an ethylene acrylate terpolymer and/or polyethylene glycol as well as at least 2 weight % of each of the steroid hormones present in the matrix mass without having been melted, and it is provided with a covering layer toward the outside. The laminate made of covering layer and steroid-containing matrix mass, with the exception of its release surface on the skin, is surrounded either by a larger active-ingredient-free skin plaster, which serves to attach the TTS to the site of application and/or for covering the active-ingredient-containing matrix at the open edges, or it has an active-ingredient-free adhesive film on the release surface. Advantageously, covalently crosslinkable acrylate copolymers or silicone-based polymers can be used as active-ingredient-free adhesive film. The release rates achievable with the TTS according to the invention are so high that the application time in comparison to the plaster system known from the state of the art can be lengthened, without increasing the application area (see FIG. 1).
In contrast to monolithic matrix systems, in the development of the TTS according to the invention, it is possible advantageously to optimize the cohesion/adhesion properties of the TTS on the one hand and the solubility dissolution rate and release behavior of the active ingredient on the other hand, largely separately. Furthermore, it is surprising regarding the TTS according to the invention that
(1) at active ingredient concentrations in the polymer matrix, which are high in comparison to the state of the art, sufficient physical stability of the system is provided during long-term storage and that
(2) the introduction of separate separating layers or membranes between the active-ingredient-containing layer and the active-ingredient-free layer can be omitted.
Surprisingly, in the type of TTS according to the present invention, the adhesion properties of the active-ingredient-containing matrix and the skin plaster provided as an attachment aid complement each other in such a way that immediately after adhesion of the TTS, an intimate contact is produced between the active-ingredient matrix and the skin, which is retained over several days even when using a relatively small-area skin plaster with an active-ingredient-free adhesive edge of about only 3.5 mm width, (Example: in the case of a square-shaped TTS with a total area of 20 cm2, with rounded edges (including attachment aid) the area of the active-ingredient-containing matrix can be up to approximately 15 cm2). If, according to the present invention, crosslinkable adhesive layers as attachment aid are coated directly onto the active ingredient layer, the self-adhesive TTS thus obtained, consisting of covering layer, active-ingredient layer and adhesive layer also provide surprisingly high steroid release rates over a long period of application (see FIG. 1, Example 2).
In spite of the high loading of the matrix mass with at least 2 weight % of active ingredient(s), due to the special qualitative and quantitative composition of the matrix mass, no tendency of the incorporated active ingredients to recrystallization is observed, although, especially in the case of hormone-containing plasters, the sensitivity to moisture is a great problem. As a result of this, the active adhesive surface of the TTS can be kept small, the functional lifetime of the TTS can be extended and thus patient compliance can be taken into consideration. Surprisingly, more than 10 weight % of NETa (=norethisterone acetate) can be incorporated into the matrix mass.
Furthermore, it was surprising that in the matrix composition according to the invention, tributyl citrate is especially advantageous as plasticizer.
The embodiment according to the invention, in which the steroid-hormone-containing matrix mass is a solid solution is especially advantageous.
Furthermore, a TTS according to the invention may contain estrogens or gestagens alone or in combinations of these.
Finally, a TTS according to the invention may contain androgens in an embodiment.
Advantageously, the carrier film used for the TTS on the matrix side has a metal vapor or metal oxide coating.
In the sense of the invention the following terms are defined as given below:
a) xe2x80x9csolvent-freexe2x80x9d: no solvent is used for the manufacture of the polymer matrices which solvent would have to be removed again largely during the manufacturing process, as it is done in the xe2x80x9csolvent-basedxe2x80x9d method.
b) xe2x80x9clonger application time periodxe2x80x9d: The TTS can be applied to the skin for therapeutic application for up to 7 days.
c) xe2x80x9csolid solutionxe2x80x9d: The pharmaceutical active ingredient is present in the plaster matrix in the molecularly dispersed form.
d) xe2x80x9ctransepidermalxe2x80x9d: Same meaning and function as transcutaneous
e) xe2x80x9cthermally minimally exposed active ingredientxe2x80x9d: The active ingredient is added without melting to the matrix mass which was heated by melt-extrusion, which is then cooled after the addition of the active ingredient.
The method of the production of the TTS according to the invention is characterized by the fact that a coatable steroid-hormone-containing matrix mass is produced by melt-extrusion, in which the active components are weighed and incorporated continuously without premelting into the hot polymer melt heated up to 200xc2x0 C., the hot active-ingredient-containing polymer melt is then coated directly onto a separable protective layer (=substrate) to a thickness of 0.02 to 0.4 mm and then the obtained 2-layer laminate is covered with a cover layer. To attach the active ingredient matrix on the skin and/or to cover the matrix at the open edges, one can use a larger active-ingredient-free skin plaster or an active-ingredient-free adhesive film made of a crosslinked acrylate copolymer can be laminated directly onto the active-ingredient-containing polymer matrix. The TTS according to the invention are provided with a protective film which is removed before application of the preparation onto the skin.
An essential advantage of the method according to the invention consists in the fact that the active ingredient reservoir (I) is produced without the use of organic solvents and (II) the preparation of the active-ingredient-containing matrix mass and its further processing to an active-ingredient-containing layer is done in a continuous and especially cost-saving process. The process times can be shortened to a few minutes and thus, at the same time, the danger of decomposition reactions in the active-ingredient-containing polymer melt can be reduced to a minimum. Surprisingly, it was found that the complete dissolution of the sex steroid(s) in the polymer melt is provided in spite of the short processing times under the process conditions explained further in the Examples.
Furthermore, as a result of the continuous manufacture of the steroid-hormone-containing polymer mass, scaling-up problems are avoided. That is, in order to increase the batch size or charge size, no changes are necessary from larger production installations for the manufacture of the active-ingredient-containing polymer melt or of the laminate, which usually requires time-consuming and expensive installation, qualification and validation work as well as optionally also changes in the formulation.

Transdermal therapeutic system (TTS) for administering sexual steroid hormones