Pharmaceutical compositions containing a carbapenem of the structural formula I

This invention relates to 2-S/O— and S/N formaldehyde acetal derivatives of carbapenem-3-carboxylic acids of the general formula I
wherein R1 denotes hydrogen, hydroxymethyl or 1-hydroxyethyl, R2 denotes hydrogen or methyl and R3 denotes a pharmaceutically acceptable group which is bonded to the remaining part of the molecule by an oxygen-carbon single bond or a nitrogen-carbon single bond and which is selected from the group comprising substituted or unsubstituted: alkoxy, alkenyloxy, alkinyloxy, cycloalkoxy, N-heterocyclyl, heterocyclyloxy, heterocyclylcarbonyloxy, heterocyclylthiocarbonyloxy, acyloxy, thioacyloxy, alkoxycarbonyloxy, carbamoyloxy, thiocarbamoyloxy, heterocyclyloxycarbonyloxy, heterocyclyloxythiocarbonyloxy, N-heterocyclycarbamoyloxy, N-heterocyclylthiocarbamoyloxy, heterocyclylcarbonylamino, heterocyclylthiocarbonylamino, heterocyclyloxycarbonylamino, acylamino, alkoxycarbonylamino, alkoxythiocarbonylamino, thioacyclamino, N-heterocyclylcarbamoylamino, N-heterocyclylthiocarbamoylamino, carbamoylamino, thiocarbamoylamino, imidoylamino, guanidino, N-heterocyclyl-alkoxycarbonylamino, N-heterocyclyl-alkylthiocarbonylamino and N-sulfonylamino where the foregoing alkyl, alkenyl, alkinyl, acyl, thioacyl or imidoyl molecule parts contain 1 to 6 carbon atoms and the heterocyclyl moiety is monocyclic or bicyclic and contains 3 to 10 ring atoms, of which one or more are selected from the series comprising: oxygen, sulphur and nitrogen and where the substituents of the above-mentioned groups R may be: alkyl, acyl, thioacyl, heterocyclyl, hydroxyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, aminoalkoxy, amidinoalkoxy, guanidinoalkoxy, acyloxy, heterocyclyloxy, alkylheterocyclyloxy, hydroxyalkylheterocyclyloxy, aminoalkylheterocyclyloxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, carbamoyloxy, alkylcarbamoyloxy, dialkylcarbamoyloxy, thiocarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, thiocarbamoyloxy, alkylthiocarbamoyloxy, dialkylthiocarbamoyloxy, mercapto, alkylthio, hydroxyalkylthio, aminoalkylthio, monoalkylaminoalkylthio, dialkylaminoalkylthio, amidinoalkylthio, acylthio, heterocyclylthio, alkylheterocyclylthio, hydroxyalkylheterocyclylthio, aminoalkylheterocyclylthio, carbamoylthio, monoalkylcarbamoylthio, dialkylcarbamoylthio, thiocarbamoylthio, alkylthiocarbamoylthio, dialkylcarbamoylthio, amino, monoalkylamino, hydroxyalkylamino, aminoalkylamino, dialkylamino, oxo, oximino, or alkylimino, imidoylamino, alkylimidoylamino, dialkylimidoylamino, tetraalkylammonium, cycloalkylamino, heterocyclylamino, alkylheterocyclylamino, heterocyclylcarbonylamino, alkylheterocyclylcarbonylamino, acylamino, amidino, monoalkylamidino, dialkylamidino, guanidino, alkylguanidino, dialkylguanidino, carbamoylamino, thiocarbamoylamino, alkylcarbamoylamino, thiocarbamoylamino, alkylthiocarbamoylamino, nitro, chloro, bromino, fluoro, iodo, azido, cyano, alkylsulphinyl, alkylsulphonyl, sulphonamido, sulphamoyloxy, alkylsulphamoyloxy, alkylsulphonyloxy or sulpho, sulphoxy, carboxamido, N-monoalkylcarboxamido, N,N-dialkylcarboxamido or carboxy, where the substituents, independently of one another, occur once or several times and their alkyl moiety contains 1 to 6 carbon atoms, and where the heterocyclic moiety is monocyclic or bicyclic and contains 3 to 10 ring atoms, of which one or more are selected from the series comprising: oxygen, sulphur and nitrogen, which compounds and their pharmaceutically acceptable salts, esters and amide derivatives are useful as antibiotics and as β-lactamase inhibitors.
Pharmaceutically acceptable groups R3, which are bonded via an oxygen-carbon single bond or a nitrogen-carbon single bond are groups as are customary, for example, in the field of β-lactam antibiotics or β-lactamase inhibitors. Such groups are found, for example, in M. S. Sassiver, A. Lewis in "Advances in Applied Microbiology", Ed. D. Perlman, Academic Press N.Y. (1970) or in many patents, e.g. U.S. Pat. No. 5,096,899.
The term "pharmaceutically acceptable salt" as used herein and in the claims, includes non-toxic acid and base salts and the salts of zwitterionic species. Salts with
a base include inorganic salts such as sodium, potassium, magnesium and calcium, or ammonium and salts with non-toxic amines such as trialkylamines, alkanolamines, arginine or cyclic amines such as piperazine, procaine and other amines, which have been used to form salts of carboxylic acids. Salts with an acid include inorganic acid salts such as hydrochloride, sulfate, phosphate and the like and organic acid salts such as acetate, maleate, citrate, succinate, ascorbate, lactate, fumarate, tartrate and oxalate and other organic salts with acids which have been used to form salts with amines.
The pharmaceutically acceptable esters and amide derivatives as used herein, serve as prodrugs by being hydrolyzed in the body to yield the antibiotic per se. They are preferably administered orally since hydrolysis occurs principally under the influence of the digestive enzymes. Parenteral administration may be used in some instances where hydrolysis occurs in the blood. Examples of pharmaceutically acceptable esters and amide derivatives include physiologically hydrolyzable esters and amides known and used in the penicillin and cephalosporin fields as, e.g. in Advances in Drug Res. 17, 197 (1988). Such esters and amide derivatives are prepared by conventional techniques known in the art.
The compounds according to the invention have several asymmetric centers and can thus exist in several stereochemical forms. The invention includes the mixture of isomers and the individual stereoisomers. The most preferred compounds of formula I have the 1R, 5S and 6S configuration of the substituted carbapenem nucleus and the 1′R or the 1′S configuration of the 6-(1-hydroxyethyl) side chain. Additionally, asymmetric carbon atoms can be included in the substituent R3. The invention includes the compounds having the R and S configuration in the substituent R3.
Moreover, the invention also relates to conventional carbapenem antibiotics, which are commercially available or investigated for clinical use. A comprehensive report about such carbapenem antibiotics is given in Heterocycles 54, 497, 2001.
This invention also relates to pharmaceutical compositions containing carbapenem antibiotics and their preparation. It relates also to methods of treatment where such compositions are used when an antibiotic effect is indicated.
The terminology for compounds of this class may either be based upon the root name "carbapenem" which employs a trivial and simple system of nomenclature (used in the general description). Alternatively, these compounds can also be described by the nomenclature according to the Chemical Abstract system (bicyclo-nomenclature),
which is more appropriate to describe individual compounds of this family. Therefore the Chemical Abstract nomenclature is used within the Example Section.

The classical β-lactam antibiotics such as the penicillins or the cephalosporins, have partly become ineffective in the therapy of infectious diseases because of bacterial resistance. Besides the natural resistance of certain bacteria, many strains of pathogenic microorganisms have acquired resistance with continuous use of antibiotics on a large scale. Thus, most species of Staphylococcus aureus have become resistant against the penicillins and many Gram-negative bacteria such as Enterobacter cloacae, Pseudomonas aeruginosa or even Escherichia coli have acquired resistance against the cephalosporins.
Although the carbapenems according to the invention are very active as mono-substances against penicillin sensitive Staph. aureus and penicillin resistant Staph. aureus that produce β-lactamase, they are not active against methicillin resistant Staph. aureus (MRSA) or methicillin resistant Staph. epidermis (MRSE). For example, four representative carbapenems exhibited only low activity against (methicillin resistant) Staph. Innsbruck with small inhibition zones of 0-12 mm in the plate test as described in U.S. Pat. No. 6,482,818 or EP 1 100 800. The lack of activity against MRSA within the class of carbapenems is also documented, e.g. in EP 384 410. Resistance levels of MRSA have been increased considerably within the last decade and already in 2000 all marketed carbapenems completely lacked anti-MRSA activity (Journal of Antimicrobial Chemotherapy 2000, 45, 379).
Consequently, current research in the field of antibiotics is focused on methods to overcome growing MRSA and MRSE resistance, which might become a major threat to human life in near future.
Staphylococcus aureus is one of the most abundant bacterial pathogens in infectious diseases. In 2004, from diseases caused by Staph. aureus, 22.6% were reported resistant to methicillin or oxacillin (PEG-Resistenzstudie, Paul Ehrlich Gesellschaft für Chemotherapie e.V, www.p-e-g.org). The eradication of MRSA and MRSE is particularly difficult, because many species of these bacteria are also resistant to antibiotics that are not β-lactams, e.g. quinolone antibiotics.
MRSA resistance is not due to the formation of β-lactamase but to an entirely different mechanism, namely a lack of, or inadequate binding of the antibiotic to a penicillin binding protein PBP 2a, present with all MRSA strains. From this viewpoint, pharmaceutical preparations of penicillins or cephalosporins with β-lactamase inhibitors are not a solution to overcome resistance of MRSA and also the combination of amoxicillin and clavulanate is inappropriate in infections due to MRSA. (Journ. Antimicrob. Ther. 1989, 49.).
Another attempted method to overcome methicillin resistance was published in EP 384 410 with the description of a synergism between three carbapenems and penicillins or cephalosporins. The use of piperacillin and cefotiam in combination with imipenem was considered to be especially preferable in EP 384410. However, the above-mentioned combinations described by prior art are hardly sufficiently effective with reported mean MICs of 27.9 μg/ml for piperacillin/imipenem or 14.4 μg/ml for cefotiam/imipenem. Also a synergism between meropenem and cefpiramide (Eur. J. Clin. Microbiol. Infect. Dis. 10, 77-84, 1991) was reported with mean MICs of 13.2 μg/ml. Such high levels are impossible or very difficult to be maintained in vivo during the entire therapy. Although these combinations of prior art were more active than the individual components alone, a substantial improvement was desirable.
The fact that in EP 384410 was not validated in Germany, in the US and in other countries in 1995, indicates that the combinations described by prior art lack practicability.
As all marketed carbapenems currently used are administered parenterally because they do not have sufficient oral activity (Infection 14, (1986), suppl. 2, S 115) an orally active composition containing an (orally active) penicillin or a cephalosporin and a carbapenem could not be prepared by prior art. An orally active composition is desirable for the so called "switched therapy" in which the treatment is started with a parenteral formulation in the hospital and continued with the oral therapy after an earlier release of the patient. A more recent overview about oral carbapenems was given in Curr. Med. Chem.—Antiinfective Agents, 2000, 1, 1.
The current antibiotic of choice against MRSA infectious diseases is linezolide, a bacteriostatic agent (Chemotherapie Journal. 2002, 11, 113-6).
In order to overcome the resistance of MRSA we investigated the compositions of 29 conventional classical β-lactam antibiotics with 15 carbapenems for a possible synergism. For these investigations two highly resistant MRSA hospital strains, i.e. Staph. Innsbruck and MRSA 7268/02 were used. Staph. Innsbruck is resistant to oxacillin, methicillin, ampicillin and ciprofloxacin, MRSA 7268/02 is multiresistant to oxacillin, methicillin, enrofloxacin, clindamycin, ciprofloxacin and moxifloxacin. Such highly resistant bacteria have emerged recently and were not frequent 10 years ago.
Surprisingly we found, that from the investigated conventional β-lactam antibiotics (12 penicillins and 17 cephalosporins) epicillin showed an outstanding effect against MRSA of high resistance when combined with carbapenems. The synergistic effect of epicillin/imipenem was much higher than that of prior art using piperacillin/imipenem or cefotiam/imipenem. Time dependent counting of colony forming units (cfu) revealed that epicillin/imipenem at 2+2 μg/ml was also much faster in eradicating MRSA 7268/02 than other investigated penicillin/imipenem or cephalosporin/imipenem preparations described by prior art, including that of ampicillin/imipenem. With the epicillin/imipenem combination the number of cfu was decreased by 99.6% after 6 hrs of incubation at 37° C., revealing that this preparation is strongly bactericidal against MRSA 7268/02. In contrast, the especially preferred combinations described by prior art, namely piperacillin/imipenem or cefotiam/imipenem were only marginally bactericidal with reductions in cfu's by 17 or 71% respectively (Table 1)
TABLE 1Bactericidal Effect of Combinations ofCarbapenems and Penicillins or Cephalosporinsagainst MRSA 7268/02
Neither epicillin, nor linezolide showed any significant reduction of cfu's, when used alone. Meropenem at 4 μg/ml was also less bactericidal than the epicillin/meropenem composition at 2+2 μg/ml (Table 2)
TABLE 2Synergistic Effect of Epicillin and Meropenemagainst MRSA 7268/02
Using the same bacterium and concentrations, the combination epicillin/meropenem gave a reduction in cfu's by 99.7% as compared to 42.5% for piperacillin/meropenem. Similarly, with Staph. aureus Innsbruck at 4+4 μg/ml, reduction of cfu's after 6 hrs of incubation at 37° C. by epicillin/meropenem was 100% as compared to a marginal 10% reduction achieved by piperacillin/meropenem (Table 3). The bactericidal activity of epicillin/meropenem was also superior to ampicillin/meropenem and amoxicillin/meropenem. Similarly, other epicillin/carbapenem combinations also had the very fast bactericidal action.
In short, the combination of epicillin with a carbapenem is more active, more bactericidal and faster than corresponding preparations of prior art in eradicating MRSA.
TABLE 3Bactericidal effect of Penicillins/Meropenem against Staph. Innsbruck
The high bactericidity of this combination is in sharp contrast to the current antibiotics used against MRSA, i.e. linezolide and vancomycin, both having only bacteriostatic activity (Chemotherapie Journal. 2002, 11, 113-6; Antimicrob. Ag. Chemother. (2005), 49, 2735).
The high synergistic activity of the combination epicillin/meropenem is also observed in the plate test with the following diameters of inhibition zones:
MRSA 7268/02Staph. InnsbruckEpicillin (alone)30μg14 mm10 mmMeropenem (alone)10μg13 mm14 mmEpi and Mero30 + 10μg23 mm20 mmVancomycin30μg19 mm20 mm
Unlike the inhibition zones caused by the single substances epicillin or meropenem, and unlike all investigated single β-lactams, those generated by the combination of epicillin and meropenem remained clear after additional incubation (40 hr) at 37° C., confirming the above-mentioned strong bactericidal effect. This effect is also observable with other epicillin/carbapenem combinations. Therefore the use of a composition of epicillin and a carbapenem is strongly preferred.
The high bactericidity of this combination is also in sharp contrast to that of e.g. oxacillin/meropenem. No synergism of the latter composition was observed in the plate test.
MRSA 7268/02Staph. InnsbruckOxacillin (alone)30μg 0 mm 0 mmMeropenem (alone)10μg13 mm13 mmOxacillin and Mero30 + 10μg13 mm13 mm
The high and fast bactericidal activity of a combination of two β-lactam compounds, e.g. epicillin and meropenem against MRSA is surprising. It has been stated by prior art, that all β-lactams should be reported "resistant" to methicillin (or oxacillin) (W. Cullmann in "Antibiotics and Chemotherapy" Vol. 47 (Oral Cephalosporins), p. 79 (1995). This citation constitutes a prejudice of prior art against the present invention.
The use of carbapenems and epicillin to eradicate MRSA or MRSE is not known by prior art. No references were available from Sci-Finder Scholar (Am. Chem. Society) using both key words "epicillin and mrsa", whereas 9082 references were available with the (single) key word "mrsa".
An objective of the present invention is to provide a novel pharmaceutical composition of a carbapenem antibiotic and epicillin which proves to have a very broad antibacterial spectrum including MRSA and MRSE. The above mentioned synergism with epicillin is also inherent to orally active carbapenems.
Epicillin was widely used in the 1970s and 1980s as orally and parenterally active antibiotic. A report of clinical experience is given e.g. in N. Z. med. J. 75, 77 (1972). The carbapenems are either commercial products or are prepared by a method described in EP 1 100 800 or are described elsewhere, e.g. in Heterocycles, 54, 497 (2001); Drugs 61, 553 (2001); Current Opinion in Anti-Infective Investigational Drugs 2, 133 (2000);
As already mentioned, the selection of carbapenems in the preparation of synergistic mixtures is not very critical. In fact all 18 carbapenems so far investigated showed a pronounced synergism against MRSA when combined with epicillin. On the other hand, the selection of partner antibiotics is more crucial. In contrast to teaching of prior art, only epicillin can provide sufficient bactericidal activity to eradicate MRSA which have a high resistance level in the synergistic action with carbapenems.
For oral use, prodrug esters or prodrug amide derivatives of epicillin can also be applied to prepare synergistic preparations. Such prodrugs are known in the art and described e.g. in Advances in Drug Res. 17, 197 (1988) or in Curr. Med. Chem.—Anti-Infective Agents 2002, 1, 1. Examples of such prodrug esters derived of similar antibiotics are pivampicillin, bacampicillin and pivcefalexin. An example for prodrug amide derivatives is hetacillin.
Examples of useful conventional carbapenems in the preparation of synergistic mixtures are the carbapenems described in EP 1 100 800, imipenem, imipenem/cilastatin, meropenem, panipenem, panipenem/betamipron, ertapenem, biapenem, doripenem, saftrinem, lenapenem, tebipenem, tomopenem S-4661, SM 216601, GV 129606, ZD-4433, ER-35786, R-83201, R 95867, DU-6681, BO-2502A, BO-3482, DK-35C, DA-1131, S-4661, L-646591, L-786,392, L-695,256, L-786,392, L-084, L-036, GV104326, GV-118819, GV 143253, MK-0826, J-110,441, J-111225, FR-21818, DX-8739, CS-023, ME-1036, CP 5068, OCA-983, CL 188624, CL-190294, T-5575, PZ-601.
Equivalently, for oral use, hydrolysable prodrug esters, also known in the field of carbapenems (Antimicrob. Agents, Chemother. 1998, 42, 1527; Heterocycles 54, 497 (2001), Curr. Med. Chem.—Anti-infective Agents 2002, 1, 1), can be used to prepare synergistic mixtures. Examples of prodrug carbapenems are CS-834, L-084, GV118819, DZ-2640, CL191121.
The ratio of carbapenem to epiciilin can vary within a large scope. Useful ratios are 1:10 to 10:1. Preferred ratios are 1:4 to 4:1. Strongly preferred ratios are 1:1 to 1:3
The above-mentioned combination of epicillin and a carbapenem can be supplemented with a variety of other biologically active ingredients. Examples are dehydropeptidase inhibitors such as betamipron or cilastatin, which is used currently to protect carbapenems such as imipenem.
The fast and progressive reduction of colony forming units makes the inventive combinations the method of choice as initial therapy for confirmed or suspected MRSA and MRSE infections.
A major drawback with infectious diseases is emergence of life threatening sepsis, a severe illness from a bloodstream infection. It is estimated that bacterial sepsis kills more than 200 000 people per year in the US (www.nursing-home-abuse-resource.com). Sepsis is also common with MRSA. To avoid such threat, bacterial units can be reduced by the initial bactericidal therapy according to the invention. Then a secondary therapy with an antibiotic, e.g. an antibiotic other than a β-lactam, can follow up to eradicate the largely diminished number of bacteria. Therefore, the inventive combination may be further supplemented with antibiotics. Examples for such supplements are sulfonamides, e.g. sulfathiazole/trimethoprim, tetracyclines, e.g. aureomycin or doxycycline, aminoglycosides, e.g. clindamycin, glycopeptides, e.g. teicoplanin, vancomycin, quinolones, e.g. ciprofloxacin, moxifloxacin, gatifloxacin or rifamycins e.g. rifampin, macrolides, e.g. erythromycin or other bacteriostatic agents, e.g. linezolid.
A selection of pharmaceutical preparations according to the invention showed also high antibacterial activity against bacteria different from staphylococci: In the disc susceptibility test, simultaneous application of 30 micrograms of epicillin and 10 micrograms of carbapenem gave the following inhibition diameters: E. coli (27-40 mm), E. cloacae (23-27 mm), Sr. pneumoniae (31-44 mm), Enterococcus faecalis (21-40 mm) and Ps. aeruginosa (13-26 mm). These data correspond to those of a clinically useful injectable carbapenem used as a single substance as described in Journ. Antimicrob. Chemotherapy 24, (1989), Suppl. A, 253.
The new pharmaceutical preparations are valuable bactericides to be used in human and veterinary medicine. Due to their large antibacterial spectrum they can also be used as medicaments for treating suspected or confirmed infections that are caused by other than the above-mentioned Gram-positive and Gram-negative bacteria, i.e. by MRSA, MRSE, Moraxella catharrhalis, Haemophilus influenzae, Klebsiella pneumoniae, Bacillus subtilis, Salmonella typhosa, Enterobacter cloacae, Citrobacter, Pseudomonas aeruginosa, Bacteriumproteus and anaerobic bacteria.
A major field of antimicrobial therapy using carbapenems as single substances is sinusitis, an inflammation of the respiratory tract. Bacterial sinusitis is caused predominantly by streptococcus pneumomiae, moraxella catharrhalis, haemophilus influenzae, some anaerobic bacteria and penicillin sensitive and penicillin resistant (β-lactamase producing) staphylococcus aureus and MRSA, often emerging also in mixed infections (Journal of laryngology and otology (2005), 119(4), 251). Carbapenems alone can eradicate efficiently all of these bacteria except MRSA. The combination of a carbapenem/epicillin composition closes the gap arising from the resistance of MRSA. Therefore, the inventive combination is especially useful to cure bacterial sinusitis. Furthermore, other infectious diseases, e.g. urinary tract infections or wounds, confirmed or assumed to be caused by MRSA or MRSE, can be cured by application of the pharmaceutical composition according to the invention.
The new bactericidal MRSA active pharmaceutical compositions according to the invention are valuable remedies which are active against most Gram-positive and Gram-negative pathogens including also most penicillin- and cephalosporin resistant and anaerobic bacteria. Due to their very broad antibacterial spectrum, they are valuable medicaments for use, e.g. in intensive care units. On the other hand, since epicillin is an orally active drug, its combination with orally active carbapenems provides also valuable remedies for rapid oral treatment of community-acquired infections.
The pharmaceutical compositions according to the invention can contain the free acid and in particular the alkaline and earth metal salts or the zwitterionic species of their components. They are useful bactericides and can be employed to remove pathogens from dental and medical equipment for removing microorganisms and for therapeutic use in humans and animals. For the latter purposes, pharmaceutically acceptable salts of their active components can be used, as are known per se and are used in the administration of penicillins and cephalosporins. These salts can be used together with pharmaceutically acceptable liquid and solid excipients to form suitable dose unit forms such as pills, tablets, capsules, suppositories, syrups, elixirs and the like, which can be prepared by processes which are known per se.
The new pharmaceutical preparations can furthermore be used as additives for animal feeds, for preserving foodstuffs or feeds and as desinfectants. For example, they can be used in aqueous preparations in concentrations in the range 0.1 to 100 parts of antibiotic/million parts of solution for destroying and inhibiting the growth of harmful bacteria on medical equipment and as bactericides in industrial applications, for example in water-based paints and in soft water for paper mills, for inhibiting the growth of harmful bacteria.
The new pharmaceutical composition according to the invention may be used alone or together with other active components in any of a large number of pharmaceutical preparations. These preparations can be used in capsule form or as tablets, powders or liquid solutions or as suspensions or elixirs. They can be administered orally, intraperitoneally, intravenously or intramuscularly.
The preparation is preferably administered in a form which is suitable for absorption through the gastrointestinal tract. Tablets and capsules for oral administration may be in dose unit form and can contain customary medicament excipients, such as binders, for example syrup, gum arabic, gelatin, sorbitol or polyvinylpyrrolidone, fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine, lubricants, for example magnesium stearate, talc, polyethylene glycol or silica, disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulfate. The tablets may be coated by processes which are known per se. Oral liquid preparations can be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs and the like or can exist as dry products, for example for reconstitution before using water or other suitable excipients. Liquid preparations of this type can contain additives which are known per se, such as suspending agents, for example sorbitol syrup, methylcellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, or hydrogenated edible oils, for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol, preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid. Suppositories contain suppository bases which are known per se, for example cocoa butter or other glycerides.
The preparations for injection can be in dose unit form in ampoules or in containers containing several doses along with an added preservative. The preparations can be in the form of suspensions, solutions or emulsions in oily or aqueous excipients, and they may contain formulation agents such as suspending agents, stabilizers and/or dispersants. Alternatively, the active component may be in powder form for reconstitution before using a suitable excipient, for example sterile, pyrogen-free water.
The preparations can also be in suitable form for absorption through the mucous membranes of the nose and of the throat or of the bronchial tissue, and can be in the form of powders or liquid sprays or inhalants, sucking sweets, as throat paints, etc.
For eye and ear medications, the preparations can be used in the form of individual capsules in liquid or semi-solid form or they can be used as drops, etc. Topical applications can exist or be formulated in hydrophobic vehicles as ointments, creams, lotions, paints, powders, etc.
The two active components, i.e. the carbapenem and epicillin may also be administered separately. For example, a carbapenem can be administered by the intravenous route and epicillin by the oral route. Conveniently however, the two active agents will be administered by the same route, e.g. the intravenous route or the oral route.
The composition according to the invention can contain, in addition to the excipient, other components such as stabilizers, binders, antioxidants, preservatives, lubricants, suspending agents, viscosity control agents or flavours or the like.
The composition according to the invention may also contain, in addition to the excipient, enzyme inhibitors, e.g. betamipron or cilastatin (Merck Index, 11th ed. 2275) to increase the therapeutic effect.
For veterinary medicine, the composition can be formulated, for example, as an intramammary preparation in either long-acting or rapid-release vehicles. The dose to be administered is highly dependent on the state of the subject to be treated and the weight of the host, and on the method and frequency of administration. In general, a daily oral dose contains about 10 to 200 mg of active component/kg of body weight of the subject in case of one or more administrations per day. A preferred daily dose for adult humans is in the range of 20 to 120 mg of active component/kg of body weight.
The preparation according to the invention can be administered in various unit dose forms, for example in solid or liquid dose forms which can be taken orally. The preparation can contain 0.1 to 99% of active material per unit dose, either in solid or in liquid form. The preferred range is about 10 to 60%. The preparations generally contain 15 to about 1500 mg of active component but it is generally preferred to use a dose amount in the range of 250 to 1000 mg. In the case of parenteral administration, the unit dose is normally the pure compound in a sterile water solution or in the form of a soluble powder, which may be dissolved.
The examples below illustrate the antibacterial activities, in comparison with pharmaceutical compositions described by prior art. In addition, preparations and methods of treatment according to the invention are exemplified.

Bactericidal anti-MRSA active pharmaceutical composition containing carbapenems

Abstract: and epicillin are strongly bactericidal against MRSA and MRSE. Equivalently, compositions of conventional carbapenem antibiotics and epicillin are highly synergistic in eradicating said bacteria.


Disclosed herein are methods to treat cognition disorders, particularly those associated with aging. The method comprises administering a combination of a carnitine and an oxidant. Preferably the oxidant is thioctic acid. Preferably 0.12 grams to 3 grams of carnitine (particularly ALC) and 0.12 and 1.5 grams of R-xcex1-lipoic acid are administered. Optionally, coenzyme Q and/or creatine also are administered. Preferably 10 mg to 500 mg/day of coenzyme Q10 and 1 to 30 grams/day of creatine are administered. The same method can be used to treat cognition deficits associated with carbon monoxide poisoning, mild traumatic brain injury, Type 2 diabetes mellitus, obsessive-compulsive disorder, environmental toxin exposure, and other conditions.

This invention is related to the prevention and amelioration of memory deficits related to aging and other causes. More specifically, this invention is related to the administration of micronutrients, such as an antioxidant, a canitine product, and optionally coenzyme Q and/or creatine to those at risk of memory loss.
Many adults gradually develop noticeable difficulties in memory, at first for names, then for events, and sometimes even occasionally for spatial relationships. The majority of healthy older people complain about forgetfulness and decreased concentration, and this compromises their quality of life. It is well established that virtually all aspects of cognitive functioning deteriorate with age. There has also been a rapid increase in the interest of clinicians, researchers and the pharmaceutical industry in the development of new classes of drugs for the palliative treatment of age-related cognitive deficits and dementing conditions. This widely experienced so-called benign forgetfulness, or benign senescent forgetfulness, bears no proven relationship to degenerative dementia but may be a forewarning, since there are some similarities.
Kral was the first to introduce diagnostic terminology for age-associated changes in memory (J Gerontol 13: 169-176, 1958; Can Med Assoc J 86: 257-260, 1962). He used the term xe2x80x9cbenign senescent forgetfulnessxe2x80x9d (BSF) to distinguish subjects with mild memory decline from those with more severe, xe2x80x9cmalignantxe2x80x9d changes (MSF), and also from those with normal memory functions.
Since then BSF and MSF have often been used in the medical literature and have become a generally accepted notion among clinicians. Generally, BSF is characterized by patchy and variable difficulties remembering details of experiences (names and places), but with relative ease in recalling the experience itself. Usually the forgotten details are recalled later. BSF is not progressive and does not increase the risk of developing dementia. MSF is characterized by an inability of the individual to recall events in the recent past, disorientation with regard to personal data, and retrogressive loss of remote memories. MSF individuals often are unaware of their deficit and may confabulate. In a four-year study of 20 cases of BSF and 34 of MSF, one patient with BSF deteriorated cognitively and all MSF patients deteriorated. A recent three-year study of 68 BSF patients reported that 9% became demented.
Because Kral did not operationalize the concept of BSF, a National Institute of Mental Health (NIMH) working group, which was set up to describe memory changes more precisely, proposed the concept of xe2x80x9cage-associated memory impairmentxe2x80x9d (AAMI) as a diagnostic entity (Crook et al. 1986, ibid.). In brief, the criteria of AAMI include the presence of subjective memory decline, objective evidence of memory loss (in a well-standardized memory test, a score at least one standard deviation below the mean of younger adults), adequate intellectual function, and the absence of dementia or other memory-affecting disease (e.g. stroke) in a person aged 50 years or older. Thus, the AAMI diagnosis identifies persons with subjectively and objectively evidenced memory loss without cognitive decline impairing enough to warrant the diagnosis of dementia. The criteria leave open the question of progression in the condition.
McEntee and Crook (Neurology 40: 526-530, 1990) estimated that AAMI might affect most of the over-50 population to some degree. However, Lane and Snowdon (Memory and dementia: A longitudinal survey of suburban elderly. In: Lovibond P, Wilson P (eds). Clinical and abnormal psychology. Elsevier, Amsterdam, 365-376, 1989) reported a prevalence rate of 35% for AAMI in subjects aged 65 years or over. The results are somewhat hampered by the low participation rate (58%) of the study population, and by the fact that the methodology used did not strictly follow the definitions of the NIMH working group. On the basis of memory test performance alone, Larrabee and Crook (Int Psychogeriatr 6: 95-104, 1994) estimated the prevalence of AAMI to vary from 39% in the age group 50 to 59 years to 85% in the age group over 80 years. In that study, no exclusion criteria were employed. Barker et al. (Br J Psychiatry 167: 642-648, 1995) identified as many as 79% of the participants in the AAMI category by memory test results. However, after applying stringent exclusion criteria, they reported a 15.8% prevalence of AAMI in 50- to 64-year-old and 24.1% in 65- to 79-year-old subjects.
A task force of the International Psychogeriatric Association (IPA) in collaboration with the World Health Organization (WHO) recently proposed diagnostic criteria for xe2x80x9caging-associated cognitive declinexe2x80x9d (AACD) (Levy, Int Psychogeriatr 6: 63-68, 1994). The diagnosis of AACD is based on a more comprehensive evaluation of cognition than that of AAMI. Deterioration in any major cognitive domain is sufficient for identifying AACD. The cognitive domains specified in the AACD criteria are memory and leaming, attention and concentration, thinking, language and visuospatial functioning. Also differing from the AAMI criteria, the subject with AACD is required to score one standard deviation below age- and education-specific standards (not those of younger adults) in tests assessing cognitive abilities. Thus, the AACD diagnosis identifies persons with subjective and objective cognitive decline, which is not impairing enough to warrant the diagnosis of dementia. In presenting the AACD criteria, the task force recognized the individual in progression or not to dementia.
AAMI may start in middle age (around the age of 40 years), as measured by some categories of cognitive tests. Age-related cognitive problems may lie dormant for decades and only become gradually or suddenly apparent as the individual realizes that some aspect of functioning is no longer what it used to be. Some propose that gradual cognitive decline may be due to accumulation of minor brain insults, such as falls from which an individual appears to completely recover. At first, these minor pathologies may have little impact but, as they accumulate with advancing age, their amassed effects result in discernible cognitive deficits. A decline in sensory, perceptual and physical performance can greatly impact general cognitive functions, even without direct or causal relation to cognitive performance. xe2x80x9cExecutive functionxe2x80x9d appears an important mediator of age-related dysfunction, as it has been shown that after correction for executive function, age was not a predictor for test performance.
Because of the high rate of memory impairment, AAMI is likely to be a phenomenon of normal aging rather than a continuum from normal aging to a pathologic state such as Alzheimer""s disease. The neuropsychological methods used for AAMI diagnosis are ambiguous and do not always differentiate subjects with very early dementia. However, these subjects can be differentiated by means of a more detailed neuropsychological evaluation. In comparison with age-matched controls, AAMI subjects appeared to be impaired not only in tests assessing memory, but also in tests of the executive finctions associated with frontal lobe finction. This finding agrees with previous reports suggesting an important role for frontal lobe dysflnction in the memory loss of elderly people. Comparing subjects with high and low frequencies of subjective complaints of memory loss suggested that these subjective feelings of memory impairment are more closely associated with personality traits than with actual memory performance in normal elderly people. This complicates the use of memory complaints in the inclusion criteria for AAMI and AACD diagnosis.
The prevalence of AACD has been found to be lower than that of AAMI. As AAMI tends to identify a very heterogeneous subject group, the AACD diagnosis might prove superior to AAMI for differentiating a meaningful subgroup from the elderly population, both for research purposes and in clinical settings. This remains to be confirmed in follow-up studies.
Prominent changes occur in the brain during aging and include a decrease in brain weight, gyral atrophy, ventricular dilation, and selective loss of neurons within different brain regions (Kemper, Neuroanatomical and neuropathological changes during aging and dementia. In: Martin A. L., Knoefel J. E. (eds). GERIATRIC NEUROLOGY (2nd ed). Oxford University Press, New York City, pp. 3-67, 1994). The relevance of these changes to behavioral measurements is still largely ambiguous (e.g., Lezak, NEUROPSYCHOLOGICAL ASSESSMENT (3rd ed). Oxford University Press, New York, 1995). In addition to biological changes, environmental contexts are reflected in age-related cognitive changes (Arbuckle et al., Psychol Aging 7: 25-36, 1992). Recent studies with advanced brain imaging methods (especially PET and functional MRI) have elucidated the neuroanatomical localization of cognitive functions (e.g., Frackowiak, Trends Neurosci 17: 109-115, 1994; Moscovitch et al., Proc Natl Acad Sci USA 92: 3721-3725, 1995; Schacter et al., Proc Natl Acad Sci USA 93: 321-325, 1996). So far, very few of these studies have considered the effects of aging (Eustache et al., Neuropsychologia 33: 867-887, 1995; Grady et al., Science 269: 218-221, 1995). However, some associations between age-related cerebral and cognitive changes have been suggested.
Eustache et al. (1995, ibid) demonstrated concomitant age-related declines in brain oxidative metabolism (in the resting condition) and tests of episodic memory, which also suggests that neurobiological changes within the neural network for episodic memory (which includes the hippocampus and the thalamus) may underlie the memory impairments of normal aging. Accordingly, Grady et al. (1995, ibid.) found age-related reductions in regional cerebral blood flow within the network including the hippocampus and the anterior cingulate cortex during the encoding phase of a face recognition task.
By using a structural equation model, Jones et al. (Exp Aging Res 17: 227-242, 1991) found evidence for a causal relationship between age-related changes in the brain (as measured by CT and EEG) and cognition in healthy individuals.
AACD and AAMI seem to overlap with various other diagnostic classifications which have been proposed (Dawe et al., Int J Geriatr Psychiatry 7: 473-479, 1992; Ebly et al., Arch Neurol 52: 612-619, 1995). The best established of these classifications are xe2x80x9cmild cognitive disorderxe2x80x9d (MCD) and xe2x80x9cage-related cognitive declinexe2x80x9d (ARCD). MCD is included in the research criteria for ICD-10 (World Health Organization 1993). This diagnosis is used only when there is an indication of a disease or condition known to cause cerebral dysfunction. The epidemiology of MCD has been considered in two recent studies with contradictory results. Christensen et al. (Age Ageing 25: 72-80, 1996) found a prevalence rate of only 4% for MCD and concluded that the diagnosis lacks validity. Ebly et al. (1995, ibid.) wanted to add the presence of subjective complaints, but otherwise agreed with the ICD- 10 criteria for MCD. ARCD is included in the DSM-IV (American Psychiatric Association 1994) defined as xe2x80x9can objectively identified decline in cognitive functioning consequent to the aging process that is within normal limits given the person""s agexe2x80x9d. However, no more detailed criteria are included in the DSM-IV, and no studies employing this construct have been conducted.
Coenzyme Q or ubiquinone plays a central role in the mitochondrial respiratory chain that captures energy from metabolism. It exists in mitochondria in the oxidized quinone form under aerobic conditions. In the reduced form ubiquinol, Q10 is an antioxidant. Q also is present in mitochondrial lipids. The structure of Q is very similar to those of vitamins K and E, which are characterized by a polyisoprenoid side chain. Coenzyme Q10 has ten polyisoprenoid side chains. Mitochondria need to maintain a large excess of Q10, compared to other respiratory enzymes. Q10 is required to act on a mobile component of respiration that collects reducing equivalents from the more fixed complexes and passes them to other compounds.
Many conflicting reports have been published on the effectiveness of Q10 in various laboratory and clinical settings. Barbiroli et al reported that Q10 administration caused marked improvement in oxidative phosphorylation in both skeletal muscles and brains of patients with mitochondrial cytopathies due to enzyme defects (Biochimie 80(10): 847-53, 1998). On the other hand, Lass et al studied the Q10 and Q9 content in brain, heart, skeletal muscle and other organs but found a decrease in mitochondrial Q9 and Q10 only in aging skeletal muscle (Biofactors 9(2-4):199-205, 1999).
Life-long Q10 supplementation was studied in male rats and mice. Q10 did not prolong or shorten the lifespan of rats or mice. Plasma and liver levels were 2.6-8.4 times higher in the supplemented rats. Q10 levels in kidney, heart and brain were not affected by Q10 supplementation (Lonnrot K et al. Biochem Mol Biol Int 44(4):727-37, 1998).
To determine if Q10 has a neuroprotective effect, mice were first treated with Q10 or a control diet for four weeks. Then their striatal nerves were poisoned 1-Me-4-Ph-1,2,3,tetrahydropyridine (MPTP). The mice continued on their assigned diets for another week before sacrifice. Both groups had considerable brain damage; however, the Q10-treated mice had 37% higher doparnine and 62% more dense neurons, indicating a protective effect of Q10. (Beal MF et al. Brain Res 783(1):109-14, 1998.
Q10 also blocks the effects of doxorubicin, which by itself stimulates mitochondrial oxidant production and a marked increase in mtDNA deletions in cardiac tissue (Adachi et al. Biochem Biophys Res Commun 195:945-51, 1993).
A group of healthy Finnish men and women aged 28-77 were tested for the total peroxyl radical-trapping capacity of human plasma LDL phospholipids. There was an age-related difference in men, but not in women. Most of the decrease occurred before age 50, remaining low into the 70""s. Supplementation with Q10 doubled the peroxyl radical-trapping capacity and thus may decrease LDL oxidation, which contributes to atherosclerosis (Aejmelaeus R et al. Mol Aspects Med 18(Supp):S113-20, 1997).
Creatine is present in muscular tissue and the heart. Small amounts are found in the blood but not in normal urine. Normally the liver and kidneys produce creatine. When creatine is metabolized, its end product is creatinine, which is excreted in the urine. Serum creatinine may increase with age. Muscle mass usually decreases with age, but it is unknown if it is entirely due to declining activity with age. Also, many older people do not eat as much meat, an important source of creatine. The greater part of creatine in muscle is combined with phosphoric acid as phosphocreatine. There it plays an important part in mitochondrial metabolism. In the mitochondria, creatine kinase isoenzymes transfer high-energy phosphate to creatine. Next, creatine phosphate is transported out of the mitochondria into the cell""s environment where it generates extramitochondrial ATP. Different isoenzymes of creatine kinase mediate transfer of high-energy phosphate to and from the various systems that utilize or generate it, e.g., muscle contraction and glucose metabolism.
Researchers administered creatine and have studied a number of different parameters including aging and muscle function. Acute supplementation (5 days) in men over 60 was found to have no effect in isometric strength and only small increases in isokinetic performance and body mass (Rawson E. S., Clarkson P. M., Int. J. Sports Med 21(1):71-5, 2000). Another study reported results on older adults (67-80 years, 16 females, 16 males) who were randomly assigned to control-creatine, control-placebo, trained-creatine and trained-placebo groups for an 8-week test. Both groups of trained subjects had significant increases in 1- and 12-repetitions maxima, but no beneficial effect was observed for creatine supplementation (Bermon S et al. Acta Physiol Scand 164(2):147-55, 1998). On the other hand, when a different parameter directly related to muscle metabolism was measured, a positive effect was seen after 7 days. Groups of male and female 30-year-olds and 50-year-olds performed single-leg knee-extension exercises inside an MRI. At the start of the study, the older group had lower resting phosphocreatine (PCr) and lower mean initial PCr resynthesis rate. After creatine supplementation, the resting PCr increased 15% (P less than 0.05) in the young group and 30% (P less than 0.05) in the middle-aged group. In the middle-aged group, mean initial PCr resynthesis rate increased significantly (P less than 0.05), to a level comparable to that of the young group. The time to exhaustion was increased in both groups combined after creatine supplementation. Smith SA et al. concluded that creatine supplementation has a greater effect on PCr availability and resynthesis rate in middle-aged compared with younger persons (J Appl Physiol 85(4):1349-56, 1998).
Schuff N et al. analyzed age-related metabolite change and volume loss in the hippocampus by MRI (Neurobiol Aging 29(3):279-85, May-June 1999). They analyzed N-acetyl aspartate (NAA, a neuron marker), volume changes, and ratios of NAA/choline (Cho) and NAA/Cr (creatine). Volume decreased about 20% between 36 and 85 years, while NAA/Cho decreased by 24% and NAA/Cr decreased by 26%, all of which were significant. The Cho/Cr ratio remained stable. The volume loss correlated with neuronal marker loss and indicated loss of neurons. In contrast, Pfefferbaum A et al. (Magn Reson Med 41(2):276-84, 1999) reported NAA, Cho and Cr signal densities for healthy groups of 15 young and 19 elderly persons. NAA was higher in gray than white matter but did not differ between young and old subjects, despite significant gray matter volume deficits in the older subjects. The available gray matter appeared to be intact in older healthy adults. Cr concentrations were much higher in gray than white matter and significantly higher in the older subjects. Cho concentration in gray matter was also significantly higher in older subjects. The findings in older subjects were confirmed in another study in which Pfefferbaum compared Alzheimer disease (AD) and normal aging (Arch Gen Psychiatry 56(2):185-92, 1999). Both groups showed cortical gray matter volume deficits. Gray matter NAA was reduced only in the AD group, compared to older and younger subjects. Cho levels were higher in the AD group versus the normal older group and were higher than in the young group. Gray matter creatine, phosphocreatine and choline concentrations in patients with AD correlated with poorer performance on recognition memory tests.
Nutritional deficiencies are known to contribute to memory difficulties. For example, the Wemnicke-Korsakoff syndrome results from a failure to ingest thiamine. The patient has continued carbohydrate intake and gradually exhausts thiamine stores in critical areas of the thalamus and brainstem reticular formation. Underlying causes include dialysis, oversights in postoperative care, hyperemesis gravidarum and severe alcoholism. Memory for new information is severely affected but memory of distant events is less impaired. Therefore, the patient""s previous experience is available to guide his actions and he may display little intellectual loss. Properly treated with fluids, calories and vitamin supplements, the condition dissipates over a period of weeks to months. Studies have demonstrated an association between the use of thiamin (vitamin B1), pyridoxine (vitamin B6) or cyanocobalamin (vitamin B12), and cognition. These vitamins are involved in carbohydrate metabolism.
Zinc levels are known to be low in the older population and zinc blood levels have positively correlated with psychological performance.
What is needed is improved nutrition to maintain brain finction and prevent and ameliorate memory impairment.
It is an object of the present invention to prevent and ameliorate the cognitive deficits which occur with aging. It is an object of the present invention to prevent and ameliorate the cognitive deficits which occur in a variety of other disorders associated with impaired metabolism of the brain, including stroke, traumatic brain injury, toxic exposure and Type 2 diabetes mellitus. It is a firther object to provide a combination of an effective amount of a suitable antioxidant and an effective amount of a carnitine to prevent and/or ameliorate the cognitive deficits associated with the above conditions.
A preferred combination of the present invention includes carnitine in the amount of 0.12 grams to 3 grams. A preferred form of carnitine is acetyl-L-carnitine (ALC).
A preferred combination of the present invention includes the antioxidant as R-xcex1-lipoic acid in the amount of about 0.12 grams to about 1.5 grams.
Optionally, coenzyme Q and/or creatine also are administered. Preferably 10 mg to 500 mg/day of coenzyme Q10 and 1 to 30 grams/day of creatine are administered.
Testing with PET, particularly enhanced with F-18 fluorodeoxyglucose (FDG) to analyze metabolic activity, has shown that two derived factors separated healthy persons below age 42 from those above age 48. Both secondary memory for material verbally processed in combination with Broca""s metabolic ratio and tests requiring sequential or organizational coding of information (executive function) combined with metabolic measures of thalamic regions were greater for the younger group than for the older group. The investigators concluded that a frontal-subcortical decrement in metabolism is present in age-dependent memory processing. Riege W. H. et al. Brain Cogn 5(4): 412-27, 1986. Thus, it may be beneficial in the late 30""s to early 40""s to begin therapy which enhances metabolism and has been proven to counteract aging in mitochondria.
Carnitine and lipoic acid, and optionally coenzyme Q and/or creatine, are administered to discourage age-related memory loss and provide improved memory older individuals and others with unhealthy mitochondria. Recent research has shown precisely how these compounds work to promote healthy mitochondria, which are the energy powerhouses of the cells. Mitochondria are responsible for the production of ATP and are present in relatively high numbers in essentially all cells of the body. The mitochondrial electron transport system consumes approximately 85% of the oxygen utilized by a cell. Cellular energy deficits caused by declines in mitochondrial function can impair normal cellular activities and compromise the cell""s ability to adapt to various physiological stresses, a major factor in aging. Because of this high oxygen use, the mitochondria also have the highest production of oxidants.
Oxidants damage mitochondria in three important ways. Oxidants damage DNA, lipids and protein. The intra-mitochondrial DNA (mtDNA) have levels of oxidative damage which are at least 10-fold higher than those of nuclear DNA, which correlates with the 17-fold higher evolutionary mutation rate in mtDNA compared with nuclear DNA. mtDNA oxidation accumulates as a function of age, which has been shown in several species, including humans. This may lead to dysfunctional mitochondria. Mitochondrial protein damage is also age-related and may decrease energy production and increase oxidant production. Oxidative damage to mitochondrial lipids contributes to the decreasing fluidity of cell membranes with age. The lipid cardiolipin is a major component of the mitochondrial membrane and facilitates the activities of critical mitochondrial inner membrane enzymes. The aged, damaged mitochondrial membrane cannot contain the oxidants nor can it maintain as high a polarity as the younger membrane.
Fatty acid oxidation is an important energy source for many tissues. The activity of carnitine-acetyl-carnitine exchange across the inner mitochondrial membrane is of great importance. The activity of this exchange reaction is decreased significantly with age, which may be due to a lower intra-mitochondrial pool of carnitine. L-carnitine or ALC has been shown to slow or reverse this age-related dysfunction. It also can reverse the age-related decrease in cardiolipin, age-associated decrease in mtDNA transcription, and decreased membrane potential. By itself, L-carnitine or ALC cannot correct the problem of excess oxidants. In fact, it was recently reported that carnitine supplementation increased oxidant production by 30% and decreased cell antioxidants markedly. Thus, ALC administration alone in older individuals may contribute to greater oxidative stress.
For the age-compromised mitochondrial engines to run on all cylinders, both carnitine and lipoic acid are essential. Lipoic acid is an antioxidant. And R-xcex1-lipoic acid is a mitochondrial enzyme which can help reverse the decline in metabolism seen with age. R-xcex1-alipoic acid supplementation has been shown to 1) reverse the age-related decrease in oxygen consumption, 2) restore the age-related decline in mitochondrial membrane potential, 3) triple the ambulatory activity of aged rats, 4) significantly lower the age-related increase in oxidants, and 5) restore glutathione and ascorbic acid levels to youthful levels.
Clearly, both carnitine and lipoic acid contribute to restoration of age-related mitochondria function and metabolic activity in individuals in which those were compromised. This contributes to improvements in energy, general health, mental acuity, immune system function, skin and hair appearance and muscle mass.
Carnitine is available in many forms and all those are included in the invention of the combination of carnitine and thioctic acid. Carnitine and carnitine derivatives have been used as metabolites in animal husbandry and for human diet and therapy. U.S. Pat. No. 5,362,753 (Method of increasing the hatchability of eggs by feeding hens carnitine); U.S. Pat. No. 4,687,782 (Nutritional composition for enhancing skeletal muscle adaptation to exercise training); U.S. Pat. No. 5,030,458 (Method for preventing diet-induced carnitine deficiency in domesticated dogs and cats); U.S. Pat. No. 5,030,657 (L-camitine supplemented catfish diet); U.S. Pat. No. 4,343,816 (Pharmaceutical composition comprising an acyl-carnitine, for treating peripheral vascular diseases); U.S. Pat. No. 5,560,928 (Nutritional and/or dietary composition and method of using the same); U.S. Pat. No. 5,504,072 (Enteral nutritional composition having balanced amino acid profile); U.S. Pat. No. 5,391,550 (Compositions of matter and methods for increasing intracellular ATP levels and physical performance levels and for increasing the rate of wound repair); U.S. Pat. No. 5,240,961 (Method of treating reduced insulin-like growth factor and bone loss associated with aging); etc. Most preferably, the carnitine is acetyl-L-carnitine.
A daily dosage of carnitine is about 10 mg to 8 g. Preferably the daily dose of carnitine is 25-1,000 mg. More preferably, the daily dose of carnitine is about 40-700 mg. Most preferably, the daily dose of carnitine is at least about 50 milligrams (0.05 g) per day.
By lipoic acid or thioctic acid is meant a mitochondrially active antioxidant which physiologically comprises a metabolically reactive thiol group. Mitochondrially active antioxidants including vitamins (especially C, E, B and D), glutathione, N-acetyl cysteine (NAC), lipoic acid, their derivatives, etc., have been used variously as human nutritional supplements and in dietary prophylaxis and therapy. For example, applications of lipoic acid have included U.S. Pat. No. 5,607,980 (Topical compositions having improved skin); U.S. Pat. No. 5,472,698 (Composition for enhancing lipid production in skin); U.S. Pat. No. 5,292,538 (Improved sustained energy and anabolic composition and method of making); U.S. Pat. No. 5,536,645 (Nutritive medium for the culture of microorganisms); U.S. Pat. No. 5,326,699 (Serum-free medium for culturing animal cells); etc. Preferably, the compound is at least one of glutathione, N-acetyl cysteine and lipoic acid. Most preferably, the compound is the Renantiomeric form of lipoic acid. Metabolites of lipoic acid have been found to have a longer half life and also are suitable for supplementation.
A daily dosage of lipoic acid is about 10 mg to 8 g. Preferably the daily dose of lipoic acid is 25-1,000 mg. More preferably, the daily dose of lipoic acid is about 40-700 mg. Most preferably, the daily dose of lipoic acid is at least about 50 milligrams (0.05 g) per day.
Q10 supplementation also is important. In groups of males and females ranging from 90-106 years, inadequate Q10 status was present in 40% for women and 24% for men. In women, the decreased Q10 was associated with impaired natural killer cell effectiveness (p less than 0.05), indicating decreased ability to fight infections and to quickly eliminate individual cancer cells as they first develop. Q10 also appears to block programmed cell death, or apoptosis, through its action in the mitochondria (Kagan T et al, Ann NY Acad Sci 887:31-47, 1999). Furthermore, Q10 in its reduced form of ubiquinol-10, which is normally present in the blood, appears to protect human lymphocytes from oxidative damage to DNA (Tomasetti et al, Free Radic Biol Med 27 (9-10):1027-32, Nov. 1999). No important adverse effects have been reported from experiments using daily supplements of up to 200 mg Q10 for 6-12 months and 100 mg daily for up to 6 y. Overvad K et al. Eur J Clin Nutr 53(10):764-70, 1999.
Q10 also may contribute to anti-aging effect by protecting against atherosclerosis which also results from oxidative stress. Pedersen HS, et al. Biofactors 9(2-4): 319-23, 1999). Protecting brain blood vessels will also help support brain function.
As for the appropriate dose of Q10, older Finnish men obtained benefit from 100 mg/day. A woman deficient in Q10 received 150 mg/kg and rapidly improved (Sobriera et al. Neurology 48:1283-43, 1997). Q10 has also been used at chronic doses of about 200 mg/day to improve heart function in persons with hypertrophic cardiomyopathy. Based on this information, a supplemental dosage ranges from about 10 mg/day to about 500 mg/day. Preferably, the Q10 dose is about 100 mg/day.
Because creatine is often deficient in older individuals, creatine supplementation is important. Many athletes have taken doses of creatine up to 75 grams a day for years without known adverse effects, aside from weight gain attributed to increased muscle mass. Creatine may be most beneficial when ingested with glucose, which tends to increase creatine absorption. Often athletes ingest loading doses of 20 g/day divided into four doses for 5 days to one week. Then they take a maintenance dose of 5 g/day. Benefit in one week in older individuals (40-73) has also been seen from a 20 g/day dose, in the form of increased skeletal muscle strength and endurance. It has been reported that 1.5 g-25 g/day are safe for period of at least a year. A suitable dosage range is 0.5 g/day to 25 g/day, preferably 1-10 grams per day and most preferably about 5 g/day. Creatine is available as a salt, monohydrate, phosphate and citrate.
In addition to the compositions mentioned above and the examples given below, breakfast products would also benefit from the addition of a carnitine, a form of thioctic acid, and optionally Q10 and/or creatine. Examples of such breakfast products include, but are not limited to, breakfast cereal (Total(copyright), etc.), breakfast bars, Poptart(copyright) pastry, and quick breakfasts in a bun or taco (e.g., McDonald(copyright) Egg McMuffin(copyright)). The camitine, thioctic acid, and optionally Q10 and/or creatine can be added to bulk powders or powder packets, for example, in the following compositions: orange juice (e.g., Tang(copyright)), coffee creamer (e.g., Cremora(copyright)), powdered milk, powdered milk shakes/ smoothies (e.g., MetaRX), butter-flavored powder, sweetener powders (e.g., Nutrasweet(copyright)), and spice and herb mixes. The combination of carnitine, thioctic acid, and optionally Q10 and/or creatine can be mixed with any cooked or uncooked food.
Premade drinks which would benefit from the inclusion of carnitine, thioctic acid, and optionally Q10 and/or creatine include, but are not limited to, pre-made smoothies, additives to drinks like Jamba Juice(copyright) and Starbucks(copyright), sports drinks such as Gatorade(copyright), diet drinks such as Weight Watchers(copyright) and Slim Fast(copyright), and herbal drinks such as SoBe(copyright) (with St. John""s Wort and other popular herbs). The formulations with carnitine, thioctic acid, and optionally Q10 and/or creatine also can include any fortified foods or meals replacement foods.
The combination of carnitine, thioctic acid, and optionally Q10 and/or creatine is provided in pet formulations, dried or canned or as a supplement for addition thereto. Animals expected to benefit from the composition include but are not limited to dogs, cats, horses, birds and fish.
The formulations and/or content of these products are on the product label or are otherwise publicly available.
Additional nutrients are particularly important in older individuals, including calcium, vitamins B12, B6, C, D or E, folic acid, niacin, iron and zinc. Many of these nutrients have been found to be deficient in the diets of elders and should be appropriately supplemented in nutritional beverages and bars.
A preferred formulation provides lipoic acid and carnitine, optionally in combination with coenzyme Q10 and/or creatine, in a timed release formulation to provide a steady supply of the nutrients to the mitochondria which work 24 hours a day. One method of accomplishing timed release is chemically combining the micronutrient(s) with other molecules, which generally slows the process of making the micronutrient(s) available. Also the use of different salts of the micronutrients with different dissolution rates provides for gradual and appropriate release of the product.
Besides these methods, two other basic systems are used to control release for oral administration: coating a core comprising the micronutrient(s) and excipients (coated system) and incorporating the micronutrient(s) into a matrix (matrix system). Coated systems involve the preparation of product-loaded cores and coating the cores with release rate-retarding materials. Product-loaded cores can be formulated as microspheres, granules, pellets or core tablets. There are many known core preparation methods, including, but not limited to, 1) producing granules by top spray fluidized bed granulation, or by solution/suspension/ powdering layering by Wurster coating, 2) producing spherical granules or pellets by extrusion-spheronization, rotary processing, and melt pelletization; 3) producing core tablets by compression and coating with a release rate-retarding material; 4) producing microspheres by emulsification and spray-drying.
Matrix systems embed the micronutrient in a slowly disintegrating or non-disintegrating matrix. Rate of release is controlled by the erosion of the matrix and/or by the diffusion of the micronutrient(s) through the matrix. In general, the active product substance, excipients and the release rate-retarding materials are mixed and then processed into matrix pellets or tablets. Matrix pellets can be formed by granulation, spheronization using cellulosic materials, or by melt pelletization using release retardant materials, while matrix tablets are prepared by compression in a tablet press. An example of a cellulosic material is hydroxypropylmethylcellulose as the release rate-retarding material.
Coated or matrix pellets can be filled into capsules or compression tabletted. The rate of release can be futrther modified by blending coated or matrix pellets with different release rates of the same product to obtain the desired product release profile. Pellets containing any of lipoic acid, camitine, coenzyme Q10 or creatine can be blended to form a combination product. Convenient assays for the requisite bioactivities are described above or in the references cited herein. For example, cardiolipin content is readily assayed as referenced in Guan, Z. Z., Soderberg, M., Sindelar, P., and Edlund, C. Content and Fatty Acid Composition of Cardiolipin in the Brain of Patients with Alzheimer""s Disease. Neurochem. Int. 25: 295-300, 1994 and oxidant production (DCFH) may be assayed as described by LeBel, C. P., Ischiropoulos, H., and Bondy, S. C. Evaluation of the Probe 2xe2x80x2,7xe2x80x2-Dichlorofluorescein as an Indicator of Reactive Oxygen Species Formation and Oxidative Stress. Chem. Res. Toxicol. 5: 227-231, 1992. Assays for parameters of memory loss associated with aging and other activities such as host activity and behavior such as grooming, sexual activity, dominance are similarly well known in the art.
Testing for AAMI or other memory deficits can be performed with the Mini-Mental Status Examination, which provides a numerical score within about 5-10 minutes. As a quick screen, simply assessing orientation and asking the patient to draw a clock with the hands at a set time (e.g., 10 min before 2:00) can be very informative regarding cognitive status, visuospatial deficits, ability to comprehend and execute instructions in logical sequence, and presence or absence of perseveration.
PET scans and functional MRI can localize and quantitate the neuroanatomical localization of cognitive deficits (e.g., Frackowiak. Trends Neurosci 17: 109-115, 1994; Moscovitch et al. Proc Natl Acad Sci USA 92: 3721-3725, 1995; Schacter et al. Proc Natl Acad Sci USA 93: 321-325, 1996). Some studies have documented the effects of aging (Eustache et al. Neuropsychologia 33: 867-887, 1995; Grady et al. Science 269: 218-221, 1995).


Paint and coating material system comprising

The invention relates to paint and coating material systems and to their use for preparing paint and coating materials.
In the field of pigmented liquid paint and coating materials, the use of aqueous or solvent dispersions of pigments and fillers, and binders, in particular, is known. Examples of suitable pigments and fillers include organic and inorganic colour pigments, i.e. white, black and chromatic pigments. Binders used include both organic and inorganic, but generally organic, network-forming or film-forming polymers which may be present in emulsified, dispersed or dissolved state in a paint material.
Pigmented paint and coating materials generally include further additives and, possibly, further solvents.
The pigmented aqueous paint and coating materials are generally prepared by dispersing the pigments and fillers in the presence of water and, where appropriate, further additions. Dispersion comprises the deaggregation or deagglomeration of the pigment and filler particles, which in their dry powder form or aqueous presscake form are in a state of high physical aggregation on account of their preparation process, and also the physical stabilization of the pigments or fillers finely distributed in this way, by means of suitable additives such as dispersants, emulsifiers or thickeners, for example, in order to achieve the desired properties of the finished liquid products (paints), such as storage stability, hiding power and whiteness (lightening), colour strength, shade and brilliance, etc. Consequently, the preparation of the aqueous paints and coating materials always involves the high energy input which, industrially, can be effected only through the use of, for example, wet comminuting machines such as dissolvers, attritors, ball mills, rotor-stator mills, stirred bead mills, high-pressure homogenises and so on.
For this reason, the dispersions can be prepared only on the industrial scale; and it is only on that scale that industrial equipment is available on the market and can be used economically. In the past, until the present day, a consequence of this has been that paint and coating materials have been obtainable exclusively as ready-formulated liquid preparations. This applies both to products intended for industrial use and to those intended for use closer to the consumer.
As well as the advantages of the ease of handling of the liquid preparations matched in this way to the use in question, however, there are considerable disadvantages. For instance, the relatively large volume of the paint and coating materials owing to the water and possibly solvents they contain (in total up to 90%; e.g. high-grade white interior paint: from 30 to 50% by volume water) is disadvantageous since it entails great expenditure as regards the nature and size of the means of packaging (tin cans, plastic buckets and drums) and as regards the storage and transport.
Moreover, the aqueous preparations often possess inadequate keeping properties and storage properties owing to:
Mould and bacterial infestation, necessitating the use of high quantities of biocide;
Sedimentation or reagglomeration of the pigments or fillers or thickening of the liquid phase, generally necessitating stirring of the products before use;
Drying (including drying-out) of the products in and to the container, always associated with noticeable quality detractions in the products, such as bittyness in the paint or in the coating, for example.
Often, a large amount of agents for improving the antifreeze qualities and resistance to drying out, such as solvents, especially glycols, polyglycols and so on, is necessary; however, such agents bring with them grave disadvantages as regards the very properties of the product, such as the microbiological keeping properties and the tackiness of the products following application, for example. Furthermore, it is nowadays becoming more and more difficult to find suitable preservatives for aqueous preparations containing, for example, glycol or polyglycol that are able to counter the increasing adaptation of microorganisms and are also environmentally acceptable.
Grave environmental disadvantages of liquid preparations relate in particular to the disposal of leftover products, product wastes and containers at all stages of the product life cycle. This applies to the production process of the aqueous preparations, storage and container filling, selling, storage and use in households and industry, and in the trade. As far as aqueous paint materials are concerned, for instance, it is easy to estimate that in private households alone the amount of leftover products and product wastes is very large. Disposing of such leftovers and wastes is known to be expensive. It is therefore an object of the present invention to provide a paint and coating material system with which the above disadvantages can be largely avoided.
A paint and coating material system has now been found comprising
a) at least one solids component comprising at least one organic or inorganic white, black or chromatic pigment, organic or inorganic fillers, or mixtures thereof, and
b) at least one binder component, characterized in that the components of the system in water, with a specific energy input of less than 150 J/cm3, based on the sum of the volumes of the components and water, produce an aqueous dispersion having a particle size of  less than 60 xcexcm, preferably less than 40 xcexcm (determined in accordance with ISO 1524: 1983).

Lacquers and paints and coating material systems

Abstract: b) at least one binder component,

Abstract: characterized in that the components of the system in water, with a specific energy input of less than 150 J/cm3, based on the sum of the volumes of the components and water, produced an aqueous dispersion having a particle size of  less than 60 xcexcm (determined in accordance with ISO 1524: 1983).


The invention relates to a device for disaggregating pieces of derived timber products from cellulose and/or lignocel-lulose-containing products, especially particle boards, medium-density fiber boards and the like, with a transport device and at least one disaggregation container. The inventive device is also characterized in that the disaggregation container and the transport device are configured as at least one common densifier screw (1) with a housing-mounted outer shell and a driven shaft located therein. The shaft is provided with helices of a predefined pitch. The pieces of derived timber products are transported in the axial direction of the densifier screw (1) from a feed opening in the outer shell towards an outlet opening on the front side thereof in the axial direction (direction of transport). A feed opening (7) for vapor is provided in the outer shell between the inlet opening and the outlet opening.

The present invention relates to a device for disaggregating derived timber products according to the preamble of the main claim and to a method for implementing the same.
A device of this type has been disclosed (DE 198 19 988). In this device, a screw feeder functions as the transport device for conveying the disaggregation material through the impregnation and pre-swell shaft, while the function of the second screw feeder is to discharge the already disaggregated material from the disaggregation shaft. In the disaggregation shaft itself, the disaggregation material is not conveyed by screw feeders. The disadvantage of this device is the fact that, during disaggregation under pressure, appropriate measures must be taken to make the filling shaft pressure-sealable.
The object he present invention is thus to create a device and a method which permit continuous, and therefore simple and economical disaggregation of derived timber products.
This object is achieved by a device for disaggregating pieces of derived timber products made from cellulose-containing and/or lignocellulose-containing materials, specifically particle board, medium-density fiberboard and the like, with a transport device and at least one disaggregation vessel, characterized in that the disaggregation vessel and the transport device are designed as at least one combined-function plug screw feeder with an outer casing attached to the housing and a drivable shaft located therein provided with helices of a predefined pitch, the pieces of derived timber products being conveyed in the plug screw feeder from a feed opening in the outer casing to an end-face discharge opening in the axial direction (direction of conveyance), and characterized in that a delivery opening for steam is provided in the outer casing between the feed opening and the discharge opening.
The object is also achieved by a process for disaggregating pieces of derived timber products made from cellulose-containing and/or lignocellulose-containing materials, specifically particle board, medium-density fiberboard and other residual materials and waste produced from lignocellulose-containing materials, using a conveyance device as well as a disaggregation vessel, characterized in that the derived timber products are conveyed continuously through pressure-sealed, sequentially arranged plug screw feeders, thereby undergoing the action of shearing and frictional forces occurring in the plug screw feeder, and in that steam is forced into at least one of the plug screw feeders which is neither the first nor the last plug screw feeder.
The surprising determination was made that an arrangement of preferably at least three plug screw feeders in tandem permits the passage of the disaggregation material such that the feedstock is able to seal the plug screw feeders to the degree necessary for performing the disaggregation process under pressure. Here the steam is introduced, preferably at a pressure of 2 bars, into one of the plug screw feeders which is neither the first nor the last one in the sequence of plug screw feeders. Arrangements of, for example, five or more plug screw feeders are preferred, the steam being introduced into the middle section of the sequentially arranged plug screw feeders, for example, into the third in a sequence of five plug screw feeders. While in the side plug screw feeder[s] here, a pressure drop reaching atmospheric pressure may be observed, the arrangement results in the working pressure being sustained in the middle section, said pressure being up to 11 bars but at least 2 to 3 bars of overpressure.
A fundamental advantage of a method thus implemented on a completely continuous basis according to the invention lies specifically in the fact that complex and expensive measures to seal the system may be dispensed with and that continuous processing is nevertheless possible. Processing is thus possible without the opening and subsequent sealing of system components, and as a result there is no concomitant loss of energy or discharge of pollutants from the system. Thus from both the standpoint of economy and ecology, the device may thus operated at an optimal level.
In the method according to the invention, specifically when at least five plug screw feeders are used, disaggregation pressures of 2 bars to 11 bars of overpressure may be sustained, the range of operation being preferably between 3 bars and 8 bars, and especially between 2 bars and 6 bars. When steam is introduced at an overpressure of 4 bars, the disaggregation temperature at the steam inlet is approximately 143xc2x0 C.
Since passage through the screw feeder entails not only the conveyance of the disaggregation material but also its homogenization, the friction of the particles against each other results in a continuous comminution mechanically and facilitates chemical hydrolysis. The result is that the disaggregation of the particles is accelerated such that a residence time of only a few minutes is sufficient to produce a high level of disaggregation. In the event the derived timber products are more hydrolysis-resistant, appropriate means may be employed to accelerate hydrolysis such as raising or lowering the pH.
The disaggregation process from the addition of the comminuted particleboard fragments through the completely disaggregated, moist wood pulp is thus effected by multiple, at least three, sequentially arranged screw feeders. These pressure-sealed plug screw feeders perform multiple functions: conveyance as well as continuous comminution and hydrolysis of the pre-swollen wood pulp, initially by the friction of the particles against each other, and the actual disaggregation process under the action of water, steam and absorption of heat within the tubular screw feeder system. Use of a modular design is possible here in which multiple identical screw feeders and drive systems are employed, which use significantly reduces cost.
The independently controllable plug screw feeders and drive systems allow the feed rate to be adapted to existing process conditions, the maximum limits being set only by the dimensioning of the conveyance systems and the reaction speed of disaggregation.
Since the entire process proceeds under pressure, the entire system must be pressure-sealed, a feature which has the advantage of preventing any harmful emissions emanating from the disaggregation process from entering the environment.
Since the system is operated without generating effluents, environmental considerations have been accorded a high priority.
It has proven useful to fill the first plug screw feeder into which the disaggregation material has been introduced with preheated water. The water temperature here can range between approximately 20xc2x0 C. and 95xc2x0 C.
Conveyance by the screw feeder within the system allows for homogenization of the wood pulp, and the constant friction caused by the conveyance creates desirable and continuous comminution, thereby facilitating wetting of the surface. The result is that the enthalpy of the steam may be utilized over the entire length of the tube since the friction continuously separates the solubilized layers mechanically and exposes the underlying, not-yet-separated layers which are then readily acted upon by the steam. The process may be further accelerated by using higher process pressures.
Waste gas heat can be almost completely utilized and is thus not lost as is the case with the discontinuous process of the prior art. The heat provided by the moist disaggregated wood pulp is also utilized by the fact that the conveyance path from the point after the material has exited the last screw feeder to the drier is extremely short. This feature minimizes heat loss and drying cost.
The absorption of water, steam and heat by the disaggregation material may be very precisely adjusted by controlling the rate of feedxe2x80x94a feature which facilitates additional optimization of the process parameters, especially energy consumption, and optimal process control.
The plug screw feeders may be arranged sequentially in any desirable configuration. To save space, the preferred arrangement is one in which the outlet of each plug screw feeder discharges at right angles into the inlet section of the following plug screw feeder.
As the material is conveyed plug screw feeders are employed, according to the invention, which create a pressure in the conveyed material. These screw feeders, which are also designated plug screw feeders, are, for example, unilaterally bearing-mounted screw feeders, the outlet opening of which runs in the axial direction. They may have a progressive or degressive pitch, that is, spacing per turn between helices may be made larger or smaller.
The temperature of disaggregation has a significant effect on the hydrolysis of the derived timber products. The higher the pressure of the steam utilized for disaggregation, the higher is the disaggregation temperature. At a steam pressure of 4 bars overpressure, the temperature is approximately 143xc2x0 C. Disaggregation temperatures in the range of 8 bars may, depending on the type of wood and other process parameters, result in undesirable discoloration of the chips. Steam pressures must therefore be carefully monitored. Generally, pressures between 7 bars and 11 bars are selected, but preferably those between 2 bars and 8 bars, and especially in the range of between 3 bars and 6 bars of overpressure.
The rate of conveyance through the plug screw feeders varies as a function of the number of screw feeders employed. Given a greater number of screw feeders, the rate of throughput may be increased, whereas for a smaller number this rate must be reduced in order to ensure the required residence time for disaggregation. Depending on the pressure, complete disaggregation may be generally achieved after a residence time of around approximately 30 minutes, and preferably 20 minutes, such that the use of more than three screw feeders entails a residence time per plug screw feeder of only a few minutes. Compared to traditional discontinuous disaggregation processes, this amounts to a considerable reduction in disaggregation time.
Under the above conditions, the plug screw feeders generally attain rotational speeds in the range of a few rotations per minute, for example, 3 rpm to 10 rpm.
When the material is introduced into the first plug screw feeder, it has proven to be advantageous to add preheated water. Water temperatures may range between 200xc2x0 C. and 95xc2x0 C. Acting together with the charged wood materials, the water creates an additional seal against the external atmospheric pressure for the overpressure utilized for disaggregation.
The wood material to be disaggregated is precomminuted at a coarse level before disaggregation, particle sizes in the range of approximately 3 cm to 10 cm, preferably 3 cm to 5 cm, having proven to be especially suitable. Comminution to less than 2 cm brings no advantage since the removal of coatings or other impurities then becomes more difficult.
Experience has shown that, under favorable conditions, for example, with proper sealing of the individual plug screw feeders, only three screw feeders arranged sequentially are sufficient to sustain the appropriate disaggregation pressure matching the pressure of the introduced steam in the middle screw feeder. In an arrangement of more than three plug screw feeders, the zone of desirable reaction pressure is extended, with the result that the throughput rate for the individual plug screw feeders may be increased.
The first plug screw feeder is advantageously equipped on the material-charging side with a high-pressure lock. Pressure control is not necessarily required at the outlet side since the pressure here is allowed to fall to ambient pressure.

Device and method for disaggregating derived timber products