MXPA06006620A - Methods of administering water-soluble prodrugs of propofol for extended sedation - Google Patents

Abstract

A method of administering a prodrug of propofol, preferably O-phosphonooxymethyl propofol disodium salt, comprises the oral, intragastric, or intraintestinal administration of the prodrug in amounts sufficient to induce or maintain a generalized anesthetized state, a conscious sedated state, or to treat insomnia, anxiety, nausea, vomiting, pruritus, epilepsy, and a range of pain syndromes and other medical conditions.

Description

METHODS FOR ADMINISTERING SOLUBLE PROPOFOL PROFARMACLES IN WATER FOR PROLONGED SEDATION FIELD OF THE INVENTION The invention relates to methods for administering prodrugs of propofol (2,6-diisopropylphenol), a low molecular weight phenol derivative which is widely used as a hypnotic or as a sedative for intravenous administration, in the induction and maintenance of anesthesia or sedation in humans and animals. Among its useful features as an anesthetic drug are: administration through the intravenous route, rapid onset and rapid termination of anesthesia, rapid elimination and a profile of side effects that makes it preferable to other injectable anesthetics, such as barbiturates.

BACKGROUND OF THE INVENTION The use of injectable anesthetic agents in general, and of propofol specifically, in the induction and maintenance of a general anesthesia, has obtained a wide acceptance in the anesthetic care during the last 15 years. It has been described that intravenous anesthesia with propofol has several advantages over previously existing methods, such as induction more easily tolerated, since patients have no fear of masks, suffocation or the imposing odor of volatile anesthetics; fast and predictable recovery; Easily adjustable anesthesia depth, when adjusting the IV dose of propofol; low incidence of adverse reactions, compared to inhaled anesthetics; and dysphoria, decreased nausea and vomiting upon recovery from anesthesia [Padfield NL, Introduction, history and development. In Padfield NL (Ed.) Ed., Total Intravenous Anesthesis. Butterworth Heinemann, Oxford 2000]. In addition to its sedative and anesthetic effects, propofol has a variety of other biological and medical applications. For example, it has been reported to be anti-emetic [McCollum JSC and coauthors, Anesthesia 43 (1988) 239], antiepileptic [Chilvers, CR, Laurie, PS, Anesthesia 45 (1990) 995], and antipruritic [Borgeat and co-authors, Anesthesiology 76 (1992) 510]. The anti-emetic and antipruritic effects are typically observed at sub-hypnotic doses, ie, at doses that reach concentrations of propofol in the plasma below those required for sedation or anesthesia. Antiepileptic activity, on the other hand, is observed on a larger scale of concentrations in plasma [Borgeat and co-authors, Anesthesiology, 80 (1994) 642]. It has been reported that short-term intravenous administration of subanesthetic doses of propofol is remarkably effective in the treatment of intractable migraine and in non-migraine headaches [Krusz, J.C. and co-authors, Headache, 40 (2000) 224-230]. It has further been speculated that propofol may be useful as anxiolytic [Kurt and co-authors, Pol. J. Pharmacol. , 55 (2003) 973-7], as a neuroprotector [Velly and coauthors, Anesthesiology, 99 (2003) 368-75], as a muscle relaxant [O'Shea and co-authors, J. Neurosci. , 24 (2004) 2322-7] and, due to its antioxidant properties in biological systems, it can be useful additionally in the treatment of inflammatory conditions, especially inflammatory conditions with a respiratory component, and in the treatment of neuronal damage related to Neurodegeneration or trauma. It is believed that such conditions are associated with the generation of reactive oxygen species and, therefore, susceptible to being treated with antioxidants [see, for example, US Patent 6,254.84 to Hendler and co-inventors]. Propofol is typically formulated for clinical use as an oil-in-water emulsion. The formulation has a limited shelf life, and has been shown to be sensitive to bacterial and fungal contamination, which has led, in some cases, to post-surgical infections [Bennett S. N. and coauthors, N. Engl. J. Med., 333 (1995) 147]. Due to the white, dense color of the formulation, bacterial or fungal contamination can not be detected by visual inspection of the vial, in the first place. Not only is propofol hardly soluble in water; in addition, it causes pain at the injection site, which must be relieved frequently using a local anesthetic [Dolin, S. J. , Drugs and pharmacology, in N. Padfield, Ed. , Total Intravenous Anesthesia, Butterworth Heinemann, Oxford 2000]. Due to its formulation in a lipid emulsion, its intravenous administration is also associated with undesirable hypertriglyceridemia in patients, especially in patients receiving prolonged infusions [Fulton B and Sor in E.M., Drugs 50 (1995) 636]. Its formulation as lipid emulsion further complicates co-administration with other IV drugs. Any physical change in the formulation, such as a change in lipid drop size, can result in changes in the drug's pharmacological properties and cause side effects, such as pulmonary emboli. It has been further reported that the use of propofol in the induction of anesthesia is associated with a significant incidence of apnea, which appears to be dependent on dose, injection rate and premedication [Revés, JG, Glass, PSA, Lubarsky, DA , Norbarbiturate intravenous anesthetics, in: RD Miller et al., Eds., Anesthesia, 5a. edition, Churchill Livingstone, Philadelphia, 2000]. The respiratory consequences of administering anesthesia-inducing propofol doses, including a reduction in reflux volume and apnea, occur in up to 83 percent of patients [Bryson and co-authors, Drugs 50 (1995) at 520]. It is also known that the induction doses of propofol have a marked hypotensive effect, which depends on the dose and the concentration in the plasma [Revés et al., Supra]. Hypotension associated with peak levels in the plasma, after rapid bolus injection of propofol, sometimes requires the use of controlled infusion pumps or the decomposition of the bolus dose of induction at several smaller incremental doses. Additionally, the short duration of unconsciousness caused by bolus induction doses makes propofol suitable only for brief surgical procedures. For all the above reasons, propofol for induction and / or maintenance of anesthesia should normally be administered in an inpatient facility, under the supervision of an anesthesiologist, and is often considered inappropriate for use by non-anesthesiologists in ambulatory facilities or daily cases. In addition to its use in the induction and maintenance of anesthesia, propofol has been used successfully as a sedative to accompany local or regional anesthesia in conscious patients. Its sedative properties have also been exploited in diagnostic procedures that have an effect that alters conscious patients, such as colonoscopy or imaging procedures. Propofol has been used as a sedative in children undergoing diagnostic imaging or radiotherapy procedures. A recent development is sedation with propofol controlled by the patient. This technique is preferred by patients, and is as effective as sedation administered by the anesthesiologist. Compared to the widely used sedative medazolam or other agents, propofol provided similar or better sedative effects when measuring the quality of sedation and / or the time the patient was at adequate levels of sedation [see Fulton B. and Sorkin EM , Drugs 50 (1995) 636]. The faster recovery and the similar or less amnesia associated with propofol make it attractive as an alternative for other sedatives, particularly for patients who require short sedation. However, due to the potential for hyperlipidemia associated with the current formulation of propofol, and the development of tolerance to its sedative effects, the utility of propofol for patients requiring longer sedation is less well established. Due to its very low oral bioavailability, propofol, in its commercially obtainable formulations, is generally recognized as not available for administration other than parenteral, and very generally, to be injected or infused intravenously. Although propofol is administered intravenously in a clinical setting, it has been suggested that it could be delivered for certain indications by other non-oral routes, such as by inhalation using a nebulizer, transmucosally, through the epithelium of the upper alimentary tract, or rectally in the form of a suppository [see, for example, Cozanitis, DA and co-authors, Acta Anesthesiol. Scand., 35 (1991) 575-7; see also U.S. Patents 5,496,537 and 5,288,597]. However, the poor bioavailability of propofol when administered by any route other than intravenous, has impeded the development of these treatments. Alternatively, safe and simple methods for administering propofol, which do not require injections or intravenous infusions, would be extremely useful in a non-clinical setting for the treatment of conditions such as, for example, migraine and other severe headaches, trigeminal facial pain or dental or arachnoiditis, to obtain moderate sedation, anxiolysis, suppression of nausea, or as an aid to sleep in individuals who need it. International patent application publication WO 02/13810, by Hendier, teaches several phosphate esters of propofol or dipropofol and carboxyl esters of propofol, which are described as being soluble in water and useful in the treatment of migraine. Methods that would particularly allow the oral administration of propofol would be extremely beneficial; however, to date, these medical needs have not been met. For all the reasons given above, there is a clear clinical need for stable formulations of safe, orally bioavailable agents in anesthetic care, and for the treatment of conditions such as epilepsy, puritus and migraine, and other severe headaches. The development of stable, water-soluble propofol prodrugs, which is described in US Pat. No. 6,204,257 to Stella and co-inventors, has made it possible to meet those unmet needs so far and to explore the pharmaceutical advantages of an orally bioavailable aqueous propofol prodrug, such as therapeutic agent. The prodrugs of the present invention differ from propofol in that the 1-hydroxy group of propofol is replaced with a phosphonooxymethyl ether group: Propofol Prodrug (Z = hydrogen, alkali metal ion or amine) Although the present invention is not bound by any theory, it is believed that it is subjected to hydrolysis by alkaline phosphatases on the surface of endothelial cells, to release propofol. Stella reports that the prodrug has good stability of pH levels suitable for the formation of pharmaceutical formulations, and that it decomposes rapidly in vivo under physiological conditions, when administered intravenously. Unexpectedly the inventors have now found that the prodrug can be administered orally to obtain a condition ranging from moderate sedation and reduced responsiveness to external stimuli, to deep sedation and loss of consciousness, depending on the dose of the prodrug administered orally. Another novel discovery of the inventors is that the prodrug causes a rapid onset of the sedated / unconscious state after ingestion, followed by a plateau effect which is reached within 5 to 20 minutes after ingestion and which, depending on the Dosage and administration route is maintained for up to one to four hours or more. Another discovery of the inventors is that the prodrugs of the invention exhibit high biological potency when administered directly into the duodenal lumen. When the upper alimentary tract - the oral cavity, the pharynx and the stomach - is "bypassed", the prodrug can be administered at doses markedly lower than those required to obtain a substantially similar pharmacological effect with intragastric administration. The prodrugs of the invention thus possess excellent unexpected properties for oral administration and a favorable pharmacological profile, such as orally bioavailable therapeutics for sedation and anesthetic care, and for the treatment of conditions such as migraine, epilepsy, pruritus, anxiety, insomnia, nausea and others. medical conditions BRIEF DESCRIPTION OF THE INVENTION The present invention provides a method for administering a compound to a patient in need thereof, comprising: administering orally or intragastrically a compound of formula I, in an amount sufficient to elicit a pharmacological effect on the patient: Formula I wherein each Z is independently selected from the group consisting of hydrogen, alkali metal ion and amine. As noted above, the compound is capable of eliciting a pharmacological effect in a patient when administered intravenously, and a substantially similar pharmacological effect when administered orally or intragastrically, in a higher dose. Thus, in this method of the invention, the amount administered orally or intragastrically is greater than the amount that would be sufficient to cause a substantially similar pharmacological effect, by intravenous administration. In a preferred aspect of this method of the invention, each Z in the compound of the formula I is an alkali metal ion. Preferably the compound of the formula I is administered orally and formulated in a solid oral pharmaceutical formulation. Optionally, the solid oral pharmaceutical formulation is adapted to release a sufficient amount of the compound directly into the stomach, after ingestion. Other formulations, useful for example, if the compound is to be administered intragastrically, through a nasogastric tube or other suitable catheter, include liquid formulations comprising the compound of formula I in a form dissolved in water, or in a suspension that comprises granules or particles which, in turn, comprise the compound of formula I. These formulations can be further adapted to allow specific, desired release characteristics of the effective amount of the compound, from the formulation, directly in the stomach, from so that a quick or sustained release is obtained for a time. An alternative method for administering a compound of formula I to a patient in need thereof, comprises introducing the compound directly into the intestine. The compound is administered in an amount sufficient to cause a pharmacological effect in the patient. As noted above, the compound of formula I, when introduced directly into the intestine, exhibits a biological potency approaching that of, and is on the scale of, potencies obtainable also with intravenous administration. Thus, the dose administered in this alternative embodiment of the invention need not be greater than the sufficient intravenous dose to cause a substantially similar pharmacological effect. This means that the dose for administration directly in the intestine to obtain a pharmacological effect is not defined with respect to a sufficient intravenous dose to obtain a substantially similar pharmacological effect. "Introduce directly into the intestine" means that the compound is administered to the patient in a manner that "bypasses" the upper alimentary tract - the oral cavity, the pharynx and the stomach - and that pharmacologically effective amounts of the compound of the formula I enter or be released, in the digestive tract only at the level of the duodenum (the upper small intestine) or below. The compound is introduced directly into the intestine preferably by oral administration in a specifically adapted pharmaceutical formulation. The formulation is specifically adapted to release a sufficient amount of the compound from the formulation only after it has passed through the upper alimentary tract. Preferred examples of such formulations are solid oral dosage forms, such as enteric coated tablets, enteric coated capsules or capsules or tablets comprising enteric coated granules or particles which, in turn, comprise the compound of the formula I, optionally adapted to allow immediate or sustained release of the compound from the formulation. Alternative oral dosage forms for practicing this aspect of the invention are liquid, viscous or semi-solid preparations comprising enteric-coated granules or particles which, in turn, comprise the compound of formula I. Alternatively, the introduction of the compound directly in the intestine is obtained by instilling a liquid preparation, preferably an aqueous solution, through a suitable catheter or tube. The methods described above for administering the compound of formula I to a patient, and any of its alternative or preferred embodiments, include the administration of a sufficient dose to obtain a pharmacological effect in a patient. A scale of doses can be selected that depend to a large extent on the pharmacological effect that is going to be obtained. Preferred doses include those that are sufficient to induce or maintain an unconscious state, to induce or maintain a sedated conscious state; to induce or maintain a drowsy state to treat insomnia, to treat sleep disorders, characterized by inappropriate awakenings; to treat anxiety; to treat nausea or vomiting; to treat itching associated with a pruritic condition; to treat an epileptic condition; to treat migraine pain; to treat cluster headache, to treat other acute headaches, to treat trigeminal facial pain, to treat dental pain, to treat neuropathic pain, to treat phantom limb pain, to treat postoperative pain, to treat inflammatory pain, to treat pain neurogenic and to treat arthritic pain. One of the new and useful discoveries of the inventors is that the compounds of the formula I can be administered orally. One aspect of the invention is directed to administering a compound of formula I employing a variety of defined doses, without being limited to the specific purpose for which they are administered. Persons of ordinary skill in the art can determine, without undue experimentation, at what dose a compound of formula I causes a pharmacological effect (including the specific pharmacological effects mentioned above) and, in such a manner, select the appropriate doses for use in the methods of this invention. For those embodiments of the invention that require oral or intragastric doses to be greater than intravenous doses, those skilled in the art can determine the intravenous dose sufficient to elicit a pharmacological effect, and then introduce a higher dose of the compound into the stomach. through oral or intragastric routes, to cause a substantially similar pharmacological effect. These steps require no more than routine experimentation by those skilled in the art, especially in light of the guides and example doses provided herein; and all this can be done within the limits of the invention. Additionally, the methods of this invention include methods for inducing or maintaining general anesthesia, for inducing or maintaining a conscious sedated condition, and for treating a variety of medical disorders, such as those listed above. In a method for treating or preventing pain, a sufficient amount of the compound of the formula I is administered orally or intragastrically to a patient in need thereof. Preferred embodiments of this aspect of the invention include methods to treat or prevent migraine pain, cluster headaches, other acute headaches, trigeminal facial pain, dental pain, neuropathic pain, phantom limb pain, postoperative pain, pain inflammatory, neurogenic pain and arthritic pain. Preferably, in these methods of treating pain syndromes, the compound of formula I is administered orally in a pharmaceutical formulation that allows the release of the compound directly into the intestine; more preferably, in the form of dosage forms with enteric coating.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates the sedative / anesthetic effect of various doses of a compound of formula I, the disodium salt of O-phosphonooxymethyl-propofol, formulated as an aqueous solution at 35 mg / mL in weight / volume, in rats, then of oral / intragastric administration. The administration of the experimental compound caused a rapid onset (within 5-20 minutes of oral administration) of sedated behavior; whose degree and duration depended on the dose administered. Figure 2 illustrates the sedative / anesthetic effects of various doses of the experimental compound, when formulated as an aqueous solution at 200 mg / mL w / v, in rats, after oral / intragastric administration. The experimental parameters were similar to those used to generate the results of Figure 1. Figure 3 illustrates the sedative / anesthetic effects of various doses of the experimental compound, when administered through the intravenous route; and Figures 4a and 4b illustrate the sedative / anesthetic effects of the experimental compound, when it was instilled directly into the intestine through an intraduodenal catheter.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES According to one embodiment of the present invention, an unconscious state is induced or maintained in a patient by oral or intragastric administration of a propofol prodrug in an amount sufficient to cause or maintain the loss of consciousness. The prodrug is a compound of the formula I: or a salt thereof, acceptable for pharmaceutical use, wherein each Z is independently selected from the group consisting of hydrogen, alkali metal ion and amine. Each Z, preferably, is an alkali metal ion, especially a sodium ion. According to an alternative embodiment of the invention, the unconscious state is induced or maintained by means of administering the compound of the formula I, in a way that bypasses the upper digestive tract and the stomach, and introduces the compound directly in the intestinal tract. "Intestinal tract" means "intestine", that is, the part of the alimentary tract that starts after the stomach and ends with the rectal cavity. This embodiment of the invention can be practiced, for example, by instilling a liquid preparation comprising the compound of formula I in the intestine, preferably in the duodenum, by the use of a suitable transgastric or transabdominal catheter catheter. Alternatively, the compound of the formula I can be administered via the oral route, in the form of suitable enteric-coated preparations, such as, without limitation, enteric-coated tablets, enteric-coated capsules; or tablets, capsules or liquid or semiliquid preparations, such as suspensions, comprising granules or other particles having enteric coatings which, in turn, comprise the compound of formula I. As will be appreciated by those skilled in the art, there are many techniques by which compounds such as those of formula I can be formulated and / or administered in a manner that prevents their release during passage through the mouth, esophagus and stomach, and allows their introduction directly into the intestine; and the examples mentioned here, by means of which this introduction can be achieved, are by no means intended to be restrictive. The compound of the formula I can be administered by itself or it can be co-administered together with one or more additional active agents. Non-limiting examples of additional active agents include hypnotic, analgesic, anti-inflammatory, amnestic, muscle relaxant and sedative agents. Said additional active agents can be incorporated into an intragastrically administrable pharmaceutical composition, comprising the compound of the formula I; or it can be administered or formulated in a manner that allows its introduction directly into the intestine, together with a compound of the formula I; or it can be administered in a separate pharmaceutical formulation. Illustrative doses suitable for inducing or maintaining an unconscious state in a patient, by a single oral or intragastric administration, or by repeated administrations, of the compound of the formula I, range from about 100 mg / kg to about 1,000 mg / kg , preferably from about 200 mg / kg to about 600 mg / kg; and more preferably, from about 250 mg / kg to about 500 mg / kg. If the unconscious state is induced or maintained by administering the compound of formula I in a manner that allows its introduction directly into the intestine, for example, by the use of suitable enteric-coated formulations, or by intraduodenal instillation, the appropriate illustrative doses vary. from about 500 mg / kg to about 15 mg / kg, preferably about 400 mg / kg to about 20 mg / kg and, more preferably, from about 300 mg / kg to about 25 mg / kg. As those with experience in the field will appreciate, many factors influence the selection of the appropriate dose, the appropriate mode, and the appropriate administration schedule. For example, the appropriate dose to induce or maintain an unconscious state in a patient, or to implement any of the other methods of this invention cited below, may depend on whether the patient is a human or other mammal, or whether it is A non-mammalian patient may depend on the patient's age, weight, sex, diet, health, underlying medical condition, and others. Therefore, an anesthesiologist, a veterinarian or another medical, scientific or health practitioner, who has experience in the subject, will be able to design, in the light of the guidelines provided here, and without undue experimentation, an appropriate treatment protocol to practice the present invention. In another embodiment of the invention a conscious sedated state is induced or maintained, for a prolonged period of time, in a patient, by oral or intragastric administration of a compound of the formula I, or by administration of a compound of the formula I in a manner that allows its introduction directly into the intestine, for example, by the use of suitable enteric-coated formulations, or by intraduodenal instillation. In another embodiment of the present invention a state of drowsiness is induced or maintained for a prolonged period of time in a patient. As in the case of a sedated conscious state, cited above, the state of somnolence can be induced or maintained by orally or intragastrically administering an effective amount of a compound of formula I, or by administering the compound in a manner that allows its introduction into the body. Directly in the first place, for example, by the use of suitable enteric coating formulations, or by intraduodenal instillation. Illustrative, appropriate dose levels for inducing or maintaining a state of drowsiness in a patient, by a single administration or by repeated oral or intragastric administration, range from about 10 mg / kg to about 300 mg / kg, preferably, from about 20 mg / kg to about 250 mg / kg and, more preferably, from about 25 mg / kg to about 200 mg / kg. Sufficient dose levels to induce a sedated conscious state overlap with doses sufficient to induce a state of drowsiness, and range from about 20 mg / kg to about 400 mg / kg, preferably about 20 mg / kg at about 300 mg / kg; more preferably, from about 50 mg / kg to about 250 mg / kg; and still more preferable, from about 30 to about 70 mg / kg. For example, it can be administered to a patient who needs to be sedated, a prodrug of the formula I, the disodium salt of O-phosphonooxymethyl-propofol, orally, in a pharmaceutical formulation that releases the prodrug in the stomach, at a dose ranging from more than 35 mg / mL to about 70 mg / mL. If the state of somnolence is induced or maintained by administering the compound of formula I in a manner that allows its introduction directly into the intestine, for example, by the use of suitable enteric-coated formulations, or by intraduodenal instillation, the appropriate illustrative doses they vary from about 1 mg / kg to about 75 mg / kg, preferably from about 2 mg / kg to about 50 mg / kg and, more preferably, from about 5 mg / kg to about 40 mg / kg. kg. Sufficient dose levels for inducing or maintaining a sedated conscious state overlap those necessary to induce or maintain a state of drowsiness, and vary, for example, from about 2 mg / kg to about 100 mg / kg, preferably around 5 mg / kg to around 75 mg / kg; more preferable, from about 10 mg / kg to about 50 mg / kg; still more preferable, from about 10 mg / kg to about 40 mg / kg; and much more preferable, from about 15 to about 35 mg / kg. The induction or maintenance of a state of drowsiness, experienced as, for example, a relaxed and moderately numbed sleep inclination, is convenient, for example, in individuals suffering from insomnia or another condition characterized by increased and inappropriate weakness with respect to societal demands, such as sleep disturbances in the circadian rhythm (for example, sleep disturbances of the delayed sleep phase disorder, time lag due to changes in travel time zones ("jet lag") or change in shift work. For the induction of a drowsy state, the compound of formula I can be administered individually or in combination with other sleep-inducing compounds, combined in a single oral formulation or by Separate dose levels sufficient to induce a sedated conscious state or a state of drowsiness, are additionally useful in the treatment of of anxiety in patients who need such treatment, as will be appreciated by those with experience in the field. Thus, the anxiolytically effective doses of the compound of the formula I will be coextensive with doses that by themselves cause conscious sedation or mild to moderate sleepiness, and can be administered to patients in need of anxiolytic therapy via the oral or oral routes. intragastric; or in a manner that allows the introduction of the compound directly into the intestine, for example, by the use of suitable formulations with enteric coating, or by intraduodenal instillation. Those of skill in the art will appreciate that the compounds of formula I, while useful in the induction and maintenance of anesthesia, sedation, sleep, and anxiolysis as defined above, are also useful in treating other medical conditions known to be They are susceptible to being treated with propofol. Therefore, a method for suppressing nausea or vomiting in a patient is provided in another aspect of this invention; where a compound of the formula I is administered orally or intratrástricamente to a patient, in an amount sufficient to suppress nausea or vomiting. Alternatively, the compound can be administered in a manner that allows its introduction directly into the intestine, for example, by the use of suitable enteric-coated formulations, or by intraduodenal instillation. This aspect of the invention has particular applications in facilities in which the patient suffers from, or is at risk for, nausea or vomiting, related to cancer chemotherapy, or where the patient suffers from, or is at risk for, nausea. and post-operative vomiting. Within that aspect of the invention, the compounds of the formula I are preferably administered at sub-hypnotic doses, ie the dose of the compound of the formula I, whether administered orally, intragastrically, or in a manner that allows its introduction directly into the intestine, does not cause loss of consciousness and, if the patient does not need sedation, preferably does not cause a sedated state. For example, doses to suppress or relieve nausea and vomiting in a patient, by repeated oral or intragastric administration, range from about 2 mg / kg to about 250 mg / kg, preferably about 5 mg / kg. at about 200 mg / kg; more preferably, from about 5 mg / kg to about 150 mg / kg, and still more preferably, from about 7.5 to about 30 mg / kg. For example, a patient suffering from nausea may be administered a prodrug of formula I, the disodium salt of O-phosphonooxymethyl-propofol, orally, in a formulation that delivers the prodrug directly into the stomach, at a dose of more from 15 to about 30 mg / kg. In general, lower effective doses can be used if the compound is administered in a manner that allows its introduction directly into the intestine. Said illustrative doses vary from about 1 mg / kg to about 50 mg / kg, preferably from about 2 mg / kg to about 30 mg / kg, more preferably from about 2 mg / kg to about 20 mg / kg. mg / kg; and still more preferable, from about 3.5 to about 12.5 mg / kg. Another aspect of the present invention provides a method for treating the itching associated with a pruritic condition in a patient; wherein a compound of the formula I is administered orally or intragastrically to a patient, in an amount sufficient to prevent, alleviate or suppress localized or general itching. Alternatively, the compound can be administered in a manner that allows its introduction directly into the intestine, for example, by intraduodenal instillation, or by the use of suitable enteric-coated formulations. Within this aspect of the invention, the compounds of the formula I are preferably administered at sub-hypnotic doses, ie, that the administered amount of the compound of the formula I does not cause loss of consciousness and, if the patient does not need sedation either , preferably not causing a sedated state. For example, appropriate doses for suppressing or alleviating local or generalized itching in a patient, by single or repeated oral or intragastric administration, range from about 2 mg / kg to about 250 mg / kg, preferably from about 5 mg / kg to about 200 mg / kg, more preferably, from about 5 mg / kg to about 150 mg / kg; and still more preferable, from about 7.5 mg / kg to about 30 mg / kg. For example, a patient suffering from generalized intractable itching can receive a prodrug of formula I, the disodium salt of O-phosphonooxymethyl-propofol, orally, in a formulation that releases the prodrug directly into the stomach, at a dose of more from 15 to about 30 mg / kg. If the compound is administered in a manner that allows its introduction directly into the intestine, lower effective doses may be used. Said illustrative doses vary from about 1 mg / kg to about 50 mg / kg, preferably from about 2 mg / kg to about 30 mg / kg; more preferably, from about 2 mg / kg to about 20 mg / kg, and still more preferably, from about 3.5 mg / kg to about 12.5 mg / kg. The compound of formula I, or a pharmaceutically acceptable salt thereof, can be administered to treat patients suffering from an epileptic condition. It is administered orally or intragastrically to a patient in need of such treatment, a dose of a compound of formula I? in an amount sufficient to prevent, suppress or alleviate the epileptic condition. Alternatively, the compound can be administered in a manner that allows its introduction directly into the intestine; for example, by intraduodenal instillation, or by the use of suitable formulations, with enteric coating. The adequate doses to bring patients suffering from an epileptic condition vary from sub-hypnotic doses, as defined above, to higher hypnotic doses, when required by the individual needs of the patient. The appropriate individual doses can be determined by those who have experience in the matter, especially in light of the guidelines provided herein. A suitable dose for an unconscious patient, who has a status epilepticus, for example, can be determined and adjusted as needed, by monitoring the stroke activity on an electroencephalogram, and a suitable liquid formulation comprising the compound of the invention can be administered. Formula I, by means of a nasogastric tube. If the epileptic condition to be treated by means of a single oral or intragastric administration, or several, of a compound of the formula I, for example, the appropriate doses typically range from about 2 mg / kg to 400 mg / kg. , more preferably, from about 5 mg / kg to about 300 mg / kg, more preferably, from about 5 mg / kg to about 200 mg / kg of body weight; and still more preferable, from about 7.5 mg / kg to about 60 mg / kg. If the epileptic condition is to be treated by administration of the compound of the formula I, in a manner that allows its introduction directly into the intestine, suitable illustrative doses range from about 1 mg / kg to about 100 mg / kg, preferably from about 1 mg / kg to about 75 mg / kg, more preferably, from about 2 mg / kg to about 50 mg / kg, and still more preferably, from about 3.5 to about 25 mg / kg body weight. In another aspect, the present invention provides a method for treating migraine pain, cluster headaches and other acute headaches. Patients in need of such treatment receive orally or intragastrically an effective amount of a compound of the formula I, or a salt thereof acceptable for pharmaceutical use, only once, or in repeated doses, until pain relief is obtained. . Alternatively, the compound or its salt can be administered in a manner that allows its introduction directly into the intestine, such as by intraduodenal instillation or by oral administration of suitable enteric-coated formulations. Exemplary oral or intragastric doses, suitable for practicing this aspect of the invention, range from about 2 mg / kg to about 300 mg / kg, preferably from about 5 mg / kg to about 250 mg / kg. kg and, more preferably, from about 5 mg / kg to about 200 mg / kg; and still more preferable, from about 10 to about 30 mg / kg of body weight. Said doses may decrease when the compound is introduced directly into the intestine, in which case typical example doses range from about 1 mg / kg to about 75 mg / kg; preferably from about 1 mg / kg to about 50 mg / kg, more preferably, from about 2 mg / kg to about 30 mg / kg and, even more preferably, from about 5 mg / kg to about 20 mg / kg of body weight. Since these doses overlap with antiemetic doses, as indicated above, they are also expected to be effective in bringing nausea frequently associated with migraine pain. As will be appreciated by those of ordinary skill in the art, pain syndromes other than acute headaches, by oral or intragastric administration of the compounds of formula I, at the preferred dose levels described in the preceding paragraph are also treatable. and it is intended that the treatment of those other pain syndromes be within the scope of this invention. Examples of such additional pain syndromes are: trigeminal or dental facial pain; neuropathic pain associated with neuropathies caused by disease (eg, diabetes or viral infections, such as herpes or HIV) or by drugs (eg, taxol, cisplatin and other anticancer agents); ghost limb pain, suffered by those who have an amputated limb; Persistent and largely untreatable postoperative pain and arthritic pain. The present invention also provides a method for the delivery of a pathological condition having an inflammatory component in a patient, wherein a pharmacologically effective amount of a compound of the formula I is administered orally or intragastrically to a patient. Alternatively, the compound can be administered in a manner that allows its introduction directly into the intestine, for example, by intraduodenal instillation, or by the use of suitable enteric-coated formulations. This embodiment of the invention has particular application in the treatment of a pathological condition of the nervous system that has an inflammatory component. In another aspect, the present invention provides a method for the treatment of a pathological respiratory condition in a patient; wherein the patient is administered, orally or intragastrically, a pharmacologically effective amount of a compound of the formula I, as defined above. Alternatively, the compound can be administered in a manner that allows its introduction directly into the intestine, for example, by intraduodenal instillation or by the use of suitable enteric-coated formulations. This embodiment of the invention has particular application in pathological respiratory conditions with tissue oxidative da. In another aspect, the present invention provides a method of treatment in which a compound of the formula I is orally or intragastrically administered to a patient in conjunction with a cytostatic chemotherapeutic agent; and where the patient suffers from cancer. In this embodiment of the invention, the compound can alternatively be administered in a manner that allows its introduction directly into the intestine, for example, by intraduodenal instillation or by the use of suitable formulations with enteric coating. In another aspect, the present invention provides a method for treating spasticity, hypereplexia, or for providing muscle relaxation in a patient in need thereof, comprising orally administering to the patient a therapeutically effective amount of a compound of the formula I, optionally in a pharmaceutical formulation that allows the release of the effective amount of the compound, directly in the intestine. The oral or intragastric doses suitable for the practice of this aspect of the invention include single or repeated oral administration of from about 10 mg / kg to about 350 mg / kg., preferably from about 30 mg / kg to about 200 mg / kg, and more preferably, from about 40 mg / kg to about 80 mg / kg body weight. If the compound is administered in a manner that allows its introduction directly into the intestine, for example, by intraduodenal instillation or by oral administration of enteric coated formulations, suitable doses range from about 5 mg / kg to about 200 mg / kg. , preferably from about 20 mg / kg to about 125 mg / kg, more preferably, from about 30 mg / kg to about 50 mg / kg body weight. In still another aspect of the present invention, there is provided a method for preventing neurodegeneration in the central nervous system, which comprises: administering orally to a patient suffering from, or at risk of, neurodegeneration caused by traumatic or vascular damage , toxicity or disease, a therapeutically effective amount of a compound of formula I. Said therapeutically effective amount is optionally administered in a pharmaceutical formulation specifically adapted to deliver the compound directly into the stomach or, alternatively, directly into the intestine. As in the case of the other treatment methods included in this invention, the formulation is optionally adapted to allow immediate or rapid release of the compound from the formulation, or for gradual release, sustained for a time. In a preferred embodiment of this aspect of the invention, the patient suffers from, or is at risk of, ischemic damage to the brain, for example, as a result of having suffered an attack. Those with practice and experience will appreciate that the methods for treating the various medical conditions described above comprise not only the administration of the prodrug of formula I to a patient who is already suffering from the symptoms and effects of the condition, but also its administration. a patient who is at risk of developing or suffering from such conditions. For example, those who suffer from migraine suffer from periodic or cyclical migraines, which allow them to predict with reasonable accuracy certain times or periods during which they are likely to experience attacks, such as certain times during the menstrual period, or during the season or during the lunar cycle. Other migraine patients will point to specific events that trigger it, such as certain odors or stresses. Many will experience prodromal signs that tell them that the beginning of a migraine attack is near, or auras that indicate that an attack is imminent. In treating such patients, the compound of formula I can be administered not only to alleviate acute pain and shorten postdromal symptoms, but also to abort the onset of a migraine attack before the onset of pain, or even to prevent the symptoms of migraine from occurring at all. In another example, it is well understood that a certain proportion of patients undergoing cancer chemotherapy or radiation therapy suffer from nausea and vomiting. The same applies for patients recovering from general anesthesia, for migraine patients and other patients suffering from intractable headaches, and for individuals who are susceptible to dizziness in land, sea or air vehicles. In such patients, who are known to have the recognized risk of suffering from nausea or vomiting, it is to be expected that preventive treatment with antiemetic doses of the compound of formula I is efficient to suppress the development of adverse symptoms. Thus, for all the medical conditions mentioned in the above lisa, the "treatment" includes not only the relief of acute symptoms, but also the prophylactic administration of adequate doses of the prodrug of the formula I to patients who are not symptomatic (yet), but that they have a recognized risk. Those with practical experience will further appreciate that the specific doses described above can be administered at various intervals and regimens, as dictated by the patient's individual needs, and the nature of the condition to be treated. Thus, in order to induce a conscious sedated state in a subject undergoing a short surgical or diagnostic procedure, the single or repeated administration of bolus doses of the prodrug of formula I may be sufficient. In other patients, for example, in cancer patients suffering from nausea during prolonged infusions of chemotherapeutic agents, in patients burned in intensive care, who require prolonged sedation, or in patients suffering from prolonged epileptic seizures, sustained or continuous administration of the prodrug may be necessary. If the needs of the patient so require, the doses exemplified above should be understood as mg / kg / h in therapeutic facilities, where the prodrug is administered not in one or several discrete boluses, but rather is supplied by continuous infusion through, for example, a suitable nasogastric or intraduodenal catheter. For example, a patient suffering from sustained epileptic seizures or epileptic status can be treated with an intragastric infusion ranging from about 2 to about 400 mg / kg / h or with intraduodenal infusions ranging from about 1 mg / g. kg up to around 100 mg / kg / h; a patient suffering from sustained nausea or vomiting can be treated with intragastric infusions of doses ranging from about 2 to about 250 mg / kg / h, or with intraduodenal infusions of doses ranging from about 1 to about 50 mg / kg / h (or, in each case, with dose infusions in any of the dose scales mentioned hereinabove). The methods for the chemical synthesis of the propofol prodrug of the formula I, starting from propofol, are described in US Pat. No. 6,204,257 to Stella and coinvenors, and are hereby incorporated in their entirety by means of this reference. The propofol prodrug of the formula I is soluble in water and can be formulated in aqueous solutions or in other suitable pharmaceutical compositions. As will be appreciated by those of ordinary skill in the art, the compounds of the formula I can be readily formulated for oral administration, by combining them with well-known, pharmaceutically acceptable carriers. Such carriers allow the compounds of the present invention to be formulated as tablets, pills, capsules, liquids, rapidly dissolving preparations, gels, syrups, thick aqueous suspensions, suspensions and the like, for oral ingestion by a patient to be treated. . Pharmaceutical preparations for oral use can be obtained by mixing the compound with a solid excipient, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets. Suitable excipients, in particular, are fillers, such as sugars, which include: lactose, sucrose, mannitol or sorbitol; cellulose preparations, such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP). In general, the pharmaceutical compositions may also comprise suitable solid or gel-phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to: calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols. If desired, disintegrating agents may be added, such as the interlaced polyvinylpyrrolidone, agar or alginic acid, or a salt thereof, such as sodium alginate; or many other disintegrators (see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., U. A., 20th edition, 2000). For liquid formulations, any pharmaceutically acceptable aqueous medium, such as sterile water, physiological saline or a mixture of water and an organic solvent, such as propylene glycol, ethanol and the like can be used. The concentration of the compound of formula I in the formulation very often ranges from about 0.5 to about 35 percent (w / v), more usually from about 1 to about 20 percent EXAMPLE 1 This example compares the pharmacological, dose-dependent effects of a propofol prodrug of formula I, the disodium salt of O-phosphonooxymethyl-propofol, in rats, when administered in a single oral dose, with the pharmacological effects observed after an intravenous infusion equipotenie. Rajas Sprague-Dawley young adult males (250-300 g, Charles River Laboratories), received oral vehicle doses (0.12 percent Tris / 0.25% monothioglycerol / saline, n = 4, orally administered) or salt of disodium of O-fosfonooximetil-propofol, at doses of 100, 200, 300 and 400 mg / kg, dissolved in a vehicle at 35 mg / mL (n = 2 per dose) or 200 mg / mL in weight / volume (n = 2 per dose). The behavior of the animal was then scored independently, by two blind but experienced observers, to be informed of five minutiae during two hours, according to the following rating scale: 4 = loss of consciousness; 3 = moderate to profound sedation, responsiveness markedly reduced to external stimuli and slow postular reflexes, but generally maintained; 2 = "sleepy", a certain slowness and looseness of postural reflexes, but maintained responsiveness to external stimuli; 1 = awake but passive; little or no locomotor or exploratory activity; 0 = normal. The results of this experiment are presented in Figures 1 to 3. The animals dosed orally with the disodium salt of O-phosphonooxymethyl-propofol exhibited a rapid onset (within 5-10 minutes of dosing) of sedated behavior, dependent on the dose, followed rapidly by loss of consciousness in the dose groups of 300 and 400 mg / kg (see Figures 1 and 2). Loss of consciousness lasted up to about an hour in animals of the highest dose group. Compared with the control animals, dosed with vehicle, the animals of the intermediate dose groups (100 to 200 mg / kg) exhibited signs of mild to moderate sedation, which lasted approximately 1 to 2 hours and more, after the oral administration (see figures 1 and 2). This study demonstrates that the tested prodrug of formula I, the disodium salt of O-phosphonooxymethyl-propofol, is orally bioavailable and capable of causing a relatively long-lasting anesthetic or sedative effect, depending on the dose, with rapid onset after of ingestion. The pharmacological effects described above, of the oral administration of the tested prodrug, were compared with those provoked by an equipotent intravenous infusion. Under anesthesia with halothane, young adult rats, which received catheters in the femoral vein, were externalized and attached to a rotating device with liquid, by means of a protective spring. Approximately 20 minutes after the catheterization, and after the full behavioral recovery of the halothane anesthesia, each animal was fixed to an electronic infusion pump and administered vehicle or test prodrug at 5, 10, 20, 30 or 40 mg / kg (n = 2 per dose), in a total volume of 1 mL, by gradual intravenous infusion at constant speed, for ten minutes. The behavioral qualification as described above began immediately after the infusion ended. The results of this experiment are illustrated in Figure 3. As in the case of the previous oral administration, the intravenous administration of the prodrug of the formula I, disodium salt of O-phosphonooxymethyl-propofol, caused a rapid onset of the sedated condition. anesthetized, depending on the dose; whose depth and duration depended on the dose administered. In general, the sedated / anesthetized state was maintained for shorter times, compared to oral administration (see Figure 3). The efficacy described above of the prodrug, tested when administered orally or intravenously, was compared to a mode of administration which allows the introduction of the prodrug directly into the intestine. For this experiment, "with gastric deviation", male Sprague Dawley rats, young adults (225-250 g of body weight) were subjected to intraduodenal catheter implantation to allow intraduodenal instillation of a regulated aqueous solution of the prodrug. After the full recovery of the catheter implant surgery, various concentrations of the disodium salt of O-phosphonooxymethyl-propofol were administered in vehicle, or vehicle alone, through the catheter, in a constant volume of 2 mL / kg of body weight, to produce doses of 0, 20, 30, 50, 100, 200, 300 and 400 mg / kg of body weight (n = 2 per dose) The behavioral determination was carried out as described above. The results of this experiment are illustrated in Figure 4. Within five minutes of intraduodenal administration, rats dosed with prodrug but without vehicle, exhibited a sedative effect of rapid onset, followed rapidly by loss of consciousness in the higher dose groups. The depth and duration of sedation and the time of unconsciousness in the higher dose groups depended on the dose administered. When administered, the test prodrug is converted in the body to propofol, its pharmacologically active metabolite. The pharmacokinetic profile, ie the concentration of propofol in the blood plasma, derived from the test prodrug, was determined in a separate experiment. Male Sprague-Dawley rats (225-250 g) were obtained with internally maintained jugular and intraduodenal catheters (Hilltop Labs, PA, E. U. A.). On the day of the test, blood samples were taken for control, from the jugular vein, before dosing. The disodium salt of O-phosphonooxymethyl-propofol was then dosed in different concentrations, in groups of 2 or 3 rats. The test prodrug was administered either orally, intravenously or intraduodenally. Blood samples (0.5 mL) were taken at 5, 15, 30, 45, 60, 120, 240 and 360 minutes after the administration of the test prodrug. The blood samples were centrifuged to obtain the plasma and stored frozen until the analysis was carried out. The results of this experiment are illustrated in the following table I: TABLE I Bioavailability of propofol from the disodium salt of O-phosphonooxymethyl-propofol, for various methods of administration, in relation to 5 mg / kg IV * Dg = Gastric bypass "Cmax" is the maximum concentration in the plasma; "F Cmax" is the calculated average bioavailability of Cmax for propofol generated from the tested prodrug (when administered through various routes and at various doses) with respect to an intravenous dose of 5 mg / kg at Cmax; "AUCt" is the average area under the curve, from time 0 to the last measured point of time (360 minutes); "F AUCt" is the average bioavailability calculated for AUCt. "Bioavailability" is the quotient, expressed as a percentage, of Cmax or AUCt for intragastric (oral) or intraduodenal (Dg) administration, and Cmax or AUCt for an intravenous dose of 5 mg / kg, adjusted for the dose. For example, for an administration of 30 mg / kg of the pro-drug tested, with gastric bypass, the bioavailability of propofol F Cmax is calculated by dividing Cmax30Dg (-27 μg / mL of plasma) between 5 mg / kg IV. Cmax (0.286 μ / mL of plasma) = 4.44; and dividing that quotient by 6 since the dose of prodrug administered by gastric bypass was six times higher than the dose of 5 mg / kg administered by IV) = 0.74. This transformation provides a reasonable measure to compare the systemic exposure to propofol, generated from the test compound (after administration of various doses by various routes) with the systemic exposure to propofol, after IV administration of the prodrug. As apparent from Table I, the Cmax bioavailability of propofol derived from the test compound administered intragastrically (orally) is limited at all dose levels tested (see F Cmax for oral 20, 50 and 100 mg / kg). However, when measuring the area under the curve, oral bioavailability compares favorably with intravenous bioavailability, especially at the highest oral dose level, where it is above 50 percent that of an intravenous dose (see F). AUCt for oral 20, 50 and 100 mg / kg). This finding is consistent with the observation that oral doses of the prodrug delivered directly into the stomach cause a lower, later peak concentration of propofol in the plasma (Cmax), but that appreciable plasma levels are sustained for longer periods of time. time, compared to the other two administration routes. Consistent with the high pharmacological efficacy of the prodrug, when administered directly into the duodenum, in the behavioral pharmacological experiments described above, it was found that the bioavailability of propofol released from the prodrug was markedly increased when administered by gastric bypass. When calculated for Cmax and AUCt, the bioavailability of propofol released from the prodrug approaches that of propofol generated after intravenous doses of the prodrug, and at higher dose levels it is essentially indistinguishable from it (see F Cmax and F AUCt for 10, 30 and 100 mg / kg, gastric bypass ["Dg"]).

These experiments demonstrate that the experimental compound is capable of causing a sedated / anesthetized state, whose onset is approximately equally as rapid with oral, intravenous or intraduodenal administration; although peak effects can be delayed with oral / intragastric administration. The pharmacological effects observed depend on the dose with the three routes of administration. Based on these experiments, it is concluded that the experimental compound is bioavailable and biologically active when administered by each of the administration routes. In the case of oral / intragastric administration, the biological potency of the peak effect in the experimental paradigm described is approximately 10 percent of that observed for intravenous administration, although the effects observed may be longer. Notably, when the stomach is bypassed (set aside), considerably lower doses of the test compound were required to obtain the observed behavioral effects, compared to oral administration. This discovery is consistent with the pharmacokinetic profile of propofol released from the prodrug after administration by gastric bypass (table I). The delivery of the test compound directly into the intestine also allowed doses that approximated those required for intravenous delivery. In a comparison of Figures 1 and 2 with Figure 4, for example, it is apparent that administration of 100 mg / kg intraduodenally, and 400 mg / kg intratranstrically, were sufficient to elicit a substantially similar pharmacological effect. A comparison of Figure 3 with Figure 4, for example, reveals that both intravenous administration of 40 mg / kg and intraduodenal administration of 50 mg / kg of the test compound are sufficient to elicit a substantially similar pharmacological effect. By studying and extrapolating the dose-activity relationship of Figures 1 to 4, it can be further expected that intraduodenal administration of about 40 mg / kg would suffice to cause a pharmacological effect substantially similar to that caused by IV administration of 20-30 mg / kg. Thus, it is concluded from the above experiments that the experimental compound, the disodium salt of O-phosphonooxymethyl-propofol, exhibits a favorable pharmacological profile as an orally ingestible agent, for example, as a sedative / hypnotic drug.

EXAMPLE 2 In a crossover study, aimed at determining the bioavailability in plasma of propofol after oral or intraduodenal administration of the disodium salt of O-phosphonooxymethyl-propofol, seven male human volunteers received 400 mg of the test compound dissolved in an aqueous solution of concentration of 35 mg / mL, orally and, on a separate occasion, by endoscopic catheter, directly in the duodenal lumen. Samples of blood plasma were taken at various points of time after administration, and were frozen until the chromatographic analysis of propofol concentrations was carried out. The concentrations of propofol in the plasma, at various points of time after administration, are given for both routes of administration in the following Table II.

TABLE II Concentrations of propofol in blood plasma, in human volunteers, at various time points after oral or intraduodenal (ID) administration of 400 mg of the disodium salt of O-phosphonooxymethyl-propofol Some of the concentrations of propofol in the plasma, of four of the subjects, were found above the upper limit of quantification (400 ng / mL) of the analysis for the second, third and fourth time points, and it was assumed that they were 400 ng / mL for the purposes of calculating mean concentrations in plasma, in this analysis.

The results of this study show that oral administration of the disodium salt of O-phosphonooxymethyl-propofol caused appreciable concentrations of propofol in the plasma in human subjects, which makes it a suitable therapeutic agent for the treatment of medical conditions that are susceptible to the treatment with propofol, but that it has the advantage of being administrable by means of the oral, therapeutically convenient route. In addition, when a similar amount of the prodrug was administered by intraduodenal instillation, the propofol in the plasma, released from the prodrug, was detected at appreciably higher levels, and at earlier time points, compared to the oral administration. This discovery confirms that therapeutically equivalent plasma concentrations of propofol can be obtained by oral / intragastric and intraduodenal administration of the prodrug, and that the prodrug dose for intraduodenal administration can be reduced from the levels necessary with oral / intragastric administration to obtain said levels of propofol in the plasma, therapeutically equivalent.

Claims (8)

1. A method for treating or preventing migraine pain in a patient, characterized in that it comprises: orally administering to the patient a therapeutically sufficient amount of the disodium salt of O-phosphonooxymethyl-propofol, formulated in an enteric-coated tablet or capsule; said tablet or capsule being specifically adapted to deliver said therapeutically sufficient amount directly into the intestine, after passing through the upper alimentary tract and the stomach.

2. A method for administering a compound to a patient in need thereof, characterized in that it comprises: administering the compound in an amount sufficient to cause a pharmacological effect in the patient; wherein the compound has the formula I, and is capable of eliciting a substantially similar pharmacological effect when administered intravenously in a lesser amount; wherein the orally administered amount is greater than the amount sufficient to elicit the substantially similar pharmacological effect by intravenous administration of the compound; being the formula I:

each Z being selected independently of the group consisting of hydrogen, alkali metal ion and amine.

3. The method according to claim 2, further characterized in that the compound is formulated in a solid oral dosage form, specifically adapted to release the compound in the stomach.

4. The method according to claim 2, further characterized in that the compound is formulated in solid oral dose form, specifically adapted to release the compound in the intestine, after passing through the upper alimentary tract.

5. The method according to claim 4, further characterized in that the formulation is in the form of an enteric coated tablet, an enteric coated capsule, a capsule comprising granules or particles with enteric coating, or a tablet containing granules or particles with enteric coating.

6. The method according to claim 2, further characterized in that the pharmacological effect is selected from the group consisting of: induce or maintain an unconscious state; induce or maintain a sedated conscious state; induce or maintain a state of drowsiness; treat insomnia; treat sleep disorders characterized by inappropriate awakening; treat anxiety, treat nausea or vomiting; treat itching associated with a pruritic condition; treat an epileptic condition;

treat migraine pain; treat cluster headaches; treat refractory headaches; bring you hear sharp headaches; bring trigeminal facial pain; treat dental pain; treat neuropathic pain; treat ghost limb pain; treat post-operative pain; treat inflammatory pain; treat neurogenic pain; treat arthritic pain; treat or prevent neurodegeneration caused by traumatic or vascular or toxic damage, or by disease; treat spasticity; treat hypereplexia, treat tetanus and cause a relaxing muscle effect.

7. The method according to claim 2, further characterized in that the pharmacological effect is to induce or maintain an unconscious state, and the amount administered orally is approximately 100 mg / kg to 1,000 mg / kg. 8. The method according to claim 7, further characterized in that the amount administered orally is approximately 200 mg / kg to 600 mg / kg. 9. The method according to claim 7, further characterized in that the amount administered orally is approximately 250 mg / kg to 500 mg / kg. 10. The method according to claim 2, further characterized in that the pharmacological effect is to induce or maintain a state of drowsiness, and the amount administered orally is approximately 10 mg / kg to 300 mg / kg. 11. The method according to claim 10, further characterized in that the amount orally administered is approximately 20 mg / kg to 250 mg / kg. 12. The method according to claim 10, further characterized in that the amount administered orally is approximately 25 mg / kg to 200 mg / kg. 3. The method according to claim 2, further characterized in that the pharmacological effect is to treat nausea or vomiting, and the amount admistated orally is approximately 2 mg / kg to 250 mg / kg. 14. The method according to claim 13, further characterized in that the amount administered orally is approximately 5 mg / kg to 200 mg / kg. 15. The method according to claim 13, further characterized in that the amount administered orally is about 5 mg / kg to 150 mg / kg. 16. The method according to claim 13, further characterized in that the amount administered orally is approximately 7.5 mg / kg to 30 mg / kg. 17. The method according to claim 2, further characterized in that the pharmacological effect is to treat the itching associated with a pruritic condition, and the amount administered orally is approximately 2 mg / kg to 250 mg / kg.

8. The method according to claim 17, further characterized in that the amount administered orally is approximately 5 mg / kg to 200 mg / kg.

19. - The method according to claim 17, further characterized in that the amount administered orally is about 5 mg / kg to 150 mg / kg. 20. The method according to claim 17, further characterized in that the amount administered orally is approximately 7.5 mg / kg to 30 mg / kg. 21. The method according to claim 2, further characterized in that the pharmacological effect is to treat an epileptic condition and the amount administered orally is approximately 2 mg / kg to 400 mg / kg. 22. The method according to claim 21, further characterized in that the amount administered orally is about 5 mg / kg to 300 mg / kg. 23. The method according to claim 21, further characterized in that the amount administered orally is approximately 5 mg / kg to 200 mg / kg. 24. The method according to claim 21, further characterized in that the amount administered orally is approximately 7.5 mg / kg to 60 mg / kg. 25. The method according to claim 2, further characterized in that the pharmacological effect is to treat migraine pain, cluster headache, refractory headaches and other acute headaches, and said amount administered orally is approximately 2 mg / kg at 300 mg / kg. 26. The method according to claim 25, further characterized in that the amount administered orally is approximately 5 mg / kg to 250 mg / kg. 27. The method according to claim 25, further characterized in that the amount administered orally is approximately 5 mg / kg to 200 mg / kg. 28. The method according to claim 25, further characterized in that the amount administered orally is approximately 10 mg / kg to 30 mg / kg. 29. The method according to claim 2, further characterized because the pharmacological effect is to treat spasticity, hyperreplexia, tetanus and cause a muscle relaxant effect; and said orally administered amount is approximately 10 mg / kg to 350 mg / kg. 30. The method according to claim 29, further characterized in that the amount administered orally is approximately 30 mg / kg to 200 mg / kg. 31. The method according to claim 29, further characterized in that the amount administered orally is approximately 40 mg / kg to 80 mg / kg. 32. A method for administering a compound to a patient in need thereof, characterized in that it comprises: directly introducing the compound into the intestine, in an amount sufficient to cause a pharmacological effect in the patient; where the compound has the formula I:

wherein each Z is independently selected from the group consisting of hydrogen, alkali metal ion and amine. 33. The method according to claim 32, further characterized in that the compound is orally administered and formulated in a solid oral dosage form, specifically adapted to release the compound in the intestine after passing through the upper alimentary touch. 34. The method according to claim 33, further characterized in that the formulation is in the form of an enteric coated tablet, an enteric coated capsule, a capsule comprising enteric coated granules or particles, or a granule-containing tablet. or particles with enteric coating. The method according to claim 32, further characterized in that the pharmacological effect of the group is selected, which consists of: inducing or maintaining an unconscious state; induce or maintain a sedated conscious state; induce or maintain a state of drowsiness; treat insomnia; bring sleep disorders characterized by inappropriate awakening; treat anxiety, treat nausea or vomiting; treat itching associated with a pruritic condition; treat an epileptic condition; treat migraine pain; treat cluster headaches; treat refractory headaches; treat other acute headaches; treat trigeminal facial pain; treat dental pain; bring neuropathic pain; bring ghost limb pain; bring posi-operative pain; irritating inflammatory pain; treat neurogenic pain; treat arthritic pain; treat or prevent neurodegeneration caused by traumatic or vascular or toxic damage, or by disease; treat spasticity; treat hypereplexia, treat tetanus and cause a relaxing muscle effect. 36. The method according to claim 32, further characterized in that the pharmacological effect is to induce or maintain an unconscious state, and the amount administered is approximately 15 mg / kg to 500 mg / kg. 37. The method according to claim 36, further characterized in that said amount is approximately 20 mg / kg to 400 mg / kg. 38. The method according to claim 36, further characterized in that said amount is approximately 25 mg / kg to 300 mg / kg. 39. The method according to claim 32, further characterized in that the pharmacological effect is to induce or maintain a state of drowsiness and the amount administered is approximately 1 mg / kg to 75 mg / kg. 40.- The method according to claim 39, further characterized in that said amount is approximately 2 mg / kg to 50 mg / kg. 41. The method according to claim 39, further characterized in that said amount is approximately 5 mg / kg to 40 mg / kg. 42. The method according to claim 32, further characterized in that the pharmacological effect is to treat nausea or vomiting and the amount administered is approximately 1 mg / kg to 50 mg / kg. 43. The method according to claim 42, further characterized in that said amount is approximately 2 mg / kg to 30 mg / kg. 44. The method according to claim 42, further characterized in that said amount is approximately 2 mg / kg to 20 mg / kg. 45. The method according to claim 42, further characterized in that said amount is approximately 3.5 mg / kg to 12.5 mg / kg. 46. The method according to claim 32, further characterized in that the pharmacological effect is to treat the itching associated with a pruritic condition and the amount administered is approximately 1 mg / kg to 50 mg / kg. 47. The method according to claim 46, further characterized in that said amount is approximately 2 mg / kg to 30 mg / kg.

48. - The method according to claim 46, further characterized in that said amount is approximately 2 mg / kg to 20 mg / kg. 49. The method according to claim 46, further characterized in that said amount is approximately 3.5 mg / kg to 12.5 mg / kg. 50. The method according to claim 32, further characterized in that the pharmacological effect is to treat an epileptic condition, and the amount administered is approximately 1 mg / kg to 100 mg / kg. 51.- The method according to claim 50, further characterized in that said amount is approximately

1 mg / kg to 75 mg / kg. 52. The method according to claim 50, further characterized in that said amount is approximately

2 mg / kg to 50 mg / kg. 53. The method according to claim 50, further characterized in that said amount is approximately 3.5 mg / kg to 25 mg / kg. 54.- The method according to claim 32, further characterized in that the pharmacological effect is to treat migraine pain, cluster headaches, refractory headaches and other acute headaches, and the amount administered is approximately 1 mg / kg a 75 mg / kg. 55. The method according to claim 54, further characterized in that said amount is approximately 1 mg / kg to 50 mg / kg. 56. The method according to claim 54, further characterized in that said amount is approximately 2 mg / kg to 30 mg / kg. 57. The method according to claim 54, further characterized in that said amount is approximately 5 mg / kg to 20 mg / kg. 58. The method according to claim 32, further characterized because the pharmacological effect is to treat spasticity, hypereplexia, tetanus and cause a muscle relaxant effect; and the amount administered is approximately 5 mg / kg to 200 mg / kg. 59. The method according to claim 58, further characterized in that the amount is approximately 20 mg / kg to 125 mg / kg. 60.- The method according to claim 58, further characterized in that said amount is approximately 30 mg / kg to 50 mg / kg.