pharmaceutical composition and its use, kit and pharmaceutical system for parenteral administration

专利摘要:
PHARMACEUTICAL COMPOSITION AND ITS USE, KIT AND PHARMACEUTICAL SYSTEM FOR PARENTERAL ADMINISTRATION. It is described by the present invention, a pharmaceutical composition and its use, in addition to a method for parenterally administering a composition, a method which includes administering parenterally to a person a composition containing at least one omega-3 fatty acid and at least one drug, in which the source of at least one omega-3 fatty acid and at least one drug are administered simultaneously.
公开号:BR112013004440B1
申请号:R112013004440-3
申请日:2011-09-12
公开日:2021-02-09
发明作者:David F. Driscoll
申请人:Stable Solutions Llc；
IPC主号:

专利说明:

CROSS REFERENCE TO RELATED REQUESTS
[0001] This claim claims the priority benefit and is partly a continuation of the claim filed in the USA on September 10, 2010 under no. 12 / 923,257, the content of which is incorporated herein by reference. BACKGROUND Field of invention
[0002] The present refers to medicinal formulations that may, for example, contain sufficient amounts of parenteral omega-3 fatty acids derived from natural marine oils and are capable of functioning as a new carrier, or "therapeutic" vehicle for drugs . This proposed new order contrasts with the “pharmaceutical” carriers of conventional drugs, or vehicles.
[0003] Formulations containing marine oil may be in the form of a drug-carrying emulsion, containing omega-3 fatty acids linked to triglyceride or ester molecules, as a component of the emulsion, in addition to an aqueous component. These two components of the emulsion, with the aid of a suitable surfactant, can exist as separate but miscible phases, together with one or more drugs that, when administered parenterally without being accompanied by marine oil containing omega-3 fatty acids, could often cause collateral damage to a vital organ. The new formulation containing marine oil can be administered intravenously as an oil-in-water emulsion containing the drug (s). The addition of omega-3 fatty acids - for example, eicosapentaenoic acid (EPA), docosaexenoic acid (DHA) and / or docosapentaenoic acid (DPA) - to formulations containing selected drugs can reduce at least one adverse event picture of these drugs after administration intravenous. This condition can result from drug toxicity and be manifested by oxidative stress, inflammation, immune stimulation or ischemia of one or more vital organs or a combination of these. Related Technique
[0004] Bioactive omega-3, or n3, fatty acids (n3-FAs) are present in the triglycerides of natural marine oil and are part of a variety of commercial products as nutritional supplements, in the form, for example, of soft gelatin capsules, food, enteral nutrition formulations and oil-in-water emulsions for parenteral nutrition. In this form, semi-synthetic derivatives of n3-FAs also exist in a highly purified form, such as ethyl esters of omega-3 acid in liquid-filled capsules, used to treat hypertriglyceridemia. The bioactive components of marine oils can consist of three main omega-3 fatty acids, namely: eicosapentaenoic acid (EPA), docosaexenoic acid (DHA) and, to a lesser extent, docosapentenoic acid (DPA).
[0005] In the adjustment of critical care, the administration of clinical nutrition supplemented with omega-3 fatty acids in injectable oily emulsions containing lipids has been shown to reduce mortality, antibiotic use and hospital stay (References [8] and [17 ]). These general beneficial effects have been observed in surgical patients with acute illnesses, but the specific reasons for these findings are still unclear, as noted in the following excerpt, drawn from the study's conclusions: “in view of the lack of substantial literature on studies involving interventions single substrate nutrients related to diagnosis in critical illnesses, the present data can be used in formulating hypotheses ... ”(Reference [8]). In other words, there is evidence to support the general, or non-specific, clinical benefits of providing n3-FAs to patients with acute illnesses, but the reasons for these benefits are poorly understood.
[0006] By comparison, in patients with critical illnesses, supplementation with fish oil-based parenteral nutrition emulsions does not affect inflammation or outcome (Reference [33]). Finally, in a recent review of the role of these emulsions, the following statement summarizes their current status in the measured clinic: “... the influence on inflammatory processes, immune function and clinical objectives is unclear, as there are very few studies and available report contradictory observations ”(Reference [31]). Due to the heterogeneity of patient populations and the complex arrangement of diseases and treatments, the present application for n3-FAs in this way is non-specific. In addition, there are significant qualitative differences with respect to fish oil emulsions and the various oily compositions available (US orders No. 12 / 382,196 and PCT / US2010 / 000723), making it even more difficult to identify any potential clinical benefits. SUMMARY
[0007] One embodiment of the present invention is a pharmaceutical composition and its use for parenteral administration containing at least one omega-3 fatty acid and at least one drug.
[0008] Another modality is a pharmaceutical composition for parenteral administration, containing: a) an omega-3 fatty acid selected from the group consisting of triglycerides and / or omega-3 fatty acid esters, such as the omega-3 fatty acid ethyl ester ; and b) at least one drug.
[0009] Preferably, parenteral administration of the composition of the invention is intravenous.
[0010] An exemplary modality can address a significant aspect of the treatment of patients with acute illnesses who need intravenous support, that is, drug therapy, which can be a significant contributor to the determination of the clinical outcome. Intravenous therapies can be prescribed in different conditions (for example, hospitals, outpatient clinics, nursing homes, home care conditions, rehabilitation or residence) depending on the patient, the disease and the prognosis. Co-administration of a parenteral drug known to damage vital organs, now accompanied by specific n3-FAs, used as a therapeutic vehicle for the drug, at the beginning of drug therapy, may allow the rapid incorporation of n3-FAs into the plasma membranes of cells. N3-FAs can replace n6-FAs from typical dietary sources and, thus, reduce damage to those vital organs, for example, by altering the production of lipid mediators and improving clinical results.
[0011] In accordance with an exemplary aspect, there is presented a method of administering a composition parenterally, which method comprises parenterally administering to a person a composition containing at least one omega-3 fatty acid and at least one drug, characterized by the fact that at least one fatty acid and one drug are administered simultaneously.
[0012] Therefore, according to a preferred embodiment of the pharmaceutical composition, at least one omega-3 fatty acid and at least one drug are administered simultaneously. In one embodiment of the present invention, the pharmaceutical composition can also consist of a pharmaceutical system in which the individual components of the composition are partially or completely separated from each other. The pharmaceutical system can have two or more compartments. Another embodiment of the invention is a pharmaceutical system for parenteral administration comprising at least two compartments: a) the first compartment comprises an omega-3 fatty acid selected from the group consisting of triglycerides of omega-3 fatty acid and an ester of that type of acid, such as the ethyl ester of omega-3 fatty acid; and b) the second compartment comprises at least one drug, wherein said omega-3 fatty acid and said drug are administered simultaneously. In an exemplary embodiment, before the administration of the components present in the pharmaceutical system compartments, a mixing step is carried out, in which the contents of the first compartment are combined with that of the second. Alternatively, the contents of the first package and that of the second package can be administered to the patient individually, but simultaneously. According to a preferred embodiment, the contents of the first compartment are administered intravenously and, at the same time, the contents of the second compartment are also administered, preferably intravenously. Preferably, the first compartment contains the omega-3 fatty acid in the form of an oil-in-water emulsion and the second compartment contains a drug dissolved in a liquid, preferably water. For hospitals and in emergencies, a kit containing the different components of the pharmaceutical composition of the invention can be useful. Another embodiment of the present invention is a kit containing: a) one or more sterile packages containing an omega-3 fatty acid selected from the group consisting of omega-3 fatty acid triglycerides and an ester of this type of acid, such as the omega acid ethyl ester -3; and b) one or more sterile packages containing at least one drug.
[0013] Before being administered to the patient, the contents of the different sterile packages of the invention kit can be mixed to form the pharmaceutical composition of the invention. Alternatively, the contents of the different sterile packages can be administered to the patient separately, but simultaneously.
[0014] According to an exemplary aspect, a composition can contain bioavailable amounts of natural or synthetic derivatives of omega-3 acids (i.e., n3 or n3-FAs fatty acids). Omega-3 fatty acids may be present in sufficient concentration to act as a pharmaceutical product, in order to offer a therapeutic benefit, along with the prescribed drug, whose side effect profile is associated with significant damage to vital organs. This combination can form a single “therapeutic drug vehicle” or “TDV”, from the English “therapeutic drug vehicle” (orders US 12 / 382,196 and PCT / US2010 / 000723).
[0015] According to another exemplary aspect, a composition containing at least one prescribed drug and the oil containing n3-FA, in the form of an injectable emulsion containing oil, is administered intravenously.
[0016] According to another exemplary aspect, a combined intravenous administration of concentrated n3-FAs and at least one prescribed drug, known to cause collateral damage to vital organs when in an injectable formulation alone, can guarantee the best bioavailability and rapid incorporation from n3-FAs to plasma membranes, not reached by oral or enteral administration.
[0017] According to another exemplary aspect, at least one adverse consequence of the toxicity of the drug to vital organs can be mitigated or eliminated by the pharmacological actions of the n3-FAs - EPA, DHA and / or DPA -, which can act to reduce the organ damage caused by severe oxidative stress, inflammation, immune modulation and / or ischemia, affecting one or more vital organs.
[0018] According to another example, quantities of bioactive n3-FAs, that is, the sum of EPA, DHA and / or DPA, ranging from a total concentration of 1 to 300 mg / kg, are present in a parenteral formulation, to mitigate the damage to one or more vital organs caused by at least one prescribed drug, also present in the composition.
[0019] According to another exemplary aspect, the type (s) and relative quantity (s) of bioactive n3-FAs present in the formulation can vary from 0 to 100% of each n3 oil component -FA - for example, EPA, DHA and DPA - for a given total concentration of n3-FA oil components.
[0020] According to another exemplary aspect, the effective combination (EPA ± DHA ± DPA) and the dose of n3-FAs (from 1 mg / kg to 300 mg / kg), together with each drug prescribed in the injectable formulation, can be n3-FA + specific drug, n3-FA + specific drug category or apply to a wide spectrum of drugs, which respond to a specific dose-n3-FA combination regimen.
[0021] According to another exemplary aspect, the prescribed drug may reside in either the oily fraction or the aqueous fraction of the injectable formulation, that is, in the "dispersed" (ie, internal) or "continuous" (ie, external) of an emulsion, depending on whether the drug is fat-soluble or water-soluble, respectively. Thus, the lack of pharmaceutical consequences of the location of the drug, that is, whether it is in the dispersed or continuous phase, is innovative in this invention. In other words, the drug in injectable emulsions based on more traditional drugs is, in general, insoluble in water and, therefore, almost always remains, necessarily, in the dispersed phase (oil). As a result, these emulsions serve primarily as drug carriers, or pharmaceutical drug carriers. In contrast, in the present invention, the "carrier" itself containing the n3-FA oil can play a pharmacological role as a therapeutic vehicle for the drug, regardless of whether the drug is in the oily or aqueous fraction of the emulsion, for example, no matter if it it is in the internal (dispersed) or external (continuous) phase of the emulsion.
[0022] According to another exemplary aspect, n3-FAs combined with a particular drug can accentuate the pharmacological actions of the intended drug therapy, regardless of the role of n3-FAs in reducing the damage to the organs that the isolated drug causes. Thus, improving the therapeutic response of treatment with the drug can improve the clinical outcome. DETAILED DESCRIPTION
[0023] One embodiment of the present invention is a pharmaceutical composition for parenteral administration containing at least one omega-3 fatty acid and at least one drug.
[0024] Another preferred embodiment is a pharmaceutical composition for parenteral administration containing: a) an omega-3 fatty acid selected from the group consisting of triglycerides of omega-3 fatty acid and / or an ester of this type of acid, such as the ethyl ester of acid omega-3 fatty; and b) at least one drug.
[0025] An exemplary embodiment is directed to a new dose composition of an injectable drug comprising: a sufficient concentration of an oily derivative, for example, of fish oil triglycerides containing omega-3, or n-3, fatty acids long chain; a drug with an adverse reaction profile, associated with damage to one or more vital organs; and an aqueous component of an emulsion developed for intravenous injection. An exemplary composition contains concentrated and specific bioactive n3-FAs with the aim of acting on particular medical conditions, which can be pharmaceutically related (order US 12 / 382,196). For example, bioactive n3-FAs are able to safely treat iatrogenic causes of kidney disease, where drug-induced nephrotoxicity is mediated, in part, by reduced blood flow, that is, ischemia, by altering the vasoconstrictor effects of thromboxane A2 (PCT / US2010 / 000723 application).
[0026] As used here, the expression “n3-FAs containing oil” refers to constituents such as triglycerides present in marine oils, as well as constituents such as ethyl esters, which are derivatives or products obtained from the transesterification of n3-FAs (from triglycerides to esters). The source of n3-FAs, however, for a given drug formulation can be, for example, entirely natural (for example, unprocessed marine oil) or semi-synthetic (for example, processed marine oil). The source of n3-FAs can provide sufficient amounts of bioactive EPA, DHA and / or DPA, for example, linked to triglyceride molecules or ethyl esters, to mitigate or reduce the adverse effects of a given drug prescribed on a system vital organic in particular. The beneficial pharmacological effects attributed to these bioactive n3-FAs include, for example, reduction of oxidative stress, inflammation, immune stimulation and ischemia arising from drug-related damage.
[0027] The provision of bioactive n3-FAs - including EPA, DHA and / or DPA - and the effects on prostaglandin metabolism, as well as the generation of important endogenous chemical mediators from these precursors of n3-FAs (for example, resolvins and protectins) can potentially have a beneficial effect on the pathophysiological effects of various diseases. This invention can extend these potential potential benefits to be applied to selected drugs that adversely affect vital organs of the body. For example, replacing diets rich in omega-6 or n6 fatty acids (linoleic and arachidonic acids) with diets rich in n3-FAs (EPA, DHA and / or DPA) can significantly alter the profile of eicosanoids (prostaglandins in the series 2 -> series 3 prostaglandins; series 2 thromboxanes -> series 3 thromboxanes; series 4 leukotrienes -> series 5 leukotrienes). For example, series 2 prostaglandins, derived from n6-FAs, are pro-inflammatory compared to series 3 prostaglandins, derived from n3-FAs; series 2 thromboxanes, obtained from n6-FAs, favor vasoconstriction / coagulation compared to series 3 thromboxanes, derived from n3-FAs; leukotrienes from series 4, derived from n6-FAs, produce an exaggerated immune response, compared to leukotrienes from series 5, derived from n3-FAs.
[0028] Recent discoveries about chemical mediators (for example, resolvins and protectins) generated from n3-FAs show that the clinical benefits in relation to inflammatory processes may extend beyond the initial effect. In addition, these mediators can actively participate in reducing the extent of oxidative stress, as well as facilitating the elimination of waste in the affected areas and reducing collateral damage in the surrounding tissues, resulting from an exaggerated systemic inflammatory response arising from various physiological causes of damage to the tissue (for example, infection, trauma, surgery, etc.). Oxidative stress, inflammation, stimulation of the immune response and ischemia can be significant etiological factors involved in the pharmacological causes of drug-induced damage to vital organs, and parenteral supplementation of n3-FAs at the beginning of drug therapy can reduce these adverse effects of the drug, as well as reducing or eliminating the morbidity and possible mortality that accompany them.
[0029] In another exemplary embodiment, the therapeutic drug carrier containing n3-FA can be used in combination with a prescribed drug intended for intravenous administration. Preferably, the pharmaceutical composition of the present invention is in the form of an oil-in-water emulsion.
[0030] Table 1 offers a variety of exemplary compositions with varying proportions of oil and water, along with the corresponding absorptions of bioactive n3-FAs from a 50 ml intravenous mixture with the drug, as normally used in the clinic. For example, the oil-to-water ratio of the composition can vary from about 0.1 to 99.9 to 20.0 to 80.0. The oil: water ratio may depend, for example, on the content of n3-FA in the oil phase, particularly on at least one drug and the marine oil used, as well as on the specific treatment.
[0031] According to another specific modality, intravenous therapies can provide greater bioavailability (for example, about 100% of the administered dose) compared to other routes of administration (for example, oral, topical, intramuscular, subcutaneous, suppositories etc.) due to changes in the absorption and / or metabolism of drugs not administered directly into the systemic circulation. As such, intravenous administration of the therapeutic drug carrier can increase the rate of incorporation of n3-FAs into plasma membranes (for example, within hours of infusion) and greatly accelerate the onset of the beneficial effects of n3-FAs compared to pathways. oral or enteral administration, which can typically include days or weeks of pre-treatment with n3-FAs alone before drug therapy can be started. For example, in a conventional process, when fish oil was used as a vehicle via gastric lavage in an animal model of experimental nephrotoxicity, a pre-treatment period of 14 days was necessary to achieve sufficient concentrations in the plasma membrane to mitigate kidney damage. (Reference [9]). In a conventional procedure, in conditions where fish oil capsules for oral use were given as therapy to, for example, patients with rheumatoid arthritis and cardiovascular disease, the clinical benefits were not realized before several months of supplementation (Reference [31] ). Therefore, the bioavailability and the rapid and successful incorporation of n3-FAs into the plasma membranes of cells are crucial to achieve the mitigation of adverse drug events when using injectable emulsions containing n3-FA as a therapeutic drug vehicle.
[0032] Another exemplary modality is directed at candidate drugs prescribed intravenously, for which use may be associated with significant adverse effects on vital organs, including toxicity mechanisms involving oxidative stress, inflammation, immune stimulation and ischemia of organic tissues ( Reference [10]). Due to the intravenous administration of these drugs, the high bioavailability achieved can increase the toxic potential of these pharmacological agents. Vital organs in the human body can include brain, heart, lungs, liver and kidneys. For example, the brain is known to be a lipid-rich environment, containing nerve cells and fibers protected by tissue containing lipids, known as myelin, which forms a protective sheath around neuronal structures. A risk of damage is offered by highly lipophilic drugs, such as the anti-arrhythmic agent amiodarone, a structural analogue of the thyroid hormone, which can accumulate in these lipid tissues, destroying the myelin sheath and interrupting the ruptured nerve conduction. These neurotoxic effects can cause peripheral neuropathy.
[0033] Other drugs that act on the central nervous system, such as levodopa, used in patients with Parkinson's disease, can benefit from n3-FAs. The prolonged use of levodopa has been associated with complications in motor function (involuntary movements), which have been linked to high concentrations of arachidonic acid in the brain. The supply of n3-FAs can compete with n6-FA, arachidonic acid, and are the preferred substrate for fatty acids important in human metabolism. Therefore, the reduction of n6-FA concentrations may be beneficial for patients with Parkinson's disease, in order to reduce the adverse effects of levodopa (Reference [11]). In another example, the anti-cancer drug doxorubicin, an antibiotic in the anthracycline class, can cause acute or chronic cardiotoxicity due to oxidative stress and the production of reactive oxygen species that induce damage to cardiac tissues. In laboratory animals, pretreatment with diets enriched in n3-FA suggested an improvement in the therapeutic index of antineoplastics in the anthracycline class (Reference [12]).
[0034] In another example, the anti-tumor drug bleomycin, a basic glycopeptide, can induce an oxidative load in lung tissues, which contain low levels of the enzyme that inactivates the drug, bleomycin hydrolase. Increased levels of bleomycin in the tissues of the lungs can lead to the release of cytokines, for example, tumor necrosis factor, and also result in the interaction with iron and molecular oxygen which, in turn, can lead to dangerous production of free radicals. In cultures of lung endothelial cells exposed to amiodarone, pretreatment with n3-FAs has been observed to protect against toxicity (Reference [13]). In another example, the anticonvulsant valproic acid, a branched-chain carboxylic acid, can cause fatty liver, or "fatty liver", leading to significant liver disease. In an animal model of necroinflammatory liver damage, pretreatment with n3-FAs reduced oxidative damage and showed protective effects (Reference [14]). In yet other examples involving animals pretreated with n3-FAs, several popular antibiotics, such as gentamicin (Reference [15]), and immunosuppressive agents, such as cyclosporine (Reference [16]), have been shown to be less damaging to the kidneys. Other candidate drugs that cause kidney damage - for example, non-steroidal anti-inflammatory drugs including ketorolac and indomethacin, as well as ionic radiocontrast agents, may also benefit from the inclusion of n3-FAs in intravenous emulsions containing these drugs or agents.
[0035] In exemplary modalities, the co-administration of specific n3-FAs, instead of pre-treatment, in high concentration and sufficient intravenous doses using, for example, marine oils containing omega-3 acids as the therapeutic vehicle of the drug can significantly increase the safety profile of drugs administered parenterally, which currently have adverse effects on vital organs. Treatment with n3-FAs prior to drug therapy is typically not a reasonable option for patients with acute illnesses who need therapy with such drugs and for whom rapid action can be vital. Therefore, in these cases, the provision of n3-FAs by oral or enteral route is not always viable or practical. This advantage is particularly important when the drug has a narrow therapeutic index (for example, ratio between lethal average dose and small desired average dose). The therapeutic index refers to the proportion between the dose necessary to produce a toxic effect and that necessary to produce the desired therapeutic response; it is a relative indication of the potency and safety of the drug. For example, a drug that has a narrow therapeutic index may have a significant overlap between effective and toxic doses.
[0036] An example of a drug with a narrow therapeutic index is the gentamicin aminoglycoside, a parenteral antibiotic that has a broad spectrum of action against gram-negative aerobic bacteria. An exemplary therapeutic range in plasma for this drug varies between 4 and 10 μg / mL, but it is toxic to the kidneys when its blood level between doses is above 2 μg / mL.
[0037] This exemplary drug has a narrow therapeutic range and its toxicity to the kidneys is associated with inadequate excretion and accumulation.
[0038] Another example of a drug with a narrow therapeutic index is the antibiotic and antifungal amphotericin B, which can also present toxicity to the kidneys within the therapeutic dose range. Other examples of drugs with a narrow therapeutic index include cyclosporine, ketorolac, cisplatin and cancer anthracycline, doxorubicin. In the case of the latter, an accumulative dose> 550 mg / m2 can be associated with cardiomyopathy. In an exemplary modality, the use of n3-FAs as a therapeutic vehicle for these drugs with a narrow therapeutic index can mitigate the toxic response on vital organs.
[0039] Table 2 presents examples of possible drugs / categories that can be associated with damage to vital organs. Others can be included in cases where, for example, the co-administration of concentrated n3-FAs can accentuate the effects of primary therapy. According to a preferred embodiment of the pharmaceutical composition, the drug is a material that damages a vital organ when it is not administered with at least one omega-3 fatty acid, for example, triglyceride and / or omega-3 fatty acid ester, like the omega-3 fatty acid ethyl ester.
[0040] The examples in Table 2 are not necessarily limiting, but examples of a wide range of possible combinations and permutations.
[0041] An exemplary modality may employ, for example, a dose range of about 1 to about 300 mg / kg, as well as combinations of n3-FAs designed to accompany a drug prescribed in a proposed intravenous formulation. Table 3 provides examples of doses (in g of n3-FAs) within the range mentioned above, for adults weighing between 40 and 100 kg. The data in Table 3 can be applied to lower weights, such as babies and other pediatric patients, where applicable. The examples in Table 3 are not necessarily limiting, but examples of a wide range of possible combinations and permutations.
[0042] According to an exemplary aspect, a source of n3-FAs can be natural, semi-synthetic, synthetic or a combination of these. For example, a natural source of n3-FAs can include fish oil triglycerides. A semi-synthetic source can include, for example, n3-FAs linked to neutral triglycerides, to ethanol - in the form of ethyl esters - or a combination of these. The source of n3-FAs can be natural, like marine oil triglycerides, but it can then be synthetically enriched. The sources of n3-FAs can be mixtures of natural products and synthetic derivatives.
[0043] For example, an oily derivative of fish oil that contains n3-FAs with a concentration greater than that which occurs in the natural source can be used.
[0044] According to a preferred embodiment of the invention, the pharmaceutical composition contains omega-3 fatty acid triglycerides and medium chain triglycerides (TCM). Preferably, the pharmaceutical composition for parenteral administration, preferably intravenous, is an emulsion containing 10 to 69% by weight of TCM, based on the total amount of oil in the emulsion.
[0045] Preferably, medium chain triglyceride (TCM) - triglyceride obtained from esterification of glycerin with medium chain fatty acids - contains more than 50%, preferably more than 80% and more especially, at least 95% of acids saturated fatty acids with 8 and 10 carbon atoms, based on the total number of fatty acids esterified in the TCM. In addition, the composition of the fatty acid fraction of the TCM may contain (based on the total number of fatty acids esterified in the TCM): - capróic acid, preferably, at most 2.0%; and / or - caprylic acid, preferably between 50.0 and 80.0%; and / or - capric acid, preferably between 20.0 and 50.0% /; and / or - lauric acid, preferably up to a maximum of 3.0% and / or - myristic acid, preferably up to a maximum of 1.0%.
[0046] Optionally, the oil can include medium chain fatty acids from medium chain triglycerides (TCMs); these can be medium chain saturated fatty acids. The oil may optionally include n6-FAs, for example, from a vegetable oil. In one embodiment, the composition in the form of an emulsion may be stable, have normal metabolic clearance and / or be well tolerated by patients. For example, the emulsion can be an oil-in-water (o / w) emulsion.
[0047] An example of oil is derived from fish and can be rich in polyunsaturated and bioactive omega-3 fatty acids. The oily component of the emulsion may contain fish oil triglycerides; for example, omega-3 acid triglycerides. Fish oil triglycerides can be present between about 31% and about 90%, or from about 41% to about 90%, or from about 45% to about 90%, or range from more than 50 % to about 90%, or from about 51% to about 90% or from about 55% to about 90%, or from about 60% to about 90%, or from about 70% to about from 90%, or from about 80% to about 90%, or from about 40% to about 80%, or from about 50% to about 70%, or from about 60% to about 65 %, based on the total weight of the oily component of the emulsion. For example, using exemplary ranges of fish oil triglycerides, the amount of esterified omega-3 fatty acids released to a human body can increase. For example, the depositor identified the clinical importance of the absolute absorption of omega-3 fatty acids and found that this can be increased by using, for example, the exemplary ranges of fish oil triglycerides. For example, depositors have observed that, at least for some applications, such as cardiovascular health, the absolute absorption of omega-3 fatty acids may be a more accurate indicator of overall effectiveness than the ratio of omega-3 to omega fatty acids -6.
[0048] They can be composed of 20 to 22 carbons and contain three or more double bonds in the third position from the terminal methyl of the long chain fatty acid molecule (AGCL). The standard notation for various fatty acids (FAs) includes: 1) number of carbons followed by, 2) number of double bonds and, finally, 3) position of the double bond in relation to methyl (or “n3” in the case of AGCL of fish oil). In particular, marine oil can be greatly enriched with two main n3-FAs, that is, eicosapentaenoic acid, or EPA (30: 5n3) and docosaexenoic acid, or DHA (22: 5n3). Marine oil may contain smaller amounts of n3-FAs, such as docosapentaenoic acid, or DPA (2: 6n3). The fish oil component of the parenteral o / a lipid emulsion may represent oils obtained from a mixture of fish from families with a high fat content, such as those of the following species: Engraulidae (eg anchovies), Carangidae (eg mackerel), Clupeidae (for example, herring), Osmeridae (for example, eperlano), Salmonidae (for example, salmon) and Scombridge (tuna).
[0049] In the European pharmacopoeia (EP), there are two monographs (EP 1352, entitled “Omega-3 Triglycerides” and EP 1912, entitled “Fish Oil, Rich in Omega-3 Acids”) relating to fish oil acceptable for use in parenteral emulsions (EP 1352, EP 1912, 2008). The EP 1352 monograph is quite different from EP 1912, both in composition and in the fact that the requirements for bioactive n3-FAs in the first are much higher than in the second (EP 1352: EPA + DHA> 45%, total n3-FAs> 60% against EP 1912: EPA> 13%, DHA> 9%, total n3-FAs> 28%). The levels of n3-FAs in EP 1912 are compatible with those found in nature. By comparison, in EP 1352, the concentrations of n3-FA are substantially higher and can be obtained by an enrichment process, such as molecular distillation, in which some undesirable fatty acids that are present, such as myristic acids, are removed. palmitic and stearic. In this process, the concentrations of all remaining fatty acids, and especially the n3-FAs, are proportionally high (Reference [32]). In an exemplary embodiment, fish oil triglycerides can include at least 60% omega-3 fatty acids, based on the total fatty acid weight of fish oil triglycerides. In an exemplary embodiment, these triglycerides can include a total of EPA and DHA of at least 45%, based on the total fatty acid weight of the fish oil triglycerides. For example, the fatty acids and omega-3 fatty acids (such as, for example, EPA and DHA) discussed here refer to the parts of those acids that make up the fish oil triglyceride, in accordance with EP 1352. For example, the fatty acids and omega-3 fatty acids (such as EPA and DHA) discussed above may be in an esterified form when present in fish oil triglycerides.
[0050] According to a preferred embodiment, the pharmaceutical composition of the invention contains an omega-3 fatty acid component that includes eicosapentaenoic acid in a proportion of 30% or more, docosaexenoic acid in a proportion of 30% or less and docosapentenoic acid in a proportion of about 40% or less, based on the weight of the total omega-3 fatty acid content.
[0051] Fish oil triglycerides can contain at least one n6-FA, for example, several n6-FAs. At least one n6-FA can include, for example, arachidonic acid or AA (20: 4n6), linoleic acid or LA (18: 2n6), alpha-linolenic acid or ALA (18: 3n3) or a combination of these. For example, the total content of at least one n6-FA can vary from about 0.1% to about 1.0%, or from about 0.2% to about 0.9%, or from about 0.3% to about 0.8%, or from about 0.4% to about 0.7%, or from about 0.5% to about 0.6%, based on the weight of the component emulsion oil.
[0052] A second exemplary component of the oil component of the emulsion may include at least one medium chain triglyceride (TCM), for example, several TCMs. For example, at least one TCM can be present in a proportion of about 10% to about 69%, or from about 10% to about 40%, or from about 10% to about 30%, or from about from 10% to about 20%, or from about 10% to about 15%, or from about 20% to about 60%, or from about 30% to about 50%, or about 40 % to about 45%, based on the total weight of the oily component of the emulsion. For example, using the exemplary TCM ranges, the amount of esterified omega-3 fatty acids released to a human body can be increased. For example, using exemplary TCM ranges, this amount can be increased by using a relatively less amount of TCM, still achieving the beneficial metabolic clearance and physico-chemical stability characteristic of the emulsion.
[0053] For example, at least one TCM can include a medium chain saturated fatty acid; for example, various medium chain saturated fatty acids. In an exemplary embodiment, TCM is a fatty acid triglyceride that has 6 to 12 carbon atoms. TCM can be derived from a plant, like a vegetable; for example, from various plants. TCM can contain caprylic acid (for example, in proportions between about 50% to about 80% by weight of TCM), an eight-carbon saturated fatty acid (8: 0). TCM can contain capric acid (for example, in proportions of about 20% to about 50% by weight of TCM), a 10-carbon saturated fatty acid (10: 0). For example, medium chain triglycerides can contain triglycerides of caprylic and capric acids in a proportion of at least 90% by weight of medium chain triglycerides. The TCM description for use in this invention can, for example, meet the requirements of the EP 0868 monograph, entitled “Tryglicerides, Medium Chain” (Triglycerida saturate media) (EP 0868, 2008).
[0054] The determination of the content of omega-3 fatty acids can be done as described in the European pharmacopoeia “Fish oil, rich in omega-3 acids”. The content of n3-FAs can come from just one n3-FA or a combination of them. In an exemplary embodiment, the composition can contain EPA, DHA, DPA or a combination of these; for example, a little bit of EPA, DHA and DPA. The individual dose, for example, the total daily dose, of eicosapentaenoic acid (EPA) can vary from 0 to 300 mg / kg of the formulation, for example, from 50 to 250 mg / kg, for example, from 100 to 200 mg / kg, based on body mass. The individual dose, for example, the total daily dose of docosaexenoic acid (DHA) can vary from 0 to 300 mg / kg of the formulation, for example, from 50 to 250 mg / kg, for example, from 100 to 200 mg / kg , based on body mass. The individual dose, for example, the total daily dose of docosapentenoic acid (DPA), can vary from 0 to 300 mg / kg of the formulation, for example, from 50 to 250 mg / kg, for example, from 100 to 200 mg / kg, based on body mass. For example, EPA, DHA and / or DPA may be present in amounts that are effective in reducing damage to at least one vital organ, which could otherwise be caused by at least one drug.
[0055] Preferably, the pharmaceutical composition of the invention is intended for use in the treatment by daily parenteral administration of omega-3 fatty acid in an amount of about 1 to about 300 mg / kg of body weight.
[0056] The individual dose of n3-FAs can be that of a single n3-FA or any combination of these acids (for example, containing EPA, DHA and DPA). In an exemplary embodiment, the total individual daily dose of n3-FAs can be from about 1 to about 300 mg / kg, for example, from about 100 to 200 mg / kg, based on body mass.
[0057] In another exemplary embodiment, various combinations of bioactive n3-FAs may be present, along with some therapeutic drug vehicles containing specific percentages of selected n3-FAs. In this context, Table 4 provides a sample of possible combinations of n3-FAs that act as therapeutic drug vehicles. For example, EPA can be present in an amount of about 0 to about 100%, for example, about 30 to about 100%, based on the weight of the total content of n3-FA. For example, DHA can be present in an amount from about 0 to about 100%, for example, from about 0 to about 30%, based on the weight of the total content of n3-FA. For example, DPA can be present in an amount of about 0 to about 100%, for example, about 0 to about 40%, based on the weight of the total content of n3-FA. The examples in Table 4 are not necessarily limiting, but examples of a wide range of possible combinations and permutations.
[0058] In some cases, it is possible that a specific prescription drug, within the scope of a defined therapeutic dose, will benefit from or need a specific dose and / or a combination of n3-FAs planned or adapted to maximize the effects reducing the toxicity of n3-FAs. Some prescription drugs within a category of pharmacological agents may benefit from a specific combination of n3-FAs, or it is possible that such a vehicle can be applied to a wide range of drugs and categories according to an exemplary modality. Table 5 provides an example of a therapeutic drug carrier for various small-volume infusions and the amounts of n3-FAs that a patient can receive in a 24-hour period. The examples in Table 5 are not necessarily limiting, but examples of a wide range of possible combinations and permutations.
[0059] The concentration of the drug in the composition and its dose, for example, the total daily dose of the drug, may depend on several factors, such as, for example, the formulation of n3-FA, the drug and the specific condition to be treated.
[0060] According to a preferred embodiment of the invention, the pharmaceutical composition includes the drug in an amount of about 0.005% by weight to about 1.5% by weight, based on the weight of the composition.
[0061] For example, at least one drug can be present in an amount of about 0.005 to about 1.5%; for example, about 0.1 to about 0.5% based on the weight of the composition.
[0062] Preferably, the pharmaceutical composition is used in the treatment by daily parenteral administration of a drug in an amount between about 0.5 to about 50 mg / kg of body weight.
The dosage of the drug can vary from about 0.5 to about 50 mg / kg, for example, from about 10 to about 30 mg / kg, based on the weight of the composition. For example, the intravenous dose volume of the composition can be about 25 to about 100 ml / dose for adults and about 1 to about 10 ml / dose for babies.
[0064] As another exemplary modality, the prescribed drug may be present in the oily fraction or in the aqueous fraction, in the form of an injectable oil-in-water emulsion containing n3-FA, depending on the physicochemical characteristics of the drug. For example, exemplary compositions and methods can be characterized by the fact that the drug is present entirely in the oily fraction, entirely in the aqueous fraction or in both fractions. For example, this approach may be contrary to the usual practice of the pharmaceutical industry, for example, when using injectable oil-in-water emulsions as a pharmaceutical drug vehicle for safe administration of water-insoluble drugs intravenously (Driscoll et al., 2009) .
[0065] For example, the anesthetic / sedative agent propofol, insoluble in water, residing in the omega-6 rich oil phase of an injectable oil-in-water emulsion is an example of conventional practice used in drug carrier applications by pharmaceutical formulators . In contrast, in an exemplary embodiment, oil containing omega-3 fatty acid can function as a new therapeutic component, and not as a mere pharmaceutical component - for example, just a carrier. Therefore, its use is not limited to a specific group of drugs based on their intrinsic solubility and their partition coefficients in relation to a given phase (for example, oil or water) of the emulsion. In an exemplary embodiment, oil containing omega-3 fatty acid may have a dual purpose, for example, to be both a drug and a therapeutic drug vehicle for selected pharmacological agents.
[0066] As another exemplary modality, the n3-FAs in a given formulation can enhance the pharmacological actions of the main prescribed drug and improve the therapeutic response to it. This action may result from additive pharmacological effects that complement the action of the main drug and improve and / or accelerate the membrane-altering properties (for example, repairing, sensitizing properties) of n3-FAs. In the first case, for example, the clinical effects of a diuretic such as furosemide (“high-limit loop diuretic”), whose pharmacological action involves stimulating the synthesis of vasodilating prostaglandins that increase blood flow to the kidneys, can be increased by the effects of n3-FAs that form thromboxanes of the A3 series, less vasoconstrictors. This can be of particular clinical importance in critically ill patients, who are overloaded with fluids and are resistant to conventional diuretic therapy. In another example, n3-FAs may have analgesic properties, capable of complementing the action of drugs used in pain management (Reference [18]). In the second case, for example, it has been suggested that n3-FAs may improve the response to chemotherapy for various types of cancer by increasing the cytotoxicity of anticancer drugs and reducing oxidative stress in animal and cell culture models (References [19 ] to [27]), as well as in humans (References [28] to [30]). In an exemplary modality, an additional benefit of using n3-FAs as a therapeutic drug vehicle can be the improvement of clinical results by intensifying the response to therapy with the main drug.
[0067] According to a preferred embodiment, the pharmaceutical composition contains: a) an omega-3 fatty acid selected from the group consisting of omega-3 fatty acid triglycerides and / or omega-3 fatty acid ethyl ester; and b) at least one drug for use in the treatment and prophylaxis of toxic side effects of said drug.
[0068] In addition, the pharmaceutical composition of the invention can be used to reduce toxic effects of the drug. Such effects are selected, preferably, from the group of oxidative stress, inflammation, adverse immune response, ischemia and damage to vital organs such as kidneys, brain, heart, liver and lungs; preferably, adverse effects of drugs selected from the group consisting of oxidative stress, inflammation, immune stimulation, ischemia of at least one vital organ and a combination of these.
[0069] In view of the complexity of the various actions of the n3-FAs capable of reducing inflammation, oxidative stress, immune modulation and ischemic damage, as well as related pharmacological actions, with emphasis on the mechanisms of damage of the drug to Organs vital organs, there are numerous exclusive exemplary aspects of this invention. Special interactions between n3-FAs and drugs associated with damage to vital organs can result in these benefits being achieved at the beginning of drug therapy by intravenous application of the therapeutic drug carrier. That is, in an exemplary modality, the almost complete bioavailability of intravenous administration is capable of allowing the rapid incorporation of n3-FAs into the plasma membranes of cells, leading to the mitigation of the toxic effects of the selected drugs.
[0070] In an exemplary modality, taking advantage of the option of administering n3-FAs in much higher concentrations than those found in natural marine sources and the use of semi-synthetic enrichment methods, through binding to triglyceride or ester molecules, one can further increase this efficient incorporation into the plasma membranes of cells. For example, a composition described in US application 12 / 382,196 filed on March 11, 2009 and still pending, as well as in the international application PCT / US2010 / 000723 filed on March 11, 2010, the contents of which are incorporated by reference, can be used in the present compositions and methods. This exemplary advantage can be particularly beneficial, as several intravenous drugs are supplied in multiple doses over 24 hours, using small volume parenteral material (for example, <100 mL). Therefore, in some cases, the use of integral natural fish oil sources, having approximately 30% n3-FAs in the total fatty acid profile, may benefit from or require higher daily volumes of the lipid emulsion, which may not be tolerated (for example, inducing hypertriglyceridemia). In addition, the use of these natural fish oils with relatively low concentrations of n3-FAs may not provide reasonable and safe effective doses of these acids as a therapeutic drug vehicle in the upper limits indicated in this invention (for example, up to 300 mg / kg). The use of exemplary aspects may not make clear the concerns associated with pretreatment with n3-FAs when other routes of administration are used (for example, oral or enteral).
[0071] In a preferred embodiment, the pharmaceutical composition is an emulsion containing an oily and an aqueous component, the first containing fish oil triglycerides in proportions between about 60% and about 90%, based on the weight of the oily component - where these triglycerides contain at least 60% omega-3 fatty acids based on the total weight of the fish oil triglyceride fatty acids and where these triglycerides contain a total amount of EPA and DHA of at least 45% , based on the total weight of the fatty acids of the fish oil triglycerides - and at least one medium chain triglyceride, whose total amount varies from about 10% to about 40%, based on the weight of the oily component.
[0072] In an exemplary aspect, the composition employed in the method can be an emulsion containing: an oily and an aqueous component, the first containing fish oil triglycerides in a proportion of about 60% to about 90% based on in the weight of the oily component - where these triglycerides contain omega-3 fatty acids in an amount of at least 60% based on the total fatty acid weight of the fish oil triglycerides and these contain a total amount of EPA and DHA of at least 45 %, based on the total fatty acid weight of the fish oil triglycerides - and at least one medium chain triglyceride, the total amount of which ranges from about 10% to about 40% based on the weight of the oily component.
[0073] According to another exemplary aspect, the composition employed in the method can be an emulsion containing an oily and an aqueous component, the first containing fish oil triglycerides in an amount greater than 50% up to about 90%, based on the weight of the oil component of the emulsion - where the fish oil triglycerides contain omega-3 fatty acids in an amount of at least 60%, based on the total fatty acid weight of these triglycerides and these contain a total amount of EPA and DHA of at least 45%, based on the total fatty acid weight of the fish oil triglyceride - and a medium chain triglyceride.
[0074] According to another exemplary aspect, the composition used in the method can be an emulsion comprising: an oily and an aqueous component, the first containing fish oil triglycerides in an amount between about 31% and about 90 % based on the weight of the oily component of the emulsion - with fish oil triglycerides containing omega-3 fatty acids in a proportion of at least 60%, based on the total fatty acid weight of fish oil triglycerides, and these triglycerides contain a total of EPA and DHA of at least 45%, based on the total weight of the triglycerides - and a medium chain triglyceride; where the emulsion is of the oil-in-water type and the concentration of the oily component in it ranges from 5 g / 100 mL to less than 20 g / 100 mL, or the concentration of the oily component in the emulsion ranges from more than 20 g / 100 mL up to 30 g / 100 mL.
[0075] In an exemplary modality, n3-FAs can, for example, exert their beneficial effect by modifying the common mechanisms of tissue damage that accompany the toxicity of the drug to vital organs. Thus, by reducing the toxic potential of drugs on vital organs, larger doses of some of them can be administered to treat the clinical problem, which can increase the clinical efficacy of some drug regimens in a dose-dependent manner. Also, in specific cases, n3-FAs can improve the therapeutic response to drugs by enhancing or complementing their mechanisms of pharmacological action.
[0076] The therapeutic drug vehicle can exert its toxicity-reducing effect on selected drugs by reducing oxidative stress, inflammation, adverse immune responses, ischemia or a combination thereof. The composition of the therapeutic vehicle containing n3-FA can be adapted to a specific drug, to a dose thereof, to several drugs of the same category and / or to several drugs belonging to different therapeutic categories. The therapeutic drug vehicle can enhance the beneficial pharmacological effects of the drug contained in the formulation in addition to reducing its toxicity. It can also accentuate the beneficial pharmacological effect of the drug by reducing the required amount of it and thus further mitigating its toxicity. The therapeutic vehicle of the drug can improve the therapeutic response to it and, therefore, the clinical result, through its repairing properties. Said vehicle can be used for parenteral administration of drugs, for example, in the form of an injectable oil-in-water emulsion in order to exert its beneficial effects at the beginning of drug therapy. The addition of the drug to a therapeutic vehicle produced from this application can be done in the "dispersed" (or "internal") phase or in the "continuous" (or "external") phase of an emulsion formulation.
[0077] In an exemplary embodiment of a method of administering the composition parenterally, at least one omega-3 fatty acid and at least one drug are administered simultaneously. For example, this simultaneous administration can be achieved because the acid and the drug are present in the same emulsion. Any suitable parenteral administration can be used, including, for example, intravenous and / or intraarterial.
[0078] In an exemplary administration, the method does not include a process of pretreating the patient with an omega-3 fatty acid prior to parenteral administration of the composition. For example, the pretreatment process dispensed according to the exemplary modality may be a daily administration of an omega-3 fatty acid. This pretreatment dispensed according to an exemplary modality is a previous treatment with an omega-3 fatty acid, which occurs one day or more before administration of the composition or, for example, three days or more before administration or, for example , seven days or more before administration or, for example, 14 days or more before administration. For example, the pretreatment process that is dispensed according to an exemplary modality is a previous treatment with an omega-3 fatty acid that occurs from 3 to 21 days before administration of the composition or, for example, from 7 to 14 days. days before administration of the composition.
[0079] The pharmaceutical composition of the present invention may preferably also comprise pharmaceutically acceptable ingredients, especially those that can be used in pharmaceutical compositions that can be administered intravenously. According to a preferred embodiment, the pharmaceutical composition contains one or more emulsifiers, preferably phospholipids, especially egg lecithin.
[0080] It is advantageous that the pharmaceutical compositions of the present invention also contain glycerin.
[0081] In addition, the composition of the present invention may comprise sodium oleate and / or pH adjusting agents, such as NaOH or HCl.
[0082] Also, preferably, the pharmaceutical composition may contain one or more antioxidants, preferably α-tocopherol.
[0083] It has been observed that excellent effects can be achieved by pharmaceutical compositions containing drugs selected from the group of antibiotics and NSAIDs, in particular when the drug is chosen from ketorolac, a pharmaceutically acceptable salt of ketorolac, gentamicin and a pharmaceutically acceptable salt of gentamicin . A preferred embodiment of the pharmaceutical composition is an oil-in-water emulsion comprising omega-3 fatty acid triglycerides, medium chain triglycerides and a drug selected from ketorolac, gentamicin and pharmaceutically acceptable salts thereof.
[0084] In particular, the composition is suitable for alleviating the nephrotoxicity of a drug selected from ketorolac, gentamicin and pharmaceutically acceptable salts thereof.
[0085] According to another preferred embodiment, the pharmaceutical composition contains at least one drug selected from a group consisting of amphotericin, quinolone, antineoplastic agents, amiodarone, loop diuretics, azathioprine, cyclosporine, tacrolimus, indomethacin, ketorolac and a combination of these .
[0086] Due to the excellent toxicity-reducing effect of the omega-3 fatty acid components, preferably combined with TCM, the pharmaceutical composition of the invention may contain several classes of drugs. Particularly good results can be obtained with a pharmaceutical composition in which at least one drug is selected from the group consisting of: a) antibiotics, preferably selected from the group consisting of aminoglycosides, amphotericin, chloramphenicol, ketoconazole, macrolides, quinolones and tetracyclines; b) antineoplastic agents, preferably selected from the group consisting of alkylating agents, antimetabolites and platinum antimitotic coordination complexes; c) anti-Parkinson agents, preferably selected from the group consisting of levodopa, pramipexole, ropinirole, rotigotine and bromocriptine; d) cardiovascular agents, preferably selected from the group consisting of adenosine, amiodarone, angiotensin-converting enzyme (ACE) inhibitors and flecainide; e) diuretics, preferably selected from the group consisting of loop diuretics, potassium-sparing diuretics and thiazides; f) immunosuppressive agents, preferably selected from the group consisting of azathioprine, cyclosporine, mycophenolate and tacrolimus; g) psychotropics, preferably selected from the group consisting of haloperidol, monoamine oxidase inhibitors, phenothiazines, serotonin reabsorption inhibitors and thioxanthines; h) Non-steroidal anti-inflammatory drugs (NSAIDs), preferably selected from the group consisting of acetaminophen, aspirin, ibuprofen, indomethacin and ketorolac; and i) Pharmaceutically acceptable salts and derivatives of drugs a) to h).
[0087] According to an especially preferred embodiment, the pharmaceutical composition contains a non-steroidal anti-inflammatory drug (NSAID) selected from the group consisting of acetaminophen, aspirin, ibuprofen, indomethacin, ketorolac, as well as pharmaceutically acceptable salts and derivatives thereof. , for use in the treatment or prophylaxis of pain, swelling, redness, fever or inflammation, especially for use in the treatment or prophylaxis of acute severe postoperative pain.
[0088] Excellent results can be achieved by a pharmaceutical composition containing as a drug ketorolac or a pharmaceutically salt thereof, such as ketorolac tromethamine, for use in the treatment or prophylaxis of pain, swelling, redness or inflammation, especially for use in treatment severe acute postoperative pain. Said pharmaceutical composition has improved effects in relation to reduced nephrotoxicity, which provides the possibility to increase the dose to be administered.
[0089] With the pharmaceutical composition of the present invention it is, in general, possible to increase the dose of the drugs to be administered, in comparison with that normally used. In general, calculating the dose of a drug is a balance between its effectiveness and the possible toxic side effects. Due to the toxicity-reducing effect of the pharmaceutical composition of the invention, the dose of the drugs can be increased, keeping their toxic effects low. As a result, drugs can be administered in higher and more effective doses.
[0090] In an exemplary embodiment, the pharmaceutical composition of the invention can be used in the treatment by daily parenteral administration of ketorolac tromethamine and a single dose greater than 60 mg, preferably greater than 75 mg; and in multiple doses greater than 120 mg / day, preferably greater than 150 mg / day.
[0091] According to another preferred embodiment, the pharmaceutical composition comprises acetaminophen for use in the treatment or prophylaxis of pain and / or fever.
[0092] The dose of acetaminophen to be administered to a patient can be increased significantly, in comparison with the usual doses. According to a preferred embodiment, the pharmaceutical composition can be used in the treatment of patients weighing> 50 kg through daily parenteral administration of acetaminophen in a single dose greater than 1000 mg, preferably greater than 1250 mg; and in multiple doses greater than 4000 mg / day, preferably greater than 5000 mg / day.
[0093] It is especially preferable that the pharmaceutical composition is used to treat patients weighing less than 50 kg, through daily parenteral administration of acetaminophen in a single dose greater than 15 mg / kg of body weight, preferably greater than 18 , 75 mg / kg of body weight; and in multiple doses greater than 75 mg / kg / day, preferably greater than 93.75 mg / kg / day.
[0094] According to a still preferred embodiment of the present invention, the pharmaceutical composition comprises indomethacin or a pharmaceutically acceptable salt of indomethacin, more preferably for use in the treatment intended to close the hemodynamically significant ductus arteriosus in premature babies weighing between 500 g and 1750 g, especially when the usual medical treatment is ineffective. Especially in the treatment of babies, a well-balanced but effective dose regimen is recommended. Therefore, in a preferred embodiment, the pharmaceutical composition contains indomethacin or a pharmaceutically acceptable salt of indomethacin for use in the treatment of premature infants weighing between 500 g and 1750 g by parenteral administration of three intravenous strokes at intervals of 12 to 24 hours, the first being dose greater than 0.2 mg / kg, preferably greater than 0.25 mg / kg, and a total dose greater than or equal to a value between 0.4 mg / kg and 0.7 mg / kg, preferably greater or equal to a value between 0.5 mg / kg and 0.875 mg / kg.
[0095] Antibiotics, in particular aminoglycosides, are especially preferred drugs. There is a huge demand for antibiotics that are highly effective, especially against multi-resistant bacterial strains. In the state of the art, the dose administered and the effectiveness of antibiotics are limited due to their toxic side effects. However, the preferred pharmaceutical composition of the present invention which comprises antibiotics is more effective, since a larger dose of these can be administered due to the toxicity-reducing effect of the composition. In a preferred embodiment, the pharmaceutical composition contains an aminoglycoside antibiotic selected from the group consisting of amikacin, gentamicin, tobramycin and pharmaceutically acceptable salts thereof, preferably for use in the treatment and prophylaxis of infections.
[0096] Preferably, the pharmaceutical composition comprises amikacin or a pharmaceutically acceptable salt, such as amikacin sulfate, for use in the treatment and prophylaxis of infections, especially those with Gram-negative bacteria resistant to multiple drugs, such as Pseudomonas aeruginosa, Acinetobacter, Enterobacter, Serratia marcescens and Providencia stuartii, or for use in the treatment or prophylaxis of non-tuberculous mycobacterial infections and tuberculosis. In an exemplary embodiment, the pharmaceutical composition is intended for use in treatment by daily parenteral administration of amikacin sulfate in a dose greater than 15 mg / kg of body weight, preferably greater than 20.25 mg / kg of body weight.
[0097] According to an additionally preferred embodiment, the pharmaceutical composition comprises as a drug gentamicin or a pharmaceutically acceptable salt thereof, such as gentamicin sulfate, for use in the treatment or prophylaxis of infections, especially systemic and urinary tract infections, infections life-threatening, chest infections, bacteremia, septicemia, severe neonatal infections, most especially infections by Escherichia coli, Klebsiella spp., Proteus spp., Pseudomonas aeruginosa, Staphylococci, Enterobacter spp., Citrobacter spp. and Providencia spp. In particular, the pharmaceutical composition is intended for use in treatment by daily parenteral administration of gentamicin sulfate in a single dose greater than 160 mg / kg of body weight, preferably greater than 224 mg / kg of body weight; and in multiple doses greater than 5 mg / kg of body weight / day, preferably greater than 7 mg / kg of body weight / day.
[0098] According to an additionally preferred embodiment, the pharmaceutical composition contains tobramycin or pharmaceutically acceptable salts of tobramycin, preferably for use in the treatment of infections, especially those of the central nervous system (including meningitis, septicemia and neonatal sepsis), or infections gastrointestinal infections (including peritonitis), or urinary tract infections (such as pyelonephritis and cystitis) or lower respiratory tract infections (including pneumonia, bronchopneumonia and acute bronchitis) or infections of the skin, bones and soft tissues, including burns. Preferably, the pharmaceutical composition is intended for use in treatment by daily parenteral administration of tobramycin in a single dose greater than 5 mg / kg of body weight, preferably greater than 6.75 mg / kg of body weight; and in multiple doses greater than 20 mg / kg of body weight / day, preferably greater than 27 mg / kg of body weight / day.
[0099] According to an additionally preferred embodiment, the pharmaceutical composition comprises amiodarone or a pharmaceutically acceptable salt thereof, such as amiodarone hydrochloride, preferably for use in the treatment or prophylaxis of cardiac arrhythmia or Wolff-Parkinson-White syndrome, especially tachyarrhythmias selected from the group consisting of supraventricular tachycardias, nodal tachycardias, ventricular tachycardias, atrial flutter, atrial fibrillation and ventricular fibrillation. Preferably, the pharmaceutical composition is intended for use in treatment by daily parenteral administration of amiodarone hydrochloride in a higher dose, in the first 24 hours, to 1000 mg, preferably greater than 1250 mg; and greater than 720 mg as a maintenance infusion in 24 hours, preferably greater than 900 mg in 24 hours.
[0100] According to another embodiment, the pharmaceutical composition of the invention contains at least one drug selected from the group consisting of antineoplastic agents for use in reducing toxicity to vital organs.
[0101] In an exemplary embodiment, the pharmaceutical composition comprises at least one drug selected from the group consisting of antineoplastic agents for use in increasing toxicity against tumor cells.
[0102] Especially preferred is a pharmaceutical composition in which at least one drug is selected from the group consisting of antineoplastic agents for use in reducing the toxicity of the drug and, simultaneously, in increasing its toxicity against tumor cells, preferably for use in treatment cancer. Table 1. Examples of various mixtures in the form of emulsions (oil: water or ratio o: a) and corresponding absorptions of n3-FA from 50 ml of co-administered dose of small volume of drug

Table 2. Examples of possible drugs / categories that affect vital organs and that could benefit from n3-FA damage reduction therapy 1) Antibiotics a) aminoglycosides b) amphotericin c) chloramphenicol d) ketoconazole e) macrolides f) quinolones g ) tetracyclines 2) Antineoplastic agents a) alkylating agents b) antimetabolites c) platinum antimitotic coordination complexes 3) Anti-Parkinson agents a) levodopa b) pramipexole c) ropinirol d) rotigotine e) bromocriptine 4) Cardiovascular agents a) adenosine b ) amiodarone c) angiotensin converting enzyme (ACE) inhibitors d) flecainide 5) diuretics a) loop diuretics b) potassium-sparing diuretics c) thiazides 6) immunosuppressive agents a) azathioprine b) cyclosporine c) mycophenolate d) tacrolimus 7 ) Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) a) acetaminophen b) aspirin c) ibuprofen d) indomethacin e) ketorolac 8) Psychotropic drugs a) haloperidol b) monoamine oxidase inhibitors c) phenothiazin as d) serotonin reabsorption inhibitors e) thioxanthines Table 3. Absorption of n3-FAs (g / dose) ranging from 1 to 100 mg / kg

Table 4. Sample of Possible n3-FAs and Dosage Ranges (% of Oil Profile n3-FA) as Drug Therapeutic Vehicles

Table 5. Small Volume Parenteral Infusions and n3-FA Absorption Using a 10% Oil in Water Emulsion with 50% of the n3-FAs in the Oily Phase

Cytotoxicity Study: I. Cell lines and culture conditions
[0103] In vitro studies using transformed SV40 mouse mesangial cells (SV40 MES 13 (CRL-1927 ™)) were performed. The cell line was purchased from the American Type Culture Collection (ATCC-LGC Standards GmbH, Wesel, Germany). SV40 MES 13 cells were cultured in complete ATCC culture medium: the basic medium for this cell line is a 3: 1 mixture of Dulbecco's modified Eagle medium formulated ATCC [ATCC (DMEM)] and Ham's F12 medium (PAA Laboratories GmbH , Colbe, Germany) with 14 mM HEPES, supplemented with 5% fetal bovine serum (SFB), 100 U / mL penicillin and 0.1 mg / mL streptomycin. Under these culture conditions, the SV40 MES 13 maintained several of the differentiated characteristics of intraglomerular mesangial cells The cells were maintained at 37 ° C in a humidified atmosphere of 5% CO2 and 95% air, the medium was changed every 48 hours. II. Tested substances
[0104] The following stock emulsions have been prepared: Table 6. LO-3 emulsion 5/5
Table 7. LO-3 emulsion 7/3

Table 8. 9/1 LO-3 emulsion

[0105] 1 Medium chain triglyceride (TCM) [triglyceride obtained by esterifying glycerin with medium chain fatty acids]; minimum 95% saturated fatty acids with 8 and 10 carbon atoms;
[0106] Fatty acid fraction composition: - caprylic acid: maximum 2.0% - caprylic acid: 50.0 to 80.0% - capric acid: 20.0 to 50.0% - lauric acid: maximum 3.0% e - myristic acid: maximum 1.0%
[0107] 2 Omega-3 fatty acid triglyceride derived from fish oil according to European Pharmacopoeia 1352: mixture of mono-, di- and triesters of omega-3 fatty acids with glycerol, containing mainly triesters, and obtained by esterification of fatty acids omega-3 concentrated and purified with glycerol or by transesterification of ethyl esters of omega-3 acid with glycerol. The origin of omega-3 acids is the body oil of fatty fish species from families such as Engraulidae, Carangidae, Clupeidae, Osmeridae, Salmonidae and Scombridae. The content: - sum of the levels of omega-3 acids EPA and DHA, expressed as triglycerides: minimum 45.0%. -total amount of omega-3 fatty acids, expressed as triglycerides: minimum 60%
[0108] An oil containing a long-chain omega-6 fatty acid triglyceride is reflected in Table 9. Table 9. O-6-LCT emulsion

[0109] As shown in Figures 2 A-C, 3 A-C, 4 A-D and 6, the stock solutions (20%) reflected in Tables 6 to 9 were diluted to the concentrations specified in those figures. The concentrations mentioned in them refer to the concentration of the sum of the components of the oil, that is, TCM plus triglyceride of omega-3 fatty acid and soybean oil, respectively, in the composition.
[0110] As an exemplary drug chosen from the list of NSAIDs, ketorolac tromethamine was tested. The following formulation was used and tested in various concentrations (see Figs. 1 to 4): Injection of ketorolac tromethamine, USP, I.V./I.M. 30 mg / ml (Hospira, inc., Lake Forest, USA).
[0111] Gentamicin aminoglycoside was tested as an exemplary drug chosen from the list of antibiotics. The following formulation was used and tested in various concentrations (see Figs. 5 and 6).
[0112] Gentamicin solution, 50 mg / mL, G1397 (Sigam-Aldrich, Saint-Louis, USA). Test Methods
[0113] In this experimental part and in the Figures, the drug "ketorolac tromethamine" will be called simply "ketorolac".
[0114] Determination of cytotoxic concentrations of Ketorolac or Gentamicin
[0115] In 96-well plates (BD Falcon ™, Becton Dickinson GmbH, Heidelberg, Germany), 2 x 103 to 4 x 103 SV40 MES 13 cells were seeded in 100 μL of medium / well. After 48 h, the medium was changed and different concentrations of ketorolac (0.1 to 1 mM) or gentamicin (0.5 to 5 mM) were tested after 24 h treatment; cytotoxicity was measured as described below (see “determination of cell cytotoxicity). As a control (= 0% cytotoxicity), cells cultured with medium were used, without the addition of ketorolac or gentamicin. Determination of the cytotoxicity-reducing effect of the emulsions tested against the cytotoxic effects of Ketorolac or Gentamicin
[0116] In 96-well plates (BD Falcon ™, Becton Dickinson GmbH, Heidelberg, Germany), 4 x 103 SV40 MES 13 cells were seeded in 100 μL of medium / well. After 48 h, the medium was changed and 50 μL of medium / well was added. Immediately, the test emulsions (Tables 6 to 9) were dissolved in the medium and 50 μL / well added to the cells in concentrations of 0.005%, 0.01% or 0.02%. As a negative control, cells were used that received 50 μL of medium without any test emulsions. After 24 h of incubation with the aforementioned test emulsions, the following concentrations of ketorolac or gentamicin were added to the MES 13 cells, which were incubated for another 24 hours: 0.25 mM, 0.5 mM or 1 mM or 0, 5 mM, 1 mM, 2.5 mM or 5 mM, respectively. Different concentrations of ketorolac or gentamicin were added to the pre-treated cells (24 h) with test emulsions (protective effect) or without previous treatment (ketorolac or gentamicin cytotoxicity [control]). Additional controls were performed: cells pretreated with test emulsions, but without ketorolac or gentamicin (control of the effect of the test emulsion), as well as cells without pretreatment of the test emulsion and without ketorolac or gentamicin (= 0% of cytotoxicity). Determination of cell cytotoxicity
[0117] Cell cytotoxicity was assessed using PrestoBlue ™ reagent (Invitrogen-Life Technologies GmbH, Darmstadt, Germany). This reagent is a solution based on resazurin, which works as an indicator of cell viability using the reducing power of living cells to measure viability quantitatively. When added to cells, the PrestoBlue ™ reagent - containing a non-fluorescent compound that permeates the cell - is modified by the reducing environment of viable cells, becoming strongly fluorescent, which can be detected by fluorescence or absorbance measurements (Reference [ 1]). The PrestoBlue ™ reagent is more sensitive than AlamarBlue®, which is a redox indicator of enzyme activity, widely used in screening complete organisms (Reference [2]) and in viability and cytotoxicity screening tests (References [2-6] ). PrestoBlue ™ was added directly to the cells in the culture medium, with a final concentration of 10%. Then, the plates were returned to the incubator. After 30 min, 1h, 2h, 3h and 4h of the addition of the reagent, the optical density (OD) was measured at 570 nm and 600 nm (reference) with an ELISA SUNRISE reader (Tecan, Salzburg, Austria). The results were expressed as% of cytotoxicity [100- (OD570 / 600 of the samples x 100 / OD570 / 600 of the control without substances). The SigmaPlot software was used to perform statistical analyzes using Student's unpaired t test. The data obtained are presented as mean ± DMP. A p-value <0.05 was considered to be statistically significant.
[0118] Figures 1 to 6 show the results of cytotoxicity measurements.
[0119] Figure 1 demonstrates the toxic effects of 24-hour treatment with ketorolac, in various concentrations, on mouse intraglomerular mesangial cells (SV40 MES 13). Values are given (in% cytotoxicity on cells without treatment (= control, = 0% cytotoxicity)] as mean + DMP; p, significance x cells without treatment (= control).
[0120] In each of Figures 2 A-C, 3 A-C, 4 A-D and 6, from left to right, the columns have the following meanings:
[0121] First column: shows the cytotoxicity of the pure emulsion, at the specified concentration, without the drug.
[0122] Second column: shows the cytotoxicity of the drug at the specified concentration, without the emulsion.
[0123] Third column: shows the cytotoxicity of the composition consisting of the emulsion at the specified concentration and the drug with the concentration specified in the second column.
[0124] Fourth column: shows the cytotoxicity of the drug at the specified concentration, without the emulsion.
[0125] Fifth column: shows the cytotoxicity of the composition consisting of the emulsion at the specified concentration and the drug at the concentration specified in the fourth column.
[0126] Sixth column: shows the cytotoxicity of the drug at the specified concentration, without the emulsion.
[0127] Seventh column: shows the cytotoxicity of the composition consisting of the emulsion at the specified concentration and the drug at the concentration specified in the sixth column.
[0128] Figures 2A to 2C show the effects of the 48 h treatment with a concentration of 0.005% of LO-3 5/5 (Fig. 2A), LO-3 7/3 (Fig. 2B) and LO-3 9 / 1 (Fig. 2C) on the cytotoxic effect of ketorolac on mouse intraglomerular mesangial cells (SV40 MES 13). Values [in% cytotoxicity in cells without treatment (= control, = 0% cytotoxicity) are given as mean + DMP; p, significance X treatment with ketorolac; n = 4 independent experiments, using 4-6 wells per treatment and per experiment.
[0129] Figures 3A to 3C show the effects of the 48 h treatment with 0.01% concentration of LO-3 5/5 (Fig. 3A), LO-3 7/3 (Fig. 3B) and LO- 3 9/1 (Fig. 3C) on the cytotoxic effect of ketorolac on mouse intraglomerular mesangial cells (SV40 MES 13). Values [in% cytotoxicity in cells without treatment (= control, = 0% cytotoxicity) are given as mean + DMP; p, significance X treatment with ketorolac; n = 4 independent experiments, using 4-6 wells per treatment and per experiment.
[0130] Figures 4A to 4D show the effects of the 48 h treatment with 0.02% concentration of LO-3 5/5 (Fig. 4A), LO-3 7/3 (Fig. 4B), LO- 3 9/1 (Fig. 4C) and O-6-LCT (Fig. 4D; comparative) on the cytotoxic effect of ketorolac on mouse intraglomerular mesangial cells (SV40 MES 13). Values [in% cytotoxicity in cells without treatment (= control, = 0% cytotoxicity) are given as mean + DMP; p, significance X treatment with ketorolac; n = 4 independent experiments, using 4-6 wells per treatment and per experiment.
[0131] Figure 5 demonstrates the cytotoxic effects of 24-hour treatment with gentamicin in various concentrations in intraglomerular mesangial mouse cells (SV40 MES 13). Values [in% cytotoxicity in cells without treatment (= control, = 0% cytotoxicity) are given as mean + DMP; p, significance X cells without treatment (= control).
[0132] Figure 6 shows the effects of the 48 h treatment with a 0.005% concentration of LO-3 9/1 on the cytotoxic effect of gentamicin on mouse intraglomerular mesangial cells (SV40 MES 13). Values [in% cytotoxicity in cells without treatment (= control, = 0% cytotoxicity) are given as mean + DMP; p, significance X treatment with gentamicin; n = 4 independent experiments, using 4-6 wells per treatment and per experiment.
[0133] Although several modalities are described in this document, it should be apparent that variations, modifications and other changes in form and details can be made without departing from the spirit and scope of the invention. Such variations and modifications must be considered within the scope and scope of the invention as described in the appended claims. List of References:
[0134] [1] http://www.invitrogen.com/site/us/en/home/brands/Molecular- Probes / Key-Molecular-Probes-Products / PrestoBlue-Cell-Viability- Reagent.html [2] Mansour NR, Bickle QD (2010). Comparison of Microscopy and Alamar Blue Reduction in a Larval Based Assay for Schistosome Drug Screening. PloS Negl Trop Dis., 4 (8): e795. doi: 10.1371 / journal.pntd.0000795. [3] Nociari MM, Shalev A, Benias P, Russo C. (1998). A novel one-step, highly sensitive fluorometric assay to evaluate cell-mediated cytotoxicity. J Immunol Meth., 213: 157-167. [4] Hamid R, Rotshteyn Y, Rabadi L, Parikh R, Bullock P. (2004). Comparison of alamarBlue and MTT assays for high through-put screening. Toxicol In Vitro, 18: 703-10. [5] Van der Harst MR, Bull S, Laffont CM, Klein WR. (2005). Gentamicin neprotoxicyty-a comparison of in vitro finding with in vivo experiments in equines. Vet Res Commun, 29 (3): 247-61. [6] AI-Nasiry S, Geusens N, Hanssens M, Luyten C, Pijnenborg R. - (2007). The use of Alamar Blue assay for quantitative analysis of viability, migration and invasion of choriocarcinoma cells. Human Reproduction, 22 (5): 1304-1309. [7] Sykes ML, Avery VM. (2009). Development of an Alamar Blue viability assay in 384-well format for high throughput whole cell screening of Trypanosoma brucei brucei bloodstream form strain 427. Am J Trop Med Hyg. 81 (4): 665-74. [8] Heller AR et al. Omega-3 fatty acids improve the diagnosis-related outcome .. Crit Care Med 2006; 34: 972-79. [9] Elzinga et al. Modification of experimental nephrotoxicity with fish oil as the vehicle for cyclosporine. Transplantation 1987; 43: 271-74. [10] Casarett and Doull's Toxicology. The Basic Science of Poisons. McGraw-Hill, NY, 1996. [11] Julien C et al. Postmortem brain fatty acid profile of levodopa-treated Parkinson disease patients and parkinsonian monkeys. Neurochem Int 2006; 48: 404-14. [12] Germain E et al. Anthracycline-induced cardiac toxicity is not increased by dietary omega-3 fatty acids. Pharmacol Res 2003; 47: 111-17. [13] Futamura Y. Toxicity of amiodarone on mouse pulmonary endothelial cells cultured with or without alveolar macrophages. J Toxicol Sci 1996; 21: 253-67. [14] Gonzalez- Periz A et al. Docosahexaenoic acid (DHA) blunts liver injury by conversion to protective lipid mediators: protectin D1 and 17S-hydroxy DHA. FASEB J 2006; 20: 2537-39. [15] Priyamvada S et al. Studies on the protective effect of dietary fish oil on gentamicin-induced nephrotoxicity and oxidative damage in rat kidney. Prostaglandins Leukotr Essent Fatty Acids 2008; 78: 369-81. [16] Yang W et al. Attenuation of ciclosporine-induced nephrotoxicity by dietary supplementation of seal oil in Sprague-Dawley rats. J Pharm Pharmacol 2005; 57: 1485-92. [17] Wichamnn MW et al. Evaluation of clinical safety and beneficial effects of a fish oil-containing (lipoplus, MLF 541): data from a prospective, randomized multicenter trial. Crit Care Med 2007; 35: 700-6. [18] Matta JA et al. TRPV1 is a novel target for omega-3 polyunsaturated fatty acids. J Physiol 2007; 578: 397-411. [19] Abulrob AN et al. The effect of fatty acids and analogues upon intracellular levels of doxorubicin in cells displaying P-glycoprotein mediated multidrug resistance. J Drug Target 2000; 8: 247-56. [20] Rudra PK et al. Cell-specific enhancement of doxorubicin toxicity in human tumor cells by docosahexaenoic acid. Anticancer Res 2001; 21: 29-38. [21] Ding WQ et al. Differential sensitivity of cancer cells to docosahexaenoic acid-induced cytotoxicity: the potential importance of down-regulation of superoxide dismutase 1 expression. Mol Cancer Ther 2004; 3: 1109-17. [22] Calviello G et al. docosahexaenoic acid enhances the susceptibility of human colorectal cancer cells to 5-fluorouracil. Cancer Chemother Pharmacol 2005; 55: 12-20. [23] Maheo K et al. Differntial sensitization of cancer cells to doxorubicin by DHA: a role for lipoperoxidation. Free Radic Biol Med 2005; 15: 742-51. [24] Menendez JA et al. Endogenous supplementation with omega- 3 polyunsaturated fatty acid (DHA: 22: 6n3) synergistically enhances taxane cytotoxicity and downregulates Her-2 / neu (c-erbB-2) oncogene expression in human breast cancer cells. Eur J Cancer Prev 2005; 14: 263-70. [25] Colas S et al. Sensitization by dietary docosahexaenoci acid of rat mammary carcinoma to anthracycline: a role for tumor vascularization. Clin Cancer Res 2006; 12: 5879.86. [26] Wang Y et al. Synthesis and preliminary antitumor activity evaluation of a DHA and doxorubicin conjugate. Bioorg Med Chem Lett 2006; 16: 2974-47. [27] Manni A et al. The impact of fish oil on the chemopreventive efficacy of tamoxifen against development of N-methyl-N-nitrosourea-induced rat mammary carcinogenesis. Cancer Prev Res 2010; 3: 322-30. [28] Harries M et al. Phase l / ll study of DHA-paclitaxel in combination with carboplatin in patients with advanced malignant solid tumors. Br J Cancer 2004; 91: 1651-55. [29] Bougnoux P et al. Improving outcome of chemotherapy of metastatic breast cancer by docosahexaenoic acid: a phase II trial. Br J Cancer 2009; 101: 1978-85. [30] Failure PM et al. Phase 1 and pharmacokinetic study of weekly docosahexaenoic acid-paclitaxel, Taxoprexin, in resistant solid tumors. Cancer Chemother Pharmacol 2009; 63: 451-58. [31] Calder PC. Fatty acids and inflammation - From the membrane to the nucleus and from the laboratory bench to the clinic. Clin Nutr 2010; 29: 5-12. [32] Driscoll et al. Pharmacopeial compliance of fish oil-containing parenteral lipid emulsion mixtures: Globule size distribution (GSD) and fatty acid analyzes. Int J Pharm 2009; 379: 125-30. [33] Frieseckes S et al. Fish oil supplementation in the parenteral nutrition of critically ill medical patients: a randomized controlled trial. Int Care Med 2008; 34: 1411-20.

权利要求:
Claims (8)
[0001]
1. Pharmaceutical composition characterized by comprising an oil-in-water emulsion comprising: a) fish oil triglycerides in a proportion between 60% and 90%, based on the weight of the oily component, in which the fish oil triglycerides comprise omega fatty acids -3 in 60% proportion, based on the total fatty acid weight of the fish oil triglycerides and in which the fish oil triglycerides comprise a total amount of 45% EPA and DHA, based on the total weight of acids fish oil triglyceride fatty acids; and a medium chain triglyceride, the total amount of which ranges from 10 to 40%, based on the weight of the oily component; and b) a drug selected from ketorolac, gentamicin or a combination thereof.
[0002]
2. Pharmaceutical composition according to claim 1, characterized in that the composition comprises 10 to 30% by weight of medium chain triglycerides (TCM) based on the total weight of the oily component of the emulsion.
[0003]
Pharmaceutical composition according to either of claims 1 or 2, characterized in that the emulsion comprises an oil component and an aqueous component, the oil component comprising fish oil triglycerides in a proportion between 60% and 90% , based on the weight of the oily component; wherein fish oil triglycerides comprise 60% omega-3 fatty acids, based on the total fatty acid weight of fish oil triglycerides; wherein these triglycerides comprise a total amount of 45% EPA and DHA, based on the total fatty acid weight of the fish oil triglycerides; and a medium chain triglyceride, whose total amount of at least one medium chain triglyceride is 10% to 40%, based on the weight of the oily component.
[0004]
Pharmaceutical composition according to any one of claims 1 to 3, characterized by the fact that the omega-3 fatty acid component comprises eicosapentaenoic acid in a proportion of 30% or more, docosahexanoic acid in a proportion of 30% or less and docosapentaenoic acid in a proportion of 40% or less, based on the total weight of omega-3 fatty acid.
[0005]
5. Use of the pharmaceutical composition, as defined in any of claims 1 to 4, characterized in that it is in the preparation of a medicament for mitigating the nephrotoxicity of a drug selected from ketorolac gentamicin or a combination thereof.
[0006]
6. Use, according to claim 5, characterized in that the drug is present in the proportion of 0.5% to 50 mg / kg of body weight and is of a material that causes damage to a vital organ when not administered simultaneously with the drug. at least one omega-3 fatty acid.
[0007]
7. Kit characterized by comprising: a. fish oil triglycerides including omega-3 fatty acids in a 60% proportion, based on the total fatty acid weight of the fish oil triglycerides and where the total amount of EPA and DHA is 45%, based on the total fatty acid weight of fish oil triglycerides; and a medium chain triglyceride; and b. one or more packages comprising ketorolac, gentamicin or a combination thereof.
[0008]
8. Pharmaceutical system for parenteral administration characterized by comprising two compartments, being that: a. the first compartment comprises fish oil triglycerides including omega-3 fatty acids in a 60% proportion, based on the total fatty acid weight of fish oil triglycerides and where the total amount of EPA and DHA is 45% , based on the total fatty acid weight of fish oil triglycerides; and a medium chain triglyceride; and b. the second compartment comprises ketorolac, gentamicin or a combination thereof.

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KR101923192B1|2018-11-28|

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RU2013115923A|2014-10-20|

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CN103200965A|2013-07-10|

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KR20130135839A|2013-12-11|

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JP6000251B2|2016-09-28|

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TW201219057A|2012-05-16|

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EP2613809B1|2019-07-24|

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IL223955A|2016-02-29|

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2020-03-10| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2020-03-24| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-07-28| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|

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2020-11-24| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-02-09| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 12/09/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US12/923,257|2010-09-10|

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US12/923,257|US20110071090A1|2009-03-11|2010-09-10|Method of mitigating adverse drug events using omega-3-fatty acids as a parenteral therapeutic drug vehicle|

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PCT/US2011/001567|WO2012033538A1|2010-09-10|2011-09-12|Method of mitigating adverse drug events using omega-3 fatty acids as a parenteral therapeutic drug vehicle|

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