The inhibition of natural bone formation experienced in the prophylaxis and/or treatment of bone resorption disease with a bisphosphonic acid or a pharmaceutically acceptable salt thereof is overcome by the concommitant administration of an agent that binds to the androgen receptor.

This invention is concerned with a novel method for the prevention and/or treatment of diseases involving calcium or phosphate metabolism. In particular it is concerned with the prevention and/or treatment of diseases involving bone resorption, especially osteoporosis, Paget""s disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, by the administration of an agent that binds to the androgen receptor to produce a beneficial effect on bone and a bisphosphonic acid or a pharmaceutically acceptable salt thereof either combined in a single pharmaceutical formulation or as separate entities administered more or less concurrently.
This invention is also concerned with a pharmaceutical formulation in which an agent that binds to the androgen receptor and a bisphosphonic acid or pharmaceutically acceptable salt thereof are combined.
In the remainder of this specification the term xe2x80x9cbisphosphonic acidxe2x80x9d is meant to refer to the acid or the pharmaceutically acceptable salt thereof. Similarly, the expression, xe2x80x9cagent that binds to the androgen receptorxe2x80x9d refers to such agents that produce a beneficial effect on bone and includes androgen antagonists, agonists and partial agonist/antagonist agents.
Several bisphosphonic acids are known in the art and known to be effective in the treatment of diseases involving bone resorption. Unfortunately they also inhibit overall bone formation. Attempts have been made to stimulate bone formation that has been inhibited by a bisphosphonic acid such as with injections of growth hormone, IGF-1, parathyroid hormone or transforming growth factor (TGFb) which is described in U.S. Pat. No. 5,118,667. None of these attempts has been successful or widely used in patients and have been only partially successful in animals. Most importantly use of these agents involves daily injections with compounds that have multiple effects. Combination of a bisphosphonic acid and a growth hormone secretogogue also has been reported in WO95/11029.
Combinations of estrogen, which is also known to prevent bone resorption, and androgens to stimulate bone formation, have been tried (Davis et al, 1996 Maturittas 21:227-236; Raisz et al., 1996 J. Clin. Endocrinol. Metab. 81: 37-43; and Watts et al., 1995 Obstet-Gynecol. 85: 529-537). However, it is not obvious from the results of these studies that androgens would stimulate the formation of bone in the presence of a strong non-hormonal inhibitor of bone formation. As a matter of fact, it has been reported that the bisphosphonic acid, tiludronate, inhibits the anabolic effect of parathyroid hormone (Delmas, Bone, 16(6), 603-610 (1995)).
Now, with the present invention there is provided a novel method for the prevention and/or treatment of disease involving bone resorption comprising the administration of a bisphosphonic acid and an agent that binds to the androgen receptor whereby bone resorption is prevented without compromising normal bone formation induced by the androgen.
The novel method of prevention and/or treatment of diseases involving bone resorption of this invention comprises the administration to a patient in need thereof of an effective amount of a bisphosphonic acid and an effective amount of an agent that binds to the androgen receptor.
The disease states involving bone resorption that can be prevented and/or treated by the novel combination of this invention are osteoporosis, Paget""s disease, malignant hypercalcemia, periodontal disease, joint prostheses loosening and metastatic bone disease, especially osteoporosis.
Examples of the bisphosphonic acids that may be used as an active ingredient in the novel method and formulation of this invention include:
4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;
N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;
4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonic acid;
3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid;
3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid;
1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid;
(dichloromethyene)-bisphosphonic acid;
[1-hydroxy-3-(1-pyrrolidinyl)-propylidene] bisphosphonic acid;
(1-hydroxyyethylidene)-bisphosphonic acid;
[(cycloheptylamino) methylene] bisphosphonic acid;
(6-amino-1-hydroxyhexylidene) bisphosphonic acid;
[[(4-chloropheny) thio] methylene] bisphosphonic acid;
[1-hydroxy-2-imidazo-(1,2a) pyridin-3-ylethylidene] bisphosphonic acid;
[1-hydroxy-2-(1H-imidazole-1-yl) ethyledene] bisphosphonic acid;
1-hydroxy-2-[3-pyridyl]ethylidene-1,1-bisphosphonic acid; and
4-(hydroxymethylene-1,1-bisphosphonic acid)piperidine;
or their pharmaceutically acceptable salts.
Methods for the preparation of bisphosphonic acids may be found in, e.g., U.S. Pat. No. 3,962,432: U.S. Pat. No. 4,054,598: U.S. Pat. No. 4,267,108: U.S. Pat. No. 4,327,039: U.S. Pat. No. 4,407,761: U.S. Pat. No. 4,621,077: U.S. Pat. No. 4,624,947: U.S. Pat. No. 4,746,654: U.S. Pat. No. 4,922,077: and EPO Patent Pub. No. 0,252,504. In particular, methods for the preparation of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt trihydrate may be found in U.S. Pat. No. 4,407,761 and U.S. Pat. No. 4,922,077, respectively.
The pharmaceutically acceptable salts of bisphosphonic acids may also be employed in the instant invention. Examples of basic salts of bisphosphonic acids include ammonium salts, alkali metal salts such as potassium and sodium (including mono-, di- and tri-sodium) salts (which are preferred), alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D- glucamine, and salts with amino acids such as arginine, lysine, and so forth. The non-toxic, physiologically acceptable salts are preferred. The salts may be prepared by methods known in the art, such as in U.S. Pat. No. 4,922,077.
In the present invention it is preferred that the bisphosphonic acid is 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid. It is even more preferred that the bisphosphonic acid is a sodium salt of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, in particular, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt trihydrate.
Examples of agents that bind to the androgen receptor that may be used as an active ingredient in the novel method and formulation of this invention include but not limited to danazol, 5a-dihydrotestosterone, testosterone, nandrolane decanoate, methyltestosterone, methanadrostenolone, stanozolol, fluoxymesterone, oxymetholone, oxandrolone, oxymethol, norethandrolone, ethylestranol, 4-androsten-19-al-3,17-dione, 19-nortestosterone, norethandrone, norethisterone, dehydroepiandrosterone, epiandrosterone sulfate, androstenedione and androstenediol, testosterone propionate, testosterone cytpionate, and testosterone enanthate, preferably testosterone.
The bisphosphonic acid and the agent that binds to the androgen receptor can be administered combined in a single dosage form, which forms another aspect of the present invention, or as separate entities administered more or less concurrently. In either method of administration, the active ingredients are provided in doses that are the same as would be administered if given as sole medicament. In the case of the bisphosphonic acid, oral doses of 2.5 to 100 mg/day are approprate. Prophylactically, doses of about 2.5 to about 10 mg/day, and especially about 5 mg/day should be employed. For the treatment of bone disease involving bone resorption daily doses of about 5 to 20 mg/day may be used, especially about 10 mg/day. In the case of the agent that binds to the androgen receptor, doses of about 0.1-100 mg/day are recommended and preferably about 0.1-10 mg/day, depending on the potency of the agent.
In the combination of the present invention the bisphosphonic acid and the agent binds to the adrogen receptor may be administered separately or in combination. In addition, the administration of one element may be prior to, concurrently with, or subsequent to the administration of the other agent.
The active ingredients of the combination of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active ingredient(s) is included in an amount sufficient to produce the desired effect upon the process or condition of the disease.
The pharmaceutical compositions containing the active ingredient(s) suitable for oral administration may be in the form of discrete units such as hard or soft capsules, tablets, troches or lozenges, each containing a predetermined amount of the active ingredient(s); in the form of a dispersible powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; in the form of syrups or elixirs; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparation.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compounds are admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods. The excipients used may be for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, or alginic acid; (3) binding agents such as starch, gelatin or- acacia; and (4) lubricating agents such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastroinestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl disearate may be employed. They may also be coated by the techniques described in the U.S. Pat. Nos. 4,256,108; 4,160,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release.
In some cases, formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
Aqueous suspensions normally contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients may be
1) suspending agents such as sodium carboxymethyl-cellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;
2) dispersing or wetting agents which may be
(a) a naturally-occuring phosphatide such as lecithin,
(b) a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene sterate,
(c) a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethyleneoxycetanol,
(d) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or
(e) a condensation product of ethylene oxide
with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate.
The aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide a palatable oral preparation. These compositions may be prepared by the addition of an antioxidant such as ascorbic acid.
Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, those sweetening, flavoring and coloring agents described above may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegatable oil such as olive oil or arachis oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifying agents may be (1) naturally-occuring gums such as gum acacia and gum tragacanth, (2) naturally-occuring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension or solution. The suspension may be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspension, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
The active ingredient(s) of this invention may also be administered in the form of suppositories for rectal administration. This composition can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at body temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene gylcols.
Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
For topical administration the active ingredient(s) of this invention may be formulated in liquid or semi-liquid preparations such as liniments or lotions; oil-in-water or water-in-oil emulsions such as creams, ointments, jellies or pastes, including tooth-pastes; or solutions or suspensions such as drops, and the like.
The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds usually applied in the treatment of the above mentioned pathological conditions, for instance vitamin D2 and D3 and hydroxylated derivatives, e.g. 1a-hydroxy-vitamin D3, 1a-hydroxy-vitamin D2, 1a-25-dihydroxy-vitamin D3, 1a-25-dihydroxy-vitamin D2, calcitonin (human, porcine or salmon), mitramycin, sodium fluoride, and non-steroid antiinflammatory drugs, such as acetylsalicyclic acid, indomethacin, naprosyn, and timegadine.
The amount of active ingredient(s) in the formulations of this invention may be varied. However, it is convenient for the unit dose, such as a tablet, to contain the amount of active ingredient(s) that would be administered in the prophylaxis or therapy of a particular bone resorption disease. Accordingly, formulations comprising 2.5 mg, 5.0 mg and 10 mg of the bisphosphonic acid and 0.125-2.5 mg, 0.25-5.0 mg and 0.5-10 mg respectively, of the androgen would be appropriate.

Combination of an agent that binds to the androgen receptor and a bisphosphonic acid in the prevention and/or treatment of diseases involving calcium or phosphate metabolism


The present invention provides an anti-inflammatory composition for treatment of joint and muscle pain through transdermnal delivery of a capsacinoid in conjunction with glucosamine. The ingredients of the composition of the present invention, namely, a capsacinoid in combination with a primary amine, such as glucosamine, at a high concentration, interact in a synergistic manner to provide a prolonged effect of pain relief when used in the treatment of joint and/or muscle pain associated with an inflammatory response. The prolonged pain relief effect is achieved without incurring the intense burning or stinging sensation usually associated with topical capsaicin administration. The present invention also provides methods for relieving joint and/or muscle pain associated with an inflammatory response, which employ the composition of the present invention.

The present invention relates to an anti-inflammatory composition for treatment of joint and muscle pain. More specifically, the present invention provides a composition that alleviates pain associated with joint and/or muscle injuries, diseases or conditions through transdermal delivery of a casaicinoid in conjunction with a primary amine, such a glucosamine. The combination of the ingredients of the present invention, namely a capsaicinoid and a primary amine, interact in a synergistic manner to provide unexpectedly beneficial results in relief of joint and/or muscle pain associated with an inflammatory response.
The connective tissue of mammals, such as humans, are subjected to a constant barrage of stresses and injuries throughout the life of the individual. These stresses may result from acute or chronic impacts or from the progress of various degenerative diseases, and produce painful inflammation in joint regions, such as the neck, back, arms, hips, ankles and feet. These afflictions are common, afflicting millions of Americans, and in many cases, debilitating. As a result, there is a great need for an effective and simple treatment to ease the pain associated with inflammatory connective tissue conditions.
There are a number of approaches directed to controlling the symptoms of such inflammatory connective tissue conditions. Steroids, especially corticosteroids, and non-steroidal anti-inflammatory drugs (so-called xe2x80x9cNSAIDsxe2x80x9d), such as aspirin (acetylsalicylic acid), ibuprofen ((2-(isobutylphenyl) propionic acid), naproxen (2-naphthaleneacetic acid, 6-methoxy-9-methyl, sodium salt), and piroxicam (4-hydroxy-2-methyl-N-2-pyridinyl-2H-1,2-benzothiazine-2-carboxamide 1,1 dioxide), are used to control the inflammation associated with connective tissue disorders. However, these drugs relieve the symptoms associated with the connective tissue disorders, but do nothing to slow the progression of the disease. Furthermore, these drugs have a number of undesirable side-effects. With respect to NSAIDS, first, NSAIDS may inhibit the body""s own natural healing mechanisms, leading to further connective tissue degeneration. Second, NSAIDS also affect enzymes involved in maintaining healthy liver and kidney function, so that administration of these drugs weakens these organ systems. Finally, NSAIDS can produce gastropathy and gastric ulceration. With respect to corticosteroids, while dramatic improvements are often seen upon initial administration, corticosteroids begin to lose their effectiveness after prolonged administration. Further increases in dosage are required to overcome the loss of effectiveness, but the higher dosages themselves also eventually lose effectiveness. Furthermore, upon cessation of corticosteroid treatment, the symptoms of inflammation and swelling recur at higher levels than were experienced prior to administration. In addition, fluid retention is a serious side effect, and can lead to significant weight gain and, more importantly, dangerous levels of hypertension. Corticosteroids may also induce or contribute to osteoporosis, exacerbating what is often already a significant problem with elderly patients.
The connective tissues of mammals are capable of being regenerated by chondrocytes, cells that are responsible for the synthesis of the major components of connective tissuesxe2x80x94collagen and proteoglycans. Collagen is a fibrous glycoprotein that is found in skin, bone, tendon, cartilage, blood vessels, and teeth. Collagen is also found in all organs, and serves as a scaffold to hold cells together. The building blocks for collagen are amino acids, and in particular the amino acids glycine, proline, hydroxyproline and hydroxylysine. Carbohydrate units are attached to collagen fibers at the hydroxylysine residues.
Proteoglycans are large, complex molecules that form the ground substance of connective tissue and determine the viscoelastic properties of joints and other structures that are subject to mechanical deformation. Proteoglycans are made up of a hyaluronic acid backbone to which are attached, at regular intervals, a core protein bearing a number of different types of modified sugars, called glycosaminoglycans. Examples of glycosaminoglycans are keratin sulfate, chondroitin sulfate, heparin, and heparin sulfate. The most important molecule in the synthesis of proteoglycans is glucosamine. Glucosamine is the precursor to the glycosaminoglycans. In addition, glucosamine forms hyaluronic acid, the backbone of proteoglycans to which the long chains of the various types of sugars are joined. Glucosamine is also a key component of synovial fluid, the liquid in joints, which provides lubrication and nutrition to cartilage.
The effects of aging and the inevitable wear and tear of daily life on structural joints mean that the structural elements of connective tissue must constantly be replaced. The rate-limiting step in the synthesis of proteoglycans is the conversion of glucose to glucosamine in the production of glycosaminoglycans. Therefore, it has been proposed to stimulate the production of proteoglycans by providing various forms of the building blocks of these complex molecules. Glucosamine administration appears to reduce the likelihood of tendon and ligament damage, as well as reducing joint inflammation, and has been shown by numerous double blind clinical trials to be both safe and effective. Administration of glucosamine appears to overcome the rate-limiting step described above by a mass action effect. U.S. Pat. No. 3,683,076, issued to Rovati et al., discloses methods for the preparation of glucosamine sulphate and glucosamine hydroiodide, useful in the treatment of degenerative joint conditions. Because these compounds oxidize readily, the compositions also preferably include a reducing agent, such as sodium hyposulfite or N-acetyl diethanolamine. U.S. Pat. No. 3,697,652, also to Rovati et al., discloses pharmaceutical preparations to treat degenerative joint conditions. Compositions contain one or more N-acyl aminocarbohydrates, preferably glucosamines and/or galactosamines. Preferably, one or more inorganic salts of alkaline earth and/or alkali metals are included (e.g., sodium sulfate, sodium iodide, etc.). U.S. Pat. No. 5,364,845, issued to Henderson, describes a therapeutic composition for the treatment and protection of connective tissue which includes glucosamine and preferably chondroitin sulfate and manganese ascorbate. U.S. Pat. No. 5,916,565, issued to Rose et al., discloses a therapeutic composition for treatment of damaged joint tissues that comprises chondroitin sulfate and glucosamine, along with multiple anti-inflammatory herbal phytochemicals, such as cayenne, which contains capsaicin.
Other components of the proteoglycans have also been provided to stimulate their production in the treatment of joint degeneration or promotion of wound healing. U.S. Pat. No. 4,801,619, issued to Lindblad, describes high molecular weight ( greater than 3xc3x97106) hyaluronic acid preparations for counteracting progressive cartilage destruction. The hyaluronic acid preparations are preferably administered by intra-articular injection, and may be combined with administration of a corticosteroid or other suitable anti-inflammatory compound. U.S. Pat. No. 5,972,906, to Asculai et al., describes topically applied compositions and methods for treatment of mucous membrane disease or trauma, particularly oral mucous membrane conditions, that comprise hyaluronic acid or fragments and/or subunits thereof, along with an NSAID anti-inflammatory agent. The hyaluronic acid preparation may further include N-acetyl glucosamine or glucosamine.
Typically, glucosamine is administered by an oral route. However, oral administration of glucosamine is relatively ineffective, because the liver breaks down up to 80% of the orally administered glucosamine. Furthermore, while orally-administered glucosamine is relatively effective in reaching joint areas, many sites of pain and inflammation are poorly vascularized, and the blood-borne glucosamine has difficulty in reaching these areas. Examples of such areas are so-called xe2x80x9ctennis elbowxe2x80x9d, xe2x80x9cpitcher""s elbowxe2x80x9d, Achilles tendonitis, pain in the tendonous areas of the back, neck, and fingers. As a result, a prolonged period of treatment is required before an beneficial effect of the drug is achieved in these sites. Glucosamine has also been administered by either a parenteral route or by intra-articular injection. While these administration methods result in an increased concentration of glucosamine in these difficult-to-reach areas, they also suffer from distinct disadvantages. For example, injections produce an increased risk of infection, and are inconvenient in comparison to oral delivery methods. In addition, parenterally-administered glucosamine still has difficulty in penetrating areas of inflammation due to the poor circulation inherent in these areas.
Capsaicin, a pungent substance derived from plants of the genus Capsicum in the Solanaceae family (e.g. hot chili peppers), is a member of a group of compounds known as capsaicinoids, which are alkaloid compounds found in high concentration in Capsicum. Capsaicinoids are responsible for the pungency, or heat, found in Capsicum. The most common capsaicinoid is capsaicin, followed by dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin and homodihydrocapsaicin. Chemically, capsaicin is trans-8-methyl-N-vanillyl-6-nonenamide, dihydrocapsaicin is 8-methyl-N-vanillyl-nonanamide, nordihydrocapsaicin is 7-methyl-N-vanillyl-octamide, homocapsaicin is trans 9-methyl-N-vanillyl-7-decenamide, and homodihydrocapsaicin is 9-methyl-N-vanillyl-decamide, as shown below:
Capsaicinoids are insoluble in water, but soluble in fats, oils and alcohols. In its purified form, capsaicin is a white to off-white powder, with a reported melting point of 65xc2x0 C. and a boiling point at 0.01 torr of 210-220xc2x0 C. Capsaicin and dihydrocapsaicin together make up between 80-90% of the capsaicinoids found in Capsicum, the other 10-20% fraction being represented by nordihydrocapsaicin (approximately 7%), homocapsaicin approximately 2%), and homodihydrocapsaicin (approximately 2%). As used herein, the terms xe2x80x9ccapsaicinxe2x80x9d and xe2x80x9ccapsaicin-like-compoundsxe2x80x9d include all naturally occurring and synthetic capsaicinoids, as well as capsaicin analogues having physiological properties similar to those of the capsaicinoids, i.e., triggering C fiber membrane depolarization by opening cation channels permeable to calcium and sodium. These physiological effects are discussed in greater detail below.
Capsaicin produces its pungent heat effect through stimulation of excitatory afferent sensory neurons upon contact with skin or mucous membranes. There are two main phases of action. First, there is an excitation of the sensory neuron which results in the release of peptide neurotransmitters, such as substance P, calcitonin gene-related peptide (CGRP), and others, and which is responsible for the burning tingling, sensation that results when capsaicin is applied to the skin or mucous membrane. The second, slower phase is a subsequent desensitization of the nerve to stimulation. The desensitization results from the depletion of neuropeptides from the neurons, accompanied by capsaicin-mediated interference with reuptake of the neuropeptides by the neuron. This desensitization is the familiar ability of chili pepper fans to endure increasingly higher concentrations of chili pepper-containing foods through repeated exposure. It is thought that capsaicin binds to a receptor at the nerve ending of primary afferent neurons and causes release of a variety of neurotransmitter peptides, as well as subsequent blockage of the reuptake of the same neurotransmitter peptides by the afferent neurons. Substance P release is involved in transmission of pain signals from the same neurons. The depletion of substance P from the local sensory neurons, and blockage of its subsequent reuptake by capsaicin, results in the blockage of pain signals to the brain, and thereby produces an effective local anaesthetic effect.
Although detailed mechanisms of capsaicin action are not yet known, capsaicin-mediated effects are know to include the following: (i) activation of nociceptors in peripheral tissues; (ii) eventual desensitization of peripheral nociceptors to one or more stimulus modalities; (iii) cellular degeneration of sensitive A-delta and C fiber afferents; (iv) activation of neuronal proteases; (v) blockage of axonal transport; and (vi) the decrease of the absolute number of nociceptive fibers without affecting the number of non-nociceptive fibers. The effects of capsaicin have been assessed in a variety of animal studies. Capsaicin causes an increase in the rates of contraction in a variety of isolated animal tissues, including ileum smooth muscles, cardiac muscles, blood vessels, and airways. Capsaicin causes increases in both contractability and beating rate of isolated guinea pig atria. The positive inotropic (increase in contraction rate) effects of capsaicin on isolated atria are thought to be due to the release of CGRP from atrial neurons. Similarly, it is thought that the increased inotropic effects on isolated ileum are caused by substance P release.
Capsaicin selectively acts on the small diameter afferent nerve fibers (C fibers and A-delta fibers). These small diameter afferent nerve fibers are believed to be the nerves involved in pain signaling. From studies in animals, capsaicin appears to trigger C fiber membrane depolarization by opening cation channels permeable to calcium and sodium. Capsaicin is believed to bind to a receptor at the nerve ending and cause a release of a variety of neuropeptides, which results in afferent nerve conduction. Recently one of the receptors for capsaicin effects has been cloned.
Because of capsaicin""s ability to desensitize nociceptors in peripheral tissues, its potential analgesic effects have been assessed in various clinical trials. Capsaicin is useful as a topical pain treatment for a wide variety of conditions, such as musculo-skeletal pain, peripheral neuropathy, post herpetic neuralgia, post-mastectomy pain, and pruritus and itching of all kinds, whether derived from contact dermatitis, insect bites, hemorrhoids, or any other source:
Synthetic capsaicin (nonyl vanillylamide, or N-vanillyl-nonanamide acts in the same manner as capsaicin, Chemically, N-vanillyl-nonanamide is as shown below:
As mentioned above, capsaicin is believed to act on a subset of primary afferent nerves mostly of the C fiber, type (polymodal, thin, unmyelinated), although some A delta (thin, myelinated) are also capsaicin sensitive. However, the application of capsaicin itself frequently causes burning pain and hyperalgesia apart from the neuropathic pain being treated. The spontaneous burning pain and hyperalgesia are believed to be due to intense activation and temporary sensitization of the peripheral nociceptors at the site of the capsaicin application. This activation and sensitization occur prior to the desensitization phase.
The use of capsaicin or capsaicin analogs as an anaesthetic is described in U.S. Pat. Nos. 4,313,958 and 4,493,848. In addition, it is known to combine capsaicin with other analgesic compounds, such as NSAIDs (U.S. Pat. No. 4,812,446) or opioids (U.S. Pat. No. 4,599,342). The combination of these different classes of analgesic compounds produced synergistic effects, in that the combination produced greater analgesic effects than either compound alone. U.S. Pat. No. 5,431,914 describes a method for treating symptoms of pathological conditions by administering capsaicin to a specific site to treat a distal organ. The method does not rely on systemic adsorption, but takes advantage of certain nerves in the skin that lead to spinal cord segments that affect the target internal organ. U.S. Pat. No. 5,665,378 describes a transdermal therapeutic composition comprising capsaicin, a nonsteroidal anti-inflammatory drug (NSAID) and pamabrom. The NSAIDs usable in the invention include such drugs as diflunisal, fenoprofen, ibuprofen, indomethacin, meclofenamate, naproxen, and the like. The composition is preferably administered in patch form.
U.S. Pat. No. 5,869,533 discloses a delivery system for administering capsaicin along with a second ingredient that is effective to reduce the skin irritation caused by the capsaicin. The delivery system may be a patch, an aerosol, or a solid form. The second ingredient active to reduce the skin irritation caused by capsaicin is preferably either a skin anaesthetic or a compound effective to bind to the capsaicin, and is further described as one of a number of plant extracts, U.S. Pat. No. 5,910,512 discloses the use of capsaicin or a capsaicin-containing extract as a topical analgesic. A water-soluble form of capsaicin or capsaicin-containing extract is combined with hydrocolloids, magnesium oxide and disodium EDTA to form a composition that was easily applied to the skin for topical relief of pain associated with arthritis, strains, bruises and sprains. As noted above, U.S. Pat. No. 5,916,565 to Rose et al., disclosed a composition for the treatment of damaged joint tissues that comprised chondroitin sulfate and glucosamine, along with various other phytochemicals, such as the capsaicin-containing herbal cayenne.
A meta-analysis of the results of numerous clinical trials of capsaicin in promoting pain relief was prepared by Zhang and Li Wan Po (Eur J Clin Pharmacol (1994) 46:517-522). They reported results from randomized, double-blind and placebo controlled studies that evaluated the effectiveness of capsaicin in treating pain associated with diabetic neuropathy, psoriasis, osteoarthritis, postherpetic neuralgia, and postmasctectomy pain. In the case of diabetic neuropathy, they reported four trials that evaluated the use of 0.075% capsaicin cream applied four times daily for 4-8 weeks. They found that overall 73% of patients responded to capsaicin, versus 49% of patients given placebo. For osteoarthritis, three trials reported use of capsaicin cream (two using 0.025%, one using 0.075%) four times daily for four weeks. Overall, 45% of patients tested responded to capsaicin, compared to 16% treated with placebo. For postherpetic neuralgia, a single trial tested 0.075% capsaicin cream three or four times daily for three weeks. In this trial, {fraction (4/16)} (25%) of those tested reported pain relief, compared to with {fraction (1/16 )} (6%) of those using only placebo. In the case of postmastectomy pain, a single trial tested 0.075% capsaicin cream applied four times daily for six weeks. In the test group, {fraction (5/13)} patients reported pain relief (38%) compared with {fraction (1/10)} (10%) of patients treated with placebo. Finally, for psoriasis, the authors reported four trials that evaluated the use of 0.025% capsaicin cream applied four times daily for 6-8 weeks. They found that overall 68% of patients responded to capsaicin, versus 42% of patients given placebo. Thus, in all the conditions examined, capsaicin showed benefits over the use of a placebo.
While capsaicin is an effective analgesic, administration of capsaicin invariably results in an initial painful burning or stinging to the skin. This painful side effect can be quite severe, and reduces patient compliance with the treatment. While repeated use of capsaicin over time periods of several weeks can cause the burning or stinging sensation to fade, a patient may choose to discontinue treatment before they can achieve beneficial levels of pain relief In addition, most capsaicin formulations require between two and four daily administrations, because the pain relief effect of the capsaicin is short-lived. Finally, the painful sensation associated with capsaicin administration may discourage extension of the use of capsaicin in the treatment of various other conditions that may be alleviated through administration of capsaicin. As noted above, others have prepared various compositions that incorporate one or more local anaesthetics to offset the painful side effects associated with topical administration of capsaicin. For example, U.S. Pat. No. 4,997,853 discloses the use of lidocaine or benzocaine to offset the painful side effects of capsaicin administration. U.S. Pat. No. 5,869,533 teaches a method for anaesthetizing against the pain caused by the topical administration of capsaicin by incorporating a second active ingredient having anaesthetic properties, and particularly various described plant extracts. However, even when these compositions were tested, not all patients experienced relief from the painful burning induced by topical capsaicin administration. Furthermore, the use of an additional anaesthetic did not reduce the requirement for repeated applications of capsaicin before the beneficial pain relief effects were obtained.
The inventor of the present application previously developed a formulation for treatment of muscle and joint pain containing capsaicin and glucosamine. In addition to capsaicin and glucosamine, that preparation also contained a number of herbal extracts, including bloodroot, blessed thistle, green tea and mint leaf that were intended to improve the palatability and anaesthetic qualities of the preparation. However, this preparation was unsatisfactory for a number of reasons. First, the preparation would separate into a number of phases within a few days, rendering it unusable. Furthermore, the preparation had an unpleasant, gritty texture. The preparation also had a dark color that was undesirable because once applied, the preparation stained clothing irreversibly. Furthermore, the preparation was not sterile, and its shelf life was only a few days. Therefore, there remains a need for an anti-inflammatory composition that is effective in treating pain and inflammation at certain sites, and which does not include the drawbacks of previous preparations. The present invention fulfills that need, and furthermore has the unexpected quality of providing an extended duration of pain relief without the intense burning or stinging feeling associated with topical administration of capsaicin-containing preparations.
The present invention provides an anti-inflammatory composition for treatment of joint and muscle pain through transdermal delivery of a capsacinoid in conjunction with a primary amine, such as glucosamine. The ingredients of the composition of the present invention, namely, a capsacinoid in combination with glucosamine at a high concentration, interact in a synergistic manner to provide a prolonged effect of pain relief when used in the treatment of joint and/or muscle pain associated with an inflammatory response. The prolonged pain relief effect is achieved without incurring the intense burning or stinging sensation usually associated with topical capsaicin administration. The present invention also provides methods for relieving joint and/or muscle pain associated with an inflammatory response, which employ the composition of the present invention.
In one aspect of the present invention, a sterile anti-inflammatory composition is provided. The composition comprises a capsaicin, a capsaicinoid or a capsaicin analogue; a primary amine or a pharmaceutically acceptable salt thereof, and a pharmaceutically effective carrier which is effective to promote transdermal movement of at least one component of the composition upon contact with the skin of a patient with the composition. The composition is sterile, and further is substantially free of herbs or herbal preparations, which can introduce undesirable properties into the composition.
In another aspect of the present invention, a method for delivering a sterile anti-inflammatory composition to a patient comprises contacting the skin of the patient with an effective amount of a sterile anti-inflammatory composition which contains a capsaicinoid and a primary amine or a pharmaceutically acceptable salt thereof, and a pharmaceutically effective carrier which is effective to promote transdermal movement of at least one component of the composition upon contact with the skin of a patient with the composition. The composition is sterile, and further is substantially free of herbs or herbal preparations, which can introduce undesirable properties into the composition.
In another aspect of the present invention, a method for treating muscle or joint pain in a patient in need of such treatment comprises contacting the skin proximal to said muscle or joint pain with an effective amount of a sterile anti-inflammatory composition which contains a capsaicinoid and a primary amine or a pharmaceutically acceptable salt thereof, and a pharmaceutically effective carrier which is effective to promote transdermal movement of at least one component of the composition upon contact with the skin of a patient with the composition. The composition is sterile, and further is substantially free of herbs or herbal preparations, which can introduce undesirable properties into the composition.
The primary amine is preferably glucosamine or galactosamine, and should be present in an amount between about 18% and 25% by weight in the composition of the present invention. Preferably, the primary amine is glucosamine, and is present at a concentration of about 25% by weight, and more preferably, the glucosamine is present at as high a concentration as possible without causing phase separation. The capsaicinoid employed in the composition of the present invention may include one or more of trans-8-methyl-N-vanillyl-6-nonenamide (capsaicin), 8-methyl-N-vanillyl-nonanamide (dihydrocapsaicin), and N-vanillyl-nonanamide. Preferably, the capsaicinoid is trans-8-methyl-N-vanillyl-6-nonenamide (capsaicin). The composition further may include menthol, preferably at a concentration between 0.5% and 5% by weight, and more preferably at a concentration of 1% by weight.
The present invention provides a composition that alleviates pain associated with joint and/or muscle injuries, diseases or conditions through transdermal delivery of a capsaicinoid in conjunction with a primary amine, such as glucosamine, in a pharmaceutically acceptable Use carrier. The composition is effective in the treatment of joint and/or muscle pain associated with arthritis, muscle aches, bruises, bumps and sprains. Importantly, the composition provides rapid pain relief without irritating side effects, particularly skin irritation, and the pain relief effect has a surprising prolonged duration.
The composition of the present invention contains capsaicin, a capsaicinoid or a capsaicin analogue; a primary amine such as glucosamine or a pharmaceutically acceptable salt thereof, and a pharmaceutically effective carrier, which is effective to promote transdermal movement of at least one component of the composition upon contact with the skin of a patient with the composition. The composition is sterile, and further is substantially free of herbs or herbal preparations, which can introduce undesirable properties into the composition. The composition optionally contains menthol.
The carrier is any pharmaceutically effective carrier that is effective to promote transdermal delivery of the composition of the present invention. Such carriers are well-known among those in the art. Preferably, the carrier is one of the compounds designated by the mark Pluronic(trademark), such as Pluronic(trademark) F-127 (BASF Corporation, Mount Olive, N.J.). The capsaicin is preferably either a natural capsaicinoid-containing extract of chili peppers, or a capsaicinoid purified from peppers or synthesized artificially. More particularly, the capsaicin may be either capsaicin trans-8-methyl-N-vanillyl-6-nonenamide), dihydrocapsaicin 8-methyl-N-vanillyl-nonanamide), the cis isomer of capsaicin cis-8-methyl-N-vanillyl-6-nonenamide), or a synthetic capsaicin., such as N-vanillyl-nonanamide or those described in U.S. Pat. No. 4,812,446 to Brand. The capsaicin may further be comprised of a combination of any of the above capsaicinoids or synthetic capsaicins. The concentration is any that is effective in producing the desired results. In general, the concentration is preferably between 0.005% by weight and 1.0% by weight. More preferably, when the capsaicinoid is capsaicin or N-vanillyl-nonanamide, the concentration preferably is between about 0.025% by weight and 0.075% by weight.
The glucosamine (2-amino-2-deoxyglucose) is preferably present at as high a concentration as possible, in order to maximize the mass action effect of the transdermally applied glucosamine. Preferably, the concentration of the glucosamine is between about 18% by weight and about 25% by weight. Most commercially available glucosamine-containing compositions contain about 4% by weight of glucosamine. If the concentration is higher than 25% by weight, the composition loses its smooth, creamy texture and instead becomes granular and gritty. Furthermore, the color of the composition changes from a light tan to a darker brown. This darker color is more noticeable than the light tan color when the composition contacts light-colored clothing. The glucosamine is preferably supplied in the form of glucosamine sulfate, but may also be supplied in the form of any other appropriate salt, such as glucosamine hydrochloride or glucosamine pentaacetate. In addition, other amines, such as galactosamine, could be substituted in place of the glucosamine.
Importantly, the composition of the present invention does not contain any additional botanicals or herbals, other than the possibility of the inclusion of capsaicin in the form of cayenne. Inclusion of such botanicals or herbals may cause the color of the composition to darken, leading to the undesirable possibility that clothing that comes into contact with the composition may be stained. In addition, it has been found by the inventor that inclusion of such additional components produces a composition having an unsatisfactory gritty texture, and also increases the possibility that the composition will separate into a plurality of physical phases.
Furthermore, the composition of the present invention is prepared in a form that is sterile. By xe2x80x9csterilexe2x80x9d, it is meant that the preparation is sufficiently devoid of additional bacteria, yeast, fungi, molds, etc. so that the preparation has a useful shelf life, under storage and transport conditions normal to this type of preparation, of at least one month. The preparation may be rendered of a sufficient degree of sterility by any appropriate means, including but not limited to autoclaving, irradiation, and ethylene oxide treatment. One or more of the components may be sterilized separately from the remainder of the mixture and thereafter added to the other components under sterile conditions. Alternately, the entire composition may be sterilized prior to dispensing the composition into separate tubes.

Transdermal delivery of an anti-inflammatory composition


A circuit breaker having a switch rated current setting on an electronic tripping unit is described. This is suitable for all circuit breakers having an electronic tripping unit that can be removed from the circuit breaker housing after removing a seal and can be lockably parameterized at the rated current of the circuit breaker.

The present invention relates to a circuit breaker having an electronic tripping unit accommodated in the circuit breaker housing for a trip magnet operating the switch contacts of the circuit breaker over a breaker mechanism.
Circuit breakers having an electronic trip such as those described in U.S. Pat. No. 4,210,887 or in U.S. Pat. No. 4,181,906, for example, have a housing with a compartment into which the tripping unit can be inserted interchangeably. Electronic tripping units may have the same design for a plurality of types of circuit breakers because the electronic circuit can easily be adapted to the rated current, the breaking capacity class and other characteristics of the switch. The parameters of the tripping unit are defined only for the current values valid for the respective circuit breaker through the rated current plug which can be plugged into the electronic circuit. The interchangeability of the tripping unit also has the advantage that it can be removed in the event of a disturbance and tested in a testing device and optionally replaced by a new unit without having to dismantle the circuit breaker. If the tripping unit is not the cause of the disturbance, this provides information at the same time that only the switch part can be responsible for the disturbance, so then the switch part is to be replaced.
U.S. Pat. No. 4,181,906 and U.S. Pat. No. 4,210,887 describe a safety device which prevents the insertion of a tripping unit which is unsuitable for a given circuit breaker into the above-mentioned compartment of the switch housing. This is accomplished through a system of coding pins on the switch side that work together with receptacle openings in the housing of the electronic tripping unit. For example, this makes it possible to prevent the use of a tripping unit without ground fault protection or a tripping unit that is not designed for the tripping characteristic of a switch of a certain breaking capacity class. This also ensures that the circuit breaker cannot be switched on if the tripping unit cannot be inserted completely into the receptacle compartment of the switch housing because of the arrangement of coding pins and the respective receptacle openings.
However, a correct and fitting match of tripping unit and circuit breaker is often not sufficient for the required protection of equipment and systems. Instead, an adapted activation and adjustment of the possible trip parameters is important for safe operation. However, this cannot be achieved through coding, because it often occurs that the settings of the tripping unit must be changed when the operating mode of a consumer changes, for example. Changes can be made in the settings of the tripping unit even if a seal is provided for the access to the adjustment components of the tripping unit as described in German Patent No. 39 26 414. In that case, the user can only see that there has been unauthorized access.
An object of the present invention is to provide a circuit breaker having an electronic tripping unit and lockable parameter assignment such that the tripping unit has a simple design and yet allows parameter assignment only by authorized personnel.
According to the present invention, this object is achieved by providing a circuit breaker having an electronic tripping unit that can be lockably parameterized to the rated current of the circuit breaker and can be removed from the circuit breaker housing after removing a seal, for a trip magnet which operates the switch contacts of the circuit breaker over a breaker mechanism and having a monitoring circuit which belongs to the tripping unit and prevents the tripping unit from being parameterized when there is an electrical connection between the trip magnet and the tripping unit.
The monitoring circuit may be designed so that its input receives a voltage which is applied to an electronic switch of the tripping unit, and the electronic switch trips the trip magnet.
When the tripping unit is removed from the housing of the circuit breaker, the electrical connection between the tripping unit and the magnet coil is interrupted so that no voltage can be measured across the electronic switch provided with the tripping unit. The monitoring circuit then allows parameterization.
This measure does not prevent the tripping unit from then being set at the wrong parameters, but it does allow parameterization only by authorized personnel, because at least one seal must be broken to remove the tripping unit.

Circuit breaker having an electronic tripping unit and parameterization locking

Abstract: In parameterization of electronic tripping units of circuit breakers, the possibility of unauthorized parties tampering with the tripping unit must be prevented.

Abstract: Therefore, the tripping unit is equipped with a monitoring circuit which prevents the possibility of parameterization of the tripping unit when there is a galvanic connection between the trip magnet and the tripping unit. This permits parameterization only when the tripping unit has been removed, i.e., only by authorized personnel.


A cable protective shield assembly is provided for managing the position of computer cables. The assembly includes a base plate having a number of spacers formed on one surface, a cover plate having a number of bores extending through the plate at locations designated in alignment with the spacers of the base plate, and a corresponding number of fasteners for insertion through the bores of the cover plate into the spacers of the base plate to rigidly couple the plates together. The height of the spacers create a standoff distance between the base plate and cover plate defining a space for computer cables to extend. The spacers are also positioned across the base plate surface as to create specific passageways for the cables to be located. One or more ports can be placed along the perimeter of the cover plate to allow access to cable connectors while generally maintaining the organized position of the cables. The assembly shields the cables from electromagnetic energy and filters noise superimposed on the cables by electromagnetic energy present in the chassis.

This invention relates generally to an apparatus for covering a surface of a computer, and, more particularly, to an apparatus for managing and protecting computer cables extending within a computer chassis while mitigating electromagnetic waves both internal of the system and conducted as a noise signal superimposed upon an intended signal.
Typical computer systems have a series of cables that are designed to carry commands and data between separate components, including peripheral devices. These cables facilitate the interfacing of a central processing unit (CPU) and related circuitry, such as a motherboard, with devices that are to be controlled. Additionally, cables are used to connect a single computer or computer terminal with other computers, such as servers.
Managing the position of a number of cables is typically carried out by cable clips, nylon cable ties or tape that position the cables adjacent to a computer frame. Cable clips often allow several cables to be bundled together to facilitate better organization of the cables along a computer frame. These devices, however, suffer from many disadvantages. First, bundling cables makes it difficult to locate and access a specific cable for servicing. Second, using cable clips, cable ties, or tape often gives a system an unfinished appearance as a group of jumbled cables extends internally along the frame. Additionally, these devices may not fully protect the cables from damage due to exposure, and often fail to correctly position the cables at ideal locations in relation to the computer system components.
Conduits have been used to arrange the cables, however, the use of conduits increases the space needed around the computer system to accommodate the cables and limits the positioning of the cables to a predefined path. Accessibility of the cables also becomes more difficult since the conduit must be removed and the specific cable located prior to servicing.
Particularly in computer server applications, a further concern arises with controlling electromagnetic waves within the chassis. The Federal Communication Commission strictly regulates the amount of electromagnetic wave emissions radiating from a product. Cables that communicate with or supply power to external devices compromise the electromagnetic compatibility (EMC) containment feature by extending through the EMC enclosure and/or by conducting the electromagnetic waves from sources within the chassis and radiating this electromagnetic energy outside the chassis. One known solution is to use a filtered connector. Filtered connectors contain an electronic circuit that shunts the high-frequency electromagnetic waves to the EMC enclosure and permits the intended electronic signals to pass unimpeded. These connectors, however, are expensive and required for any breach of the EMC enclosure even for applications that do not require a connector.
Another known solution involves passing the cables through a cylindrically shaped ferrite bead. The ferrite bead introduces an inductance for high-frequency alternating currents without affecting the desired direct currents on the cables. Ferrite conduits are costly, space-consuming, and the physical size of the ferrite bead makes routing of the cable through the chassis more difficult during assembly.
Thus, what is needed is an apparatus for efficiently and conveniently managing the position of computer cables adjacent to a computer system frame while mitigating electromagnetic waves both internal of the system and conducted as a noise signal superimposed upon the intended signal. Such an assembly should control these electromagnetic waves internally of the chassis to prevent these waves from subsequently leaving the chassis and further serves to improve the product performance. Such an apparatus should be easy to secure to the desired component of a computer system by generally restricting the position of the cables such that the connector is adjacent the component, and easy to remove to allow access to the cables. As another feature, the apparatus should be configured for different sizes of cables and should allow some freedom of movement for adjusting the position of the cables relative to components of the computer system. Further, the apparatus should ensure that cables are located out of the way of, and protected from, other objects that could damage or become entangled with the cables.
It is therefore an object of the present invention to provide a cable protective shield assembly for attachment to a computer system to manage the position of computer cables. It is another object of the present invention to provide such an assembly with spacers configured to provide a standoff distance or spacing for housing a series of computer cables and to provide a means of positioning and guiding the cables to desired locations. It is a further object of the present invention to provide fasteners to facilitate secure placement of the shield assembly and ease in removal of the cover plate to access the cables. It is another object of the present invention to provide such a cable assembly that mitigates electromagnetic waves and filters noise from the series of cables. It is yet another object of the present invention to provide such an assembly that is neat in appearance and protects the cables from contacting potentially damaging objects.
A cable protective shield assembly of the present invention meets these objects by managing the position of cables of a computer system and providing control for electromagnetic waves internal of the chassis. The assembly comprises a base plate section, a cover plate substantially aligned with the base plate and positioned parallel to the base plate at a stand-off distance, and fasteners for coupling the cover plate to the base plate.
The perimeter of the base plate is configured for attachment to a computer system. In one embodiment, a number of spacers are formed on the upper surface of the base plate presenting a generally flat surface parallel to the base plate surface. These spacers are located at various positions to facilitate support of the cover plate at a desired distance above the base plate and are adapted for receiving a fastener. Another function of the spacers is to restrict the movement of computer cables in a two-dimensional plane to specific paths along the top surface of the base plate.
The cover plate is sized and configured to overlay the base plate to ensure the computer cables are confined to locations between the base and cover plates. Thus, the cover plate restricts the movement of the cables perpendicularly away from the base plate. A number of bores extend through the cover plate at specific locations designated to be aligned with the spacers of the base plate when the cover plate is properly positioned. The cover plate is also provided with one or more ports. The ports serve as a location for exposing a cable connector for connecting to various computer system components. Additionally, the ports restrict the movement of the cable connector by preventing it from sliding under the cover plate.
A corresponding number of fasteners are provided for insertion through the bores of the cover plate into the spacers of the base plate to connect both plates. The fasteners also ensure that the cover plate rests against the spacers at the desired standoff distance. The fasteners are ideally of the kind that are easy to install and remove as desired to access the cables located between the base plate and cover plate.
The present invention provides a cable protective shield assembly that is easy to install on a typical computer system and facilitates the management of computer cables to desired locations. Within the assembly, the cables are allowed some freedom of movement between the spacers such that it is unnecessary to precisely position the cables. The shield assembly further provides a control for electromagnetic waves of the chassis by conducting electromagnetic waves to ground for the series of cable. Additionally, the openings of the cover plate provide for convenient access to the cable connectors at desired locations around the computer frame.

Hewlett-Packard Development Company, L.P.


An ultrasonic imaging system is provided for forming an orthographic and a tomographic image of an object. The system comprises a receiving transducer array having a plurality of elements positioned at the lattice points of a parallelogram and a transmitting transducer array having a plurality of elements arranged in a straight line parallel to one side of the parallelogram at a period equivalent to the length of the side. A receiving beam former compensates for the delay time of the received signal for each element in the receiving transducer array and adds the compensated signals for all the elements. The receiving beam former comprises a quadrature demodulator which decomposes the output of a receiving transducer element into the inphase component and the quadrature component of a transmitting carrier signal. The beam former also includes means for delaying the components, means for performing the complex multiplication of the delayed components, means for adding the real parts of the output of the complex multiplication means for all channels, means for adding the imaginary parts of the output of the complex multiplication means for all channels, a pair of square circuits for providing the square of the real sum and the imaginary sum respectively, and an adder for adding the outputs of the square circuits. Further, means are provided for extracting the received beams in accordance with the timing of the transmitted beam and are provided for displaying the extracted received beams thereby forming an image.

The present invention relates to an ultrasonic imaging system by which both orthographic images and tomographic images of high resolution can be obtained, in particular, relates to such an apparatus employing only a few transducers.
Some of the application fields of the present invention are the medical field, sonar, and non-destructive inspection.
There have been two kinds of conventional ultrasonic imaging systems having a three-dimensional imaging function capable of obtaining orthographic and tomographic images simultaneously. The first one employs an acoustic lens and a plane transducer array for both transmission and reception, and scans an object by sequentially switching on and off the transducer elements in the array. The second one employs a variable delay line and plane transducers for transmission and reception, and scans electronically the directions and the focal distance of the transmitting and receiving beams (for instance, "Acoustic Imaging" by G. Wade, Plenum Press (1976), PP171-181).
However, the prior ultrasonic imaging systems have the disadvantage that a plane transducer array must have almost the same number of elements as the number of picture cells of an object. Therefore, the number of transducer elements becomes enormous when an image of high resolution must be obtained, thus, the system is almost impracticable. Further, the first prior art has the disadvantage that dynamic focusing is not possible for tomographic imaging since the focal distance is fixed, although the signal processing is simple since the image is obtained by the image formation of the acoustic lens. The impossibility of dynamic focusing restricts the bearing resolving power. The second prior art can perform dynamic focusing, but the signal processing is complex, the size of the circuitry is large, and in fact, the second prior art is almost impracticable.


A method and system for converting mail between trays in a multiple pass mail sorting system using a plurality of different tray types. Mail from a first type of tray is unloaded and stacked along with mail from other trays to form a large stack. The large stack of mail is then broken down into smaller stacks which are transferred to one of several outputs where the mail is loaded into different types of trays.

1. Field of the Invention
The present invention relates generally to mail sorting systems and, more particularly, to a method and system for converting mail between trays in a multiple pass mail sorting system.
2. Discussion of the Related Art
Currently, a variety of automated systems are used to sort flats mail. These automated mail sorting systems reduce cost and increase efficiency. The cost is reduced in automated mail systems by the use of less floor space and less manpower. The efficiency is increased because the time and space required to sort the mail in an automated system is much less than when sorting is performed manually. Some automated mail sorting systems require more than one pass and more than one type of tray in order to sort the mail into a desired sequence, such as carrier route. One of the biggest issues with multiple pass sorting systems is transferring mail back to the input of the sorting system after the first pass (or any pass other than the final pass). Another issue can be the need for multiple, separate systems for feeding the mail back into the sorter or sending mail to dispatch. This can lead to the use of more floor space and all but one of the systems will always not be in use (e.g., when mail is being sent to dispatch the system for sending mail to the sorting system will not be used and visa-versa).
One solution to transferring mail between passes is to use a system that would unload the mail from one tray and place it directly into another. This system does a one-to-one transfer (e.g., mail from the first tray goes directly into the second tray). A one-to-one transfer hurts efficiency, especially in systems where the various types of trays used have different maximum capacities. The efficiency is hurt firstly by the fact that if a tray is only partially filled then the transfer system will still transfer the mail to the next tray without trying to create a larger stack to fill the next tray (e.g., if the first tray has one inch of mail then the second tray will receive one inch of mail). Secondly, the system is limited by the maximum capacity of the smallest tray (e.g., if the tray used for dispatch has a maximum capacity of 15 inches and the tray used for sorting has a maximum capacity of 9 inches, then in a system with one-to-one transfer the dispatch trays will always have at least 6 inches of empty space).
Therefore, a need exists for an improved method and system for transferring mail between trays in a multiple pass mail sorting system.