Topical compositions which include urea and carbamide peroxide are described. Compositions having a pH in the acidic range, particularly in the range of about 2.5 to about 9 are also described. Methods for treating dermatological disorders using the composition are also described.

This present disclosure relates to compositions containing carbamide peroxide and urea as components for the treatment of dermatological disorders.
There is a need to provide carbamide peroxide compositions, which are easily and economically prepared, which have a smooth texture appropriate for cosmetic products, and which are enhanced by exhibiting greater keratolytic and antibacterial effects. Compositions having carbamide peroxide and urea as components might satisfy such a need because urea has keratolytic activity and has the property of denaturing and solubilizing proteins in addition to antimicrobial activity. However, urea containing formulations generally tend to be neutral to slightly alkaline, while carbamide peroxide formulations are generally most stable under acidic conditions.
The present invention relates to a topical composition that combines the benefits of urea and carbamide peroxide and yet achieves a stable formulation. In one embodiment the topical composition comprises carbamide peroxide, urea, and a dermatologically acceptable carrier, wherein the composition has a pH between about 2.5 and about 9. In another embodiment the topical composition comprises about 0.5 to about 30% by weight carbamide peroxide, about 0.1 to about 40% urea by weight; and a dermatologically acceptable carrier.
The topical composition of the invention can be useful in treating dermatological disorders. Examples of dermatological disorders that can be treated by the composition include disorders due to changes in normal keratinization, epidermal formation or pilosebaceous function, such as acne, psoriasis, seborrhea, ingrown hairs and pseudofolliculitis barbae, and hyperpigmented skin.
In one embodiment, the invention provides a method for treating a dermatological disorder comprising administering to a subject in need thereof a topical composition of the invention.
Overview
Carbamide peroxide and urea are pharmacological agents useful for the treatment of dermatological disorders. However, carbamide peroxide and urea have generally been considered incompatible. Carbamide peroxide can be extremely unstable. Thus, stability of carbamide peroxide is an important factor in formulating compositions containing carbamide peroxide. Carbamide peroxide formulations are generally most stable under acidic conditions. However, urea containing formulations generally tend to be neutral to slightly alkaline.
The novel compositions disclosed herein combine the benefits of urea and carbamide peroxide and yet achieve a stable formulation. In one embodiment, such a composition is achieved by use of an optimized buffer system that maintains the pH of the formulation at an optimal acidic range.
Topical Composition
The invention provides topical compositions comprising carbamide peroxide and urea. The desired amount of urea and carbamide peroxide can vary from composition to composition depending on the particular disorder or disorders being treated, the severity of the disorder, the duration of the treatment, the other specific components of the composition being used, and like factors. In one embodiment, the carbamide peroxide can be present in the composition at a concentration from about 0.5% to about 30% by weight and the urea can be present from about 0.1% to about 40% by weight, relative to the weight of the composition. In another embodiment, the carbamide peroxide can be present in the composition at a concentration from about 4 to about 15% by weight. In yet another embodiment, the carbamide peroxide can be present in the composition from about 4.5% to about 9% by weight. In still another embodiment, the urea can be present from about 5% to about 20% by weight, relative to the weight of the composition.
In one embodiment, the compositions of the invention are acidic. Carbamide peroxide is generally most stable under acidic conditions, while urea containing formulations generally tend to be neutral to slightly alkaline. As disclosed herein, acidic compositions including both carbamide peroxide and urea tend to be more stable under acidic conditions. In addition to allowing formation of a stable composition, a pH in an acidic range is also therapeutically useful. Generally, traumatized skin tends to have a higher pH and skin healing is aided by maintaining a slightly acidic pH. Thus, the novel formulations of this invention combine the benefits of urea and carbamide peroxide and yet achieve a stable formulation by the use of an optimized buffer system which maintains the pH of the formulation at an optimal acidic range. According to one embodiment of the invention, the composition has a pH less than 9. In another embodiment, the compositions have a pH in the range of about 2.5 to about 9.
Any dermatologically acceptable carrier can be used in the compositions of the invention. As used herein, xe2x80x9cdetermatologically acceptable carrierxe2x80x9d refers to vehicles, diluents, carries, which can include adjuvants, additives, or excipients, known for use in dermatological compositions. The compositions of the invention include, but are not limited to, creams, ointments, solutions, lacquers, sticks, pledgets, wipes, cleansers and/or gels.
In one embodiment, the topical composition is a semi-solid at room temperature but is easily absorbed into the stratum comeum. The semi-solid composition can be a cream. Such a composition can include petroleum-based liquids and solid fractions as skin protectants. The solid skin protectant can be semi-solid. The solid skin protectant can be present in about 1.0% to about 20% in the composition and includes petrolatum or a synthetic or semi-synthetic hydrocarbon of the same nature as petrolatum. Mixtures of such ingredients can also be used. Liquid skin protectants can be petrolatum and contained in the composition in about 1.0% to about 20% and include any synthetic or semi-synthetic oleaginous liquid fraction. The liquid skin protectant can be mineral oil, which is a liquid mixture of hydrocarbons obtained from petroleum.
The compositions of the invention can include propylene glycol. Propylene glycol can be present in the composition up to about 5%. In one embodiment, propylene glycol is present in the composition at about 1% to about 5%.
The compositions can contain conventional preservatives, such as methyl paraben, propyl and butyl imidazolidinylurea, diazolidinylurea, methylchloroiso-thiazolinone and methylisothiazolinone. Although not to be held by theory, it is believed that the antibacterial properties of the urea and carbamide peroxide and propylene glycol allow the composition of the present invention to be free of conventional preservatives.
The present compositions can also contain dermatologically acceptable excipients, such as for example emulsifiers and thickeners. Among these are for example C16 to C18 straight or branched chain fatty alcohols or fatty acids or mixtures thereof. Examples of emulsifiers and thickeners include cetyl alcohol, stearyl alcohol, stearic acid, palmitic acid, nor mixtures thereof. Fatty acids or fatty alcohols may be present in from about 0.25 to 2 wt-%.
Another ingredient useful in the composition of the present invention may be glyceryl stearate, which is a monoester of glycerine and stearic acid, or other suitable forms of glyceryl stearate for example glyceryl stearate SE, which is a commercially available self-emulsifying grade of glycerol stearate that contains some sodium and/or potassium stearate. Glyceryl stearate may be in the composition anywhere from about 1 to about 3% by weight.
Xanthan gum is another ingredient which may be used in the present compositions. Xanthan gum is a high molecular weight heteropolysaccharide gum produced by pure-culture fermentation of a carbohydrate with Xanthomonas campestris. The gum is also commercially available from various sources.
The composition can be an emulsion including liposomes. The emulsion can contain a fatty phase in the range of about 5% to about 80% by weight. Typically, the fatty phase will range from about 5% to about 50% by weight, with respect to the total weight of the composition. Known oils, waxes, emulsifiers and coemulsifiers can be used in compositions in the emulsion form. The emulsifier and the coemulsifier can be present, in the composition, in a proportion ranging from about 0.3% to about 30% by weight. Typically the emulsifier and the coemulsifier are present in a proportion ranging from about 0.5 to about 20% by weight. The emulsion can also contain lipid vesicles.
In one embodiment, the composition can include thickeners which provide a high viscosity cream designed to remain in place upon application to the skin. By way of example, thickeners can include a mixture of a carbomer and triethanolamine. The mixture can be combined together and added to the composition in an amount totaling anywhere from about 0.05 to 30% by weight. Triethanolamine can be purchased as Trolamine NF from BASF. Carbomers come in various molecular weights and are identified by numbers. These are otherwise known as Carbopol. Exemplary Carbopols include is Carbopol 940, 910, 2984, 5984, 954, 980, 981, 941 and 934. Carbopol ETD 2001, 2020, and 2050 and Ultrez 20 are also commercially available and can be used. The carbomer or Carbopols are resins which are known thickening agents. They are homopolymers of acrylic acid crosslinked with an allyl ether of pentaerythritol, an allyl ether of sucrose or an allyl ether of propylene. The carbomer can be present in the composition as a thickener and also can be used to suspend and stabilize the emulsion.
The composition can also contain known adjuvants and additives, such as bactericides, fungicides, virucides, light filter substances, active ingredients with a cooling action, antioxidants, plant extracts, anti-inflammatories, substances which promote wound healing, skin-lightening agents, screening agents, odor absorbers, skin-coloring agents, perfumes, antifoams, dyes, pigments which have a coloring action, thickeners, surface-active substances, emulsifiers, emollients, moisturizers and/or humectants, fats, oils, waxes, alcohols, polyols, polymers, foam stabilizers, electrolytes, organic solvents, silicone derivatives or chelating agents. These additives and adjuvants, depending on their nature, can be introduced into the fatty phase, into the aqueous phase and/or into the lipid spherules.
Exemplary oils or waxes suitable for use in the compositions include mineral oils (liquid petrolatum), vegetable oils (liquid fraction of karite butter, sunflower oil), animal oils (perhydrosqualene), synthetic oils (purcellin oil), silicone oils or waxes (cyclomethicone) and fluorinated oils (perfluoropolyethers), beeswax, camauba wax or paraffin wax. Fatty alcohols and fatty acids (stearic acid) can be added to these oils.
Exemplary emulsifiers which are suitable include glyceryl stearate, polysorbate 60 and the PEG-6/PEG-32/glycol stearate mixture marketed under the trademark Tefose.RTM. 63 by Gattefosse.
Exemplary solvents which can be used in the compositions include the lower alcohols, such as ethanol, isopropanol, acetone and propylene glycol.
Exemplary hydrophilic gelling agents suitable for use in the compositions include carboxyvinyl polymers (carbomer), acrylic copolymers such as acrylate/alkyl acrylate copolymers, polyacrylamides, polysaccharides such as hydroxypropylcellulose, natural gums and clays. And exemplary lipophilic gelling agents include modified clays such as bentones, metal salts of fatty acids such as aluminum stearates, and hydrophobic silica, ethylcellulose or polyethylene.
The compositions can contain other hydrophilic active principles, such as proteins or protein hydrolysates, amino acids, polyols, urea, allantoin, sugars and sugar derivatives, water-soluble vitamins, plant extracts, e.g. aloe and hydroxy acids.
Representative lipophilic active principles include retinol (vitamin A) and derivatives thereof, tocopherol (vitamin E) and derivatives thereof, essential fatty acids, ceramides, essential oils or salicylic acid and derivatives thereof.
Suitable antioxidants that can be used in the compositions include tocopherols (vitamin E), tocopherol derivatives, tocotrienols, ascorbic acid (vitamin C), ascorbic acid derivatives, carotenoids, vitamin A or derivatives thereof, butylated hydroxytoluene, butylated hydroxyanisole, gallic esters, flavonoids such as, for example, quercetin or myricetin, catechins such as, for example, epicatechin, epicatechingallate, epigallocatechin or epigallocatechingallate, sulfur-containing molecules such as, for example, glutathione, cysteine, lipoic acid, N-acetylcysteine, chelating agents such as, for example, ethylenediamine tetraacetic acid or other customary antioxidants. Antioxidants can be included in the compositions at about 0.0001 to about 30% by weight. Typically antioxidants will be included from about 0.0001 to about 20% by weight. Most often antioxidants will be included from about 0.0001 to about 5% by weight, based on the total weight of the preparation.
Additional antibiotic agents can be included in the compositions of the invention. Preferably the antibiotics are dermatologically absorbable. Suitable dermatologically absorbable antimicrobial, antibiotic, antibacterial or antifungal agents include erythromycin, bacitracin, zinc bacitracin, polymycin, neomycin, chloramphenicol, tetracycline, minocycline, clindamycin, doxycycline, undecylenic acid and salts thereof, propionic acid and salts thereof, caprylic acid and salts thereof, ciprofloxacin, cephlasporins, benzoic acid, ciclopiroxolamine, clotrimazole, econazole nitrate, metronizadole, miconazole nitrate, ketacanazole, oxiconazole, tolnaftate.
Antifungal agents can also be included in the compositions of the invention. These include, for example, amoroline, betadine, bifonazole, clotrimazole, econazole nitrate, isoconazole, ketoconazole, miconazole nitrate, naftifine hydrochloride, oxiconazole, sulfanazole, terbinafine, ticonazole, tolnaftate, and undecenoates.
Additional keratolytic agents such as salicylic acid and alpha hydroxy acids can be included in the composition.
Dermatological Disorders
The invention provides a method for treating a dermatological disorder comprising administering to a subject in need thereof a topical composition of the invention. As used herein, xe2x80x9ctreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d means the prevention or reduction of severity of symptoms or effect of a dermatological disorder. A xe2x80x9csubjectxe2x80x9d according to the invention refers to any multicellular organism having skin. Typically, the subject will be a mammal, such as a mouse, a rat, a pig, a horse, a cat, a dog, an elephant, a giraffe, a monkey, or a human, and the like. Typically, the mammal will be a human.
The term xe2x80x9cadministeringxe2x80x9d as used herein refers to any method which, in sound medical practice, delivers the composition to a subject in such a manner to so as to be effective in the treatment of a dermatological disorder. The compositions are preferably administered such that they cover the entire area to be treated.
The phrase xe2x80x9csafe and effective amountxe2x80x9d, as used herein, means an amount of a composition or component thereof sufficient enough to positively modify the disorder to be treated but low enough to avoid serious side effects, within the scope of sound medical advice. Safe and effective amounts will vary with the particular disorder or disorders being treated, the severity of the disorder, the duration of the treatment, the specific components of the composition being used, and like factors as are known by health-care providers, including physicians.
As used herein, xe2x80x9cdermatological disorderxe2x80x9d refers to any disorder of skin, hair, or glands. A dermatological disorder can be manifest in the form of visible lesions, pre-emergent lesions, pain, sensitivity to touch, irritation, inflammation, or the like. Dermatological disorders include disorders of the cutaneous and pilosebaceous unit or the process of keratogenesis. For example, a dermatological disorder can be a disorder of the epidermis or dermis, or within and surrounding the pilosebaceous follicle, which is located within the skin""s epidermis, dermis, or both. Examples of dermatological disorders include acne, psoriasis, seborrhea, ingrown hairs and pseudofolliculitis barbae, and hyperpigmented skin, cutaneous infections, and the like.
The invention provides a composition comprising carbamide peroxide and urea. Accordingly, the compositions can be useful for treating dermatological disorders for which carbamide peroxide or urea are known to be useful. Urea has been long recognized as a cosmetic ingredient in formulations acting as a humectant and moisturizer. Urea also has keratolytic activity and has the property of denaturing and solubilizing proteins. Additionally, it has been found that urea has mild antimicrobial activity. Carbamide peroxide has been employed as a keratolytic drug and as an antibacterial agent in the past, but is mostly used in to soften earwax. The combination of urea and carbamide peroxide provides synergistic antimicrobial activity. Keratolytic agents are agents that can remove or sluff dead cells of the horny outer layer of the skin (stratus corneum), which are composed largely of keratin. Such agents can prevent obstruction of follicular ducts or reopen obstructed ducts. Thus, the compositions can be useful for treating dermatological disorders in which a humectant, moisturizer, keratolytic agent, antibacterial agent, protein denaturant or solubilizer, or a combination thereof would be beneficial. Such disorders include any disorder involving obstruction of a follicular duct or bacterial infection. In addition, carbamide peroxide has been useful, and thus the compositions of the invention would be useful, in the topical treatment of skin lesions such as acne, burns, varicose ulcers, sycosis vulgaris, seborrhea and rosacea.
The compositions of the invention can also be used to treat dermatological disorders resulting in visible lesions. Examples of such disorders include acne, cutaneous infections, psoriasis and other disorders of the cutaneous and pilosebaceous unit or the process of keratogenesis. Visible lesions include closed comedones, open comedones, red or pustular-looking inflamed papules, pustules, nodules and cysts of acne or cutaneous infection; visible ingrown hairs of pseudofolliculitis barbae; visible scales of seborrhea, ichthyosis and psoriasis; and the like. Visible lesions can be due to obstruction of follicular ducts, thickened sebum, bacterial infection, or a combination thereof. Accordingly, the compositions can be used to prevent obstruction of follicular ducts, to reopen a duct if it has become blocked, to combat thickened sebum, to combat bacterial infection, or a combination thereof Treatment of visible lesions can be evaluated based on the effectiveness of the treatment in reducing the number and severity of visible lesions. Any reduction in number or severity of visible lesions as a result of administration a composition would be considered treatment of visible lesions.
In one embodiment, the compositions of the invention can be used to treat pre-emergent lesions. As used herein, xe2x80x9cpre-emergent lesionsxe2x80x9d refers to non-visible lesions present within the skin prior to eruption of visible lesions on the surface of the skin. Like visible lesions, pre-emergent lesions can be due to obstruction of follicular ducts, thickened sebum, bacterial infection, or a combination thereof. Accordingly, the compositions can be used to treat pre-emergent lesions by preventing obstruction of follicular ducts, reopening a duct if it has become blocked, combating thickened sebum, combating bacterial infection, or a combination thereof While pre-emergent lesions are insufficiently visible to be graded in conventional clinical studies, their presence within the skin can be discerned by the tactile sense of feel and/or by pain and tension within the skin. Any reduction in number of locations within the skin in which pre-emergent lesions exist as a result of administration of a composition would be considered treatment of pre-emergent lesions. Similarly, any reduction in the severity of the symptoms of a pre-emergent lesion as a result of administration of a composition would be considered treatment of the pre-emergent lesion.
In another embodiment, the compositions of the invention can be used to treat acne. As used herein, xe2x80x9cacnexe2x80x9d means a disorder of the skin caused by inflammation of skin glands or hair follicles. The compositions of the invention can be used to treat acne at early pre-emergent stages or later stages where lesions from acne are visible. Early pre-emergent stages of acne usually begins with an excessive secretion of sebum or dermal oil from the sebaceous glands located in the pilosebaceous apparatus. Sebum reaches the skin surface through the duct of the hair follicle. The presence of excessive amounts of sebum in the duct and on the skin tends to obstruct or stagnate the normal flow of sebum from the follicular duct, thus producing a thickening and solidification of the sebum to create a solid plug known as a comedone. In the normal sequence of developing acne, hyperkeratinazation of the follicular opening is stimulated, thus completing blocking of the duct. The usual results are papules, pustules, or cysts, often contaminated with bacteria, which cause secondary infections. Acne is characterized particularly by the presence of comedones, inflammatory papules, or cysts. The appearance of acne may range from slight skin irritation to pitting and even the development of disfiguring scars. Accordingly, the compositions of the invention can be used, but not limited, to treat skin irritation, pitting, development of scars, comedones, inflammatory papules, cysts, hyperkeratinazation, and thickening and hardening of sebum associated with acne.
All patent and literature references cited in the present specification are hereby incorporated by reference in their entirety. All parts and percentages are by weight unless otherwise specified. All scientific and technical terms used in this application have meanings commonly used in the art unless otherwise specified.

Carbamide peroxide compositions for the treatment of dermatological disorders and methods for their use


Xanthines of the formula I

Cyclosporin A (CysA) is a cyclic undecapeptide which is obtained from a fungus (CAS No.59865-13-3; U.S. Pat. No. 3,737,433). Its immunosuppressive effect has been known since 1972, but nevertheless it still took about 10 years until CysA found its way into the treatment of the acute rejection reaction of transplants (Borel J. F.: Cyclosporine. In: Dale M., Foreman J. C., Fan T. P. D. (eds.): Textbook of Immunology (3rd ed.). Blackwell Scient. Publ. Oxford 1994 pp 320-329). Today, as a result of its outstanding properties, CysA can no longer be overlooked in immunosuppression, even if its use is accompanied by a number of sometimes serious side effects.
The immunosuppressive action of CysA is very selective and concentrates on T-cell-dependent mechanisms. CysA inhibits the proliferation of T-lymphocytes, which normally respond to a proliferative stimulus (produced e.g. by antigen or nitogen) with cell replication and cell differentiation but also the release of lymphokines (e.g. various interleukins such as IL-2, IL-3 and IL-4, but also xcex3-interferon) and in this way start the cellular immune response. T-cell-independant B cell-dependent mechanisms (e.g. the humoral immune response via certain antibodies) cannot be inhibited, however, under the therapeutically achievable CysA concentrations. The immuno-suppression produced by CysA is completely reversible after removing or washing out the substance (Thomson A. W. (ed.): Cyclosporin: Mode of Action and Clinical Applications. Kluwer Acad. Publ. Dordrecht 1989), which points to the fact that it is not a general lymphocytotoxic reaction which we are dealing with here, instead the release of IL-2 by T-helper cells primarily appears to be inhibited, which brings about a blockade of secondary immunological reactions. In this case the expression of the IL-2 gene represents the biochemical response of the T-helper cell to an immunological stimulus, which is fed from the cell membrane into the nucleus in the course of a xe2x80x9csignal chainxe2x80x9d. Although the individual biochemical chain constituents and their sequence have not yet been elucidated in detail, the activation and translocation of a cytosolic xe2x80x9cnuclear factorxe2x80x9d (NF-AT=nuclear factor of activated T cells) can be assumed as an important step which then causes the transcription of the IL-2 gene in the nucleus. This activation of NF-AT which is controlled by the Ca2+/calmodulin/calcineurin system is inhibited by CysA, which joins intracellularly with a protein called xe2x80x9ccyclophilinoxe2x80x9d to give a complex (Handschumacher R. E. et al.: Science 226 (1984), 544-546), with the result that despite the presence of an immunological stimulus no IL-2 is formed which, however, is of crucial importance for the further course of the cellular immune response (inter alia for the formation of cytotoxic T-cells).
This immunosuppressive action appears CysA to be suitable not only for allogeneic transplantations, but also for autoimmune disorders of different manifestation. In fact, numerous respective therapeutic attempts have been undertaken, from rheumatoid arthritis through psoriasis up to juvenile diabetes (Schindler R. (ed.): Cyclosporin in Autoimmune Diseases. Springer Verlag Berlin 1985; Thomson A. W. et al.: Br. Med. J. 302 (1991), 4-5). Despite various successful results, however, CysA has not been able to establish itself as the drug of choice in these indications, the reason for this being exclusively to be sought in the toxicity of this substance. In the first place, its marked nephrotoxicity which in some cases is irreversible has to be mentioned here, but also other phenomena such as high blood pressure, nausea, diarrhoea, tremor, tingling or gingival hypertrophy (Palestine A. R. et al.; Am. J. Med. 77 (1984), 652-656) represent complications to be taken seriously, which usually cannot be avoided even with systematic checking of the serum level. At the same timexe2x80x94as with any effective immunosuppressionxe2x80x94opportunistic infections additionally have to be considered (Dawson T. et al.: J. Rheumattl. 19 (1992), 997), so that by critical benefit-risk assessment an otherwise advantageous CysA medication in many cases has to be sacrificed.
Xanthines have already been taken by people for many hundreds of years in the form of aqueous extracts, and the stimulating as well as diuretic properties of tea or coffee are generally known. About 70 years ago, theophylline was then introduced into medicine as a pure substance for the treatment of pulmonary complaints (e.g. asthma attack), followed 50 years later by pentoxifylline (POF), which is employed for the treatment of peripheral and cerebral circulatory disorders (Ward A. et al.: Drugs 34 (1987), 50-97). The latter xanthine derivative, which clearly differs from theophylline due to its extensive lack of central and cardiac effects, in the following was subject of in-depth investigations on its mechanism of action, in the course of which also effects on the immune system have been detected. Thus, for example, it was already found at the start of the ""80s that POF significantly prolonged the survival rate of heart and kidney transplants in the rat model, although these findings, at that time, have primarily been attributed to improved circulatory phenomena (Kostakis A. J. et al.: IRCS 8 (1980), 15; Kostakis A. J. et al.: IRCS Med. Sci. 10 (1982), 77-78). Only later was it recognized that POFxe2x80x94together with other representatives of the xanthine familyxe2x80x94interacts with the immunologically important cytokine network. This is not only true for tumor necrosis factor (TNF), which plays a central role in a number of very different disorders and whose formation is inhibited on the transcriptional level by POF (Strieter R. M. et al.: Biochem. Biophys. Res. Commun. 155 (1988), 1230-1236), but also for other cytokines such as IL-2 or IFNxcex3 (Rieneck K. et al.: Immunol. Lett. 37 (1993), 131-138; Thanhxc3xa4user A. et al.: Immunology 80 (1993), 151-156; Tilg H. et al.: Transplantation 56 (1993), 196-201). Since, in addition antiproliferative effects of POF also became known in the meantime (Singer J. W. et al.: Bone Marrow Transplant. 10 (1992), 19-25), it is not astonishing that today certain immunomodulatory properties are ascribed to POF, which have already given rise to speculations about an extension of its present applications (Zabel P. et al.: Immun. Infect. Dis. 3 (1993), 175-180).
As far as the mechanism of action of xanthines is concerned, the cAMP system may play a predominant role. cAMP (cyclic 3xe2x80x2,5xe2x80x2-adenosine monophosphate) is a xe2x80x9csecond messengerxe2x80x9d and able to control the activity state of the cell: the higher the intracellular cAMP level, the less activated the cell. The height of the cAMP level may generally be affected by two different mechanisms: increase in formation by adenylate cyclase (AC) or inhibition of degradation by phosphodi-esterase(s) (PDE). Xanthines from the POF series are prone to both of these possibilities, i.e. directly via inhibition of PDE and indirectly via stimulation of the release of prostaglandins, which themselves stimulate AC""s. Actually, the increase in intracellular cAMP level due to xanthine actionxe2x80x94with all its consequencesxe2x80x94is not restricted to T-lymphocytes, however, but is also found in other immunocompetent cells such as monocytes or granulocytes, which in the former leads to the inhibition of TNF synthesis (Strieter R. M. et al.: Diochem, Biophys. Res. Commun. 155 (1988), 1230-1236) but in the latter suppresses the xe2x80x9cmetabolic burstxe2x80x9d (=oxygen free radical formation and release of lytic enzymes from the granules for bacterial infection defence (Hammerschmidt D. E. et al.: J. Lab. Clin. Med. 112 (1988), 254-263)), both reactions of whichxe2x80x94intravasally inducedxe2x80x94being able to cause massive complications in the microcirculation. This mechanism, which in the various representatives of the xanthine family may differ markedly (Semmler J. et al.: Immunology 78 (1993), 520-525), indeed leads to very selective interventions in the cytokine network (the formation of IL-1, for example, is nearly not affected at all (Tannenbaum C. S. et al.: J. Immunol. 142 (1989), 1274-1280; Endres S. et al. Immunology 72 (1991), 56-60), thus reducing the vascular and the immunological modes of action of xanthines to a common biochemical basis (Schbnharting M. M.: In: Kark B., Werner H. (eds.): Herz- und Kreislaufer-krankungen im Alter. Steinkopff-Verlag Darmstadt 1990, pp 3-13).
Apart from its general potential to increase cAMP levels both directly and indirectly, however, there must exist an additional site of action for the xanthines allowing them to interfere with the signal transduction pathway by a different, although still unknown mechanism. This can be deduced from the fact that under stimulation of the T-cell by the cytokine IL-2 which represents a cAMP-independent stimulation of the immune response via the IL-2 receptor (Smith K. A.: Science 240 (1988), 1169-1175), xanthines (but not CysA) are potent down-regulators of this activation. A representative example will be given in Table 3 of this application.
On account of the global circulation-promoting effect of POF, coupled with good tolerability, various examples of a comedication of this xanthine with other pharmaceuticals such as anticoagulants, cyto-statics, virustatics, antibiotics or antimycotics are already known. In addition, a pharmacodynamic interaction of POF with dexamethasone in vitro and with OKT3 has also been reported (Han J. et al.: J. Exp. Med. 172 (1990), 391-394; Weinberg J. B. et al.: Blood 79 (1992), 3337-3343 ; Zabel P. et al.: Z. Transplantationsmed. 3 (1991), 62-65; Alxc3xa9gre M. L. et al.: Transplantation 52 (1991), 674-679). As far as a combination with CysA is concerned, the general possibility that a comedication with immunosuppressives such as CysA can occur when using xanthines in immunological problems is already addressed in the patent applications EP 0 493 682 and EP 0 490 181. Although immunosuppressive properties are ascribed to the xanthines in these two patents, nevertheless no respective combination effect with other immunosuppressives has been derived therefrom. Independently, reports of a positive interaction of POF with CysA are known but relate exclusively to the tolerability problems (Brunner L. J. et al.: Renal Fail. 11 (1989), 97-104; Berkenboom G. et al.: J. Cardiovasc. Pharmacol. 18 (1991), 761-768; Rossi S. J. et al.: Drug Saf. 9 (1993), 104-131; WO 93/17684 caused by CysA medication, which presumably can be understood through inhibition of the formation of cytokines and endothelin (Carrier M. et al.: Ann. Thorac. Surg. 55 (1993), 490-492; Bennett W. M. et al.: Transplantation 54 (1992), 1118-1120) or an increase in renal prostaglandin synthesis (Brunnar L. J. at al. Renal Fail. 11 (1989), 97-104; Bennett W. M. et al.: Transplantation 54 (1992), 1118-1120, Bianco J. et al.: Blood 78 (1991), 1205-1211). Even when using POF in transplantation-related indications such as the GvH (graft-versus-host) reaction in which the treatment with CysA is part of the standard medication, the question is addressed exclusively to reduction of the toxicity of CysA (Bianco J. et al.: Blood 78 (1991), 1205-1211: Vogelsang G. B.: Curr. Opin. Oncol. 5 (1993), 276-281), although even this POF effect is not undisputed (Attal M. et al.: Blood 82 (1993), 732-736; van der Jagt R. H. C. et al.: Bone marrow Transplant. 13 (1994), 203-207).
FK506 (Tacrolimus) is a macrolide which exerts largely similar effects as CysA, both with regard to its molecular mode of action and its clinical efficacy (Liu J.: Immunol. Today 14 (1993), 290-295; Schreiber S. L. et al.: Immunol. Today 13 (1992), 136-142); respective effects, however, may be found already at doses which are less by the factor 20 to 100 compared to CysA (Peters D. H. et al.: Drugs 46 (1993), 746-794). The same is true for rapamycin (RPM) which again is a macrolide binding intracellularly to the same immunophilin as FK506, although the following biochemical events are differing somewhat (Morris R. E.: Transplant. Rev. 6 (1992), 39-87).
Various models of different estimations are available for testing an immunosuppressive action. In vivo, for example, different transplantation models are established presenting with different immunogenicities, depending on the donor and recipient species used and depending on the nature of the transplanted organ. The comparison of the length of the survival time of the transplanted organ in vivo with and without pharmacological intervention can thus be used as a quantitative measure for the suppression of the immune response. In vitro, there exist likewise various models of differing value. The best known are lymphocyte activation tests, in which the extent of the activation is measured via lymphocyte proliferation. Inhibition of proliferation thus always means immunosuppression under the experimental conditions applied. There exist different stimuli for lymphocyte activation:
coculture of lymphocytes of different species (MLR=mixed lymphocyte reaction): lymphocytes containing different antigens of the HLA-DR type (=allogens) activate each other non-specifically.
CD3 assay: specific activation of the T-lymphocytes via an exogenously added antibody (OKT3) against the CD3 marker molecule located on the lymphocyte membrane, together with a costimulatory signal. This activation proceeds via the Ca2+/calmodulin/calcineurin system and can be inhibited by CysA
CD28 assay: specific activation of the T-lymphocyte via an exogenously added antibody against the CD28 marker molecule located on the lymphocyte membrane, together with a costimulatory signal. This activation is Ca2+-independent and thus cannot be inhibited by CysA.
IL-2R assay: specific activation of the lymphocyte via the exogenously added cytokine IL-2 which binds to the IL-2 receptor (IL-2R) located on the lymphocyte membrane. This activation is Ca2+/cAMP-independent and cannot be inhibited by CysA.
It has now been found that the comedication of an immunosuppressive compound such as CysA or FK506 or RPM with a xanthine derivative leads to a superadditive increase in the immunosuppressive action. This becomes clear from Table 2 where each immunosuppressive, in combination with compound no. 1 (=xanthine derivative), demonstrates superadditive effect with regard to inhibition of proliferation in the MLR assay, as compared with the effect of the respective monosubstances. Under in vivo conditions in the rat heart allograft model this synergistic effect could indeed be confirmed, as treatment of the recipient animal with subtherapeutic doses of both compound no. 1 and CysA results in a significant prolongation of the survival time of the transplant (Table 4). As no interference with the respective drug levels could be found, this effect cannot be explained by changed pharmacokinetics, instead it is obviously a matter of increased pharmacodynamics.
Interestingly, xanthines are found to exert their actions by different mechanistic ways as compared to CysA, FK506, or RPM. Whereas compound no. 1 is active in all the applied in vitro tests regardless whether the stimulation of the immune response is dependent on specific intracellular levels of cAMP and/or Ca2+ or not, CysA exerts its effect only in the MLR and the CD3 assays but not in the CD28 or IL-2R assays (Table 3). The same is true for FK506, whereas RPM is known to be effective in the IL-2R assay but, in contrast to the other immunosuppressives, not effective if IL-2 production itself is addressed (Morris R. E.: Rev. 6 (1992), 39-87). These data indicate that in combinations of xanthines with either CysA, FK506, or RPM, the resulting superadditive immunosuppressive effect may not only quantitatively be increased, but should also qualitatively be changed. This interpretation is supported by in vivo data demonstrating an indefinite survival of the transplant under special experimental conditions even after stop of the combination treatment, which may be explained by induction of immune tolerance (Table 5).
The therapeutic spectrum of action of the individual components is thus quantitatively and qualitatively broadened by a combination of this type. Moreover, it makes possible, by means of a dose reduction without reduced efficacy but with increased safety associated therewith, the treatment of even those immune disorders which were hitherto closed to immunosuppressive therapy as a result of intolerable incompatibility phenomena. At the same time, the therapy costs can be decreased to an appreciable extent. The invention therefore relates to a combination preparation, containing
1) cyclosporin A or FK506 or rapamycin,
2) at least one xanthine of the formula I,
where R2 is (C1-C4)-alkyl, and
xe2x80x83one of the radicals R1 or R3 is a radical of the formula II
xe2x80x94(CH2)nxe2x80x94Axe2x80x94CH3xe2x80x83xe2x80x83(II)
in which A
a) is a covalent single bond, where n is the integer 0, 1, 2, 3, 4, 5, 6 or 7,
b) is a radical
where n is the integer 1, 2, 3, 4, 5 or 6, or
c) is a radical
where n is the integer 1, 2, 3, 4, 5 or 6 and
R4 is
a) a hydrogen atom or
b) (C1-C3)-alkyl,
and the other radical R1 or R3 is
a) a hydrogen atom,
b) (C1-C7)-alkyl,
c) (C4-C8)-cycloalkyl-alkyl or
d) alkyl having 1 to 6 carbon atoms, whose carbon chain is interrupted by an oxygen atom, and
3) a pharmaceutical excipient,
for the simultaneous, separate or sequential use in organ transplantation,
with the exception of the case in which cyclosporin A and 3,7-dimethyl-1-(5-oxohexyl)xanthine are employed for the treatment of bone marrow transplantations.
A xanthine of the formula I is preferred where R2 is (C1-C4)-alkyl, one of the radicals R1 or R3 is a radical of the formula II,
in which A is
a) a radical
or
b) a radical
where n is the integer 3, 4, 5 or 6 and R4 has the abovementioned meaning, and
the other radical R1 or R3 is (C1-C7-alkyl or (C4-C8)cycloalkyl-alkyl.
A xanthine of the formula I is especially preferred where
R1 and R3 have the abovementioned meaning and
R2 is (C1-C2)-alkyl and R4 is a hydrogen atom or (C1-C2-alkyl.
A xanthine of the formula I is particularly preferred where
R2 is (C1-C2)-alkyl,
R1 is the radical of the formula II, in which A is
a) a radical
b) a radical
where n is the integer 3, 4, 5 or 6 and
R4 is
a) a hydrogen atom or
b) (C1-C2)-alkyl, and
R3 is (C1-C7)-alkyl or (C4-C8)-cycloalkyl-alkyl.
A xanthine of the formula I is very particularly preferred where
R2 is (C1-C2)-alkyl,
R1 is the radical of the formula II, in which A is
a) a radical
b) a radical
where n is the integer 3, 4, 5 or 6 and
R4 is
a) a hydrogen atom or
b) (C1-C2)-alkyl, and
R3 is (C2-C5)-alkyl or (C4-C6)-cycloalkyl-alkyl.
The compounds 1,3-dimethylxanthine, 3,7-dimethylxanthine, 1,3,7-trimethylxanthine, 1-hexyl-3,7-dimethylxanthine, 3,7-dimethyl-1-(5-oxohexyl)xanthine, 1-(5-hydroxyhexyl)-3,7-dimethylxanthine, 1,3-dimethyl-7-(5-oxohexyl)-xanthine, 7-(5-hydroxyhexyl)-1,3-dimethylxanthine, 1,3-di-n-butyl-7-(2-oxopropyl)xanthine, 1,3-di-n-butyl-7-(3-oxobutyl)-xanthine, 3-methyl-1-(5-oxohexyl)-7-propylxanthine, 1-(5-hydroxyhexyl)-3-methyl-7-propyl-xanthine, 1-(5-hydroxy-5-methylhexyl)-3-methyl-7-propylxanthine, 7-ethoxymethyl-1-(5-hydroxy-5-methylhexyl)-3-methylxanthine, 1 -(5hydroxy-5-methylhexyl)-3-methylxanthine, 1-(5-hydroxy-5-methylhexyl)-3-methyl-7-butylxanthine, 1-(5-hydroxy-5-methylhexyl)-3,7-dimethylxanthine, 1-(6-hydroxy-6-methylheptyl)-3-methyl-7-propylxanthine, 3-ethyl-1-(5-hydroxy-5-methylhexyl)-7-propylxanthine, 3-ethyl-1-(6-hydroxy-6-methylheptyl)-7-propylxanthine, 7-butyl-3-ethyl-1-(6-hydroxy-6-methylheptyl)-xanthine or 7-cyclopropylmethyl-1-(5-hydroxy-5-methylhexyl)-3-methylxanthine are employed by way of example in the combination preparation according to the invention in combination with CysA or FK506 or rapamycin.
The term xe2x80x9c(C4-C8)xe2x80x9d is understood as an alkyl residue, which is substituted by a (C3-C6)-cycloalkyl and wherein the number of all carbon-atoms are from 4 to 8. Examples if these residues are cyclopropylmethyl, cyclopropylpentyl, cyclohexylmethyl or cyclohexylethyl. The term xe2x80x9c(C4-C6)-cycloalkyl-alkylxe2x80x9d is understood as an alkyl residue, which is substituted by a (C3-C5)-cycloalkyl and wherein the number of all carbon-atoms are from 4 to 6.
The term xe2x80x9corganxe2x80x9d is understood as meaning all organs or parts of organs (even several) in mammals, in particular humans, for example kidney, heart, skin, liver, muscle, cornea, bone, bone marrow, lung, pancreas, intestine or stomach.
In organ transplantation, rejection reactions of the organ recipient to the transplanted organ or rejection reactions of the transplanted organ to the recipient (host-versus-graft reaction or graft-versus-host reaction) occur. Rejection reactions mean all reactions of the recipient body or of the transplanted organ which in the end lead to cell or tissue death in the transplanted organ or adversely affect the functional ability and viability of the transplanted organ or the recipient. In particular, this means acute and chronic rejection reactions.
The term xe2x80x9csuperadditive actionsxe2x80x9d is understood as meaning effects which are greater than the sum of the actions of the individual components.
The xanthine derivatives are prepared by known processes (U.S. Pat. Nos. 3,737,433; 4,108,995; 4,833,146).
The invention also relates to novel trisubstituted xanthine derivatives of the formula I, in which
R3 denotes butyl, and where
a)R1 denotes 5-hydroxy-5-methylhexyl and R2 denotes methyl, or
b)R1 denotes 6-hydroxy-6-methylheptyl and R2 denotes ethyl.
A further embodiment of the invention concerns novel xanthine compounds of the formula I,
where R2 is (C1-C4)-alkyl, and
one of the radicals R1 or R3 is a radical of the formula II
xe2x80x94(CH2)nxe2x80x94Axe2x80x94CH3xe2x80x83xe2x80x83(II)
in which A
a) is a covalent single bond, where n is the integer 0, 1, 2, 3, 4, 5, 6 or 7,
b) is a radical
where n is the integer 1, 2, 3, 4, 5 or 6, or
c) is a radical
where n is the integer 1, 2, 3, 4, 5 or 6 and
R4 is a hydrogen atom or (C1-C3)-alkyl,
and the other radical R1 or R3 is (C4-C8)-cycloalkyl-alkyl.
The invention further relates to compounds of the formula I,
where R2 is (C1-C4)-alkyl,
one of the radicals R1 or R5 is a radical of the formula II, in which A is
a) a radical
b) a radical
where n is the integer 3, 4, 5 or 6 and R4 has the abovementioned meaning,
and the other radical R1 or R3 is (C4-C8)-cycloalkyl-alkyl.
The invention especially relates to compounds of the formula I, where
R2 is (C1-C2)-alkyl,
R1 is the radical of the formula II, in which A is
a) a radical
b) a radical
where n is the integer 3, 4, 5 or 6 and
R4 is
a) a hydrogen atom or
b) (C1-C2)-alkyl, and
R3 is (C4-C8)-cycloalkyl-alkyl.
The invention also relates to compounds of the formula I, where
R2 is (C1-C2)-alkyl,
R1 is the radical of the formula II, in which A is
a) a radical
b) a radical
where n is the integer 3, 4, 5 or 6 and
R4 is
a) a hydrogen atom or
b) (C1-C2)-alkyl, and
R3 is (C4-C6)-cycloalkyl-alkyl.
The invention especially relates to the novel compound 7-cyclopropylmethyl-1-(5-hydroxy-5-methylhexyl)-3-methylxanthine.
The invention further relates to a combination preparation, containing 1) cyclosporin A or FK506 or rapamycin, 2) at least one xanthine of the formula I, and 3) a pharmaceutical excipient, for simultaneous, separate or sequential use in (auto)immune disorders.
These include, inter alia, systemic lupus erythematosus, rheumatoid arthritis, psoriasis, pemphigus, atopic dermatitis, myositis, multiple sclerosis, nephrotic syndrome (in particular glomerulonephritis), ulcerative colitis or juvenile diabetes.
The invention further relates to the use of cyclosporin A or FK506 or RPM and at least one xanthine of the formula I for the production of a pharmaceutical for inhibiting the replication of viruses such as picorna-, toga-, bunya-, orthomyxo-, paramyxo-, rhabdo-, retro-, arena-, hepatitis B-, hepatitis C-, hepatitis D-, adeno-, vaccinia-, papilloma-, herpes-, varicella-zoster-virus or human immunodeficiency virus (HIV); or for treating of cancer such as lung cancers, leukaemia, ovarian cancers, sarcoma, Kaposi""s sarcoma, meningioma, colon cancers, lymph node tumors, glioblastoma multiforme, prostate cancers or skin carcinoses.
The invention further relates to the use of cyclosporin A or FK506 or rapamycin and at least one xanthine of the formula I for the production of a pharmaceutical for the treatment of humans after organ transplantation or of (auto)immune disorders.
The invention further relates to a combination preparation, containing 1) cyclosporin A or FK506 or rapamycin, and 2) at least one xanthine of the formula I, in a quantity producing a superadditive immunosuppressive effect.
The weight ratio of CysA (component 1) to the compound of the formula I is in general from 1:1 to 1:50, preferably from 1:2 to 1:25, in particular from 1:5 to 1:20. The weight ratios of FK506 or RPM (component 1) to the component 2 is in general from 1:50 to 1:2500, preferably from 1:100 to 1:1250, in particular from 1:250 to 1:1000.
The combination preparation according to the invention can be present as a dose unit in the form of pharmaceutical forms such as capsules (including microcapsules), tablets (including coated tablets and pills) or suppositories, when using capsules it being possible for the capsule material to take the function of the excipient and the contents to be present e.g. as a powder, gel, emulsion, dispersion or solution. It is particularly advantageous and simple, however, to prepare oral (peroral) formulations containing the two active compound components 1) and 2), which contain the calculated amounts of the active compounds together with any desired pharmaceutical excipient. An appropriate formulation (suppository) can also be used for rectal therapy. The transdermal, parenteral (intraperitoneal, intravasal, subcutaneous or intramuscular) or oral administration of solutions which contain the combinations according to the invention is possible as well.
The tablets, pills or granule bodies can be prepared by customary methods such as pressing, immersion or fluidized bed methods or pan coating and contain excipients and other customary auxiliaries, such as gelatine, agarose, starch, e.g. potato, corn or wheat starch, cellulose such as ethylcellulose, silica, various sugars such as lactose, magnesium carbonate and/or calcium phosphates. The coating solution usually comprises sugar and/or starch syrup and usually additionally contains gelatine, gum arabic, polyvinylpyrrolidone, synthetic cellulose esters, surface-active substances, plasticizers, pigments and similar additives according to the prior art. To prepare the pharmaceutical forms, any customary flow-regulating agent, lubricant or glidant such as magnesium stearate, and release agents can be used.
The preparations preferably have the form of coated/core tablets or multilayer tablets, the xanthine of the formula I being in the coating or in the core or in a layer, while cyclosporin A or FK506 or RPM is in the core or in the coating or in another layer. The active compound components can also be present in depot form or adsorbed on depot material or included in the depot material (e.g. those based on cellulose or polystyrene resin, e.g. hydroxyethylcellulose). Suitable xanthine components are also commercially available pharmaceutical preparations which are released with a time delay, e.g. only in the intestinal tract. A delayed release of the active compounds can also be aehieved by providing the layer or the compartment concerned with customary enteric coatings.
The dosage to be used is of course dependent on various factors such as the organism to be treated (e.g. human or animal, age, weight, general state of health), the severity of the symptoms, the disorder to be treated, possible accompanying disorders, (if present) the nature of the accompanying treatment with other pharmaceuticals, or the frequency of the treatment. The dosages are in general administered several times per day and preferably once to three times per day. The amounts of the individual active compounds should be within the range given below, e.g. within the tolerable, efficacious dosage range for the organism to be treated.
Suitable therapy with the combinations according to the invention thus comprises e.g. the administration of one, two or 3 to 8 individual dosages of the combination preparations according to the invention of 1) 25 mg to 100 mg each, preferably from 10 to 20 mg of cyclosporin A, and 2)100 to 1200 mg, preferably 400 to 600 mg, of xanthine of the formula I, the amount naturally being dependent on the number of individual dosages and on the disorder to be treated and it also being possible for an individual dose to comprise several dose units administered simultaneously. The dose in the case of oral administration is in general at most 5 to 10 mg/kg/day of CysA (component 1), where a serum level of 100 ng/ml to 200 ng/ml should not be exceeded, and at most 20 mg/kg/day of a compound of the formula I, in particular in the case of oral or rectal administration. In the case of i.v. or i.p. administration, the upper daily dose of these active compounds in general is by 40% to 50% lower.
If FK506 or RPM is employed instead of CysA the dosage is distinctly lower. In the case of oral administration, in general from 0.02 to 0.2 mg/kg/day, preferably 0.035 to 0.1 mg/kg/day, in particular 0.04 to 0.08 mg/kg/day, of FK506 or RPM is employed as component 1.
The combination preparation according to the invention can also include combination packs or compositions in which the constituents are placed side by side and can therefore be administered simultaneously, separately or sequentially to one and the same human or animal body.

Combination preparation, containing cyclosporin a or FK506 or rapamycin and a xanthine derivative

Abstract: Xanthines of the formula I

Abstract: are useful in producing a superadditive increase in immunosuppressive action when combined with immunosuppressive compounds such as CysA or FK506.


Installation for the drying, heating, sterilization or disinfection of dry, moist or wet materials or materials in a moist environment and of liquids, particularly waste which may be infected, e.g., medical waste, in which the materials to be treated are introduced into a microwave-permeable vessel in a pressure-proof treatment space which can be acted upon by microwaves and sealed in a pressure-tight manner, wherein a plurality of magnetrons are coupled into the resonant space forming the treatment space in such a way that microwave dead spaces are prevented, wherein the physical parameters in the device are monitored and utilized for controlling the installation, and wherein added units are also provided for influencing the course of the process.

The invention is directed to a n apparatus for the drying, heating , sterilization and/or disinfection of dry, moist or wet materials or materials in a moist environment and of liquids, particularly waste which may be infected, e.g., medical waste, in which the materials to be treated are introduced into a microwave-permeable vessel in a pressure-proof treatment space which can be acted upon by microwaves and sealed in a pressure-tight manner, wherein a plurality of magnetrons are coupled into the resonant space forming the treatment space in such a way that microwave dead spaces are prevented, wherein the physical parameters in the device are monitored and utilized, when appropriate, for controlling the installation, and wherein added units are also provided for influencing the course of the process, as well as to processes for pasteurization, disinfection or sterilization of dry, moist, or wet materials or materials in a moist environment and of liquids.
An installation of this kind is known, for example, from WO 86/02842 in which there is provided a cylindrical interior space which can withstand internal pressures of up to 5 atmospheres or a partial vacuum. The top of this cylindrical space can be closed by a cover. The magnetrons are provided at the bottom end face of the cylindrical vessel, this underside being closed by a microwave-permeable pressure-proof wall. In order to achieve the most uniform possible distribution of microwave energy in this known construction, the inner cylindrical chamber is suspended so as to be rotatable in order to achieve control of the irradiation density of the individual particles by way of the movement of this cylindrical chamber. Further, because of this construction, the chamber of the known arrangement can only be loaded or charged from the top, which can quickly lead to difficulties when larger quantities of material packed in a drum must be introduced into the vessel. Further, condensation water can form on the wall in this known construction during cooling and must be removed from the vessel.
Another installation of the type mentioned above which is known from EP 0 476 004 B1 is also provided with a cylindrical treatment chamber which can be closed at the top. This treatment chamber (referred to in this reference as a cavity resonator) is lined with a vessel 1 which can be closed so as to be gastight, and the magnetrons are coupled into the treatment space laterally and from the bottom end face. Due to the lining provided in this known construction, the distance of the interior space from the microwave generators is controlled in such a way that a corresponding energy density is also present in this outer area.
This known construction also has the disadvantage that it is chargeable from the top, which accordingly impedes loading. Further, as can be gathered from this reference, the device must be charged with decalcified water because calcium deposits would otherwise occur in the lining. The construction according to this reference is also capable of operating with overpressure or underpressure.
It is known from EP 0 287 549 B1, whose subject matter also refers back to an invention of the Applicant of the present application as co-inventor, to couple a plurality of magnetrons into a cavity resonator in such a way that microwave dead spaces are prevented, wherein the coupling in is carried out via waveguides. However, this known construction is not provided as an overpressure sterilizer.
EP 0 483 104 B1 also cites the present Applicant as co-inventor, wherein, in an installation according to the above-cited EP 0 287 549, a vessel containing infectious waste is introduced into the cavity resonator, that is, the treatment chamber, and this vessel can be closed by a cover so that it can serve as a collecting vessel for this infectious waste. A carrier with physical measurement sensors can be lowered into the vessel from the top through an opening in the cover of this vessel, and water can also be sprayed in via this carrier when the quantity of water or moisture contained in the infectious material is too small. According to the known construction, the quantity of water or moisture is determined by an appropriate weighing device, and the supply of water is controlled by means of a central control device which controls the microwave generators corresponding to the measured physical data.
It is the object of the present invention to provide an installation of the type mentioned above which has the advantages of the side-charging treatment chamber according to EP 483 104 A2 as well as the advantages of a pressure chamber and which can therefore be used as an autoclave.
According to the invention, this is accomplished in that the magnetrons are coupled into the treatment space in a pressure-tight manner via waveguides, known per se, this treatment space being provided with a side charging opening for introducing the microwave-permeable vessel while leaving a free space between the vessel and the inner wall of the treatment space, wherein the treatment space has a cylindrical or polygonal prismatic shape with vertically extending longitudinal axis, and wherein the devices for monitoring the physical parameters are arranged at carriers communicating with the interior of the vessel. In this way, the distance between the material to be treated and the microwave generators can be controlled via the waveguides and intermediate space remaining between the vessel and the inner wall of the treatment space in such a way that the entire interior of the vessel receives the full microwave output, so that the irradiated microwave energy is sufficient for generating the necessary steam to achieve the operating overpressure. Further, the side charging opening makes it possible for larger-volume vessels that would no longer be manageable in practice with out auxiliary equipment to be introduced into th e treatment s pace.
The charging opening can be advantageously produced by parts of the treatment chamber along an off-center plane extending parallel to the longitudinal axis of the treatment chamber, wherein the bottom wall and top wall are also divided. Accordingly, a portion of the top wall and also a portion of the bottom of the treatment chamber are divided, which considerably facilitates insertion of the vessel by auxiliary means such as a suitably constructed trolley, lift truck or the like. However, the charging opening can be made by cutting out the casing wall of the treatment chamber along two generatrices and parallel to the bottom wall and top wall, so that the entire bottom surface and top surface remain intact and the charging opening is provided only in the wall, which can be advantageous under certain circumstances for purposes of economizing on space.
For a particularly space-saving construction, a combination of wave trap, known per se, and seal, preferably a hose seal which can be acted upon by internal pressure, can be provided along the charging opening for tightly closing this opening by means of the associated closing part. This offers the possibility of a compact construction of the seal for preventing the escape of microwaves and pressure without impairing the free through-opening.
In order to ensure that the sterilizing/disinfecting process actually occurs at the correct temperature within the material and not only at the temperature of the interior space, a thermal sensor by which carriers communicating with the interior of the vessel can be introduced into the microwave-permeable vessel or a noncontacting thermal sensor connected with a control device having a reference value storage and a comparator for comparing with the determined actual value can be provided for determining the regulating variable for the output of the magnetrons. The temperature in the material can be detected in a much more direct manner in this way because the temperature is measured there and then, and the steam or compressed steam flowing out is measured inside the entire installation in the immediate vicinity of the material. In this way, it can also be ensured that the desired temperature is reliably maintained over the given period within the material. In addition, a pressure sensor extending outside of the microwave-permeable vessel into the interior of the resonant chamber can be connected with the comparator, so that the ratios in the area of the resonator chamber located outside of the vessel can also be determined.
In order to prevent condensation from forming on the wall of the resonant chamber in the event of temperature differences, the wall of the resonant chamber can be provided with a heating device. The output of the heating device can be regulated depending on the temperature prevailing in the vessel for a particularly exact control.
In order to make possible controlled cooling and a controlled pressure drop in the resonant chamber, magnetic or solenoid valves provided in the outlet lines can be connected with the control device.
Finally, the interior of the resonant chamber and/or of the pressure hose of the seal can be connected with a compressor and/or a pressure accumulator, so that it is possible to apply pressure to the resonant chamber without waiting for the required amount of steam to be formed. This has the advantage that the corresponding temperature within the liquid proceeds without evaporation of the same, wherein energy can also be spared insofar as less water needs to be evaporated to build up pressure due to the pressure which is introduced externally. Moreover, the pressure can be stored in the resonant chamber and used for the next application of pressure to the pressure seal.
In order to prevent hot steam from flowing against the operating and display devices when the treatment chamber is opened, a nozzle strip or flat nozzle can be provided along one of the free edges of the charging opening at a housing which encloses the treatment chamber in conventional manner for blowing out the compressed air transversely or diagonally relative to the direction of the rising steam.
Therefore, when suitably outfitted and controlled, an installation which is generally constructed in this way can also be used as a standard autoclave.
In an advantageous process for pasteurization, disinfection/sterilization of dry, moist, or wet materials or materials in a moist environment or of liquids by means of the installation according to the invention, the materials to be treated can be introduced into a microwave-permeable, heat-resistant vessel, this vessel can then be inserted into the resonant chamber and, where appropriate, water is added to this vessel, whereupon the resonant chamber is closed in a pressure-tight manner and the resonant chamber is subsequently acted upon by microwaves and the materials located therein are heated to the desired temperature accompanied by an increase in pressure in the resonant chamber, wherein the output of the magnetrons is regulated by measuring the temperature of the steam flowing out of the materials and the temperature and pressure are maintained over the desired treatment period corresponding to a preselected model.
Since the total amount of water used for steam generation is in the vessel or in the material to be sterilized, there is no need for a water supply outside of the vessel in the pressure space or, therefore, for decalcified water, because any occurring residue remains on the materials to be sterilized and disinfected and is removed along with the latter. However, the material to be treated can also be introduced into a microwave-permeable vessel in the resonant chamber and the latter can be closed in a pressure-tight manner, whereupon the material to be treated is acted upon by microwaves, wherein the heating of the material and accordingly also the degree of drying is monitored by measuring the temperature of the steam flowing out of the material, and, as the case may be, the course of pressure is controlled over the treatment period corresponding to a preselected model via the output of the magnetrons. In this way, with a pressure-tight, pressure-resistant inner vessel, the high temperature need only be applied within the vessel, wherein the steam flowing off in the resonant chamber is again heated within the resonant chamber by the coupled in microwaves so that contamination of the resonant chamber is prevented. Further, after the vessel which is filled with liquid has been introduced and heated by means of the microwaves, the temperature and the pressure inside the vessel are monitored and the pressure in the resonant chamber outside the vessel is maintained identical to the pressure inside the vessel by means of a pressure source, wherein the material is gradually cooled by means of a gradual reduction in pressure within the resonant chamber. This prevents a boiling delay or other foaming over or escape of the contents of the vessel into the resonant chamber.
Finally, after the end of the sterilization/disinfection cycle and reduction of pressure in the resonant chamber to atmospheric pressure, vacuum pressure is applied to the resonant chamber and, along with it, the vessel interior, so that the disinfected or sterilized material is quickly dried and utilized further in this dry form.
An embodiment example of the subject matter of the invention is shown in the drawing.


In a multi-level memory cell, when data to be programmed arrives, the cell is programmed to the lowest-charge state in which any bit position that is being programmed or has already been programmed has the correct value, regardless of the value in that state of any bit position that has not yet been programmed and is not being programmed. The programming of other bit positions based on subsequently arriving data should not then require a transition to an impermissible lower energy state. Although this may result in a transient condition in which some bits have the wrong value, by the time programming is complete, all bits would be expected to have the correct value. A cell may contain any number of bits equal to or greater than two, and programming may be performed cyclically (e.g., from LSB to MSB), anticyclically (e.g., from MSB to LSB), or in any random order.

This invention relates to a method and system for writing data to a memory or storage device that stores multiple bits per cell, and particularly to a method and system for reducing latency in writing data to such a storage device.
As discussed in more detail below, flash memory cells (in particular, floating gate flash memory cells) store data by changing the number of electrons trapped on the floating gate. A memory cell may be programmed by inserting electrons onto the floating gate (e.g., via channel hot-electron programming or Fowler-Nordheim tunneling), and a memory cell may be erased by extracting electrons from the floating gate. Programming a cell corresponds to moving the cell from a lower state (e.g., an erase state) to a higher state. Programming can be addressed to individual flash cells within an array of cells, while erasing typically can be performed only on all cells in an array of memory cells. Thus, during flash programming, only state transitions from a lower state to a higher state are permitted. Transitions in the other direction are not permitted, because moving to a lower state would mean erasing not only the cell being programmed, but all cells in the array.
When a flash device is being used as multilevel cell (MLC) flash memory to store multiple bits per cell, the physics of the device, as described above, may limit the state transitions that are permitted without completely erasing the cell and therefore the array. In known methods for programming such memory cells, whenever data are received that require changing the value of a bit position, the memory state of the cell is changed in such a way that all other bit positions retain their previous values. However, in such techniques, depending on the order in which bits arrive, this may require an invalid state transition for programming of a subsequent bit position, causing an error condition or failure.
Alternatively, the cell may not be rewritten until data for all bit positions to be programmed arrive, so that the final state is known before any writing occurs. The resulting latency may be particularly acute if the different bits, as is frequently the case, belong to different logical data pages. According to another alternative, the encoded states may be mapped to a different set of states that do not result in invalid state transitions, but this also requires waiting for all memory pages to arrive, causing latency.

Method and system for programming multi-state memory


Apparatus for cleaning well bore tubulars comprises an ultrasound source suspended on a work string adapted to be run in the well, wherein the ultrasound source provides sufficient ultrasonic energy to remove scale or other undesirable debris or particles from, the well bore tubular.

This invention relates to the use of ultrasonics as a means of cleaning tubulars. The invention provides or an ultrasonic tool that finds one application in the cleaning of down-hole completions. Other applications include production pipelines, sewage pipes, power stations, process facilities, refineries etc.
Herein, references to scale should be construed broadly and other deposits, particles, debris or the like, including for example waxes, grease and ashphaltines, may be substituted as alternatives to this term.
The development of scale in down-hole completions is known to have detrimental implications for the economic prosperity and operating efficiency of a well. Specifically, the collection of scale on a well""s production tubing, casing and perforations serves to impose a constriction on the circulation and production flow paths, thereby limiting production capability. The full extent of the problem may be further realised in light of the additional costs associated with the removal of the scale, together with the loss of production while so doing.
Typically, scale may comprise strontium sulphate (notably a radioactive substance), barium sulphate, calcium carbonate and so on and may result from precipitation of fluids in the well or pipeline. For example, the formation of scale may result from these substances coming out of solution of the production fluid as it undergoes a pressure drop when, such as in an oil well, it passes from the oil reservoir into the well bore via perforations in the production casing. Furthermore, this may be exacerbated as a result of water flooding a reservoir using seawater. Seawater eventually xe2x80x9cbreaks throughxe2x80x9d to the production perforations resulting in the formation of other scales, typically barium sulphate.
The scale, while known to form in the production flow paths, often collects in areas that are difficult to clean or access, such as side pockets, production devices and the perforations in production casing.
In the past a number of alternative methods of removing or mitigating the effect of the formation of scale have been contemplated. In one case, the use of chemicals has been employed; the chemicals being adapted to inhibit the adherence of the scale deposits on the reservoir rock and well tubing. However, a disadvantage associated with this solution is that the chemicals only have a finite life and lose their effectiveness over time, necessitating regular re-application.
Another proposed method involves the use of chemicals in a remedial manner, namely to remove scale that has formed on the tubing. The chemicals, of this type, incorporate dissolving agents to attack the scale deposits. Unfortunately, these chemicals tend to be relatively expensive and slow acting.
Additional, both of the above types of chemicals can be detrimental to the surrounding environment, and usually involve the production or wastage of by-products arising from their manufacture or use, which may be abrasive in the well bore or harmful to the environment upon their disposal. Some of these chemicals are also hazardous to handle and, in this way, further undesirable.
Other methods of attacking or minimising scale involve physical means, but again, operations such as milling or grinding are slow, expensive and not entirely effective. Other physical operations involve bead blasting and have the aforementioned drawbacks with the added difficulty of handling the beads, both before and after use.
It may be seen therefore that until now there has been a lack of an effective or satisfactory system for scale removal in down-hole oil field applications that removes all scale, including the scale formed in remote or difficult areas such as side pockets or perforations, and which does not damage the tubular/cement/formation bond or have a waste by product of its own.
Another desirable attribute of a suitable means or agent for scale removal or prevention is that the means or agent should be deployed using standard running or well equipment.
In the present invention it is understood that the use of ultrasonics may provide an effective method for removing the scale or other matter such as wax or asphaltines.
Ultrasound is highly versatile and can be used in a broad range of applications from medical treatments to chemical transformations.
The effects of ultrasound are achieved by the formation of cavities in the medium through which the ultrasound is used. The formation of the cavities is as a result of the rarefaction of the medium and as a consequence bubbles are formed. Cavitation bubbles are created at sites of rarefaction as the liquid fractures or tears because of the negative pressure of the sound wave in the liquid. As the wave fronts pass, the cavitation bubbles oselate under the influence of positive pressure, eventually growing to an unstable size. Finally, the violent collapse of the cavitation bubbles results in implosions, which cause shock waves to be radiated from the sites of the collapse. The collapse and implosion of meriede cavitation bubbles throughout an ultrasonically activated liquid result in the effect commonly associated with ultrasonics. It has been calculated that temperatures in excess of 10,000 degrees fahrenheit and pressures in excess of 10,000 psi are generated at the implosion sites of cavitation bubbles.
British Patent GB 2 165 330A provides an example of the use of ultrasound as a cleaning system. This system relies on the focussing of the ultrasonic energy using a parabolic curve or a flat array in combination with a focusing means. However, this system would not be suitable for general cleaning operations that require precise focussing of the ultrasonic energy.
It is an object of the present invention to provide an ultrasonic tool that may be used in the cleaning of down-hole completions.
A further object of the invention is to provide an ultrasonic tool that is equally suitable for cleaning well casing, well liner or the well riser, irrespective of varying diameters.
A yet additional and desirable objective would be to provide an ultrasonic tool that, while capable of providing a cleaning function in a oil or gas drilling well, also had the capability of stimulating production by a process of mircofracturing rock formation so as to create additional flow paths in the producing zone. It is intended that the present invention meets this objective.
According to a first aspect or the present invention there is provided apparatus for cleaning tubulars, the apparatus comprising mechanical vibration means for creating acoustic waves, a high frequency current electrical source and a polarisation current source, wherein electrical current generated by the said sources is used to excite or activate the mechanical vibration means.
Preferably the mechanical vibration means is a submersible magnetostriction vibrator.
The apparatus is most typically suitable for cleaning well bore tubulars, and may further comprise an electric conductive wireline cable on which the acoustic vibrator is adapted to be run into the well, wherein the high frequency and polarisation electrical sources are adapted to be positioned at surface, and physically connected to the wireline cable for the conducting of electrical current to the vibrator.
Also according to the first aspect of the present invention there is provided apparatus for cleaning well bore tubulars, the apparatus comprising an ultrasound source suspended on a work string adapted to be run in the well, wherein the ultrasound source provides sufficient ultrasonic energy to remove scale or other undesirable debris or particles from the well bore tubular.
The ultrasound source may be a sonic horn or node. An alternative or additional ultrasound source may also be employed.
The work string may be wireline cable, drill pipe or coil tubing.
The apparatus may further comprise an insulator for preventing the diffusion of sonic energy in a direction up the work string to which the acoustic vibrator may be attached, in use.
The apparatus may further be provided with means for directing the ultrasonic energy; for example one or more nozzles may be incorporated onto the tool and associated with the ultrasound source for the purpose of directing the emitted energy.
Optionally, the apparatus comprises an ultrasound source comprising a body member having an internal profile adapted to manipulate fluid pressure therein. For this reason, the tool may advantageously be provided with a means for regulating the internal pressure. Such means may comprise one or more valves that co-operate to prevent relatively high pressures from migrating back up the tool string. The valves should be provided in sufficient quantity and positioned to enable such pressures to be distributed and to provide back-up in the event of partial failure.
Typically, the profile of the tool body would include convergent and divergent flow paths for the purpose or manipulating and increasing the fluid pressure.
Where, as is preferred, the ultrasound source is a magnetostriction vibrator it may comprise of two blended packages connected by a wave guide means, wherein the blended packages include cores to which excitation and polarisation windings are applied.
According to a second aspect to the present invention there is provided a method for cleaning a tubular, the tubular supporting or containing a fluid, the method comprising the steps of introducing an ultrasound source into the liquid within the tubular and activating same so as to provide ultrasonic energy from the source via the fluid in order to remove scale or other debris or particles from the tubular.
The method may comprise the steps of generating high energy fluid in the ultrasound source, thereby emitting ultrasonic energy from the source via the fluid in order to remove scale from the tubular.
The tubular may be provided in a oil or gas well bore, such as well casing, well liner or well riser. Therefore, the method may further comprise attaching the ultrasound source to a work string and lowering said work string into the well bore.
The method may also involve the adjustment of the output of the tool to achieve the required de-scaling without damaging the down-hole completion.
The method may further involve the recycling of dislodged material through the tool to assist the removal of scale.
Also according to the second aspect of the present invention there is provided a method for cleaning a well bore, the method comprising the steps of activating a submersible magnetostriction vibrator provided on a conductive wireline cable suspended in the well bore by means of surface modules adapted to generate appropriate electrical current to the magnetostriction vibrator via the wireline cable, wherein the said electrical current is converted by the magnetostriction vibrator into. mechanical vibrations adapted to generate ultrasonic energy, and wherein said ultrasonic energy is adapted to clean the well bore tubular.
Preferably also, the activation of the magnetostriction vibrator provides a combined acoustic-thermal effect on the well and any oil therein.
Preferably also, the method comprises a means of cleaning the pores or passageways in the oil bearing layer of the well bore formation.
Preferably also, the method comprises the process of thinning oil in the vicinity of the ultrasound source.

Ultrasonic cleanout tool and method of use thereof


An air conditioner is provided of the type having an indoor section, which includes a housing, evaporator coil and an indoor grille adapted to be mounted to the housing in spaced relation to the evaporator coil. The grille includes a front wall having a return opening therein to admit return air to be conditioned into the evaporator coil. The front wall also has an elongated opening adjacent to an edge thereof, which is adapted to receive a filter for insertion and removal of the filter into the space between the back wall of the indoor grille and the evaporator coil. The filter includes a rectangular frame having a leading edge and a trailing edge and laterally spaced edges interconnecting the leading and trailing edges. A filter guide structure is integrally formed with the grille and is adapted to receive the leading edge of the filter with the filter frame angularly disposed with respect to the front wall and for directing the rectangular frame into the space between the back wall of the indoor grille and the evaporator coil without contacting the evaporator coil. In a preferred embodiment, the trailing edge defines an ornamental outer wall similar in configuration to the structure defining the return air openings in the front wall of the grille. Structure is provided on the ornamental outer wall and the filter guide structure for supporting and positioning the outer wall with respect to the outer grille structure.

The present invention relates to air conditioners and, more particularly, to an arrangement for facilitating the installation of a filter in the indoor grille of a room air conditioner.
Room air conditioners typically have an indoor section and an outdoor section. The indoor section is responsible for cooling and dehumidifying the interior of a room while the outdoor section is responsible for exhausting heat into the outdoor environment. The indoor and outdoor sections each have a heat exchanger coil and a fan, and each has a return air opening and a discharge opening. A grille structure is normally installed over each section to prevent the entry of foreign objects, while allowing the free-flow of air to and from the sections as well as for aesthetic considerations.
It is common practice to have associated with the indoor grille structure a filter element, through which the indoor air passing to the indoor coil must pass. Such a filter is designed to remove substantially smaller contaminants from the air than the indoor grille. Quite often the indoor grille must be removed from the air conditioner in order to gain access to the filter. Other air conditioners are known which have a rectangularly shaped reusable filter, which slides into a slot oriented above the grille such that the filter may be installed or withdrawn from a location behind the grille and in front of the evaporator coil by vertically displacing the filter within the slot.
It is also known to provide a filter assembly, which is provided with moveable guides which receive the filter and prevent the filter assembly from contacting and possibly damaging the fragile heat exchange fins of the evaporator coil as the filter is installed and removed from its mounting in an indoor grille.
It is deemed desirable to have a structure which is formed integrally with the indoor grille which facilitates easy insertion and removal of the indoor grille and which provides positioning and support of the filter assembly in a spaced relationship with the evaporator coil.

Air filter inlet and positioning guide for an air conditioner


A method and tool for producing bipolar plates having liquid channels and gas channels, and having sealing elements made of polymer material for fuel cells. The bipolar plates are stamped, i.e., liquid and gas channels are impressed into the bipolar plates, and sealing elements are applied to the bipolar plates in one tool in two steps directly following each other.

Electrochemical fuels cells are gaining increasing importance. They are made essentially of two separating plates, so-called bipolar plates, between which an ion-exchange membrane is arranged. The plates are provided with channels for gases and liquids, and are produced predominantly of graphite or metal. The manufacturing methods for their production are relatively costly, since a high degree of imperviousness is required when assembling the plates, so that the reaction and cooling media remain separated from each other during the operation of the fuel cell.
The PCT Application WO 93/06627 deals with the assembly of a fuel cell in detail. The separating plates are made of graphite. However, the publication gives no more precise information as to how these separating plates were manufactured. There is also no detailed information with respect to the seals between the individual gas-containing and liquid-containing channels; the publication merely mentions that the periphery of the individual plates is provided with a seal.
In the European Patent Application EP 0 604 683, reference is made to a method, customary until now, for producing a fuel cell, in which separating plates made of graphite are employed and a sealing material made of silicon, rubber or extrudable, elastomeric material is suggested. The sealing material is injected into the mechanically introduced grooves of the separating plate before the plates are assembled. However, this publication provides little further information concerning the injection process.
It is generally known to produce the separating plates and the seals separately, and in a subsequent step, to cement the seals individually into place in the preselected grooves of the separating plates. This process is time-consuming, difficult to control, and involves the danger of production errors. To avoid this, it has already been suggested (see European Patent Application EP 0 774 794) to produce the separating plate from a flexible, plastically deformable material and to provide it with integrated elevations which, at the same time, can be used as seals. Such plates can be produced in an embossing process, it being necessary that the embossing die utilized have suitable elevations for forming the gas and liquid channels and suitable depressions for forming the sealing arrangement. It may be that, in this case, the separating plate and the seal are produced in one work operation, however, with the disadvantage that both are made of the same material and thus are restricted in their sealing function.
The object of the present invention is to develop a method and a tool for creating bipolar plates, the method being simple to implement and allowing quick and reliable bonding of the seal to the bipolar plate. Consequently, simple and rapid assembly of the fuel cell should also be made possible. The method is intended to be usable both for bipolar plates made of super-refined steel plate and those made of graphite.
The objective is achieved according to the invention in a method for producing bipolar plates having liquid channels and gas channels and having sealing elements of polymer material for fuels cells, in that the bipolar plates are stamped, i.e., the liquid and gas channels are impressed into the bipolar plates, and the sealing elements are applied to the bipolar plates in one tool with two steps immediately following each other. Therefore, a tool is employed which is used both for imprinting the channels and the grooves, as well as for applying the sealing elements.
According to this method, it is possible to injection-mold the sealing elements onto the bipolar plates. However, it is also possible to join the sealing elements to the bipolar plates in the pressing process. The attachment of the sealing elements to the locations on the bipolar plates provided for that purpose can be carried out directly on the even surfaces of the bipolar plates. However, it is beneficial to provide the bipolar plates with grooves for the sealing elements. If the bipolar plates are to be furnished with grooves for the sealing elements, it is advantageous if the mutually opposing grooves are applied in a manner that they are laterally offset relative to each other. In this manner, a counterpressure can very conveniently be built up when introducing or securing the sealing elements in the groove. However, this does not rule out that the mutually opposing grooves on both sides of a bipolar plate can be applied in alignment relative to each other.
Also provided is a tool for implementing the method. This tool is designed as a combined embossing die and injection-molding die or compression molding die. The tool is used first to carry out the stamping process, for which there are two possibilities. In the event that the bipolar plate is made of a super-refined steel plate, the appropriate channels and grooves are impressed into the flat sheet. In the case of bipolar plates made of graphite, the graphite material is subjected to a compression process and the appropriate channels and grooves are produced during this process. In the areas corresponding to the groove areas provided on the bipolar plates, the tool is furnished with separate dies stamps which, after the embossing process, clear the space for the seal to be introduced. If the injection-molding process is provided, the dies are only pulled back to the point that they clear the space needed for the seal. Thus, they represent the delimitation for the sealing surface of the sealing element. It is also possible to use dies, inserted into the tool, which are removed before the injection molding. After the injection-molding process is completed, the tool is opened and the plate, provided with the seals, is removed.
However, it is also possible to utilize the dies for the stamping process and for a pressing process. In this case, the tool is first used to produce the bipolar plate with the suitable channels and grooves. The dies are then completely drawn back out of the tool and a pre-fabricated seal blank is inserted in the resulting space into the grooves. The dies thereupon travel back again and press the seal against the bipolar plate. When working with seals made of elastomers or silicon, the process can be supported by supplying heat, making it possible to carry out a hot vulcanization process. In the case of seals made of thermoplastically workable materials, the hardening is effected by solidification after the withdrawal of heat. Another alternative is that the groove dies are separate dies which are removed after the stamping process. After that, the seal blank is inserted into the grooves and compression molding is carried out by closing the mold.
To avoid damaging the plates at the high pressures which occur particularly during the pressing process, it is beneficial if the mutually opposing dies of the tool are actuated in succession over time for the injection process. In this manner, the seal can first be applied on one side of the plate, while from the other side, the die remaining in its original position exerts a counterpressure on the bipolar plate. After the seals are applied on the one side of the plate, the dies of the opposite side are retracted and the sealing elements are introduced. During this process, the dies of the first side remain in normal position and are used as an abutment. This method can be used both for bipolar plates which have grooves lying opposite each other on both sides in alignment, as well as for plates in which the opposite grooves are applied in a manner that they are laterally offset relative to each other.

Method and tool for producing bipolar plates


Shield apparatus for portable wireless telephones or personal communication apparatus includes electromagnetic radio frequency radiation absorption and blocking materials disposed about the antenna and any other electromagnetic transmitting portion of the wireless portable telephone or personal communication apparatus adjacent to, or in the direction of, the user of the wireless communication apparatus. The absorption and blocking or shield area absorbs and blocks the radiation and protects the user from the radiation, and metallic elements redirect the electromagnetic radiation away from the user and extend the transmission range of the communication apparatus. The portion of the antenna remote from the user is free or open, and thus permeable to the electromagnetic radiation, typically in the microwave frequency band, so that the communication signal may be appropriately transmitted from the wireless portable telephone or personal communication apparatus, and may be received by the hand held portable telephone or personal communication apparatus.

1. Field of the Invention
This invention relates to portable telephone and other personal communication apparatus and, more particularly, to protective shield apparatus for absorbing microwave energy to protect a user of the portable telephone and personal communication apparatus from the electromagnetic microwave frequency radiation emanating from such apparatus and to extend the transmission range of such apparatus by redirecting the microwave radiation away from the user of the apparatus.
2. Description of the Prior Art
There have been a number of contemporary inquiries regarding the safety of portable telephones and, more particularly, cellular telephones and wireless communication devices, with respect to the potential danger to the user from electromagnetic microwave radiation associated with the transmission of the signals from such apparatus. Contemporary inquiries are investigating the possibilities that the radiation may cause cancer or create other health risks or hazards to the user in association with the use of such apparatus. In response thereto, the apparatus of the present invention utilizes electromagnetic radiation absorbing materials disposed about the antenna and portable wireless transmitting apparatus and between the user and the antenna and transmitting apparatus to shield or protect the user from the potentially harmful radiation emissions from the wireless communication apparatus, and to extend the transmission range of such apparatus by redirecting the microwave radiation away from the user of the apparatus.
Typically, the broadcast from the portable telephones and wireless communication apparatus emit electromagnetic radiation in the microwave frequency range. The shield apparatus of the present invention is disposed primarily about the antenna and transmitting apparatus both inside and outside of the portable telephone and wireless communication apparatus itself.

Shield apparatus for absorbing microwave energy for hand held telephones