The present invention provides methods for preventing, treating, and/or managing one or more cancerous conditions in a patient, such as a human. A multivalent metal oxide, such as Ag(I,III), Cu(I,III), Pr(III,IV), and Bi(III,V) oxides or a pharmaceutically acceptable derivative thereof, may be administered to the patient in an amount and for a period of time which is therapeutically effective to prevent, treat, and/or manage such condition(s). These cancerous conditions include systemic and external cancers, and may also include conditions and symptoms associated with cancer. The present invention also provides a pharmaceutical composition suitable for treating such cancerous conditions. The compositions of the invention may be adapted for at least one of subcutaneous injection, intramuscular injection, intravenous injection, infusion, transdermal, or topical application.

The invention relates to pharmaceutical compositions including at least one metal oxide, such as an electron active metal oxide, and methods of using such compositions, for the prevention, treatment, and management of cancer and conditions or diseases related to the presence of cancer or a predisposition to cancer.
Cancers are a leading cause of death in animals and humans. The exact cause of cancer is not known, but links between certain factors, such as smoking or exposure to carcinogens including tobacco smoke and chromium (VI), exposure to radiation, such as from x-rays, radioisotopes, and ultra-violet light, viruses, such as papaloma, Espstein Barr, and Raus sarcoma virus and the incidence of certain types of cancers and tumors has been shown by a number of researchers. Genetic factors and genome defects such as those found a chromosome 11 have also been linked to cancer. Traditional methods of cancer therapy include treatment with chemotherapeutic agents that inhibit cell division or radiation therapy that disrupts DNA in dividing cells. These treatments, however, may also adversely affect normal cells that happen to be dividing or synthesizing DNA at the time of treatment. Dosage levels low enough to insure survival of a cancer patient often are not sufficiently cytotoxic to tumor cells to retard continuing cell division after treatment. Additionally, the mechanism for the action of these chemotherapeutic agents is frequently unknown, which complicates the safe and effective use of these agents. Several different cancers and conditions associated with cancer are discussed below as examples illustrating the importance of combating cancer and associated conditions.
Breast carcinoma is the most common malignancy among women and shares with lung carcinoma the highest fatality rate of all cancers affecting females. For example, approximately one of every 11 women in the U.S.A. will develop breast cancer. For white women, the probability is about 1 in 10; for African American women, the rate is close to 1 in 14. The annual mortality rate from 1930 to the present has remained fairly constant at about 27 deaths per 1000,000 females, and is slightly higher for whites than African Americans.
In women, breast carcinoma is rare before age 30 but the incidence rises rapidly after menopause. Post-menopausal breast masses are typically considered cancerous until biopsy proves otherwise. Cystosarcoma phyllodes, which are a non-cancerous tumor, are the most common tumor of the breast; other malignancies are significantly more rare. Breast cancer in men is rare and tends not to be recognized until late with poor therapeutic results.
Most breast cancers, including those frequently designated as scirrhus, infiltrative, papillary, ductile, medullary, and lobular, appear as a slowly growing, painless mass, though a vague discomfort may be present. Physical signs typically include a retracted nipple, bleeding from the nipple, a distorted areola or breast contour, skin dimpling over the lesion, attachment of the mass to surrounding tissue, including the underlying fascia and overlying skin, edema of the skin of the breast with an orange peel appearance, and axillary or supraclavicular lymph nodes. In advanced cases, skin nodules with ultimate breakdown and ulcer formation may be seen.
The presence of metastases should always be suspected as the disease metastasizes by direct extension and via the lymph system and the bloodstream. Among the most common sites are the lungs and pleura, the skeleton (especially skull, spine, and pelvis), and the liver. Although the exact causes of breast cancer are not known, a doctor from France discovered a virus called mice breast tumor virus (vtmr) in 1985 that was later described as an oncomavirus with particules type B. This virus caused breast cancer in mice breast. It can be transmitted by breast milk or it can be incorporated in the human genome. Current treatments for breast cancer in general include surgery, radiotherapy, chemotherapy and hormonal therapy.
Cervical cancer includes those cancer moieties which are indigenous to the cervix. These cancer moieties are referred to generally as cervical carcinomas of which 85-90% are squamous cell carcinomas, and the balance are largely adenocarcinomas. The severity of cervical cancers are gauged by the clinical tests called PAP smears which indicate whether the carcinoma cells are confined to the cervix or have penetrated beyond it but not to the pelvic wall, or to the pelvic wall itself and even beyond the pelvis. Cervical cancers kill about 33% of their victims annually in the United States.
Carcinoma of the uterine cervix, the second most common malignancy of the female reproductive tract, most commonly affects women aged 40 to 56 years old. The incidence is higher among women from lower socioeconomic groups and among those with a history of early and frequent coitus and multiple sexual partners. Recently, venereal transmission of human papilloma virus (hpv) and herpes virus type 2 (nsv-2) have been implicated as important in the etiology of cervical neoplasia.
The earliest histologic change in what is considered a continuum from normal to invasive cancer is minimal cervical dysplasia, in which abnormal cell proliferation occurs in the lower third of the epithelium. Most of the minimal dysplasias are self-limiting and regress to normal tissue. Most severe dysplasias in the upper two-thirds of the epithelium showing abnormal proliferation, however, progress to carcinoma in situ, in which a full thickness of the epithelium contains abnormal calls. When cancer cells penetrate the basement membrane and invade the stroma (invasive carcinoma) they can spread by direct extension to adjacent pelvic organs or by lymphatic permeation and dissemination.
Of cervical carcinomas, 85 to 90% are squamous cell carcinoma. These vary from well-differentiated cells with keratinization to the highly anaplastic spindle cells of cervical tumors. Adenocarcinomas, observed in only 10 to 15% of cases, are more rare.
Early cervical neoplasia can be detected pre-clinically by cytologic examination of cervical smears obtained during routine annual pelvic examinations. At this stage, the disease is asymptomatic. The cervical smears (pap test) can detect 90% of early cervical neoplasias. Thus, the use of cervical smears has reduced the death rate from cervical cancer by more than 50% through recognition and treatment of pre-invasive neoplasia. Treatment of cervical cancer typically involves conization, radiotherapy, surgical therapy, and chemotherapy.
For diagnostic and prognostic purposes, the results of cervical smear tests may be grouped into four categories: class I characterized by the absence of observed abnormal cells; class II characterized by the presence of atypical cells and usually associated with inflammation; class III characterized by the presence of cells representative of or suspicious of carcinoma; and classes IV and V each characterized by the presence of carcinoma cells.
Additionally, the clinical stage or progression of the cervical carcinoma may be further characterized as follows. Stage 0 is characterized by carcinoma in situ with intra epithelial carcinoma. Stage I includes carcinomas strictly confined to the cervix. Stage IA is characterized by micro invasive carcinoma and stage IB is characterized by occult cancer.
In stage II, the carcinoma extends beyond the cervix but not onto the pelvic wall. Stage IIA exhibits no obvious parametrial involvement while stage IIB exhibits obvious parametrial involvement. In stage III, the carcinoma extends onto the pelvic wall. Stage IIIA is characterized by the lack of extension onto the pelvic wall and stage IIIB is characterized by extension onto the pelvic wall.
In stage IV, the carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the bladder. Stage IVA is characterized by the spread of the growth to adjacent organs. Stage IVB is characterized by the spread to distant organs.
Skin cancer is a disease in which cancer (malignant) cells are found in the layers of the skin. The skin has two main layers and several kinds of cells: a top layer called the epidermis, which contains three kinds of cells: flat, scaly cells on the surface called squamous cells; round cells called basal cells; and cells called melanocytes, which give the skin its color. The dermis is the inner, second layer of the skin.
The skin is the most environmentally-stressed organ in mammals, particularly in humans. The skin is subjected to toxic chemicals and hostile environments, as well as being the only organ directly exposed to ultraviolet (xe2x80x9cUVxe2x80x9d) light in the presence of oxygen. Lengthy exposure of the skin to UV light typically damages the skin, resulting, in sunburn, photo-aging, carcinogenesis, and other related skin disorders. xe2x80x9cSkin cancerxe2x80x9d is generally used to describe the three major forms of skin cancer; basal cell and squamous carcinoma together with melanoma. These carcinomas account for about 97% of skin cancers. Melanoma, however, accounts for over 87% of deaths due to said cancers.
Melanoma is a disease of the skin in which cancer (malignant) cells are associated with the cells that color the skin (melanocytes). Melanoma usually occurs in adults, but it may occasionally be found in children and adolescents. Melanoma is sometimes called cutaneous melanoma or malignant melanoma. Melanoma can spread (metastasize) quickly to other parts of the body through the lymph system or through the blood.
About 80% of non-melanoma skin cancer will be basal cell carcinoma. It can occur at any location on the body surface, but occurs more commonly on sun-exposed surfaces, such as the face. The earliest sign may be a red flat area, a small nodule, a small spot that bleeds on rubbing, a small ulcer, or a scaly patch. About 20% of non-melanoma skin cancer will be squamous cell carcinoma. The difference between basal cell carcinoma and squamous cell carcinoma is often discernable only at the microscopic level, as the two may look identical. Squamous cell carcinoma, however, tends to grow more rapidly, and form an ulcer sooner. Squamous cell carcinoma may afflict any skin surface, but is common on the lips and ears.
Neurofibromatosis is a hereditary autosomal dominant disorder that is accompanied by a predisposition to cancer. Neurofibromatosis produces pigmented spots and tumors of the skin and of peripheral, optic and acoustic nerves. Subcutaneous and bony deformities may also be observed. One third of the patients with neurofibromatosis are asymptomatic and the condition is discovered during routine examination. In one-third of patients, cosmetic problems are the initial complaints. Characteristic skin lesions, apparent at birth or in infancy in 90% of the patients, include medium brown patches distributed most commonly over the trunk, pelvis, and flexor creases of elbows and knees. For diagnostic purposes, the presence of six or more of these freckle-like lesions with one larger than 1.5 cm is characteristic of neurofibromatosis. Multiple cutaneous tumors, flesh colored and of variable size and shape typically appear in late childhood.
The above-mentioned discussion merely illustrates the breadth and importance of cancer as an affliction of animals and humans in particular. Those of ordinary skill in the art will understand that various other types of cancers exist that also require suitable prevention, treatment, and/or management. In view of this discussion, there is a need for pharmaceutical compositions that can be administered at dosage levels low enough to insure survival of a cancer patient but which are sufficiently cytotoxic to cancer cells or cells associated with cancer to retard or eliminate continuing cell division after treatment, i.e., management or treatment of the cancer.
Metal oxides, such as electron active metal oxides comprising multivalent silver cations, have been disclosed for various uses, as they are reported to be non-toxic to animals and humans. M. Antelman, xe2x80x9cAnti-Pathogenic Multivalent Silver Molecular Semiconductors,xe2x80x9d Precious Metals, vol. 16:141-149 (1992); M. Antelman, xe2x80x9cMultivalent Silver Bactericides,xe2x80x9d Precious Metals, vol. 16:151-163 (1992). For example, tetrasilver tetroxide activated with an oxidizing agent is disclosed for use in bactericidal, fungicidal, and algicidal use, such as in municipal and industrial water treatment applications and for the treatment of AIDS.
A variety of sources also report the use of certain divalent silver compounds for water treatment, as well as the use of such compounds, typically in combination with certain oxidizing agents, metals, or other compounds, as disinfectants, bactericides, algicides, and fungicides. One source also reports a single in vitro study of the use of such compounds for the treatment of AIDS. These sources include M. Antelman, xe2x80x9cSilver (II, III) Disinfectants,xe2x80x9d Soap/Cosmetics/Chemical Specialties, pp. 52-59 (March, 1994), and U.S. Pat. Nos. 5,017,295; 5,073,382; 5,078,902; 5,089,275; 5,098,582; 5,211,855; 5,223,149; 5,336,416; and 5,772,896.
U.S. Pat. No. 5,336,499 discloses tetrasilver tetroxide and persulfate compositions having certain in vitro anti-pathogenic properties, i.e., bactericidal, fungicidal, viricidal, and algicidal, in certain concentrations as low as 0.3 ppm, particularly in nutrient broth cultures. The persulfate is disclosed to be an oxidizing agent that activates the tetroxide crystals. Also disclosed are an in vitro study regarding the inhibition of yeast growth in nutrient broth and the formulation of a gynecological cream and douche based on these results, and a report of an in vitro AIDS test with the compositions indicating total suppression of the virus at 18 ppm.
In vitro assays, such as those disclosed in Ahmed, S. A., Gogal Jr., R. M. and Walsh, J. E., a New Rapid and Simple Non-radioactive Assay to Monitor and Determine the Proliferation of Lymphocytes: an Alternative to [3H]-thymidine Incorporation Assay, Journal of Immunological Methods 1994; 170: 211-224; Boyd, M. R., Status of the NCI Preclinical Antitumor Drug Discovery Screen, J. B. Lippincott Company, Philadelphia, Principles and Practices of Oncology Updates 1989; 3 # 10: 1-12, and Boyd, M. R. et al. Data Display and Analysis Strategies for the NCI Disease-oriented in Vitro Antitummor Drug Screen in Cytotoxic Anti-cancer Drugs: Models and Concepts for Drug Discovery and Development, Kluwer Academic, Boston, 1992: 11-34; each of which is hereby incorporated herein in its entirety by express reference thereto, have been used to estimate the cyto-toxicity of anti-cancer therapeutics. One of ordinary skill in the art understands, however, that, although in vitro testing provides a useful screen for potentially useful compounds, animals such as humans are sufficiently complex that the actual in vivo cytotoxicity of a compound is often surprisingly different than that predicted upon the basis of an in vitro toxicity screen.
U.S. Pat. No. 5,571,520 discloses the use of molecular crystals of tetrasilver tetroxide, particularly with oxidizing agents to enhance the efficiency of such devices, for killing pathogenic microorganisms, such as staph infections. Amounts of 10 ppm sodium persulfate as an oxidizing agent were used with certain amounts of silver tetroxide in the reported in vitro testing. One human study involved in vivo curing of a gynecological yeast infection with 10 ppm of the silver tetroxide and 40 ppm sodium persulfate. Other in vivo topical studies report in conclusory fashion the cure of a single case of athlete""s foot with a solution of 100 ppm of the composition and the cure of a single case of toenail fungus with a 25% suspension of the composition.
U.S. Pat. No. 5,676,977 discloses intravenously injected tetrasilver tetroxide crystals used for destroying the AIDS virus, AIDS synergistic pathogens, and immunity suppressing moieties (ISM) in humans. The crystals were formulated for a single injection at about 40 ppm of human blood. This reference also discloses the compositions cause hepatomegaly, also known as enlarged liver, albeit with no reported loss of liver function.
The aforementioned references report detailed descriptions of the mechanism via which the multivalent silver molecular crystal devices were believed to operate. The instant inventor also presented a discussion of such results and concepts at a Seminar entitled xe2x80x9cIncurable Diseases Updatexe2x80x9d (Weizmann Institute of Science, Rehovot, Israel, Feb. 11, 1998). The title of this presentation was xe2x80x9cBeyond Antibiotics, Non Toxic Disinfectants and Tetrasil(trademark) (Trademark of applicant for the tetroxide).xe2x80x9d
In this paper, it was reported that the effects of the electron transfer involved with respect to the tetroxide, rendered it a more powerful germicide than other silver entities. The instant inventor holds patents for multivalent silver antimicrobials, e.g., U.S. Pat. No. 5,017,295 for Ag(II) and U.S. Pat. No. 5,223,149 for Ag (III); and while these entities are stronger antimicrobials than Ag (I) compounds, they pale by comparison to the tetroxide and so does colloidal silver that derives its germicidal properties from trace silver (I) ions it generates in various environments. Accordingly, the oligodynamic properties of these entities may be summarized as follows, which is referred to as the Horsfal series:
Ag4O4 greater than Ag(III) greater than Ag(II) greater than  greater than  greater than  greater than Ag(I)
The other unique property of the tetroxide was that it did not stain organic matter such as skin in like manner as Ag(I) compounds do. In addition, it was light stable.
Thus, it is desired to find pharmaceutical compositions and methods for preventing, treating, or managing one or more cancers or associated conditions. It is also desired to facilitate the prevention of future outbreaks of one or more disorders, as well as preventing, treating, and managing one or more cancerous or related disorder while avoiding the adverse effects present in many conventional treatments.
The present invention relates to a method for preventing, treating, or managing one or more cancerous conditions or dysplastic proliferations in an animal. The method preferably comprises administering at least one metal oxide compound or a pharmaceutically acceptable derivative thereof, to the animal. The metal oxide compound or derivative thereof preferably comprises a first metal cation having a first valence state and a second metal cation having a second, different valence state, such as, for example, an electron active metal oxide compound. The at least one metal oxide compound or a pharmaceutically acceptable derivative thereof is preferably administered in an amount and for a period of time which is therapeutically effective to treat such condition(s).
In a preferred embodiment, the at least one metal oxide compound or pharmaceutically acceptable derivative thereof comprises at least one of Bi(III,V) oxide, Co(II,I) oxide, Cu(I,III) oxide, Fe(II,III) oxide, Mn(II,III) oxide, Pr(III,IV) oxide, or Ag(I,III) oxide.
The metal oxide compound or derivative thereof is preferably substantially free of added persulfate.
The invention is preferably adapted to preventing, treating, or managing systemic cancerous conditions. Preferably, the animal is an mammal, such as, for example, a human. The metal oxide compound is preferably administered via intravenous injection or infusion, when the animal is a human. The intravenous injection or infusion is preferably subcutaneous, intramuscular, or comprises infusion into the bloodstream of the animal. Preferably, the administration provides an amount of the metal oxide sufficient to provide about 1 to about 75 ppm of the metal oxide compound or derivative thereof in the bloodstream. The metal oxide is preferably administered via infusion over a period of time sufficient to inhibit adverse side effects, such as over a time period of from about 30 minutes to about 300 minutes.
The metal oxide compound or derivative thereof may preferably be administered by a controlled release vehicle. The controlled release vehicle is preferably implanted in the body at a location suitable for providing a therapeutically effective amount of metal oxide compound or derivative thereof to the patient, preferably, without affecting proper functioning of the animal""s liver.
The method of the invention is preferably suitable for cancers or dysplastic proliferations including at least one of colon cancer, lung cancer, throat cancer, breast cancer, kidney cancer, pancreatic cancer, bladder cancer, prostate cancer, uterine cancer, brain cancer, liver cancer, skin cancer, testicular cancer, stomach cancer, adrenal gland cancer, cancer of the ovaries, thyroid cancer, bronchial cancer, tracheal cancer, eye cancer, bone cancer, cervical cancer, oral cavity cancer, soft tissue cancer, pituitary gland cancer, myeloma, rectal cancer, esophageal cancer, leukemia, lymphoma, cancerous fibroid tumors, non-cancerous fibroid tumors, or liver cancer. The method is preferably suitable for cancers including skin cancer that has metastasized.
In a preferred embodiment, the metal oxide compound or derivative thereof is administered in conjunction with at least one other chemotherapeutic agent. The at least one other chemotherapeutic agent is preferably administered concurrently with the metal oxide compound or derivative thereof.
Another embodiment of the invention relates to a method for preventing, treating, or managing one or more cancerous conditions or dysplastic proliferations associated with a patient""s skin, which method preferably comprises administering at least one metal oxide compound or a pharmaceutically acceptable derivative thereof to the skin in an amount and for a period of time which is therapeutically effective to treat such cancerous or associated condition(s). The metal oxide compound or derivative thereof preferably comprises a first metal cation having a first valence state and a second metal cation having a second, different valence state.
In a preferred embodiment, the at least one metal oxide compound or pharmaceutically acceptable derivative thereof comprises at least one of Bi(III,V) oxide, Co(II,III) oxide, Cu(I,III) oxide, Fe(II,III) oxide, Mn(II,III) oxide, Pr(III,IV) oxide, or Ag(I,III) oxide.
The metal oxide compound or derivative thereof is preferably substantially free of added persulfate.
The method of the invention is preferably suitable for preventing, treating, or managing cancerous conditions or dysplastic proliferations comprising at least one of dysplastic nevi, neurofibromatosis, basal cell carcinoma, squamous carcinoma, or melanoma. The method is preferably suitable for preventing, treating, or managing conditions comprising symptoms of cancer or conditions associated with a predisposition to cancer, such as neurofibromatosis.
The administering preferably comprises a carrier medium in which the at least one metal oxide compound or pharmaceutically acceptable derivative thereof, is dispersed. Preferably the therapeutically effective amount of the metal oxide or derivative thereof is from about 50 ppm to 500,000 ppm, such as from about 400 ppm to about 100,000 ppm, based on the weight of the carrier medium. The carrier medium may preferably comprise petroleum jelly. The administering of the composition is preferably topical or transdermal, such as directly to the skin.
Preferably, the at least one metal oxide compound or pharmaceutically acceptable derivative thereof, further comprises a thixotropic agent sufficient to increase adherence of the composition to the skin without excessive runoff.
The at least one metal oxide compound or pharmaceutically acceptable derivative thereof may, preferably, be administered in the form of a powder, such as in the form of metal oxide crystals. The administering of the powder is preferably topical or transdermal, such as directly to the skin. Preferably the metal oxide or derivative thereof is administered at a dosage level of about 10 mg to 500 mg per cm2 of skin surface. A preferred embodiment of a composition suitable for application as a powder comprises about 5% metal oxide, such as tetrasilver tetroxide, and about 95% bismuth subgallate.
Yet another embodiment of the invention relates to a method for preventing, treating, or managing one or more cancerous conditions associated with a cervix of a female animal. The method preferably comprises administering at least one metal oxide compound or a pharmaceutically acceptable derivative thereof to the cervix in an amount and for a period of time which is therapeutically effective to treat such cancerous or associated condition(s). Each metal oxide compound or derivative thereof preferably comprises a first metal cation having a first valence state and a second metal cation having a second, different valence state.
In a preferred embodiment, the at least one metal oxide compound or pharmaceutically acceptable derivative thereof comprises at least one of Bi(III,V) oxide, Co(II,III) oxide, Cu(I,III) oxide, Fe(II,III) oxide, Mn(II,III) oxide, Pr(III,IV) oxide, or Ag(I,III) oxide.
The metal oxide compound or derivative thereof is preferably substantially free of added persulfate.
The metal oxide compound or derivative thereof are preferably applied directly to the cervix. The administering preferably comprises a carrier medium, such as petroleum jelly, in which the at least one metal oxide compound or pharmaceutically acceptable derivative thereof, is dispersed, preferably in a therapeutically effective amount from about 50 ppm to 500,000 ppm, based on the weight of the carrier medium. The at least one metal oxide compound or pharmaceutically acceptable derivative thereof is preferably applied in an amount sufficient to obtain a desired effect and to substantially inhibit undesirable side effects.
Definitions Section
Suitable definitions are provided herein for some of the terms relating to the present invention.
The terms xe2x80x9cpatientxe2x80x9d or xe2x80x9csubjectxe2x80x9d as used herein refer to animals, particularly to mammals. In a preferred embodiment, the terms xe2x80x9cpatientxe2x80x9d or xe2x80x9csubjectxe2x80x9d refer to humans.
As used herein, the terms xe2x80x9cadverse effects,xe2x80x9d xe2x80x9cadverse side effects,xe2x80x9d and xe2x80x9cside effectsxe2x80x9d include, but are not limited to, staining of the skin, headache, dry mouth, constipation, diarrhea, gastrointestinal disorders, dry skin, staining of the skin, hepatomegaly, fever, fatigue, and the like.
The phrase xe2x80x9ctherapeutically effective amountxe2x80x9d when used herein in connection with the compositions and methods of the invention, means that amount of metal oxide composition, or a derivative thereof, which, alone or in combination with other drugs or treatment modalities, provides a therapeutic benefit in the prevention, treatment, or management, of one or more of forms of cancer or a symptom or related condition thereof. Preferably, the therapeutically effective amount of a component yields the desired therapeutic benefit without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention.
The term xe2x80x9csubstantially freexe2x80x9d means less than about 10 weight percent, preferably less than about 5 weight percent, more preferably less than about 1 weight percent, and most preferably less than about 0.1 weight percent of added persulfate is present according to the invention. In another embodiment, the term xe2x80x9csubstantially freexe2x80x9d refers to the same amounts of other added oxidizing agents present in the compositions.
The term xe2x80x9ccontrolled-release componentxe2x80x9d in the context of the present invention is defined herein as a compound or compounds, including polymers, polymer matrices, gels, permeable membranes, liposomes, microspheres, or the like, or a combination thereof, that facilitates the controlled-release of the active ingredient (e.g., tetrasilver tetroxide) in the pharmaceutical composition.
The term xe2x80x9cabout,xe2x80x9d as used herein, should generally be understood to refer to both numbers in a range of numerals. Moreover, all numerical ranges herein should be understood to include each whole integer within the range.
It has now been discovered that pharmaceutical compositions comprising at least one oxide compound or a pharmaceutically acceptable derivative thereof can be used as advantageous active ingredients in the prevention, treatment, or management of various cancerous conditions. The oxide compound preferably comprises a metal oxide, such as an electron active metal oxide. The metal oxide compound or pharmaceutically acceptable derivative thereof preferably comprise a first metal cation having a first valence state and a second metal cation having a second, different valence state. One of ordinary skill in the art understands that, in general, the valence state of a species, such as a metal cation, is related to the charge associated with or assigned to the species.
Preferably, the at least one metal oxide compound or a pharmaceutically acceptable derivative comprises at least one electron active metal oxide compound, such as, for example, at least one of Bi(III,V) oxide, Co(II,III) oxide, Cu(I,III) oxide, Fe(II,III) oxide, Mn(II,III) oxide, Pr(II,IV) oxide, or Ag(I,III) oxide. Preferred compounds of the invention comprise at least one metal tetroxide, such as silver tetroxide. The terms metal tetroxide and metal tetraoxide, are synonymous as used herein.
In one preferred embodiment, the metal oxide compound compositions are substantially free of added persulfate or other added oxidizing agents, since, when applied topically, such agents may cause adverse effects, such as skin irritation and skin over-drying. In another preferred embodiment, the compositions are substantially free of any oxidizing agents. More particularly, the invention relates to methods for preventing, treating, and managing cancerous conditions and conditions associated with cancer.
In one embodiment, the compositions include a molecular scale device comprising at least one crystal of a metal oxide compound. A plurality of these metal oxide crystals, such as on the order of trillions, may be employed in various pharmaceutical formulations and therapies to effectuate the prevention, treatment, and/or management of various cancers and conditions associated with cancer. The compositions of the invention include powders comprising metal oxide crystals of the invention.
The compositions and methods of the invention advantageously provide a desired effect such as preventing, treating, or managing cancer or conditions associated with cancer. xe2x80x9cManagement,xe2x80x9d as used herein, includes controlling one or more cancers, or conditions associated with such cancer(s), that cannot be cured completely, reducing the severity of affliction of such cancers or related conditions, and the like. Thus, a preferred embodiment of the invention relates to a method of inducing cytotoxicity (cell killing) in cancer cells or reducing the viability of cancer cells. In one embodiment, the invention relates to the treatment or management of cancer and/or diseases or conditions associated with cancer, while in another embodiment the invention relates to the prevention, of cancer and/or diseases or conditions associated with cancer.
Preferred metal oxides of the invention comprise a first metal cation having a first valency state and a second metal cation having a second valency state, which differs from the first valency, preferably by at least one charge. The first and second metal cations are preferably the same metal. Without being bound by theory, it is believed that the metal oxides of the present invention operate by transferring electrons between cations of differing valency, the electrons contributing to the death of the cancer cells by traversing the cell membrane. By way of non-limiting example, it is believed that the crystal lattice of a silver tetroxide (Ag4O4) molecular device operates against cancer, tumors, or cells associated with cancer by transferring electrons from its two monovalent silver ions to the two trivalent silver ions in the crystal, contributing to the death of the cancer cells by traversing their cell membrane surface. This in effect xe2x80x9celectrocutesxe2x80x9d the cancer cells. The electrons are forced out of their balanced crystals by such labile groups as NH, NH2, Sxe2x80x94S, and SH associated with the cellular surface. Normal cells are not believed to be affected, because they are not believed to proliferate fast enough to expose these labile bonds.
The metal oxides of the invention are preferably stable as determined by the dissociation constants of the compounds. For example, the dissociation constant (KA) of Ag4O4 is 7.9xc3x9710xe2x88x9213. Therefore the molecule is not believed to be disturbed unless more stable complexes are formed with such ligands as those associated with the cancer cell membrane surface in a dynamic state. Indeed, the end result of the electron transfer, which is a redox reaction, is believed to result in the metal ions of a lower valency being oxidized to a higher valency state and metal ions of a higher valency state being reduced to a lower valency state.
Returning to the non-limiting example of silver tetroxide, it is believed that monovalent Ag ions are oxidized to Ag(II) and the trivalent Ag ions are reduced to the same end product, Ag(II). Accordingly, the well-known affinity of monovalent silver for certain elements such as sulfur and nitrogen is believed to be far exceeded here, for divalent silver is believed to not merely bind to these elements as does silver, but to actually form chelate complexes with their ligands. The molecular crystal attraction for the cell membrane surfaces is thus believed to be driven by powerful covalent bonding forces.
The electron transfer occurring in the example of silver tetroxide can be depicted by the following redox half reactions:
Ag+xe2x88x92e=Ag+2
Ag+3+e=Ag+2
It was found by rigorous testing that certain silver tetroxide containing-compositions were comparatively non- toxic in comparison to monovalent silver salts. Since these silver tetroxide compositions were effective at certain ppm concentrations in killing pathogens in nutrient broth and for water treatment, commercial concentrates were formulated with 2% of the tetroxide. Prior to the acceptance of the oxide in commerce, for which EPA registration No. 3432-64 was obtained, it was necessary for the oxide to undergo a series of toxicity tests. A 3% concentrate was used and evaluated by a certified laboratory employing good laboratory practice (GLP) according to the Code of Federal Regulations for this purpose.
The results were as follows:
Subsequent evaluations conducted according to the invention showed that unless persons were prone to silver allergies, the pure tetroxide compositions according to the invention could be applied to, for example, the skin without any ill effects or evidence of irritation, despite the fact that the compositions of the invention can be a powerful oxidizing agent. This can perhaps be explained by the stability manifested by the above-noted KA of the silver compositions. Accordingly, in a preferred embodiment, the metal oxides of the invention are applied directly in a powder or composition form to afflicted areas, such as the skin, cervix, or cervical pelvic region of an animal afflicted with cancer. Preferred routes of administration include topically and application to mucosa. Application can be made, for example, digitally or using a suitable applicator.
One embodiment of the present invention relates to compositions and methods of using the metal oxide compositions of the invention while minimizing the amount of additional oxidizer, such as persulfate. It has been found in accordance with the present invention that the additional oxide is not required and in some circumstances is undesirable when the oxide is applied to, for example, the skin or cervix, in part due to the undesirable side effect of irritation. In one embodiment, the compositions are substantially free of added persulfates, while in a preferred embodiment, the compositions are completely free of added persulfates. In one preferred embodiment, the compositions are substantially free of added oxidizer, while in another preferred embodiment they are completely free of added oxidizer. The aforementioned compositions may be applied topically or to mucosa associated with, for example, the skin, cervix, vagina, or colon.
The metal oxide compound, such as tetrasilver tetroxide, may be black in color, such that care must be taken when formulating suitable topical pharmaceutical compositions according to the invention to inhibit or avoid blackening or staining of the skin. Without being bound by theory, it is believed that larger amounts of the silver tetroxide composition promote increased staining. Thus, in one embodiment, the pharmaceutical compositions preferably have an insufficient amount of metal oxide compound to cause visible skin staining.
Where the metal oxide compositions according to the invention are applied to the skin, they may be combined with a carrier at an amount from about 5 ppm to 500,000 ppm, more preferably from about 50 ppm to 250,000 ppm of the metal oxide composition, based on the weight of the carrier. In various embodiments, the compositions are provided in amounts from about 400 ppm to 100,000 ppm, from about 1,000 ppm to 70,000 ppm, from about 10,000 ppm to 50,000 ppm, or from about 20,000 ppm to 40,000 ppm. In one preferred embodiment, the compositions are formulated with about 25,000 ppm to 35,000 ppm of metal oxide. It will be readily understood by those of ordinary skill in the art that the administration of 0.005 g of metal oxide to an adult human being provides about 1 ppm of the metal oxide in the bloodstream of the human. In another embodiment, the concentration of the metal oxide crystals dispersed in the carrier ranges from about 0.1 to 10% by weight, more preferably from about 0.25 to 5% by weight and most preferably from about 2 to 4% by weight. The compositions, when applied topically, can be applied to the skin about 1 to 3 times per day until the condition is suitably cured or satisfactorily controlled. In one embodiment, the composition may generally be topically applied at a dosage level of from about 1 mg to 1000 mg per cm2 of skin surface, preferably about 10 mg to 500 mg per cm2 of skin surface.
A preferred carrier for topical formulations and administration includes petroleum jelly, such as white petroleum jelly. For example, a suitable white petroleum jelly is available from Penreco of Houston, Tex.
A preferred mode of application of the oxide of the invention is as an ointment. Suitable formulations include, but are not limited to, salves and the like. If desired, these may be sterilized or mixed with auxiliary agents, e.g., thixotropes, stabilizers, wetting agents, and the like. Preferred vehicles include ointment bases, e.g., polyethylene glycol-1000 (PEG-1000); conventional ophthalmic vehicles; creams; and gels, as well as petroleum jelly and the like.
The cancerous conditions and diseases that may be prevented, treated, or managed with the compositions of the invention vary and include, but are not limited to, cancers including any of the various malignant neoplasms, tumors, or cells, such as, for example, those marked by a proliferation of anaplastic cells. In particular, the term cancer includes any cancers that involve specific organs or regions of the body such as the colon, lung, throat, breast, kidney, pancreas, bladder, prostate, uterus, brain, liver, skin, testicles, stomach, adrenal gland, ovaries, thyroid, rectum, bronchus, trachea, eye, bone, cervix, oral cavity, soft tissue, pituitary gland, myeloma, rectum, esophagus or liver. The invention is also suited for the prevention, treatment, or management of cancerous fibroid tumors and non-cancerous fibroid tumors. Prevention, treatment, or management of any of the above conditions, as well as any others described herein, individually or in any combination, simultaneously or concurrently, is contemplated according to the invention.
Also included are various cell proliferations such as leukemia, which is a malignant overproduction of white blood cells, lymphoma, and metastasized melanoma which has proliferated from skin via blood and/or the lymphatic system. Conditions or diseases associated with a predisposition to cancer, such as, for example, neurofibromatosis are also included. The present invention preferably allows treatment or management of conditions or diseases associated with a predisposition to cancer even if those conditions or diseases have not fully progressed to a cancerous or malignant stage.
The present invention is also adapted to treating or managing atypical proliferations of cells, such as those characterized by nuclear enlargement and failure of maturation and differentiation. Such proliferations may be short of malignancy. Atypical proliferations suitable for treatment, management, or prevention by the present invention include dysplasia or dysplastic proliferations, such as dysplastic nevi or neurofibromatosis, which are recognized by alterations in the appearance of cells (cytology). Dysplastic cells may have some of the features of malignant cells but the changes are less pronounced. As the dysplasia progresses, the nuclei of cells become more hyperchromatic and the nuclear membranes become more irregular; the size of the nucleus increases and the cytoplasm does not increase proportionately, so the that the nuclear:cytoplasmic ratio increases.
Different therapeutically effective amounts and deliver systems may be applicable for each disorder, as will be readily known or determined by those of ordinary skill in the art.
Tumors or neoplasms include new growths of tissue in which the multiplication of cells is uncontrolled and progressive. Some such growths are benign, but others are termed xe2x80x9cmalignant,xe2x80x9d leading to death of the organism. Malignant neoplasms or xe2x80x9ccancersxe2x80x9d are distinguished from benign growths in that, in addition to exhibiting aggressive cellular proliferation, they invade surrounding tissues and metastasize. Moreover, malignant neoplasms are characterized in that they show a greater loss of differentiation (greater xe2x80x9cdedifferentiationxe2x80x9d), and a greater loss of their organization relative to one another and their surrounding tissues. This property is also called xe2x80x9canaplasia.xe2x80x9d
Neoplasms preventable, treatable, or manageable by the present invention include all solid tumors, i.e., carcinomas and sarcomas. Carcinomas include those malignant neoplasms derived from epithelial cells which tend to infiltrate (invade) the surrounding tissues and give rise to metastases. Adenocarcinomas are carcinomas derived from glandular tissue or in which the tumor cells form recognizable glandular structures. Sarcomas broadly include tumors whose cells are embedded in a fibrillar or homogeneous substance like embryonic connective tissue.
The invention can also be practiced by administering the metal oxide compositions in conjunction with one or more other anti-cancer compatible chemotherapeutic agents, such as any conventional chemotherapeutic agent. The combination of the metal oxide with such other agents can potentiate the chemotherapeutic protocol. Numerous chemotherapeutic protocols will present themselves in the mind of the ordinary-skilled practitioner as being capable of use according to the methods of the invention. Any compatible chemotherapeutic agent can be used, including antimetabolites, hormones and antagonists, radioisotopes, as well as natural products. For example, the metal oxide can be administered with taxol and its natural and synthetic derivatives, and the like, and combinations thereof. As another example, in the case of mixed tumors, such as adenocarcinomas of the breast and prostate, in which the tumors can include gonadotropin-dependent and gonadotropin-independent cells, the metal oxide can be administered in conjunction with leuprolide or goserelin (synthetic peptide analogs of LH-RH), or both. Other antineoplastic protocols include the use of a metal oxide with another treatment modality, e.g., surgery, radiation, other chemotherapeutic agent, etc., referred to herein as xe2x80x9cadjunct antineoplastic modalities.xe2x80x9d Thus, the method of the invention can be employed with such conventional regimens with the benefit of reducing side effects and enhancing efficacy. These other anti-cancer chemotherapeutic agents and modalities may be administered either concurrently or sequentially with the metal oxide compositions of the invention.
A preferred metal oxide for use according to the invention, tetrasilver tetroxide, has been commercially sold under the poorly named xe2x80x9cAg(II) OXIDExe2x80x9d tradename. It may also be obtained from Aldrich Chemical Co., Milwaukee, Wis. The chemical synthesis of silver oxide compounds according to the invention can be performed according to the method described on page 148 in M. Antelman, xe2x80x9cAnti-Pathogenic Multivalent Silver Molecular Semiconductors,xe2x80x9d Precious Metals, vol. 16:141-149 (1992) by reacting silver nitrate with potassium peroxydisulfate according to the following equation in alkali solutions:
4AgNO3+2K2S2O8+8NaOHAg4O4+3Na2SO4+2NaNO3+2KNO330 4H2O
The magnitude of a prophylactic or therapeutic dose of metal oxide composition(s), or a derivative thereof, in the acute or chronic management of diseases and disorders described herein will vary with the severity of the condition to be prevented, treated, or managed and the route of administration. For example, oral, mucosal (including vaginal and rectal), parenteral (including subcutaneous, intramuscular, bolus injection, and intravenous, such as by infusion), sublingual, transdermal, nasal, buccal, and like may be employed. Dosage forms include tablets, troches, lozenges, dispersions, suspensions, suppositories, solutions, capsules, soft elastic gelatin capsules, patches, and the like. The dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient. Suitable dosing regimens can be readily selected by those of ordinary skill in the art with due consideration of such factors.
In general, for topical and mucosal application, such as application to the skin or cervix, the total daily dosage for the conditions described herein can be from about 1 mg to 500 mg of the metal oxide or derivative thereof, while in another embodiment, the daily dosage can be from about 2 mg to 200 mg of the metal oxide composition. A unit dosage can include, for example, 30 mg, 60 mg, 90 mg, 120 mg, or 200 mg of metal oxide composition. Preferably, the active ingredient is administered in single or divided doses from one to four times a day.
In another embodiment, the compositions are administered by an oral route of administration. The oral dosage forms may be conveniently presented in unit dosage forms and prepared by any methods available to those of ordinary skill in the art of pharmacy.
In managing the patient, the therapy may be initiated at a lower dose, e.g., from about 1 mg, and increased up to the recommended daily dose or higher depending on the patient""s global response. It is further recommended that children, patients over 65 years, and those with impaired renal or hepatic function, initially receive low doses when administered systemically, and that they be titrated based on individual response(s) and blood level(s). It may be necessary to use dosages outside these ranges in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response.
Any suitable route of administration may be employed for providing the patient with an effective dosage of metal oxide, or a pharmaceutically acceptable derivative thereof. The most suitable route in any given case will depend on the nature and severity of the condition being prevented, treated, or managed. One preferred route is parenterally, preferably intravenously. In this embodiment, a preferred intravenous route of administration is by infusion.
In practical use, metal oxide, or a derivative thereof, can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms and may include a number of components depending on the form of preparation desired for administration. The compositions of the present invention include, but are not limited to, suspensions, solutions and elixirs; aerosols; or carriers, including, but not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like.
Another suitable route of administration of the silver tetroxide compositions of the invention is topically, e.g., either directly as a powder or in non-sprayable or sprayable form. Topical administration is a preferred route of administration for treating topical cancerous conditions, such as skin cancer that has not metastasized or cervical cancer. In one embodiment, the metal oxide may be applied topically to the affected skin areas directly in powder form or in compounded formulations.
Non-sprayable forms can be semi-solid or solid forms including a carrier indigenous to topical application and preferably having a dynamic viscosity greater than that of water. Suitable formulations include, but are not limited to, suspensions, emulsions, creams, ointments, powders, liniments, salves and the like. If desired, these may be sterilized or mixed with any available auxiliary agents, carriers, or excipients, e.g., thixotropes, stabilizers, wetting agents, and the like. One or more thixotropic agents can be included in types and amounts sufficient to increase adhesion of topically applied compositions of the invention to a surface or mucosa associated with a treatment zone such as, for example, the skin, vagina, or cervix, so as to inhibit or prevent runoff or other loss of the composition from the treatment zone, particularly when the compositions are formulated for topical administration. With respect to conditions associated with the skin, the compositions preferably prevent, treat, or manage such conditions or diseases without visibly staining the skin, i.e., no staining to the naked eye.
Preferred vehicles for non-sprayable topical preparations include ointment bases, e.g., polyethylene glycol-1000 (PEG-1000); conventional ophthalmic vehicles; creams; and gels, as well as petroleum jelly and the like. In one preferred topical embodiment, the carrier includes a petroleum jelly. In another preferred topical embodiment, the carrier is formulated as a cream, gel, or lotion. A preferred composition comprises about 3% metal oxide, such as tetrasilver tetroxide, about 47% white petrolatum, about 36% heavy mineral oil, and about 14% TIVAWAX P Tivian Laboratories Inc., Providence, R.I. These topical preparations may also contain emollients, perfumes and/or pigments to enhance their acceptability for various uses.
In a preferred embodiment, a metal oxide, or a derivative thereof, is formulated for parenteral administration by injection (subcutaneous, bolus injection, intramuscular, or intravenous, such as by infusion), and may be dispensed in a unit dosage form, such as a multidose container or an ampule. Parenteral administration is a preferred administration route when the cancer is systemic, i.e., has a locus inside the body. Preferably, the formulation adapted for parenteral administration includes an insufficient amount of persulfate to induce irritation or adverse side effects. In one preferred embodiment, the formulation is substantially free of added persulfate, while in another more preferred embodiment, the formulation is completely free of added persulfate.
When administered intravenously, such as by infusion, the dosage preferably provides a concentration of the metal oxide in the blood stream of about 1 ppm to about 75 ppm, more preferably from about 5 ppm to about 50 ppm, such as from about 10 ppm to about 40 ppm or about 50 to 200 mg. In a preferred embodiment, a one-time dosage is infused or injected directly into the bloodstream.
The intravenous dosage is preferably delivered over a period of time sufficient to substantially inhibit or even avoid the occurrence of side effects. For example, the dosage can be delivered by intravenously or by infusion over a time from about 10 minutes to about 300 minutes, preferably from about 20 minutes to about 240 minutes.
Compositions of the metal oxide, or a pharmaceutically acceptable derivative thereof, for parenteral administration may be in the form of suspensions, solutions, emulsions, or the like, in aqueous or oily vehicles, and in addition to the active ingredient may contain one or more formulary agents, such as dispersing agents, suspending agents, stabilizing agents, preservatives, and the like.
Pharmaceutical compositions of the present invention may be orally administered in discrete pharmaceutical unit dosage forms, such as capsules, cachets, soft elastic gelatin capsules, tablets, or aerosols sprays, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the pharmaceutically acceptable carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. Suitable types of oral administration include oral solid preparations, such as capsules or tablets, or oral liquid preparations. If desired, tablets may be coated by standard aqueous or non-aqueous techniques.
For example, a tablet may be prepared by compression or molding, optionally, with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, granulating agent, surface active agent, dispersing agent, or the like. Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. In one embodiment, each tablet, capsule, cachet, or gel cap contains from about 0.5 mg to about 500 mg of the active ingredient, while in another embodiment, each tablet contains from about 1 mg to about 250 mg of the active ingredient. The amount of active ingredient found in the composition, however, may vary depending on the amount of active ingredient to be administered to the patient.
Another suitable route of administration is transdermal delivery, for example, via an abdominal skin patch.
The metal oxide, or a suitable derivative thereof, may be formulated as a pharmaceutical composition in a soft elastic gelatin capsule unit dosage form by using conventional methods well known in the art, such as in Ebert, Pharm. Tech, 1(5):44-50 (1977). Soft elastic gelatin capsules have a soft, globular gelatin shell somewhat thicker than that of hard gelatin capsules, wherein a gelatin is plasticized by the addition of plasticizing agent, e.g., glycerin, sorbitol, or a similar polyol. The hardness of the capsule shell may be changed by varying the type of gelatin used and the amounts of plasticizer and water. The soft gelatin shells may contain a preservative, such as methyl- and propylparabens and sorbic acid, to prevent the growth of fungi. The active ingredient may be dissolved or suspended in a liquid vehicle or carrier, such as vegetable or mineral oils, triglycerides, surfactants such as polysorbates, or a combination thereof.
In the case of tumors having loci inside the body, e.g., brain tumors, prostate tumors, and the like, the metal oxide can be delivered via a controlled release delivery vehicle. In a preferred embodiment, the controlled release vehicle includes a polymeric material, delivered or surgically implanted at or near the lesion site. One of ordinary skill in the art will be familiar with controlled release means and delivery devices, such as those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566, the disclosures of which are hereby incorporated herein by express reference thereto. These pharmaceutical compositions can be used to provide slow or controlled-release of the active ingredient therein using, for example, hydropropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or the like, or a combination thereof. Suitable controlled-release formulations available to those of ordinary skill in the art, including those described herein, may be readily selected for use with the metal oxide compositions of the invention. Thus, single unit dosage forms suitable for topical, parenteral, or oral administration, such as infusions, intravenous drips, gels, lotions, cremes, tablets, capsules, gelcaps, caplets, and the like, that are adapted for controlled-release are encompassed by the present invention.
All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations may include: 1) extended activity of the drug; 2) reduced dosage frequency; and 3) increased patient compliance.
Most controlled-release formulations are designed to initially release an amount of drug that promptly produces the desired therapeutic effect, and gradual and continual release of other amounts of drug to maintain this level of therapeutic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug should be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.
The controlled-release of the active ingredient may be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds. The pharmaceutical compositions for use in the present invention include the metal oxide, or a derivative thereof, as the active ingredient, and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients. Suitable derivatives include any available xe2x80x9cpharmaceutically acceptable salts,xe2x80x9d which refer to a salt prepared from pharmaceutically acceptable non-toxic acids including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof. Preferably, in the case of silver (I,III), the salts do not comprise halides. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, and phosphoric. Appropriate organic acids may be selected, for example, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, citric, fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric, para-toluenesulfonic, glycolic, glucuronic, maleic, furoic, glutamic, salicylic, mandelic, methanesulfonic, ethanesulfonic, benzenesulfonic (besylate), sulfanilic, alginic, galacturonic, and the like. Particularly preferred acids phosphoric, methanesulfonic, and glycolic.

Methods of using electron active compounds for managing cancer


A developing device which is capable of being detachably mounted to a rotary unit of an image forming apparatus and which includes a developer carrying member for forming a development region together with an image carrying member and rotating as carrying a developer, a developer containing section for containing the developer to be supplied to the developer carrying member, and a pressure relief portion provided in a surface substantially perpendicular to the rotational axis of the rotary unit, of the developer containing section.

1. Field of the Invention
The present invention relates to a developing device for developing an electrostatic image on an image carrying member, used in an image forming apparatus such as an electrophotographic apparatus or an electrostatic recording apparatus.
2. Related Background Art
Conventionally proposed as a configuration of apparatus for forming a multi-color image by the electrophotographic method is a method for locating a plurality of developing devices containing respective developing agents or developers of different colors (each of which will be referred to as "toner") on a rotating/selecting mechanism with respect to a photosensitive drum being an electrophotographic, photosensitive member, opposing either one developing device containing the toner of a predetermined color to the photosensitive drum to form a developed image, transferring this developed image onto a recording medium, and further carrying out these developing and transferring operations for each of the colors, thereby obtaining the multi-color image. Some apparatuses employ the cartridge structure for the foregoing developing devices arranged to be detachably mounted on the image forming apparatus, thereby lightening the maintenance work of user.
Such developing devices are normally constructed in such a way that a toner supply roll obtained by attaching a sponge roll to a metal core is pressed against a developing roller in order to supply the toner in a toner container to the developing roller being a toner carrying member.
In such toner supply structure, air pressure inside the toner container increases with rotation of the developing roller and toner supply roll, and the air therein leaks from a portion of weak seal strength to the outside.
In order to prevent the toner inside the toner container from leaking out with the air at this time, a pressure relief portion for relief of the air within the toner container to the outside is provided and a filter is attached to the pressure escape portion, thereby allowing only the air to escape to the outside.
With use of the conventional developing devices the filter, however, tends to cause clogging due to the toner or the like and the filter might be damaged when pressure is applied on the filter because of movement of toner or the like in the toner container during physical distribution or when something hits the toner container from the outside.


In various embodiments, metallic products are formed by alloying niobium with at least one of yttrium, aluminum, hafnium, titanium, zirconium, thorium, lanthanum, or cerium and processing the alloy.

The present invention relates to a process for manufacturing niobium plates or sheets as well as uses thereof, such as for deep drawn cups and sputtering targets.
Niobium ingots can be rolled to plate and sheet dimensions using known methods in the art. Such plates and sheets can be used, for example, by being deep drawn into cups for the synthetic diamond industry. The niobium foil used typically has an inconsistent and coarse grain size, which leads to poor flatness and smoothness of the deep drawn cup bottom. Poor flatness and/or smoothness (orange peel) result in a synthetic diamond that requires excessive grinding to correct deficiencies. The problem ultimately relates to a coarse grain structure in the niobium sheet. The coarse grain structure can also cause tearing of the sheet during deep-draw operations.
The grain size of typical, commercially available niobium sheet is variable, ranging from an ASTM grain size of from 4 to 10. It is, however, desirable to use niobium sheet with an ASTM grain size finer than 7.5 with at least 90% recrystallization for deep draw applications, although this still produces a high rejection rate for flatness and surface finish. An ASTM grain size finer than 8.0 with at least 90% recrystallization almost completely eliminates these issues.
It would be desirable to provide a method of producing niobium sheet having a consistent ASTM grain size and sufficient recrystallization to minimize or prevent flatness and/or smoothness problems with the sheet.
U.S. application Ser. No. 10/974,519, filed Oct. 27, 2004 describes a silicon-containing alloy of niobium that solves the above-identified problem.

This patent is subject to a terminal disclaimer.

Fine grain niobium sheet via ingot metallurgy


This method permits manufacturing EPDM rocket motor insulation in which carbon fibers are dispersed and immobilized in the EPDM polymeric matrix but are not excessively fractured or fragmentized, i.e., broken into smaller fragments, when encountering degrees of shear necessary to homogeneously or otherwise distribute or disperse the carbon fibers in the EPDM polymeric matrix. The method is substantially solvent free and is performed via distributive/reduced shear mixing to distribute the fragile carbon fibers into a rubber matrix without excessive damage. According to one embodiment, at least about 50% of the elastomer composition introduced into the mixing apparatus is liquid EPDM terpolymer having sufficiently low molecular weight and high diene content to permit dispersion of the carbon fibers in the EPDM without substantial fragmentation of the fibers. According to another embodiment, mixing takes place in a kneader capable of rotating a screw having a discontinuous screw thread about the screw axis while superimposing an axially reciprocating stroke to the screw. The kneader imparts low shear distributive mixing of the carbon fibers in the EPDM terpolymer.

1. Field of the Invention
This invention is directed to a process for making elastomer-based insulation for rocket motors and, in particular, to a process in which fragile carbon fibers are mixed with and preferably homogeneously dispersed in ethylene propylene diene monomer (EPDM) without requiring the use of a volatile solvent for dissolution of EPDM during fiber incorporation. The insulation of this invention is especially useful for placement in the nozzle or case, including between a solid propellant grain and a rocket motor case for protecting the case from high temperatures experienced during burning of solid propellant grains.
2. State of the Art
Solid rocket motors typically include an outer case or shell housing a solid propellant grain. The rocket motor case is conventionally manufactured from a rigid, yet durable, material such as steel or filament-wound composite. The propellant is housed within the case and is formulated from a composition designed to undergo combustion and thereby produce the requisite thrust for attaining rocket motor propulsion.
During operation, a heat insulating layer (insulation) protects the rocket motor case from heat and particle streams generated by the combusting propellant. Typically, the insulation is bonded to the inner surface of the case and is generally fabricated from a composition capable of withstanding the high temperature gases produced when the propellant grain bums. A liner layer (liner) functions to bond the propellant grain to the insulating layer and to any noninsulated portions of the case, as well as to inhibit interfacial burning. Liner compositions are generally known to those skilled in the art. An exemplary liner composition and process of applying the same to a case is disclosed in U.S. Pat. No. 5,767,221, the complete disclosure of which is incorporated herein by reference to the extent that it is compatible with this specification.
The combustion of solid rocket propellant generates extreme conditions within the case of the rocket motor. For example, temperatures inside the rocket motor case typically reach 2,760° C. (5,000° F.) and interior pressures may exceed 1,500 psi. These factors combine to create a high degree of turbulence within the rocket motor case. In addition, particles are typically entrained in the gases produced during propellant combustion. Under the turbulent environment, these entrained particles can erode the rocket motor insulation. If the insulating layer and liner are pierced during rocket motor operation, the casing is susceptible to melting or degradation, which can result in failure of the rocket motor. Thus, it is crucial that insulation compositions withstand the extreme conditions experienced during propellant combustion and protect the case from the burning propellant. It is also crucial that insulation compositions possess acceptable shelf life characteristics such that they remain sufficiently pliable, without becoming fully cured, until used in application to the rocket motor casing. This requirement is essential because the production of a given lot of insulation may have to wait in storage for a number of months prior to use. Typically, the insulation may be stored in large rolls in an uncured, or at most, a partially cured, state until ready for use. A number of curing agents are well known and are conventionally employed but still must be compatible with the overall EPDM formulation to permit satisfactory shelf life. This in turn requires a balancing of curing agent activity.
In the past, attempts at producing insulating materials that would protect the rocket motor case focused on filled and unfilled rubbers and plastics, such as phenolic resins, epoxy resins, high temperature melamine-formaldehyde coatings, ceramics, polyester resins, and the like. These plastics, however, crack and/or blister as a result of the rapid temperature and pressure fluctuations experienced during combustion.
Elastomeric compositions have also been used as rocket motor insulation materials in a large number of rocket motors. The elastomeric compositions have been selected because their mechanical, thermal, and ablative properties are particularly suited for rocket motor applications. However, the ablative properties of elastomers are often inadequate for rocket motor operation. For example, insulation, whether thermosetting or thermoplastic, is characterized by relatively high erosion rates unless reinforced with a suitable filler. The criticality of avoiding such high erosion rates is demonstrated by the severity and magnitude of the risk of failure due to erosion. Most insulation is, of necessity, "man-rated," in the sense that a catastrophic failure can result in the loss of human life whether the rocket motor is used as a booster for launch of a space shuttle or is carried tactically underneath the wing of an attack aircraft. The monetary cost of failure in satellite launches is well publicized and can run into the hundreds of millions of dollars.
In order to improve the ablative properties of elastomeric compositions, it has been proposed to reinforce the elastomeric compositions with fillers, such as organic-based fibers or carbon fibers. For instance, an exemplary carbon fiber-filled rocket motor insulation composed of solid NORDEL® 1040 as the primary terpolymer is commonly known in the industry as the STW4-2868 thermal insulation and has the following composition:
TABLE ASTW4-2868 THERMAL INSULATION FORMULATION(carbon fiber; parts by weight)Parts byIngredientFunctionWeightNORDEL ® 1040Primary EPDM terpolymer base80Neoprene FBSecondary polymer base20Zinc oxideActivator5SulfurCurative1HAF carbon blackPigment1MBTAccelerator1AGERITE ® Resin DAntioxidant2AGERITE ® HPSAntioxidant1TELLURAC ®Accelerator0.50SULFADS ®Accelerator0.75VCM carbon fibersFiller41Total Parts by Weight153.25
Although organic-based fibers can be dispersed within the EPDM without too much difficulty, the homogeneous dispersion of carbon fibers in an elastomeric composition presents a difficult processing problem. The mixing process is complicated by the fragility of the carbon fibers. Mixing of carbon fibers into a solid elastomer under high shear physically deteriorates the carbon fibers into smaller particles or shreds, thereby negating the advantageous physical attributes that the carbon fibers would otherwise have contributed to the insulation.
Conventionally, the problem of carbon fiber fragility has been addressed by dissolving the elastomer into a solution with an appropriate organic solvent to lower the viscosity of the elastomer or elastomer mixture. Suitable solvents include, by way of example, hydrocarbons such as hexanes, heptanes, and/or cyclohexane. The frangible graphitized carbon fibers can then be mixed with the solution in, for example, a sigma-blade mixer without significant breakage of or damage to the carbon fibers. The material is then sheeted out and the solvent is allowed to evaporate at ambient atmosphere or in an oven.
The use of solvent in this processing technique presents several drawbacks. For example, solvent processing techniques, such as those conventionally used to disperse carbon fibers in EPDM rubber, are relatively expensive. Material costs are increased by the use of solvents, as are processing costs, since additional workers and equipment are required to handle and process the solvents. Further, considerable costs and worker safety issues are associated with the disposal of hazardous volatile organic solvents.
Thus, although it has been long recognized that carbon fiber-filled EPDM is an excellent candidate for rocket motor insulation, a low cost and nonhazardous solvent-free synthesis route that produces EPDM insulation having carbon fibers homogeneously dispersed therein, but without being subject to significant breakage or damage would be desirable.

Method of insulating a case of a solid propellant rocket motor


A sealable, composite cushion is disclosed having a plurality of resilient support member horizontally disposed to one another and surrounded by a fluid impervious membrane. Each resilient support member has a known Indentation Force Deflection (IFD) value and is located in the cushion based upon medical criteria to provide zones of varying support. In an embodiment, the resilient members are bonded to the membrane and act as tension members to maintain the cushion's form while under a load. As a result, the cushion resists further deflection not only by the resilient members' resistance to compression, but also by an increased internal pressure. Accordingly, the cushion of the present invention is a composite of fluid flotation and compression resistance. A valve may be incorporated into the cushion to regulate the fluid floatation characteristics of the cushion or to assist in its transportation. In another embodiment, the resilient support members are not bonded to an upper membrane portion, thereby decreasing shear forces acting upon the resilient members when the cushion is under load. Further, excess membrane may be located at the cushion periphery. When subject to a load, this excess membrane material can migrate to the upper portion of the cushion, thereby decreasing undesirable peripheral distortion of the cushion.

Persons who must spend long periods of time in one position, whether sifting or lying, often experience tissue injury and discomfort because the interaction between the supporting structure and the area of the person being supported often produces pressure sores and related conditions. Persons in wheelchairs are especially susceptible to the formation of pressure sores and the related tissue injury and discomfort they cause. Typically, persons who use wheelchairs have more of the factors that are considered to promote formation of pressure sores, e.g. age, activity levels (either very active or inactive), general health, weight, etc. Therefore, a need exists to modify the physical attributes of the supporting device that cause pressure sores to form in the first place.
To better understand the need for the present invention, an analysis of the likely causes of tissue injury is necessary. Pressure sores and related degenerative conditions result from an ulceration of the skin and/or deeper tissue due to unrelieved pressure, shear forces, and/or frictional forces. This condition occurs most frequently in persons confined to a bed or a wheelchair for long periods of time. The onset of these ulcers is believed to be triggered by a hypoxia condition--the decrease flow of or lack of oxygen to the subject tissue. As a consequence of this diminished oxygen supply to hard and soft tissue sites, aerobic and/or anaerobic microorganisms and their waste products can accumulate in these areas and cause infection and bacteremia leading to increased tissue breakdown and decreased healing abilities. Research has shown that healing wounds had absolutely no anaerobic bacteria and that few colonies and types of aerobic bacteria were present. Non-healing wounds, however, had very high counts of both aerobic and anaerobic bacteria. Consequently, hypoxia of tissue subject to pressure not only is the likely cause of pressure sores, but also interferes with the natural healing process.
Because the number of persons who lack full mobility has increased as the median age of the population has increased, there is a greater number of mobility impaired persons using wheelchairs or spending considerable time in bed. Until recently, little attention had been given to modifying the supporting devices used by these people. Now, the combination of a greater segment of the population using or confined to these devices, and an increased understanding of the causes and effects of pressure sores, has created a need for products to make these supporting devices more comfortable and therapeutic. Ideally, these products alleviate pressure sore formation, increase user comfort, and enhance body support and position.
In the art to which this invention is directed, comfort is associated with reduction of pressure in critical areas. The less pressure in critical areas, the greater the comfort and the fewer number of pressure sores. Because pressure occurring at any given point on a person's body is a result of the force, i.e. the weight acting on the person per unit area affected, the goal is to increase the area subject to this force, thereby decreasing effective localized pressure. Therefore, the ideal cushion would have a custom base molded to the user to maximize comfort while enhancing support. Ideally, the user would never shift his or her position nor change his or her physical attributes. Of course, such conditions and restraints are not practical. Hence, a cushion must be adaptable to various sitting positions that might occur through normal use and weight shifting, and be adaptable to changes in the person's physical attributes. To meet these needs, a variety of seat cushions have been proposed and used.
In the field of wheelchair cushions, four types of cushions predominate: foam devices, viscoelastic foam devices, gel devices, and fluid flotation devices. Research has shown that in addition to the discomfort and health risk associated with pressure sores, a person's comfort when using a cushion type device is also affected by poor distribution of stresses, moisture accumulation, heat transfer (either excess accumulation or loss), and stability. Research has also shown that the efficacy of the cushion (i.e. its support) includes such parameters as stability, weight of the cushion, frictional properties, thickness of the cushion, cost, and durability. Each type of cushion has its advantages and disadvantages. Some cushions distribute pressure very well but do so at the cost of excess heat transfer, moisture accumulation, or weight. Other cushions provide low humidities due to their porous properties but do not allow heat to flow freely from a person's skin, thus increasing perspiration and decreasing comfort. Still other cushions are light and easy to transport but do not offer an effective support in areas.
While each type of cushion has successfully been used to mitigate specific instances of the formation of pressure sores, recent advances in foam technology has made foam type cushion, a cost verses performance leader. When discussing foam type cushions, two measurements are primarily used: Indentation Force Deflection (IFD) and foam modulus. IFD values are measured by taking a 15".times.15".times.4" foam sample and measuring the force needed to cause a 25% reduction in foam thickness by depressing an eight inch diameter disk therein. For example, an IFD value of 40 pounds means that a force of 40 pounds is required to depress the eight inch diameter disk, having an area of approximately 50 in.sup.2, one inch into the foam sample. Modulus is defined as the IFD at 65% of the sample thickness divided by the IFD at 25% of the sample thickness. These two methods for determining the characteristics of a foam sample provide the best measure for determining what type of foam should be used for a particular application.
Traditionally, foam type cushions of the prior art comprised a single section of foam. The foam may or may not have been contoured and may or may not have had a cover. More recent cushions have incorporated multiple sections of foam. These cushions essentially stacked sections of foam, with or without inserts, upon one another to achieve a cushion having varying properties.

Sealed composite cushion having multiple indentation force deflection zones


A preferred joint movement monitoring system (10) includes a carrier (18) configured for wearing by a subject about a wrist thereof and a plurality of position sensors (12, 14, 16) coupled with the carrier (18) for sensing various hand positions of the subject. The preferred carrier (18) is in the form of an elastic wrist band that encompasses the wrist and adjacent portions of the hand and forearm without covering any portions of the subject's fingers. The preferred sensors (12, 14, 16) include Hall effect sensors mounted to the carrier (18) on the forearm side of the wrist.

1. Field of the Invention
The present invention is concerned with the field of monitoring joint movements of a subject. In particular, a preferred joint movement monitoring system includes a carrier configured for wearing by a subject about a wrist thereof and a plurality of position sensors coupled with the carrier for sensing various hand positions of the subject.
2. Description of the Prior Art
With advances in medical science, it is now better appreciated that repetitive motion can sometimes lead to injury such as carpal tunnel syndrome. In response, devices have been developed to monitor the motions of body parts with respect to a joint.
One such device includes a glove with portions of the glove fingers removed and with sensors positioned adjacent the back of the hand. Such a device inhibits natural motion of the fingers and of the hand itself, leading to less realistic data. Moreover, the bulk of the glove is sometimes objectionable by wearers.


A handheld implement with a replaceable work tool includes a handle body which is equipped with a locking device for detachably mounting the work tool. The locking device includes a movable member, at least one retaining member and a first spring. The first spring abuts against the retaining member so that the retaining member is inserted into a locking hole of the work tool while remaining in an extended state. The retaining member includes a first mating body including at least one second mating body. The second mating body includes a mating portion, and the movable member performs translational movement so that the mating portion and the first mating body cooperate with each other to drive the retaining member to retreat and then withdraw from the locking hole of the work tool.

Currently, many garden tools or agricultural implements with work tools are carried in agricultural or gardening work, which makes it quite inconvenient to go out therewith. Therefore, a garden tool or an agricultural implement with a replaceable work tool has been developed. Accordingly, it is only necessary to go out with a handheld implement and a work tool box (with multiple work tools stored inside) that matches the handheld implement, thereby improving the convenience in soil work. However, garden tools or agricultural implements with replaceable work tools existing on the market in the prior art have replacement structures in which the work tools are detachably mounted on the handheld implements by means of bolts or clamps, etc., but such mode makes it quite inconvenient to replace and use the work tools due to frequent replacement of the work tools, which further affects the operating efficiency of agricultural or gardening work.

Handheld implement with replaceable work tool


Provided are methods for the synthesis of N-cyclic maleamic acids and N-cyclic maleimide derivatives, as well as N-cyclic maleamic acids and N-cyclic maleimides synthesized thereby. The method for synthesis of an N-cyclic maleamic acid involves reacting an amino group-containing N-cyclic compound with maleic anhydride in acetic acid to obtain an N-cyclic maleamic acid. An N-cyclic maleimide can be formed by adding hexamethyldisilazane to an N-cyclic maleamic acid prepared according to the above-described method, thereby cyclizing a maleamic acid site of the N-cyclic maleamic acid. The described methods allow for the products to be obtained at high yields.

1. Field of the Invention
The present invention relates to novel methods for the synthesis of N-cyclic maleimide acids and N-cyclic maleimide derivatives, and to novel N-cyclic maleimide acids and N-cyclic maleimide derivatives formed thereby.
2. Description of the Related Art
There are many known N-cyclic maleimide derivatives which are fluorescent substances. At present, such materials are widely used for the detection of nucleic acids, proteins, etc. In addition, these N-cyclic maleimides have many applications, such as use as monomers for raw materials in the chemical process industry. There is, therefore, an increasing demand for N-cyclic maleimide compounds.
Various techniques for the synthesis of maleimide derivatives have heretofore been proposed, all of which, however, result in low yields of maleimide derivatives.
Among the conventional methods for the synthesis of maleimide derivatives, a first method comprises reacting maleic anhydride with amines in ether to obtain a nearly quantitative yield of the corresponding N-substituted maleimide acid. Then, acetic anhydride and sodium acetate are added to the resulting maleamic acid, followed by heating at 100.degree. C. for dehydration to obtain the corresponding maleimide derivatives at a yield of 50 to 70% (see Mehta et al., J. Org. Chem., 1960, 25, 1012).
A second method comprises reacting maleic anhydride with an appropriate amino compound in ether to obtain a nearly quantitative yield of the corresponding maleamic acid. This is followed by heating under reflux in a mixture of triethylamine and toluene for dehydration of the maleamic acid to obtain the corresponding maleimide at a yield of 20% (see Meyers et al., J. Org. Chem., 1989, 54, 4243).
A third method comprises reacting maleic anhydride with an appropriate amino compound in ether to obtain a nearly quantitative yield of the corresponding maleamic acid, and then adding thereto a carbodiimide to obtain an isoimide. This is followed by heating the resulting isoimide in a mixture of hydroxybenzotriazole and toluene for 18 hours at 100.degree. C., to obtain the corresponding maleimide at a yield of 47% (see Garner et al., J. Org. Chem., 1991, 55, 5893).
A fourth method comprises reacting maleic anhydride with an amino compound in ether to obtain a nearly quantitative yield of the corresponding maleamic acid. This is then reacted with dicyclohexylcarbodiimide in a solvent of acetic acid and dimethylformamide for dehydration of the maleamic acid to obtain the corresponding maleimide at a yield of 75% (see Nielsen et al., Synthesis, 1991, 819).
The above-described methods are, however, not suitable for the synthesis of aliphatic maleimide derivatives. Furthermore, these methods result in N-cyclic maleimides of low yield.
A fifth method comprises reacting a maleimide with an aliphatic alcohol in a mixture of diisopropyl azodicarboxylate and acetic acid at room temperature for 18 hours. The corresponding aliphatic maleimide derivatives are obtained at a yield of from 83 to 92% (see Walker, J. Org. Chem., 1995, 60, 5352). This method is suitable for the synthesis of aliphatic maleimides, but could not be used for synthesizing N-aromatic maleimides.
A sixth method comprises an acid catalyzed dehydration of an amine and anhydride at reflux temperature. This results in the corresponding maleimide at a yield of 82% (see Yuichi Kita et al., Report in the 72nd Spring Meeting of the Chemical Society of Japan). The yield for this method is low. In addition, fluorescent aromatic maleimide derivatives synthesized according to this method provide low yields.
A seventh method comprises reacting maleic anhydride with an amine in benzene at room temperature, and then adding thereto hexamethyldisilazane, and zinc bromide or zinc chloride. This is followed by heating under reflux in benzene to obtain an aliphatic or benzyl-type maleimide at a yield of from 73 to 98% (see P. Y. Reddy, Toru et al., J. Org. Chem. in press). When fluorescent aromatic maleimides are synthesized according to this method, the starting compounds used remain in the reaction mixture without being reacted completely. This results in a low yield of maleimide derivatives.
As mentioned above, the conventional methods for synthesis of N-cyclic maleirnide derivatives are all problematic, and the yields associated therewith are low. In addition, some types of N-cyclic maleimides are difficult to produce thereby.

Efficient method for the synthesis of N-cyclic maleamic acids and N-cyclic maleimides


An auxiliary active heating and air conditioning system which uses a fuel fired heater as an energy source for both heating and air conditioning a passenger area of a motor vehicle. The system also utilizes a single heat exchanger to supply both heated and cooled air to the passenger area. The system includes a fuel fired heater for heating heat transfer fluid and a two bed sorber cooling system. The system being operable in a heating mode and a cooling mode. In the heating mode, the heated heat transfer fluid from the fuel fired heater is directed to heat exchanger in order to heat the passenger compartment. In the cooling mode, the heat transfer fluid from the heater is alternately directed to the two sorber beds such that one sorber bed is heated while the other bed cools. The alternate heating and cooling of the sorber beds in the cooling mode causes the sorber cooling system to operate and thereby deliver cooled heat transfer fluid to the heat exchanger in the passenger area.

Large over the road vehicles such as tractor-trailer trucks frequently are used to transport cargo over great distances. During these long runs the drivers of these vehicles take periodic rest breaks and often sleep in the vehicle. In order to accommodate this, the passenger compartment of a tractor-trailer vehicle is typically divided such that it has a bunk or sleeper area just behind the cab of the truck. This sleeper area can be separated from the cab by a divider such as a curtain.
Generally, the vehicle also includes some sort of heating, ventilation, and air conditioning system that maintains the temperature in the sleeper area at a comfortable level while the driver is sleeping. Presently, there are several different types of heating and air conditioning systems that can be used for this purpose. One way to maintain the appropriate temperature in the sleeper area, simply is to use the heating and air conditioning system of the vehicle. This can be done either by leaving the truck running in idle while the driver sleeps or by "superheating" or "supercooling" the sleep area prior to shutting off the truck engine. However, both of these approaches have significant drawbacks. For example, running the truck in idle while the driver sleeps generates both air and noise pollution, requires a significant amount of fuel, and unnecessarily wears the engine parts. Likewise, superheating or supercooling of the sleeper area is only effective for a short period of time or when the temperature of the outside air is mild.
Another method for heating and cooling the sleeper compartment is to use a heating and air conditioning system which is auxiliary in nature in that it is capable of operating when the engine of the truck is shut off. For example, proposals have been made for heating and air conditioning the sleeper compartment which involve what will be termed "passive" auxiliary systems in that they use thermal storage media to store thermal energy during normal operation of the truck and then deliver that thermal energy in the form of heating or air conditioning when the engine of the truck is shut down. While these systems use some of the same components which are utilized in the present system, the components are used in a different manner, in that the passive nature of the system requires that sufficient energy be stored during normal operation of the truck to provide heating and air conditioning when the engine is shut down. Thus, these types of systems can only heat or cool the passenger compartment for a limited period of time. In particular, in order to heat or cool the sleeper area for a prolonged period of time, the thermal storage media must be charged by the operation of the truck for a prolonged period. More significantly, the thermal storage media must be capable of storing a large amount of thermal energy. Therefore, using this type of system to heat or cool a sleeper area for a prolonged period would likely impose cost, weight, and space requirements that are unacceptable.
In contrast to passive systems, heating and air conditioning systems which are "active" are those systems which are connected to their own independent power source and do not rely on any sort of thermal storage media. Thus, these systems have a relatively unlimited supply of energy to drive the heating air conditioning system for as long as needed. Active heating and air conditioning systems are well known in stationary installations. Typically stationary installations utilize furnaces for heating and compressor driven air conditioners for air conditioning. Some systems use common elements for both heating and air conditioning such as the heat pump. In general, however, these systems are stationary, and have fixed connections, particularly in the case of conventional air conditioners which must have connections to fixed electrical power sources in order to provide the relatively large amounts of power needed to drive the system.
As a result of the need for a sufficient power source, using active heating and air conditioning systems as auxiliary systems for motor vehicles present a different array of problems from passive systems. In particular, in a motor vehicle there is no massive electrical generating capacity which is capable of driving a conventional air conditioner when the engine is shut down nor is there a fixed heat sink such as is required by a heat pump. Fuel fired heaters have been capable of solving this problem for auxiliary heating systems, but insofar as applicant are aware, no active auxiliary refrigeration system has been available for dealing with the air conditioning problem. In order to drive a conventional rotary compressor driven auxiliary air conditioning system which is capable of producing the approximately 2,000 BTU/hr of cooling energy necessary for air conditioning a typical passenger compartment, a fairly large energy source must be incorporated into the motor vehicle.
Sorption cooling systems are also known, and it is known that they use the adsorption/desorption process to drive refrigerant around a refrigerant loop thus eliminating the need for a high powered rotary compressor. Insofar as applicants are aware, sorption cooling has certain niche applications, typically in fixed installations for specialized air conditioning and refrigeration requirements. Sorption air conditioning systems are generally driven by some type of heater. In smaller systems it is generally preferable to use an electric resistance heater. However, as the sorption system gets larger, the electric heater has to draw more power to operate the system. As a result expensive wires, switches, and controls which are capable of handling large currents must be provided. Thus, in larger sorption systems, steam heat from a boiler is generally used to drive the system.

Auxiliary active heating and air conditioning system for motor vehicle applications