It is believed that rheumatoid arthritis and related collagen and auto-immune diseases are an infection and that various species of free-living (limax) amoebae are the aetiological agent of these diseases. It has been discovered that tinidazole and related compounds, antimycotic drugs with anti-protozoal activity, are effective for the treatment of rheumatoid arthritis and other collagen and auto-immune (rheumatoid) diseases.

Men and other animals are continually exposed to infection and re-infection by various species and strains of free-living limax amoebae which can be detected in the faeces, nasopharynx and bronchi. In all parts of the world they form part of the environment. Experimentally in animals they induce changes like those of collagen and auto-immune diseases and are characterized by vasculitis, myosotis, hepatitis, pyelitis and spelenomegaly. They can often be seen in the tissues of animals. Such animals shown lymphadenopathy with an appearance like that of human Hodgkin's disease or a state like that of advanced malignant disease. These organisms may also be recovered from all the tissues of cases of collagen and auto-immune diseases and from human and many animal tumors and may also occur in the tissues of apparently healthy individuals. They cannot be identified in ordinary histological sections, but can be demonstrated by immunofluorescent methods.
The definite cause of rheumatoid arthritis is presently unknown. Rheumatoid arthritis is a crippling disease, characterized by the inflammation of several joints of the body, with swelling, pain and stiffness. Rheumatoid arthritis is a disorder that afflicts about fifteen million people in the Western World alone. Successful early treatment may avert the destructive, deforming phase of the disease. Therapy has been directed largely at non-specific suppression of inflammatory and immunoligic processes. Aspirin is the cornerstone of therapy for rheumatoid arthritis and can reduce synovial inflammation, improve function and reduce pain in a majority of patients in view of its analgesic action. Widespread interest in rheumatoid arthritis arose when Hench (1949) introduced the use of cortisone in treatment. Chemical compounds which have been commonly used in treating rheumatoid arthritis are corticosteroids, gold salts, antimalarial drugs, immunosuppressive agents and a whole range of so-called non-steroidal drugs, e.g. indomethacin, phenylacetic acid (Ibuprofen), propionic acid (Naproxen) and D-Penicillamine. Most of these drugs bring temporary relief to the arthritic patient but present the danger of side effects and the physician has to balance the potential benefit against the risks. However, arthritis reoccurs following withdrawal of such chemical treatment. For many years rheumatoid arthritis was considered to be an infection (Hollander et al., 1960; Robinson, 1967), but with the advent of the concept of auto-immunity this idea lost favor. Such a view has recently been revived (Lancet, 1970, 2, 303) and is supported by many observations. It is highly likely that the limax amoebae, found in all the collagen and auto-immune diseases, may well be the aetiological agent of these conditions and that anti-protozoal drugs may help by their action on these organisms.
The use of a bis-phenyl (2-halophenyl)-1-imidazolylmethane and clotrimazole for treatment of Rheumatoid Arthritis is disclosed in my U.S. patent application Ser. No. 700,914 filed June 29, 1976. It has also been suggested to use a nitroimidazole in the treatment of rheumatoid arthritis in the Journal of Tropical Medicine and Hygiene (vol. 75) pgs. 64 to 66 March 1972. It is believed that the nitro group in the imidazole ring is related to metronidiazole which is not effective in the treatment of rheumatoid arthritis.
Tinidazole and related compounds for use as antiprotozal agents is disclosed in a number of articles such as pages 257 to 259 of Antimicrobial Agents and Chemotheraphy-1969 (copyright 1970 American Society for Microbiology (Miller, Howes & English) & Current Medical Research and Opinion, vol. 2, No. 3, pages 178 to 179 (article entitled "Single-dose treatment of vaginal trichomoniasis with tinidazole (`Fasigyn`)" by Thavabalan and Oriel)
It has been found that certain imidazole compounds which have antiprotozoal activity are effective when administered internally for treating rheumatoid arthritis and related collagen and auto-immune (rheumatoid) diseases. Of this group compounds, tinidazole has proven most effective. This compound has the following chemical structural formula: ##STR1##
Various other anti-protozoal drugs were tried on the cases of rheumatoid disease or of various localized manifestations of this. The substances investigated were 4-aminoquinolines (chloroquine), hydroxychloroquine (plaquenil), amodiaquine (camoquin); copper sulphate; bile salts (dehydrocholine), which are effective in killing the trophozooites of many amoebae in the concentration found in the small intestine; and clotrimazole (canesten). All of these were actually shown experimentally to kill limax amoebae. In addition, other anti-protozoal drugs were also investigated. They included suramin, pentamidine, dehydro-emetine (DHE or mebadin), metronidiazole (flagyl), nitroimidazole (naxogin (Ergba)), phanquone (entobex) and diloxanide (furamide).
The 4-aminoquinolines were given by mouth in a dose of 200 and 400 mg. daily, reduced after a month to 200 mg. twice weekly, care being taken to examine the eyes at intervals to guard against keratitis or macular changes. Copper salts were administered as 25 mg. of copper sulfate in aqua chloroformi by mouth three times daily. This may produce vomiting and/or diarrhea and the dose has to be decreased to 10 mg. three times daily. Only a small amount of the metal is absorbed, however, and no other side effects are observed even when taken over several months. Bile salts as dehydrocholine were given in a dose of 500-1000 mg. three times a day by mouth. They may produce mild colic. This may be prevented by simultaneous administration of a kaolin mixture. Pentamidine was at first given by intramuscular injection into the buttock in doses of 200 mg. daily for 10 days. The course was repeated twice with intervals of 7 days between. This substance is liable to produce local necrosis or abscess formation. Pentamidine can be given by mouth, but tis absorption is uncertain. Moreover, it may produce nausea, vomiting and diarrhea. However, many patients tolerate it by this route. Capsules containing 200 mg. were especially made and a dose of 200 mg. twice daily to 400 mg. three times daily by mouth were tried in various combinations. Suramin was given by intravenous injection of 500 mg. in 10 ml. of water and after this every 4 days 1 G was injected until 10 G had been given. The course was repeated once after 4 months. Dehydro-emetine(DHE) was given by intramuscular injection in doses of 60 mg. daily for 10 days and repeated after 7 days, or 60 mg. three times daily by mouth for 7-12 days, repeated after an interval of 10 days. Before commencing treatment E.C.G.'s were taken and repeated before each successive injection. Metronidiazole (flagyl) was given in doses of 400-600 mg. three times daily by mouth and nitromidazole (naxogin) in doses of 75 mg. three times daily. Phanquone (entobex) was given in doses of 100 mg. twice daily by mouth for 7 days, repeated at intervals of a week, Diloxanide (furamide) was given in doses of 500 mg. three times daily for 10 days and repeated once.
The various substances tested above were tried on cases of rheumatoid arthritis of varying severity, systemic lupus erythematosus, dermatomyositis and other manifestations of collagen and auto-immune disease and observations made on the clinical condition, oedema, morning stiffness, E.S.R., plasma proteins, RF, ANF and organ-specific antibodies in the serum. No attempt at a double-blind trial was made as it became obvious, fairly early or even the day after commencing treatment, whether beneficial effect was obtained and furthermore, symptomatic improvement is associated with improvement or disappearance of the abnormal blood changes, indicating that the drug was effective and improvement not due to suggestion. No beneficial effect was obtained from flagyl, naxogin, entobex, suramin or furamide in the doses used. However, Abd-Rabbo et al. (1972), using a derivative of nitro-imidazole (naxogin), BT 985 Merck A.G., which is active against amoebae, giardia and trichomonas, obtained beneficial effects in one case of systemic lupus erythematosus and nine of ten cases of rheumatoid disease. The drug was given in doses of 250 mg. daily for 14-39 days. In the follow-up period of 3-6 months no treatment was given and it was noted that the pain recurred, yet not to the same degree as before medication.
Tinidazole is an antimycotic drug, synthesized by Pfizer Medical Research Laboratories, Groton, Conn. (pgs. 257-260, Antimicrobial Agents and Chemotheray-1969) and known as "Fasigyn". It is chemically ethyl [2-(2-methyl 5-nitro-1-imidazolyl) ethyl] sulfone. It has been successfully used in the treatment of a number of protozoal diseases, such as amoebiasis, giardiasis and trichomonas infections.
The method of determining the anti-protozoal activity of drugs on limax amoebae was described by Fulton, C. Methods in Cell Biology (edited by D. M. Prescott), p. 341, New York, 1970 and followed by Jamieson and Anderson in Lancet, 1974, 1, 261. All experiments were preformed using 5-day-old 5 ml. cultures of amoebae in the axenic medium "A" of Fulton. A standard inoculum of 100 c.mm. of differing concentrations of amoebae was added to each 1 ml. tube containing the dilutions of the compound to be tested (disolved initially in dimethyl sulfoxide) or other drugs in the axenic medium. The tubes were incubated for 5 days and 37 C. and the final concentration per c.mm. was compared with the initial count to determine percentage kill.
It has now been found that rheumatoid arthritis can be effectively treated with compounds having antiprotozoal activity of the formula: ##STR2## wherein R & R' are each alkylene having 1 to 7 carbon atoms and X is a lower alkylsulfonyl and the pharmaceutically acceptable acid addition salts thereof. Particularly effective compounds are those wherein R' is methylene. These compounds and their preparation, are disclosed in U.S. Pat. No. 3,376,311 issue Apr. 2, 1966 to Kenneth Butler. Typical of these compounds are:
1-(2-ethylsulfonylethyl)-5-nitroimidazole PA1 1-(2-ethylsulfonylethyl)-2-methyl-5-nitroimidazole PA1 1-(2-propylsulfonylethyl)-2-methylnitroimidazole PA1 1-(2-methylsulfonylethyl)-2-methyl-5-nitroimidazole PA1 1-(2-isopropylsulfonylethyl)-2-methyl-5-nitroimidazole
The salts of such N-trityl-imidazoles are the pharmaceutically acceptable non-toxic acid addition salts. Examples of suitable acids are the hydrohalic acids (hydrochloric being particularly preferred), phosphoric acid, mono-and bi-functional carboxylic acids, such as acetic acid, propionic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid, lactic acid and 1.5-napththalene- disulphonic acid. The hydrohalides, especially the hydrochlorides, lactates and salicylates are of particular value.
The diagnosis of active rheumatoid arthritis in 25 cases, was consistent with the criteria of the American Rheumatism Association. The patients were not hospitalized or confined to bed. They continued to take the drugs they were being treated with when first seen. Serial investigations were carried out before and repeatedly during and after treatment. Tinidazole was administered orally in a dosage of four tablets of 500 mg. each once per week for ten weeks (approximately 35 mg. per kilogram of body weight) suitable doses range from about 20 to 50 mg. per kilogram of body weight. With this dosage of the drug beginning 24-36 hours after taking it there almost invariably occurs an exacerbation of the active inflammatory changes in the affected joints with increased heat, pain and swelling and other parts of the body not previously affected may also be involved with generalized malaise and often sweating. This may last for 2-3 days and then disappear with general improvement in the patients symptoms. With successive doses this reaction become less and finally disappears and as the course of treatment progresses the signs of active rheumatoid disease also disappear. Steroid and other treatments may then be tapered off. This response constitutes an Herxheimer reaction and its occurrence with Tinidazole, an antimycotic and antiprotozoal drug, indicates with certainty the presence in the affected tissues of an organism which is acted on by Tinidazole. This reaction does not occur when the drug is used in the treatment of amoebic dysentery or trichomonas infection. In order to obviate this reaction in later cases the dosage of Tinidazole was altered and reduced to 2 (500 mg.) tablets (1G) on alternate days. This dosage avoided the above reaction and was continued for 10 weeks with similar results to those obtained using the original manner of administration. By neither method is there reversal of bone or cartilage changes already present when treatment was begun. Tinidazole was administered to 10 males and 15 females, their ages ranging from 24-64 years. Symptoms had been present for 23 months to 33 years. Patients have been followed for 6-9 months without evidence of recurrence of activity of the disease and with return of the sedimentation rate to normal. The drug thus eventually completely reversed all the manifestations of activity in rheumatoid disease when other drugs had failed. In larger doses it may cause an Herxheimer response indicating the existence in the lesions of rheumatoid disease of an organism, presumably a protozoan, affected by the drug. It caused no other side effects except occasional pruritus when alcohol was taken.
The therapeutically effective compound can be used either as such or in combination with pharmaceutically acceptable carriers. Suitable forms of administration in combination with various inert carriers are tablets, capsules, powders, aqueous suspensions, syrups and the like. In the aforesaid case, the therapeutically active compound should be present in the total mixture at a concentration of about 0.5 to 90 percent by weight, i.e., in quantities which suffice to attain the range of dosage mentioned above. Tablets may also contain fillers such as starch, avicel, lactose, calcium carbonate or dicalcium phosphate together with various additives such as dyes and binders such as polyvinylpyrrolidine, methylcellulose, gelatin and the like. It is further required to add lubricants such as magnesium stearate, sodium lauryl-sulphate and talc for producing tablets. Tablets may be filmcoated.

Treatment of rheumatoid arthritis and related diseases


Compositions comprising lycopene, Serenoa repens, Pygeum africanum, and Urtica dioica are provided. The compositions are preferably formulated with an alcohol extract of the dried, cut plant parts. Methods of using such compositions for treating various conditions and diseases, including benign prostatic hypertrophy and prostate cancer are also provided.

1. Field of the Invention
The invention relates to a method and composition for the treatment and alleviation of symptoms of benign prostatic hypertrophy (BPH) and prevention of prostate cancer.
2. Discussion of Related Art
Prostate cancer is a leading cause of death among men. The American Cancer Society estimates that about 180,400 men will be diagnosed with prostate cancer during 2000. An estimated 31,900 men will die in the year 2000, making prostate cancer the second leading cause of cancer death in men in the United States. Eighty-nine percent of men with prostate cancer live at least five years, and 63% survive at least 10 years. However, if the cancer is found before it has spread outside the prostate, the five year relative survival rate is 100%. If the cancer has spread to tissue near the prostate, the survival rate is 94%. If the cancer has spread to distant parts of the body when it is found, only about 31% will live at least five years.
Studies have shown a correlation between BPH and prostate cancer. Physicians have used the prostate specific antigen (PSA) blood test to test their patients for prostate cancer. The PSA blood test measures the prostate specific antigen made by prostate cells. PSA blood test results are reported as ng/ml. Results under 4 ng/ml are usually considered normal. Results over 10 ng/ml are high and values between 4-10 ng/ml are considered borderline. Conditions such as BPH and inflammation of the prostate (prostatis) can cause high PSA values. In one study to determine the correlation between BPH and prostate cancer, Perrin et al., state that an increase in serum levels of PSA correlates with similar increased levels of PSA in prostate cancers [Perrin P, Francois O, Maquet J H, Bringeon G, Duteil P, Devonec M, (1991) Presse Med 20(28):1313-1319]. Another study states that urethra blockage caused by BPH is responsible for cysts observed in prostate cancer [Harvey, H, (1995) Pathol Res Prac 191(9):924-934]. Therefore, studies support the proposition that treatments to reduce BPH will also reduce the incidence of prostate cancer.
Some of the most common symptoms of BPH include: 1) a need to urinate often (especially disturbing at night); 2) a weak or interrupted urinary stream; 3) a feeling that you cannot empty your bladder completely; 4) a feeling of delay or hesitation when you start to urinate; 5) a feeling that you must urinate right away; and 6) continuing pain in the lower back, pelvis or upper thighs. These symptoms are caused by the way in which BPH affects the urethra and, later, the bladder. If a urinary tract infection develops, there may also be burning or pain during urination. In the early phase of prostatic enlargement, the bladder muscle has to force urine through the narrowed urethra by contracting more forcefully. Over a period of time, the forcing causes the bladder muscle to become stronger, thicker, and overly sensitive. In some cases, as prostate enlargement progresses and the urethra is squeezed more tightly, the bladder cannot overcome the problems created by the greatly narrowed urethra. If this happens, the bladder can not empty completely. This situation creates a need to urinate more frequently. In a small percentage of men, incomplete emptying of the bladder may lead to repeated urinary track infections, sudden inability to urinate, or gradual bladder and/or kidney damage. An enlarged prostate can even result in total blockage of the urethra, a very serious condition.
Symptoms of advanced prostate cancer include: 1) having trouble having or keeping an erection; 2) blood in the urine; 3) swollen lymph nodes in the groin area; and 4) pain in the pelvis, spine, hips, or ribs. Known risk factors for prostate cancers include age, family history, diet and race. After the age of 50, both incidence and mortality from a prostate cancer increase at a nearly exponential rate. For example, more than 75% of all cancers are diagnosed in men over the age of 65. Kupelian et al., have shown that the younger age of an onset of the disease is associated with family history of prostate cancer [Kupelian P A, Klein E A, Witte J S, Kupelian V A, Suh J H, (1997) J of Urol 158(6):2197-2201]. Their studies showed that 18% of patients under age of 65 at the onset of the disease have a positive family history, compared to 6% of those diagnosed with the disease over age 65. Carter et al., showed that the risk of developing the disease increases with the number of affected first-degree relatives [Carter B S, Beaty T H, Steinberg G D, Childs B, Walsh P C, (1992) Proc Natl Academy Science USA 89:3367-3371]. Family history also suggests that a high penetrant allele is responsible for this inherited form of prostate cancer [Carter et al., supra; Walsh P C, Partin A W, (1997) Cancer 80:1871-74; Cooney K A, McCarthy J D, Lange E, Huang L, Miesfeldt S, Montie J E, Oesterling J E, Sandier H M, Lange K, (1997) Natl Cancer Inst 89:955-959]. Moreover, the inherited high penetrant allele suggests an explanation for the higher incidence of prostate cancer among African Americans, compared to other race groups. Prostate cancer is about twice as common among African-American men as it is among white American men. Increased incidence of the disease also exists in North America and northwestern Europe, but the incidence is very low in Asian countries, such as China and Japan, and in Central and South America. A diet high in fat may also play a part in causing prostate cancer.
Recent studies have shown that DNA mutations in certain genes may predispose persons to the disease. One candidate gene, Hereditary Prostate Cancer Gene 1 (HPC1), is situated on the long arm of chromosome 1 [Smith J R, Freije D, Carpten J D, Gronberg H, Xu J, Isaacs S D, Brownstein M J, Bova G S, Guo H, Bujnovszky P, Nusskern D R, Damber J E, Bergh A, Emanueisson M, Kallioniemi O P, Walker-Daniels J, Bailey-Wilson J E, Beaty T H, Meyers D A, Walsh P C, Collins F S, Trent J M, Isaacs W, (1996) Science 274:1371-1374]. This gene has been shown to contribute to prostate cancer [Smith et al., supra; Gronberg H, Smith J, Emanuelsson M, Jonsson B A, Bergh A, Carpten J, Isaacs W, Xu J, Meyers D, Trent J, Damber J E, (1999) Am J of Hum Genet 65(1):134-140]. Another candidate gene is PTEN, a putative protein tyrosine phosphatase. Mutations of PTEN have been detected in various cancer cell lines, including prostate cancer cells lines [Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang S I, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner S H, Giovanella B C, Ittmann M, Tycko B, Hibshoosh H, Wigler M H, Parsons R, (1997) Science 275:1943-1947]. Research on HPC1, PTEN, and related genes, is still preliminary and genetic tests and are not known to be available. Therefore, in the absence of a genetic test, early detection, treatment and prevention are the best therapies for prostate cancer.
There is also evidence that the development of prostate cancer is linked to increased levels of hormones, or androgens. Androgens are known to be important in promoting the growth of both normal and cancerous prostate cells. The Prostate Cancer Prevention Trial is a study (currently underway) to determine whether medications to lower androgen levels can reduce prostate cancer. Previous studies have shown that high levels of androgens, more specifically testosterone and conversion of its more active metabolite dihydrotestosterone (DHT), stimulate BPH. BPH is considered to be normal after the age of 45, however, it becomes problematic when the benign tumor begins to obstruct sections of the urethra and interferes with normal urinary discharge.
The use of herbal medicines to treat cancers is an alternative method of treatment. Certain herbal medications tend to have an affinity for particular tumor types and can therefore be selected based on their specific indications. It is estimated that approximately 50 percent of the thousands of drugs commonly used and prescribed today are either derived from a plant source or contain chemical imitations of a plant compound [Mindell, E., Earl Mindell""s Herb Bible, A Fireside Book (1992)]. Currently, a number of medicinal formulations contain herbal components or extracts from herbs. Many chemotherapeutic agents such as taxol and vincrinstine are derivatives of botanical or herbal medicines that have successfully treated cancers.
In Europe the use of herbal supplements comprising Serenoa repens (saw palmetto) to treat BPH and prostatic cancer is widespread. Serenoa repens is a small shrubby palm tree found in the southeastern coastal United States. A recent review of studies completed by Harvard researchers concluded that saw palmetto extract was effective as Proscar(copyright) in the treatment of BPH. Many studies have reported Serenoa repens acts as a major inhibitor of 5-alpha-reductase [Bayne C W, Donnelly F, Ross M, Habib F K, (1999) Prostate 40(4):232-241; Wilt T J, Ishani A, Stark G, MacDonald R, Lau J, Muirow C, (1998) JAMA 280(18):1604-1609; Delos S, Carsol J L, Ghazarossian E, Raynaud J P, Martin P M, (1995) J Steroid Biochem Mol Biol 55(3-4):375-383; Schroder F, (1994) Clin Endocrinol 41(2):139-147]. 5-alpha-reductase is an enzyme which cleaves testosterone to form 5-alpha-dihydrotestosterone, or DHT. DHT levels in BPH are significantly higher compared to controls. In a recent study, Bayne et al., (supra) showed that a commercial form of Serenoa repens, Permixon, was an effective inhibitor of 5-alpha-reductase. This study supports a previous study by Delos et al., (supra) which showed that Serenoa repens (Permixon) alone was able to inhibit 5-alpha-reductase activities in both normal primary cultures of epithelial cells and in fibroblasts separated from BPH and prostate cancer tissues. Furthermore, the Bayne et al. study showed that the activity of Serenoa repens does not influence the secretion of prostate specific antigen (PSA), permitting the continued use of PSA blood measurements for prostate cancer screening. Additionally, treatments of BPH with Serenoa repens in Europe are documented to be well tolerated and appear to have few, if any, significant adverse side effects [Wilt et al., supra].
Many studies have also shown that increased beta-carotenoids reduce the incidences of BPH and prostate cancer. These studies also support the proposition that treatments to reduce BPH will also reduce the incidence of prostate cancer. [Gann P H, Ma J, Giovannucci E, Willett W, Sacks F M, Hennekens C H, Stampfer M J, (1999) Cancer Res 59(6):1225-1230; Giovannucci E, (1999) J Natl Cancer Inst 91(4):317-331; Rao A V, Fleshner N, Agarwal S, (1999) Nutr Cancer 33(2):159-164; Pastori M, Pfander H, Boscoboinik D, Azzi A, (1998) Biochem Biophys Res Commun 250(3):582-585]. Carotenoids are naturally-occurring compounds found abundantly in many plants including tomatoes and tomato products. The major carotenoids are beta-carotene, alpha-carotene, lutein, zeaxanthin, cryptoxanthis, and lycopene. Many studies show that of the major carotenoids, lycopene is the most effective and significant in quenching free oxygen radicals [Gann et al., (supra); Rao et al., (supra); Pastori, et al., (supra); Giovannucci, et al., (supra)]. Free radicals are thought to be involved in the process of many human diseases. Although they may not singly cause the disease, free radicals may predispose conditions for occurrences of such diseases. Free radicals are produced as normal by-products of metabolic processes. They can also originate from environmental pollutants such as nitrogen dioxide, heavy metals, ionizing radiation, and cigarette smoke. They are highly reactive and can damage the structure and functions of cell membranes, nucleic acids and proteins. These damages can result in cell death and mutations of cells, potentially leading to a cancer type situation. Treatment with lycopene, an antioxidant, will reduce free oxygen radicals and therefore reduce BPH, to prevent prostate cancer.
Men with BPH suffer a variety of micturitional disorders, as discussed above. When prostatic tissue becomes enlarged and inflamed there is increased pressure on the urethra, causing micturition dysfunction such as weak or interrupted urine discharge. An herbal supplement from a tree called Pygeum africanum has been shown to alleviate many of these symptoms and restore function, as compared to a control group [Barlet A, Albrecht J, Aubert A, Fischer M, Grof F, Grothuesmann H G, Masson J C, Mazeman E, Mermon R, Reichelt H, (1990) Wien Klin Wochenschr 22:667-673; Carani C, Salvioli V, Scuteri A, Borelli A, Baidini A, Granata A R, Marrama P, (1991) Arch Ital Urol Nefrol Androl 63:341-345]. Pygeum africanum contains three groups of active lipid-soluble substances: phystosterols, pentacyclic triterpenoids and ferulic esters of fatty acid alcohols. Physterols, particularly, beta-isoterols have been shown to reduce elevated levels of prostaglandins in those suffering from BPH. Reduction in prostaglandins helps to reduce the size of prostate adenomas. The triterpenoids are effective anti edema agents. Lastly, the ferulic esters of fatty acid alcohols help to inhibit the absorption and metabolism of cholesterol. Levels of cholesterol in men suffering from BPH is higher as compared to levels from normal healthy individuals. Additionally, treatments using both Pygeum africanum and Serenoa repens have been documented in the literature, but each may have different mechanisms of action.
Another symptom of BPH is increased fluid retention. To alleviate this symptom, Urtica dioica (common stinging nettle) has been used in the herbal treatment of BPH and prostate cancer. Utica dioica has diuretic properties which make it useful for treatment [Varro, T. Herbs of Choice, (1994) Pharmaceutical Press]. Also, Urtica dioica produces a lectin which to binds to human sex hormone-binding globulin (SHBG) [Schottner M, Gansser D, Spiteller G, (1997) Planta Med 63(6):529-532; Hryb D J, Khan M S, Romas N A, Rosner W, (1995) Planta Med 61(1):31-32]. SHBG is a plasma glycoprotein that binds to circulating plasma steroids (i.e., testosterone, DHT and estradiol), thus regulating plasma levels of free steroids [Rosner W, Hryb D J, Khan M S, Nakhla A M, Romas N A, (1999) J Steroid Biochem Mol Biol 69(1-6):481-485]. Urtica dioica lectins binding to SHBG prevents SHBG from binding to its receptors on various sex glands, including the prostate and testes. In the absence of the SHBG ligand, hormone up-take is prevented by glandular cells. Therefore, Urtica dioica lectins effectively reduce plasma testosterone. High levels of testosterone and DHT are observed in both BPH and prostate cancer.
The amino acids glycine, alanine and glutamine in combination have also been used successfully to alleviate the urinary symptoms associated with BPH [Damrau, F. (1958) J. Maine Medical Association 49:99-102]. In that study, three months of treatment with this combination resulted in 43-66% improvements in urgency, nocturia, delay in starting the flow, maintenance of flow and frequency. Similar improvements were seen in a Japanese study (Aito, K and Iwatsubo, E (1972) Hinyokika Kiyoxe2x80x94Acta Urologica Japonica. 18(1):41-4), and a single blind study that compared the combination with placebo [Feinblatt, H M and Gant, J (1958), J Maine Medical Assoc. 49:99-124].
Zinc supplementation has been well-established as beneficial to male sexual function. Mahajan, S K, Prasad, A S, Rabbani, P, Briggs, W A and McDonald, F D (1982), Amer J Clin Nutr 36: 1177-1183; Leake, Chisholm and Harib (1984), J Steroid Biochem 20:651-655; Fahim, Wang Sutcu and Fahim (1993), Andrologia 25:369-75, Antoniou, Sudhakar, Shalhoub and Smith (1977), Lancet Oct.: 895-898. Zinc has also been shown to have an inverse relationship with 5 alpha-reductase activity in human prostatic tissue. Wallace, A M, and Grant, J K (1975) Biochemical Society Transactions 3:540-542.
Prostatitis and protatodynia have been treated successfully with bee pollen, Buck A C, Rees, R W M, Ebeling, L (1989), Brit J Urology 64:496-499, Rugendorff, E W et.al. (1993), Brit J. Urology 71:433-438. In vitro studies on the inhibition of cancerous cell growths have demonstrated a beneficial effect of bee pollen. Habib, F K (1990), Brit J Urology 66:393-397; Zhang, X (1995) J Med Chem 38:735-738. Hydrangea arborescens and Panax ginseng extracts have been used in maintaining the health of the prostate, Simon, H B, (2000) Harvard Mens Health Watch. 4(9):8. Panax ginseng has also been shown to reduce the prostatic weight in male rats while increasing blood testosterone levels. Fahim M S. Fahim Z. Harman J M. Clevenger T E. Mullins W. Hafez E S. (1982) Archives of Andrology. 8(4):261-3, 1982 June.
Vitamin B6, along with zinc has been associated with a reduced risk of prostatic cancer. Key T J. Silcocks P B. Davey G K. Appleby P N. Bishop D T. (1997) Brit. J. Cancer. 76(5):678-87. Deficiency of Vitamin B6 may be associated with increased prostatic estradiol, that is known to sensitize it to steroidal hormonal effects. Bender D A, Ghartey-Sam K, Singh A. (1989) Brit. J. Nutrition, 61(3):619-28. Vitamin A is also believed to be a useful in the prevention of prostate cancer, Olson K B and Pienta K J. (1998) J. Nat. Cancer Institute. 90(6):414-5. Copper has been shown to reduce levels of plasma testosterone and several of the enzymes involved in its production. Chattopadhyay A. Sarkar M. Sengupta R. Roychowdhury G. Biswas N M. (1999) J. Toxicological Sciences. 24(5):393-7.
Currently, methods of treatment for BPH and prostatic cancers include surgery, radiation therapy, and chemotherapy. The two most common operations for prostate cancer are radical prostatectomy and transurethral resection of the prostate (TURP). Radical prostatectomy removes the entire prostate gland and some tissue around it and carries a high risk of impotence and incontinence following surgery. The radical prostatectomy operation lasts from 1.5 to 4 hours, followed by an average hospital stay of three days and an average time away from work of three to five weeks. The TURP procedure last about 1 hours, followed by an average hospital stay of 1-2 days and 1-2 weeks time away from work and also has the adverse side effect of loss of bladder control. The side effects of radiation therapy can include diarrhea and irritated intestines, frequent urination, burning while urinating and blood in the urine, and a feeling of tiredness. Side effects of chemotherapy can include nausea and vomiting, loss of appetite, loss of hair, and mouth sores. Chemotherapy can also effect blood cells, which can increase the chance of infection, bleeding or bruising after minor injuries, as well as tiredness. Thus, alternative, non-invasive, treatments of BPH and prevention of prostate cancer are needed which have low toxicity and few side effects.
The present invention provides a composition of herbs and their extracts for treatments of BPH and the symptoms thereof and the prevention of prostate cancer. The present invention also provides a composition to effectively reduce micturitional disorders including prostate volume, residual urine, frequency of urination, and to improve urine flow rate, and balance hormone levels. This invention can also be used as a dietary supplement to prevent BPH and prostate cancer.
The composition comprises lycopene, Serenoa repens, Pygeum africanum, and Urtica dioica, or extracts thereof. The composition to be administered may be prepared with any dose preparation in the art, including alcohol extracts, powders, mixing and encapsulation, and is not limited to any particular form. The components of the composition may be added in any order without limitation. More preferably the composition of the present invention comprises, by weight,: lycopene in an amount from about 0.1 to 10%, Serenoa repens in an amount from about 30 to 60%, Pygeum africanum in an amount from about 4 to 25%, and Urtica dioica in an amount from about 30 to 60%.
The invention further provides a method of treating BPH and prostate cancer or at least alleviate their symptoms in an subject in need thereof which comprises administering a therapeutic amount of the composition described herein.
The present invention ameliorates at least some of the disadvantages or the prior art therapies and methods, or at least provides a useful alternative. The availability of the herbs and the ease of formulation (powdering, extractions, etc) provides a less costly alternative medicament. The treatment may also be individualized as well as prepared by standard formulation, making the treatment more broadly applicable and effective over both short and long term administration.
These and other features, aspects, and advantages of the present invention will become better understood with regard to the following detailed description and accompanying claims.
The composition of this invention includes a combination of the herbs, Serenoa repens, Pygeum africanum, and Urtica dioica, or extracts thereof, and the pytochemical lycopene, which were specifically chosen and combined according to their biological activities. The term xe2x80x9cherbxe2x80x9d as used herein refers to the whole herb or tuber, or to the seeds, leaves, stems, flowers, roots, berries, bark, or any other plant parts that are used for healing.
The lycopene component of the composition was obtained is available commercially from Hoffman La Roche, of Nutley, N.J., U.S.A, as a synthetic chemical available at a 5% strength that is chemically identical to the lycopene extracted from tomato fruit using standard methods. The natural standardized extract is available from many sources well known to those of ordinary skill in the art at a strength of 3%, including Brainway, Inc., Senovazne 23, Praha 1, 110 Czech Republic.
The Serenoa repens component of the composition is available commercially around the world, through distributors such as Amira, Box 1717, Alachua Fla., U.S.A. The component is obtained from the Berry portion of the herb and the component is preferably powdered but may also be cut, and preferably contains about 40% fatty acids.
The Pygeum africanum component of the composition is available commercially around the world, through distributors, such as Advanced Alternatives for Better Health, 1344 Lansing Avenue, Lansing Mich., U.S.A. Preferably, the powdered bark is used and contains about 2.0-2.5% steroids.
The Urtica dioca component of the composition is available commercially around the world, through distributors such as Advanced Alternatives for Better Health, 1344 Lansing Avenue, Lansing Mich. 48915 and Amira, Box 1717, Alachua Fla., U.S.A. The preferred embodiment of the invention contains the component from the powdered root, with 0.8% sterols, but alternatively the root may be cut or powdered or cut leaves may be utilized.
The methods for combining the herbs, extracts, and vitamins are well known to those of ordinary skill in the art and may be accomplished at a number of commercial production laboratories around the world.
Each herbal component selected in this group has been well characterized and used individually before for the treatment of BPH and for the prevention of prostate cancer. However, they have not, to date, been used together as is disclosed in this invention. It is the synergism between all of the herbs that renders the administration of a combination containing each of the herbs desirable. As a holistic approach to combating the treatment of BPH and prevention of prostate cancer, herbs were selected which possess the following biological activities: (1) anti-tumor activity; (2) immune stimulating activity; (3) anti-androgen activity; (4) anti-BPH activity; and (5) activities to restore micturitional disorders. Most of the herbs have multi functional activities.
In a specific embodiment of the invention, the composition comprises between 0.1 and 180 mg lycopene, an amount that will comprise from 0.1 to 10% by weight of a tablet or capsule having a total weight of 100 to 1800 mg, between 30 and 1080 mg Serenoa repens, an amount that will comprise from 30 to 60% by weight of a tablet or capsule having a total weight of 100 to 1800 mg, between 4 and 450 mg Pygeum africanum, and amount that will comprise from 4 to 25% by weight of a tablet or capsule having a total weight of 100 to 1800 mg, and between 30 and 1080 mg Urtica dioica, an amount that will comprise from 30 to 60% by weight of a tablet or capsule having a total weight of 100 to 1800 mg.
In yet another embodiment of the invention, the composition comprises between 0.1 and 60 mg lycopene, an amount that will comprise from 0.1 to 10% by weight of a tablet or capsule having a total weight of 100 to 600 mg, between 30 and 360 mg Serenoa repens, an amount that will comprise from 30 to 60% by weight of a tablet or capsule having a total weight of 100 to 600 mg, between 4 and 150 mg Pygeum africanum, and amount that will comprise from 4 to 25% by weight of a tablet of capsule having a total weight of 100 to 600 mg, and between 30 and 360 mg Urtica dioica, an amount that will comprise from 30 to 60% by weight of a tablet or capsule having a total weight of 100 to 600 mg. In yet another embodiment of the invention, the composition comprises about 50 mg lycopene, about 150 mg Serenoa repens, about 50 mg Pygeum africanum, and about 150 mg Urtica diocia.
In a preferred embodiment, the composition further comprises between about 3 and 3 mg Vitamin A; between about 5 and 150 mg Vitamin B6; between about 1 mg and 25 mg zinc; between about .1 and 5 mg copper; between about 10 mg and 600 mg bee pollen powder; between about 10 mg and 1800 mg each of the amino acids alanine, glutamine, and glycine; between about 5 mg and 500 mg Panax ginseng extract; and between about 1 and 100 mg Hydrangea arborescens extract. In yet another embodiment, the composition further comprises between 1 and 2 mg Vitamin A, between 5 and 50 mg Vitamin B6, between 1 and 15 mg zinc, between 0.1 and 2 mg copper, between 10 mg and 240 mg Bee pollen powder, between 10 and 600 mg each of alanine, glutamine, and glycine, between 5 and 100 mg Panax ginseng extract and between 1 and 25 mg Hydrangea arborescens extract. In yet another embodiment, the composition further comprises about 1.5 mg Vitamin A, about 15 mg Vitamin B6, about 5 mg Zinc, about 0.5 mg Copper; about 60 mg Bee pollen powder, about 60 mg each of Alanine, Glutamine, and Glycine, about 10 mg Panax ginseng extract, and about 5 mg Hydrangea arborescens extract.
In a more preferred embodiment the composition is present in a 500 mg tablet or capsule containing about 50 mg lycopene, an amount that will comprise about 10% by weight of the tablet or capsule, about 150 mg Serenoa repens, and amount that will comprise about 30% by weight of the tablet or capsule, about 50 mg Pygeum africanum, an amount that will comprise about 10% by weight of the tablet or capsule, and about 150 mg Urtica dioica, and amount that will comprise about 30% by weight of the tablet or capsule, and about 1.5 mg Vitamin A, about 15 mg Vitamin B6, about 5 mg Zinc, about 0.5 mg Copper, about 60 mg bee pollen powder, about 60 mg each of alanine, glutamine, and glycine, about 10 mg Panax ginseng extract, and about 5 mg Hydrangea arborescens extract.
In a further embodiment, the composition is administered in four tablets, each comprising about 500 mg red yeast rice, about 15 mg coenzyme Q10, about 50 mcg chromium, about 13 mg inositol, about 50 mcg selenium, and about 20 IU mixed tocopherols to provide a total daily dose of about 2 gm red yeast rice, about 60 mg Coenzyme Q10, about 200 mcg chromium, about 52 mg inositol, about 200 mcg selenium and about 80 IU mixed tocopherols.
Preferably, the compositions of the present invention are prepared in a tablet dosage form, however it will be understood by those skilled in the art that other dosage forms may also be suitably prepared by known methods, for example, capsules, caplets, powders, pastes, liquids and similar dosage forms. Also, it will be understood that the compositions may also contain one or more conventional pharmaceutically acceptable excipients, adjuvants, solvents or carriers and may also include flavors, colorings, coatings, etc.
One dose of the pharmaceutical composition for the treatment of BPH, for example one tablet or one capsule, may contain, for example 100-600 mg of the composition of the present invention. One dose of the pharmaceutical composition for the prevention of prostatic cancers may contain, for example, 600-1800 mg of the composition of the present invention. The compositions are preferably administered in spaced dosages throughout the day, for example, administered every three to six hours, so as to maintain the level of active ingredients in the system of the mammal. The dose may be administered in single or divided doses throughout the day and is preferably taken with food.
A person skilled in the art will understand that the therapeutic effects of the compositions result from a plurality of active agents in each herb which when combined, act synergistically to enhance efficacy. It will also be understood that the compositions comprising all agents, are also contemplated herein, as are liquid or slow release formulations of the composition. Thus, it will be understood that the compositions of the invention can be administered orally, rectally (as suppositories), intravenously, topically or by other known means. As a capsule, the formulation should be stored at a temperature of 80xc2x0 or less.
The administration of the composition would be in accordance with a predetermined regimen, which would be at least once daily and over an extended period of time as a chronic treatment, and could last for one year or more, including the life of the host. The dosage administered will depend upon the frequency of the administration, the blood level desired, other concurrent therapeutic treatments, the severity of the condition, whether the treatment is for prophylaxis or therapy, the age of the patient, the levels of LDL-cholesterol and HDL-cholesterol in the patient, and the like.
The following examples will serve to further typify the nature of the invention, but is not limited on the scope thereof, which is defined solely by the appended claims.

Method and composition for the treatment of benign prostate hypertrophy (BPH) and prevention of prostate cancer


Polycarbonate substrates having low concentration of defects are disclosed. The substrates are suitable for producing molded articles characterized by low cloudiness.

The invention provides polycarbonate substrates and their use for preparing moulded items with especially high purity and extremely high surface brilliance and the moulded items which can be prepared from the polycarbonate substrate.
For certain moulded items such as in particular glazing for motor vehicles and headlamps, glazing of other types such as so-called twin-wall sheets or hollow chamber sheets or solid sheets, high purity polycarbonate is required.
Polycarbonate is prepared by the so-called phase boundary process in which dihydroxydiarylalkanes, in the form of their alkali metal salts, are reacted with phosgene in heterogeneous phase in the presence of inorganic bases such as sodium hydroxide solution and an organic solvent in which the product polycarbonate is very soluble. During reaction, the aqueous phase is distributed within the organic phase and after reaction the organic polycarbonate-containing phase is washed with an aqueous liquid, wherein, inter alia, electrolytes are removed and the wash liquid is then separated.
In order to wash the polycarbonate-containing solution, EP-A-264 885 suggests stirring up the aqueous wash liquid with the polycarbonate solution and separating the aqueous phase by centrifuging.
Japanese application JP-A-07 19 67 83 describes a process for preparing polycarbonate in which the concentration of iron in the sodium hydroxide solution used is intended to be less than 2 ppm, in order to produce favourable colour characteristics.
The object of the present invention is the provision of an alternative and improved process for preparing pure polycarbonate substrates and the provision of polycarbonate moulded items with especially high purity and high surface brilliance.
Surprisingly, it has now been found that polycarbonate moulded items with especially high purity and high surface brilliance are obtained from polycarbonate substrates which are prepared by a special process.
Therefore, the application provides polycarbonate substrates with a low concentration of foreign particles and the polycarbonate moulded items with high surface brilliance prepared therefrom which are obtained by a process for preparing polycarbonate by the phase boundary method which is characterised in that, from the group of feedstocks, at least the feedstock sodium hydroxide solution contains very little Fe, Cr, Ni, Zn, Ca, Mg, Al or their chemical homologues.
The application therefore provides a process for preparing polycarbonate by the phase boundary process, wherein dihydroxydiarylalkanes in the form of their alkali metal salts are reacted with phosgene in heterogeneous phase in the presence of sodium hydroxide solution and an organic solvent, characterised in that
a) the feedstocks are low in the metals Fe, Cr, Ni, Zn, Ca, Mg, Al or their homologues
b) the organic solvent is separated off and
c) the polycarbonate obtained is worked up.
In the context of the invention, low in the metals mentioned or their chemical homologues means that preferably not more than 2 ppm, more preferably not more than 1 ppm and particularly preferably not more than 0.5 ppm and very particularly preferably not more than 0.2 ppm of total metal, in particular of the metals listed above and their homologues is contained in the feedstocks. These limiting values do not apply to the alkali metals.
It is intended that the feedstock sodium hydroxide solution should preferably be low in the metals mentioned. In particular, with reference to a 100 wt. % strength NaOH concentration, the sodium hydroxide solution should contain not more than 1 ppm, preferably not more than 0.5 ppm, more preferably not more than 0.3 ppm of alkaline earth metals or their homologues. In particular, with reference to a 100 wt. % strength NaOH concentration, the feedstock sodium hydroxide solution should contain not more than 1 ppm, advantageously not more than 0.5 ppm, preferably not more than 0.1 ppm of iron.
The sodium hydroxide solution is preferably used in the process according to the invention as a 20-55 wt. % strength, particularly preferably a 30-50 wt. % strength solution.
Sodium hydroxide solution with the limiting values mentioned above is obtainable by membrane processes known from the literature.
In a preferred embodiment, in addition to the sodium hydroxide solution, the feedstocks bisphenol, in particular bisphenol and water, very particularly preferably bisphenol, water and the organic solvent are low in metals, in particular low in Fe, Cr, Ni, Zn, Ca, Mg, Al or their chemical homologues.
Embodiments in which a sodium bisphenolate (solution) has been previously prepared from sodium hydroxide solution and bisphenol(s) are also included.
These feedstocks which are low in metal are obtained, in a preferred variant, by distilling the solvent, crystallising the bisphenol, preferably crystallising or distilling the bisphenol several times and using the water in a fully deionised quality.
The fully deionised water is preferably desalted, degassed and/or desilicified. The electrical conductivity (sum parameter for ionogenic substances from salts which are still present in trace amounts in the water) is used as a quality criterion, wherein in the process according to the invention the fully deionised water is characterised by an electrical conductivity of 0.2 xcexcS/cm (DIN 38404 C 8) and a SiO2 concentration of 0.02 mg/kg (VGB 22.214.171.124), or less than each of these.
The concentration of dissolved oxygen in the fully deionised water is advantageously less than 1 ppm, preferably less than 100 ppb. This oxygen concentration is preferably applied to all starting substances and process steps.
In a further preferred embodiment, from among the group of feedstocks, at least the sodium hydroxide solution, preferably also the bisphenol, particularly preferably the sodium hydroxide solution, the bisphenol and the water, most preferably the sodium hydroxide solution, the bisphenol, the water and the organic solvent are filtered once, preferably twice, particularly preferably three times step-wise, before the start of reaction.
The invention also provides a process for preparing polycarbonate by the phase boundary process, wherein dihydroxydiarylalkanes in the form of their alkali metal salts are reacted with phosgene in heterogeneous phase in the presence of sodium hydroxide solution and an organic solvent, characterised in that
a) the feedstocks are low in the metals Fe, Cr, Ni, Zn, Ca, Mg, Al or their homologues
b) the aqueous phase being produced during reaction is separated and the separated organic polycarbonate phase is washed with an aqueous liquid and
c) the washed, and separated from the wash liquid, organic polycarbonate phase, optionally after filtration, is heated and filtered hot at least once;
d) the organic solvent is separated off and
e) the polycarbonate obtained is worked up.
In a preferred embodiment, in process step d), the reaction mixture is filtered directly after reaction and/or the organic polycarbonate phase obtained and separated is filtered and/or the organic polycarbonate phase separated in process step e) is filtered.
Preferably at least two of these filtration procedures, in particular all three filtration procedures, are performed.
In a preferred variant, in particular in the case of hot filtration, the mixture is filtered at least once, preferably twice, particularly preferably at least three times, in particular step-wise. In the case of step-wise filtration, coarser filters are used first and then these are replaced by finer filters. The filtration procedure for the two-phase media in process step d) is preferably performed with coarse filters.
In process step e), filters with smaller pore sizes are used for hot filtration. In this case it is important that the polycarbonate phase is present as the most homogeneous solution possible. This is achieved by heating the organic polycarbonate phase, which generally still contains residues of aqueous wash liquid. The wash liquid then dissolves and a clear solution is produced. The previously dissolved contaminants, in particular dissolved alkali metal salts, precipitate out and can be filtered off
In order to achieve a homogeneous solution, the well-known freezing out method may be used in addition to the method described above.
To perform filtration in accordance with the invention, membrane filters and sintered metal filters or also bag filters may be used as filters. The pore size of the filters is generally 0.01 to 5 xcexcm, preferably 0.02 to 1.5 xcexcm, more preferably 0.05 to 1.0 xcexcm. These types of filters are commercially available, for example from Pall GmbH, D-63363 Dreieich, and Krebsbxc3x6ge GmbH, D-42477 Radevormwald (SIKA-R CU1AS type).
Greatly improved filter lifetimes are obtained by the combination in the process according to the invention.
Performing the other process steps is generally well-known. Thus, the aqueous phase is emulsified in the organic phase during reaction. Droplets of differing sizes are then produced. After reaction, the organic polycarbonate-containing phase is normally washed several times with an aqueous liquid and separated as far as possible from the aqueous phase after each wash process. Washing is preferably performed with very finely filtered water which has a very low metal content. The polymer solution is normally cloudy after washing and separation of the wash liquid. The wash liquids used are aqueous liquids, a dilute inorganic acid such as HCl or H3PO4 to separate the catalyst, and fully deionised water for further purification. The concentration of HCl or H3PO4 in the wash liquid may be, for example, 0.5 to 1.0 wt. %. The organic phase is washed, for example and preferably, five times.
Well-recognised separating funnels, phase separators, centrifuges or coalescers or also combinations of these devices may be used as phase separation devices to separate the wash liquid from the organic phase.
The solvent is evaporated off to obtain the high purity polycarbonate. Evaporation may take place in several evaporation stages. In accordance with a further preferred embodiment of this invention, the solvent or some of the solvent is removed by spray drying. The high purity polycarbonate is then obtained as a powder. The same applies to recovering the high purity polycarbonate by precipitation from the organic solution and then removing residues by drying. Extrusion, for example, is a suitable means of evaporating residual solvent. Extrusion-evaporation technology is another means.
Compounds which are preferably used as feedstocks are bisphenols of the general formula HO-Z-OH, in which Z is an organic group with 6 to 30 carbon atoms, which contain one or more aromatic groups. Examples of such compounds are bisphenols which belong to the group of dihydroxyphenyls, bis(hydroxyphenyl)alkanes, indanebisphenols, bis(hydroxyphenyl)ethers, bis(hydroxyphenyl)sulfones, bis(hydroxyphenyl)ketones and xcex1,xcex1xe2x80x2-bis(hydroxyphenyl)diisopropylbenzenes.
Particularly preferred bisphenols which belong to the previously mentioned group of compounds are 2,2-bis-(4-hydroxyphenyl)-propane (BPA/bisphenol-A), tetraalkyl-bisphenol-A, 4,4-(meta-phenylenediisopropyl)-diphenol (bisphenol M), 1,1-bis-(4-hydroxyphenyl)-3,3,5-trimethylcyclohexanone and optionally mixtures of these. Particularly preferred copolycarbonates are those based on monomeric bisphenol-A and 1,1-bis-(4-hydroxyphenyl)-3,3,5-trimethylcyclohexane. The bisphenol compounds to be used according to the invention are reacted with carbonic acid compounds, in particular phosgene.
Polyestercarbonates are obtained by reaction of the bisphenols already mentioned, at least one aromatic dicarboxylic acid and optionally carbon dioxide. Suitable aromatic dicarboxylic acids are, for example, orthophthalic acid, terephthalic acid, isophthalic acid, 3,3xe2x80x2- or 4,4xe2x80x2-diphenyldicarboxyilic acid and benzophenonedicarboxylic acid.
Inert organic solvents used in the process are, for example, dichloromethane, the various dichloroethanes and chloropropane compounds, chlorobenzene and chlorotoluene. Dichloromethane and mixtures of dichloromethane and chlorobenzene are preferably used.
The reaction can be accelerated by catalysts such as tertiary amines, N-alkylpiperidines or onium salts. Tributylamine, triethylamine and N-ethylpiperidine are preferably used. A monofunctional phenol such as phenol, cumylphenol, p-tert.-butylphenol or 4-(1,1,3,3-tetramethylbutyl)phenol may be used as chain terminators and molecular weight regulators. Isatin-biscresol, for example, may be used as a branching agent.
To prepare high purity polycarbonates, the bisphenols are dissolved in an aqueous alkaline phase, preferably sodium hydroxide solution. The chain terminators optionally required for preparing copolycarbonates are dissolved in the aqueous alkaline phase or added to this as such in an inert organic phase in amounts of 1.0 to 20.0 mol % per mole of bisphenol. Then phosgene is passed into the mixer which contains the remainder of the reaction constituents and polymerisation is performed.
Optionally used chain terminators are either monophenols or monocarboxylic acids. Suitable monophenols are phenol itself, alkyl phenols such as cresols, p-tert.-butylphenol, p-cumylphenol, p-n-octylphenol, p-iso-octylphenol, p-n-nonylphenol and p-iso-nonylphenol, halophenols such as p-chlorophenol, 2,4-dichlorophenol, p-bromophenol and 2,4,6-tribromophenol and mixtures of these.
Suitable monocarboxylic acids are benzoic acid, alkylbenzoic acids and halobenzoic acids.
Preferred chain terminators are phenols of the formula (I)
in which
R is hydrogen, tert.-butyl or a branched or unbranched C8 and/or C9 alkyl group.
Preferred chain terminators are phenol and p-tert.-butylphenol.
The amount of chain terminator to be used is 0.1 mol % to 5 mol %, with respect to moles of each of the diphenols used. The addition of a chain terminator may take place before, during or after phosgenation.
Optionally, a branching agent may also be added to the reaction. Preferred branching agents are the trifunctional or more than trifunctional compounds known from polycarbonate chemistry, in particular those with three or more than three phenolic OH groups.
Branching agents are also, for example and preferably, phloroglucine, 4,6-dimethyl-2,4,6-tri-(4-hydroxyphenyl)-hept-2-ene, 4,6-dimethyl-2,4,6-tri-(4-hydroxyphenyl)-heptane, 1,3,5-tri-(4-hydroxyphenyl)-benzene, 1,1,1-tri-(4-hydroxyphenyl)ethane, tri-(4-hydroxyphenyl)-phenylmethane, 2,2-bis-[4,4-bis-(4-hydroxyphenyl)-cyclohexyl]-propane, 2,4-bis-(4-hydroxyphenyl-isopropyl)-phenol, 2,6-bis-(2-hydroxy-5xe2x80x2-methylbenzyl)-4-methylphenol, 2-(4-hydroxyphenyl)-2-(2,4-dihydroxyphenyl)-propane, esters of hexa-(4-(4-hydroxyphenyl-isopropyl)-phenyl)-orthoterephthalic acid, tetra-4-hydroxyphenyl)-methane, tetra-(4-(4-hydroxyphenyl-isopropyl)-phenoxy)-methane and 1,4-bis-(4xe2x80x2,4xe2x80x3-dihydroxytriphenyl)-methyl)-benzene and also 2,4-dihydroxybenzoic acid, trimesic acid, cyanuric chloride and 3,3-bis-(3-methyl-4-hydroxyphenyl)-2-oxo-2,3-dihydroindole.
The amount of optionally used branching agent is 0.05 mol % to 2 mol %, again with respect to moles of each of the diphenols used.
The branching agent may be either initially introduced in the aqueous alkaline phase with the diphenols and the chain terminators, or added before phosgenation dissolved in an organic solvent.
Some, up to 80 mol %, preferably 20 to 50 mol %, of the carbonate groups in the polycarbonates may be replaced by aromatic dicarboxylic ester groups.
Polycarbonates according to the invention are either homopolycarbonates or copolycarbonates and mixtures of these. Polycarbonates according to the invention may be aromatic polyestercarbonates or polycarbonates which are present in a mixture with aromatic polyestercarbonates. The expression polycarbonate is regarded as representing the polycarbonate substrate obtainable by the process according to the invention.
Polycarbonates according to the invention have average molecular weights Mw (determined by measuring the relative viscosity at 25xc2x0 C. in dichloromethane and at a concentration of 0.5 g of polycarbonate per 100 ml of dichloromethane) of 12,000 to 400,000, preferably 23,000 to 80,000 and in particular 24,000 to 40,000.
Moulded items according to the invention which can be made from the high purity polycarbonate according to the invention are in particular glazing for motor vehicles and headlamps, glazing of other types such as for greenhouses, so-called twin-walled sheets or hollow chamber sheets or solid sheets. These moulded items are prepared by known methods such as e.g. injection moulding, extrusion and extrusion blow moulding processes using polycarbonates according to the invention.
Moulded items produced from polycarbonates according to the invention have a particularly low number, fewer than 250, preferably fewer than 150, of defects per m2 measured on a 200 xcexcm extruded film.
The advantage of moulded items according to the invention, in particular for solid sheets and twin-walled sheets, is their extremely low number of optically detectable surface defects and their outstanding brilliance.
Another advantage of moulded items according to the invention, in for particular discs and headlamp diffusers, is the low cloudiness of less than 0.5%, in particular less than 0.4%, associated with long-term durability.


The invention provides a method of growing plants in a non-fibrous growth substrate, the method comprises providing at least one non-fibrous growth substrate comprising wetting agent, positioning one or more plants for growth in the growth substrate, characterized in that the wetting agent comprises ionic surfactant and the non-fibrous growth substrate is selected from the group consisting of urea formaldehyde foam, perlite, vermiculite, expanded clay, coco chips, coco dust, lava, pumice and mixtures thereof.

The invention relates to growth substrates. The growth substrate comprises a wetting agent which provides water handling characteristics. The invention also relates to methods of growing plants using the growth substrate and to the use of specific types of wetting agent to provide particular characteristics to a growth substrate.
It has been well known for many years to grow plants in growth substrates formed from mineral wool, and from a variety of other materials including inorganics such as perlite, organics such as coconut based materials, and organic foam materials such as those sold under the trade names Oasis and Phytocell. Products which are to be used as growth substrates must have a capacity to take up and hold water, which is routinely supplied by an irrigation system to the growth substrate, and re-wetting properties. Accordingly, it has been proposed to include a wetting agent in products which are to be used as growth substrates.
Two examples of this are U.S. Pat. No. 4,174,957 and U.S. Pat. No. 4,240,817. Each of these describes application of a wetting agent to urea formaldehyde foam. In U.S. Pat. No. 4,174,957 the wetting agent is "alcohol or various phosphates such as those used in detergents" and Surfside 30 is given as an example. U.S. Pat. No. 4,240,817 describes the use of alkylene glycol (a non-ionic material).
The commercial field itself has generally followed this approach and when surfactant is used it is normally a non-ionic surfactant.
This approach has certain problems. The first is that the water handling capabilities of the substrate, although good, show room for improvement. Thus, it would be desirable to provide systems which show improved re-saturation properties (ability of the growth substrate to take up water a second time once it has been wetted and then dried), improved water distribution properties (ability of the growth substrate to hold water at a more uniform concentration throughout the height of the growth substrate rather than concentrating at the base), and water retention.
Additionally, one problem which tends to arise with the non-ionic surfactants which have conventionally been used is that they are, during irrigation of the growth substrate, gradually lost from the growth substrate rather than being retained in the growth substrate structure. This means that the wettability properties of the growth substrate gradually decrease over time. This can have an impact on, for instance, the re-saturation properties and also on the water handling properties of a substrate which has been in place for a considerable time, and thus on the performance of the plant and growing process.
In particular, it is a constant aim of the growth substrate industry to provide a growth substrate which has improved water distribution over its height. It is required to achieve a water to air ratio throughout the growth substrate which is as close as possible to optimum. Naturally, when a growth substrate is irrigated with water, there is a tendency for water concentration at the base to be higher, and often significantly higher, than water concentration in the top region, purely due to the influence of gravity.
Accordingly, it is still, despite the many years during which the industry has used synthetic materials as growth substrates, an aim to provide materials which exhibit excellent water distribution properties and water retention properties, and which maintain these properties over time, during use, and thus can exhibit excellent re-saturation properties. It is also desirable to achieve this in the context of a product which has good structural integrity and can be made in conventional manner.
EP-A-1226749 discloses a process for the production of water-absorbing fiber products, which can be used for growing plants. According to this process, during production of the fibers, material is applied to the fibers after formation and before collection, comprising binder, wetting agent and aliphatic polyol. The binder can be a conventional phenol-based resin. The polyol can preferably be ethylene glycol, propylene glycol or trimethylolpropane. The wetting agent can be selected from a long list including salts of higher fatty acids, alkyl or aralkyl sulfates or sulfonates, fatty alcohol sulfates, alkyl phosphates, fatty alcohol ethoxylates, alkyl phenol ethoxylates, fatty amine ethoxylates, fatty acid ethoxylates, alkyl ammonium compounds. Alkyl benzene sulfonate is said to be preferred. No reason is given for this preference in the context of the fiber products disclosed.
Other disclosures of growth substrate include EP-A-313255, which describes a plant growth medium formed from a solid porous medium comprising an open cell foamed homo- or co-polymer of monomers selected from olefins, unsaturated monocarboxylic acid esters and unsaturated monocarboxylic acids (or ionomer derivatives). This is said to overcome disadvantages with rockwool substrates and polyurethane foam substrates. It is mentioned that a wetting agent may be included which is preferably a non-ionic surfactant, and anionic surfactants are also mentioned.
U.S. Pat. No. 3,336,129 discloses a growth substrate which comprises a substrate which can be for instance soil, sand, peat moss or vermiculite, in admixture with a water-swellable capable of absorbing water. It is also mentioned that the product can contain a wetting agent which can be anionic, non-ionic or cationic.
WO03/041487 describes a product which is intended to give improved properties versus growth substrates such as peat moss. The solution involves coconut coir pith and it is generally discussed that other non-coir/non-peat materials may be present. Examples are composted yard waste, composted bark, composted manure, peat humus, composted agricultural waste, composted animal byproducts, treated sewage sludge, animal and/or vegetable-based landfill waste, vermiculite, perlite, glass beads, foamed plastics and mixtures thereof. There is also disclosure that a horticulturally acceptable surfactant maybe included in the growth substrate. The majority discussed are non-ionic and there is mention of an ionic surfactant. There is one example involving ionic surfactants and dry coconut coir pith. There is separate mention of growth media which can be used including peat moss, top soil, sphagnum peat, perlite, vermiculite and Styrofoam.
According to the disclosed technology the growth substrate can exhibit improved physical properties, for instance improved bending properties. This can apply whilst maintaining firmness properties.
The root development properties of the product can be improved. For instance, more roots can be generated. The finer roots can exhibit better branching. The root distribution can be better—for instance there can be more roots in the top layer.
This can apply even if the product appears wetter to the user.
According to the disclosed technology, in a first aspect we provide a method of growing plants in a synthetic growth substrate, the method comprising:
providing at least one non-fibrous growth substrate comprising wetting agent,
positioning one or more plants for growth in the growth substrate,
characterized in that
the wetting agent comprises ionic surfactant and the non-fibrous growth substrate is selected from the group consisting of urea formaldehyde foam, perlite, vermiculite, expanded clay, coco chips, coco dust, lava, pumice and mixtures thereof.
The growth substrate itself is novel and so in a second aspect we provide a non-fibrous growth substrate comprising wetting agent. wherein the wetting agent comprises ionic surfactant and the non-fibrous growth substrate is selected from the group consisting of urea formaldehyde foam, perlite, vermiculite, expanded clay, coco chips, coco dust, lava, pumice and mixtures thereof.
We find that this particular combination of substrate and ionic surfactant, especially linear alkyl benzene sulfonate surfactant, provides a surprisingly effective combination of water handling properties. This combination of substrate and surfactant and its effectiveness is not recognized in any of the citations mentioned above.
Furthermore, the choice of ionic, especially anionic surfactant, especially linear alkyl benzene sulfonate (LAS), appears to lead to greatly reduced loss of wetting agent during irrigation and consequently minimizes foaming problems during the irrigation process. LAS also has the advantage of being aerobically biodegradable in water. Phytotoxicity is low.
As a result of this recognition of the beneficial properties of ionic surfactants in particular, we also provide, in a second aspect of the disclosed technology, the use of an ionic surfactant to improve the water distribution characteristics of a non-fibrous growth substrate. Improvement is shown in particular in comparison with growth substrates containing a conventional wetting agent such as a non-ionic surfactant. The improvement can be shown either by replacement of a conventional non-ionic wetting agent or by addition of the ionic surfactant to the growth substrate, but generally is shown by replacement of the conventional wetting agent.
The growth substrate is non-fibrous. It is usually either formed of foam or is particulate.
If it is foam, it is urea formaldehyde foam (sold as Oasis and Phytocell).
If it is a particulate material it can be inorganic. Examples of inorganic particulate materials are perlite, vermiculite, lava granules, expanded clay granules, pumice.
Organic particulate materials include coco chips, coco dust, and peat.
Usually either foam or particulate is used, but blends can be used, in particular if the foam is granulated before blending. Blends of different particulates can also be used.
Some fibrous material may be included but the growth substrate as a whole is non-fibrous, so amounts of any fibrous material should be below 20%, in particular below 10% (by weight of the substrate as a whole). Fibrous materials include mineral wool (although this is less preferred), wood fibers, coco fibers.
Preferably the growth substrate is particulate and is selected from the group consisting of perlite, vermiculite, expanded clay, coco chips, coco dust, lava, pumice and mixtures thereof. Preferably it is selected from perlite, expanded clay, coco chips, coco dust, lava and pumice and mixtures thereof. More preferably it is selected from expanded clay, lava, pumice and mixtures thereof.
The growth substrate is normally a soil substitute, so generally is a non-soil material. Soil and peat may be included in small amounts, e.g. below 20%, in particular below 10% (by weight of the growth substrate).
Density of the growth substrate in the consolidated form depends on the particular material used. Foam products preferably have density from 20 to 125 kg/m3. Clay products preferably have density for 300 to 700 kg/m3. Coco products preferably have density from 55 to 125 kg/m3. Lava products preferably have density from 50 to 300 kg/m3. Perlite products preferably have density from 40 to 175 kg/m3. Pumice products preferably have density from 300 to 500 kg/m3. Vermiculite products preferably have density from 30 to 100 kg/m3.
Generally, the density of the product can range from 10 to 600 kg/m3, preferably 30 to 200 kg/m3, preferably 30 to 100 kg/m3.
When the growth substrate comprises foam, it can also comprise binder if required to provide physical integrity. If used, it is usually an organic binder, which is generally heat-curable. In such a case the growth substrate is preferably a coherent matrix connected by cured binder. The disclosed technology is particularly valuable when the binder is an organic hydrophobic binder, and in particular when it is a conventional heat-curable (thermosetting), hydrophobic binder. This has the advantage of convenience and economy. Thus, the binder is preferably a phenol formaldehyde resin or urea formaldehyde resin, in particular phenol urea formaldehyde (PUF) resin.
The binder is generally present in the growth substrate in amounts of from 0.1 to 10% based on the substrate, usually 0.5 to 5%, most preferably 1.5 to 5%.
The growth substrate comprises a wetting agent which is an ionic surfactant.
Preferably it is an anionic surfactant. Suitable anionic surfactants include salts (including, for example, sodium, potassium, ammonium and substituted ammonium salts such as mono-, di- and triethanolamine salts) of the anionic sulfate, sulfonate, carboxylate and sarcosinate surfactants. Other anionic surfactants include isethionates such as the acyl isethionates, N-acyl taurates, fatty acid amines of methyl tauride, alkyl succinates and sulfosuccinates, mono esters of sulfosuccinates, di-esters of sulfosuccinates and N-acyl sarcosinates. Preferred are anionic sulfate surfactants and anionic sulfonate surfactants, anionic carboxylate surfactants and anionic soap surfactants.
Particularly preferred are the anionic sulfonate surfactants such as linear and branched alkyl benzene sulfonates, alkyl ester sulfonates, primary or secondary alkylene sulfonates, olefin sulfonates, sulfonated polycarboxylic acids, alkyl glycerol sulfonates, fatty acyl glycerol sulfonates, fatty oleyl glycerol sulfonates and mixtures thereof.
Most preferably the anionic surfactant is a linear alkyl benzene sulfonate in which the alkyl chain has from 5 to 20 carbon atoms. The sodium salt is preferred. This type of surfactant provides particularly beneficial water distribution properties and also provides excellent re-saturation properties and does not lead to foaming problems in the irrigation water. Conventional non-ionic surfactants allow the growth substrate to take up water but its water retaining capacity is not as good as with the type of surfactant used in the disclosed technology.
Preferably the alkyl chain length is in the range 8 to 16, and more preferably at least 90% of the chains are in the range 10 to 13 and more preferably at least 90% (by weight) are in the range 10 to 12.
Alternatively, the ionic surfactant may be cationic or zwitterionic. Examples of cationic surfactants include quaternary ammonium surfactants. These can, for instance, be selected from mono C6 to mono C16, preferably C6 to C10 N-alkyl or alkenyl ammonium surfactants wherein the remaining N positions are substituted by groups such as methyl, hydroxyethyl and hydroxypropyl.
Suitable zwitterionic surfactants include derivatives of secondary and tertiary amines, derivatives of heterocyclic secondary and tertiary amines, or derivatives of quaternary ammonium, quaternary phosphonium or tertiary sulfonium compounds. Betaine and sultaine surfactants are examples of zwitterionic surfactants.
The ionic surfactant is present in the growth substrate in amounts preferably from 0.03 to 5% (by weight), based on growth substrate, more preferably 0.01 to 3%, in particular, 0.15 to 2%.
If binder is used, preferably the amount (by weight) of ionic surfactant based on the weight of binder (dry matter) is in the range 0.01 to 5%, preferably 0.5 to 4%.
It is preferred that there is substantially no other wetting agent than the ionic surfactant, and it is particularly preferred that there is substantially no other wetting agent than linear alkyl benzene sulfonate. Thus, levels of such other materials are preferably below 0.1% (by weight) in particular below 0.01%, based on the growth substrate.
If the growth substrate comprises foam, it may contain other types of conventional additives in addition to binder and wetting agent, for instance salts such as ammonium sulfate and adhesion promoters such as silanes.
In the method, plants are positioned in the synthetic growth substrate for growth. One plant, or more than one, may be positioned in a single block of growth substrate.
The method may be any method of growing plants in a mineral wool substrate. These applications include germination of seedlings, propagation of cuttings, growth of plants in containers, freely planted cultures and sucking beds.
In all cases, it is a particular benefit of the growth substrates defined that they can be re-used. Thus, in the disclosed technology it is also possible to position the plants in a block of growth substrate which has previously been used and wetted and allowed to dry out.
The growth substrate can be provided in the form of a coherent mass. The growth substrate may be in any integral form, for instance in the form of small blocks or plugs, larger blocks, or an extensive mat/slab. Other dimensions may be selected as convenient. The growth substrate can thus be a coherent matrix, which has been produced as such, but can be formed by granulating a slab of growth substrate material and consolidating the granulated material. Alternatively, it may be used as a flowable particulate or granular composition, which is given shape by being held in a container. Which form is used will depend on the type of material used for the growth substrate.
The mass of growth substrate may have a variety of height, width and length dimensions, as conventional.
During the method the plants are irrigated with water and nutrients, as is conventional. The use of ionic surfactant has the advantage that loss of the wetting agent to the irrigation water is minimal, allowing for a system in which there is essentially no anti foam material in the irrigation water.
In use we find that the growth substrate exhibits a particularly desirable distribution of water over height. This distribution can be determined by comparing the water content at the top of the substrate with the water content at the bottom of the substrate. Each of these values are usually expressed as percentages and the difference between them is preferably less than 40%, more preferably less than 35% and in particular less than 30%. This may even be a negative value, when the water content is greater at the top than at the bottom. It may be up to −10%.
The beneficial properties of the ionic surfactant allow the use of the growth substrate of the disclosed technology in specific ways to obtain particular advantages not achievable with conventional non-fibrous growth substrates.
Thus we also provide a method of growing plants in a growth substrate of the disclosed technology, the method comprising:
providing at least one growth substrate of the disclosed technology,
positioning one or more plants for growth in the growth substrate,
wherein the height of the growth substrate is at least 53 mm.
We find that this particular ionic surfactant, especially linear alkyl benzene sulfonate surfactant, provides a surprisingly effective combination of water handling properties.
Particular benefits are seen in water distribution properties. Water distribution properties are especially important when a growth substrate having relatively large height is used, because it is such materials which suffer most from problems of water concentrating in the lower regions of the substrate.
We also provide a method of growing at least 3 plants in growth substrate of the disclosed technology, the method comprising positioning the plants for growth in the growth substrate so that the roots of each plant are positioned in a growth region, and irrigating the plants with irrigation water over a period of at least three days, wherein during the irrigation period at least one water content parameter as measured in the growth regions surrounding the plant roots varies over the set of all growth regions by not more than 30%.
We find that the particular ionic surfactant, especially anionic surfactant, in particular linear alkyl benzene sulfonate surfactant (LAS), provides a surprisingly improved homogeneity of the growth substrate when used. In particular the homogeneity achieved is generally consistently better than with conventional non-ionic based wetting agent.
Thus, in the disclosed technology, inclusion in the growth substrate of ionic surfactant as the wetting agent contributes towards the ability of the substrate to result in homogeneity of water properties (including water retention, resaturation and hydraulic conductivity) within a single mass of growth substrate, between masses of growth substrate produced in a single batch, and between batches of growth substrate. Accordingly, growers can confidently apply plants to potentially huge areas of the same growth substrate and maintain, over that entire area, a very narrow range of water contents, using the same irrigation system, so that as many plants as possible are maintained at optimum water content and there is minimal wastage of irrigation water and additives.
We also provide a method of growing plants in a growth substrate of the disclosed technology, the method comprising:
providing at least one growth substrate of the disclosed technology,
positioning one or more plants for growth in the growth substrate,
wherein there are plants grown in the growth substrate for a growth period of at least 3 months.
Particular benefits are seen in resaturation properties and retention of wettability over time.
The resaturation properties mean that this growth substrate is especially beneficial in processes where the substrate must be dried out and rewetted. Thus, in a further aspect we provide a method of growing plants in a growth substrate of the disclosed technology, the method comprising:
providing at least one growth substrate of the disclosed technology,
positioning one or more plants for growth in the growth substrate,
wherein in the method there is a first growing period during which the growth substrate contains plants and contains water, and after this growing period there is at least one dry period of at least one week during which the substrate does not contain plants and is dry, and after this dry period there is at least one second growing period during which the substrate is rewetted and plants are positioned in it for growth.
Details of these preferred methods, when used with mineral wool growth substrates, are set out in our copending applications filed today under refs LAS01882WO, LAS01891WO and LAS01895WO.
According to the disclosed technology the growth substrate can exhibit improved physical properties, for instance improved bending properties. This can apply whilst maintaining firmness properties.
The root development properties of the product can be improved. For instance, more roots can be generated. The finer roots can exhibit better branching. The root distribution can be better—for instance there can be more roots in the top layer.
This can apply even if the product appears wetter to the user.


An optical fiber cable including a buffer tube wherein the optical unit is maintained in an axial center location of the buffer tube and protected from contact with an inner wall of the buffer tube. At least first and second gel layers are interposed between the buffer tube and the optical unit, wherein the first gel layer surrounds the optical unit, the second gel layer surrounds the first gel layer, and the first and second gel layers have different rheological properties. The inner gel layer may have a yield stress and a viscosity which are lower than a yield stress and a viscosity of the outer gel layer. The lower yield stress and viscosity of the inner gel layer serves to maintain the optical unit in an axial center position within the buffer tube and facilitates easy re-positioning of the optical unit to the axial center position when the buffer tube is flexed or bent. As a result, the optical unit may be maintained in a low stress state and stress-induced attenuation may be prevented.

The present invention relates to an optical fiber cable comprising an optical unit and a plurality of gel layers surrounding the optical unit. In particular, the present invention relates to an optical fiber cable comprising a buffer tube housing an optical unit and a plurality of gel layers having different rheological properties surrounding an optical fiber.
Optical fiber cables are used to transmit information at very high rates over long distances. Optical fiber cables may be classified into three general classifications based on cable structure: loose tube, monotube, and slotted core. In loose tube and monotube cables, buffer tubes are utilized as the primary structure for protecting the thin optical fibers contained within. In particular, the buffer tubes typically house an optical unit such as one or more loose optical fibers or an optical fiber ribbon stack having a plurality of optical fibers held together in a planar array by a common matrix material.
In a loose tube cable, a plurality of buffer tubes are stranded, helically or reverse helically, around a central strength member to form a stranded core. In addition to the buffer tubes, filler rods may be stranded around the central strength member in order to provide symmetry in design for fiber counts lower than that of a full fiber count cable. In a monotube cable, one or more optical fibers are housed in a single, centrally located buffer tube. Typically, the buffer tubes or stranded core is jacketed with an additional protective layer. Further, reinforcing yarns or fibers as well as waterblocking materials in the form of gels or hot melts, water swellable powers, yarns or tapes, and/or corrugated armor may be place between the jacket and the inner cable layers.
In a slotted core cable, the optical fibers reside in channels or slots which are generally filled with a gel material. These channels form a helical path along the longitudinal axis of the cable.
The buffer tubes"" primary function is protect the delicate optical fibers housed therein. Accordingly, control of the modulus, percent elongation to break, coefficient of thermal expansion, shrinkage, swelling and other physical properties of the buffer tubes is very important. Buffer tubes are typically made from xe2x80x9cengineering resinsxe2x80x9d such as polybutylene terepthalate (PBT), polycarbonate (PC), polyarnides such as nylon-12, polyolefin materials such as polyethylene-polypropylene copolymers and isotactic polypropylene (I-PP), or some layer combination of the above. See U.S. Pat. No. 6,085,009.
In the cable industry, it is well known that changes in ambient conditions lead to differences in water vapor pressure between the inside and the outside of a plastic cable jacket. This generally operates to diffuse moisture in a unidirectional manner from the outside of the cable to the inside of the cable. Eventually, this will lead to an undesirably high moisture level within the cable, especially if a plastic jacket is the only barrier to the ingress of the moisture. Water may also enter the cable because of rodent attacks or mechanical impacts that cause openings in the sheath system. While the presence of water within an optical fiber cable may not immediately impact its performance, the passage of the water along the cable interior to connection points or terminals or associated equipment inside closures, for example, may cause problems, especially in freezing environments and should be prevented.
The buffer tubes may be filled with a water blocking compound such as a thixotropic gel to prevent water ingress while allowing fiber movement during cable expansion or contraction. It is also know to use water swellable or superabsorbent materials, such as tape, power or yarn formed of polyacrylates with carboxylate functional groups, partially neutralized polyacrylic acid, polyarnides, or copolymers thereof, which can absorb water in the buffer tubes. Further, it is known to use a secondary low molecular weight oil to pre-wet the optical fibers and optical fiber ribbons in order to prevent water migration down interstices through the optical unit by way of capillary action.
Conventional buffer tubes are typically manufactured with a single thixotropic gel surrounding the optical unit. The yield stress of the gel allows the optical unit to freely move within the buffer tube so that the optical fiber may drift to locations other than the axial center of the buffer tube. However, it is important to prevent the optical unit from contacting the buffer tube wall which may result attenuation problems due to microbending and high stress.
The thixotropic gel material generally includes a thickening or gelling agent in a liquid carrier. Traditionally, three types of gels materials have been used in fiber-optic cables: (1) gels based on polar oils such as polyols; (2) gels based on natural or synthetic hydrocarbon oils; and (3) gels based on silicone oils. Organic and non-organic thickeners are typically present as relatively isometric colloidal particles. Gelling agents form a physical network structure in which the polymeric base oil molecules interact with the gelling agent through entanglements, adsorption onto the surface of particles such as pyrogenic silica, and/or some other secondary interaction. When a low stress is applied to a gel-like composition, the material acts substantially as a solid. If the stress is above a critical value (commonly known as the yield-stress of the material), then the secondary interactions are disturbed, the material flows, and as shear rate increases, viscosity decreases rapidly (i.e., materials having such characteristics are called xe2x80x9cthixotropicxe2x80x9d). This decrease in viscosity is largely reversible because it is typically caused by the temporary breakdown of secondary interactions between gelling agents and polymeric base oils. These interactions can reform following the release of shearing forces on the material.
The selection of gel materials is an important consideration in buffer tube manufacture since gel materials which are compatible with the material of the buffer tube may not be compatible with or protective of the optical unit it surrounds. Non-compatible gel materials can swell buffer tube polymers and are able to extract the additives therein and reduce the thermo-oxidative stability of the buffer tubes. U.S. Pat. No. 6,085,009 discloses a water blocking gel which is compatible with polyefin buffer tubes and is made of a polyolefin oil, wherein only a very small fraction of the polyolefin species have a molecular weight below about 2000.
The present invention is adapted to provide an optical fiber cable including a buffer tube structure wherein the optical unit is located in the buffer tube and protected from contact with an inner wall of the buffer tube. According to the present invention, there is provided an optical fiber cable comprising a buffer tube housing an optical unit including at least one optical fiber, and at least first and second gel layers interposed between the buffer tube and the optical unit, wherein the first and second gel layers have different rheological properties. The first gel layer surrounds the optical unit and the second gel layer surrounds the first gel layer.
In accordance with a preferred embodiment of the present invention, the inner gel layer may have a yield stress and a viscosity which are lower than a yield stress and a viscosity of the outer gel layer. The lower yield stress and viscosity of the inner gel layer serve to maintain the optical unit in an axial center position within the buffer tube and facilitate easy re-positioning of the optical unit to the axial center position when the buffer tube is flexed or bent. As a result, the optical unit may be maintained in a low stress state and stress-induced attenuation may be prevented.
The above and other features of the invention including various and novel details of construction and process steps will now be more particularly described with reference to the accompanying drawings and pointed out in the claims. It will be understood that the particular optical fiber cable embodying the invention is shown by way of illustration only and not as a limitation of the invention. The principles and features of this invention may be employed in varied and numerous embodiments without departing from the scope of the invention.

Optical cable housing an optical unit surrounded by a plurality of gel layers


Surgical instrumentation for use in placing an implant into a disc space between a pair of spinal vertebrae may include: (a) a distractor having a distal end that may be placed into the disc space between the pair of spinal vertebrae; (b) an inserter for use in moving the implant toward the disc space between the pair of spinal vertebrae; and, (c) a distractor/inserter rail/groove interconnection that interconnects the distractor and the inserter for relative movement thereby.

A. Field of Invention
This invention pertains to the art of methods and apparatuses regarding spine surgery and more specifically relates to surgical procedures and associated instrumentation used to position an implant within an intradiscal space between two adjacent vertebral bodies.
B. Description of the Related Art
The volume of spinal surgeries to treat degenerative disc and facet disease has steadily increased over the past decade, fueled by population demographics and advancements in diagnostic and instrumentation adjuncts. Improvements in intraoperative radiological imaging and surgical technique have generated a great deal of interest in applying minimally invasive surgical (MIS) techniques to spinal applications. As in other surgical subspecialties, it is hoped such minimally invasive techniques applied to spinal surgery will result in less soft tissue trauma, less operative blood loss, reduced operative time, faster recovery periods and lower costs.
Known spinal surgical techniques, though generally working well for their intended purposes, have been adopted from traditional open surgical (non-MIS) techniques. As a result, known spinal surgical methods, instrumentation and interbody implants have limitations. One limitation is that the physical components are relatively large and bulky. This reduces surgeon visualization of the surgical site. Another limitation of known spinal surgical methods is that known surgical tools and implants are cumbersome and difficult to maneuver within the limited surgical space available. The limitations of current instrumentation in MIS spine surgery are noted particularly with regards to interbody fusion surgery.
The present invention provides methods and apparatuses for overcoming these limitations by providing surgical instrumentation that allows for minimally invasive spinal surgery and that provides for precise movement and placement of an implant into the disc space. The inventive instrumentation provides centralized distraction of the disc space, assuring optimized interspace sizing and annular distraction, without inhibiting the placement of interbody fusion devices.

Spine surgery method and instrumentation