MXPA98007474A - Nasal administration of agents for the treatment of retard attack emesis - Google Patents

Abstract

The present invention is directed to a method for the prophylactic control of delayed emesis by the use of nasal spray with metocloprami

Description

NASAL ADMINISTRATION OF AGENTS FOR THE TREATMENT OF DELAYED ATTACK EMESIS BACKGROUND OF THE INVENTION Field of the Invention The present invention is directed to a method for the treatment of an emetogenic reaction. More specifically, the present invention is directed to a method for treating a delayed-attack emetogenic reaction, more commonly associated with chemotherapy. Description of the Related Art The emetogenic reaction refers to vomiting (ie, actual vomiting or dry bowel or dry nausea). ) and / or nausea. The emetogenic reaction is most commonly found in response to chemotherapeutic agents, such as bleomycin, vincristine, vinblastine, adriamycin, etoposide, methotrexate, doxorubicin, cyclophosphamide, 5-fluorouracil, cisplatin, and some combinations thf. Among these chemotherapeutic agents, the most sevemetogenic reaction is usually associated with cisplatin-based therapy. In general, thare emetogenic reactions of acute attack (henceforth synonymous with "acute emesis" or "acute attack emesis") and delayed attack emetogenic reactions (henceforth synonymous with "delayed emesis" or "delayed attack emesis"). Acute emesis and delayed emesis usually include episodes of vomiting (real and / or dry bowel or dry nausea) and / or sensations of nausea. However, in acute emesis, vomiting and / or nausea occurs in the first 24 hours after chemotherapy. In contrast, in delayed emesis, vomiting and / or nausea occurs after the first 24 hours of chemotherapy. Delayed emesis is a syndrome difft from acute emesis that occurs more than 24 hours after the administration of anticancer agents, especially cisplatin. In a study by Kris et al., Entitled Controlling Delayed Vomiting: Double-Blind, Randomized Trial Comparing Placebo, Dexa ethasone Alone, and Metoclopramide Plus Dexamethosone in Patients Receiving Cisplatin published in the Journal of Clinical Oncology, vol. 7, No. 1, at pp. 108-114 (January 1989), the authors report that delayed vomiting was observed within a period of 4 days after cisplatin therapy (at a dose level of 120 mg / m2 body surface area) in 74% of patients. patients and that delayed nausea was observed in 87% of the same patients during the same period of 4 days after the cisplatin treatment. Kris et al. Also reported that the incidence severity of delayed emesis was more prevalent (ie, worse) during the 48-72 hour period (ie, 2-3 days after cisplatin administration) after that cisplatin therapy was given. In addition, according to Kris et al. As control of acute emesis after high doses of cisplatin had improved the need to consider the additional problem of delayed nausea and vomiting [ie, delayed emesis] initiated, persistent, for more than 24 hours after cisplatin was evident. (Emphasis added) Id. On page 113.

Patients in the study by Kris et al. Received a regimen of two oral dexamethasone drugs (ie, DSM po) and oral metoclopramide (ie, MCP po). The side effects observed in patients in the study by Kris et al. They included hiccups, bowel movements (LBM), heartburn, restlessness, drowsiness, insomnia, and acute dystonic reactions. Among these symptoms, restlessness and drowsiness are the most common. In another study, the side effects of oral MCP for the prophylaxis of delayed emesis (ie, delayed nausea and / or vomiting) induced by cisplatin wreported by Gunberg. et al. , in Oral Metoclopramide With or Without Diphenhydramine: Potential for Prevention of Late Nausea and Vomiting Induced by Cisplatin, published in the Journal of the National Cancer Institute, vol. 80, No. 11, pp. 864-868 (August 3, 1988). The most sevtoxic effects observed wextrapyral symptoms of agitation and depression. Side effects can interfwith compliance (compliance = follow-up in the prescribed dosing regimen) with the prescribed medication regimen as well as interfwith the patient's ability to effectively communicate the nature and severity of these and other side effects. Even with a short-term medication regimen, poor compliance or non-compliance is observed in approximately 25% of patients. In addition, oral therapy may be inadequate for some patients who experience a delayed emetogenic reaction. Due to nausea and / or vomiting you may still be more reluctant to comply with the oral medication regimen. There is therefore a need to avoid treatment or prophylaxis (ie, complete or partial prophylaxis for delayed emesis in an appropriate dosage form wherein the problems associated with non-compliance (eg, with oral or intravenous dosage forms) are US Pat. No. 4,624,965 (hereinafter Wenig) describes the nasal administration of MCP In Wenig, in column 1, lines 40-52 mention that: A number of antinausea and antiemetic agents are already known. widely used in therapy, mainly in the treatment of emesis and nausea .... Unfortunately, many of these agents, when used: (1) cause undesirable side effects, (2) are inefficiently and variably absorbed from the forms of current dosage (3) are difficult or inconvenient for administration in the current dosage forms [eg, oral, intravenous, intramuscular or subcutaneous dosage forms]. (Emphasis added). In addition, in Examples 8 and 9 of Weing (see columns 11 and 12 therein) human individuals were studied. However, an intranasal gel formulation is used contrary to a nasal spray. No experience with human subjects using a nasal spray formulation of the MCP (MCP rn) is described in Weing. Since chronic or severe nausea and / or vomiting can significantly influence a patient's ability to maintain an acceptable level of health, for example, after chemotherapy, it is desirable to provide a method for treatment and sufficient control (control prophylactic) of these emetogenic reactions. In the case of delayed emesis induced by chemotherapy, the control and treatment of nausea and / or vomiting can not only help maintain an acceptable level of health but can also help maintain an aggressive cancer treatment program. For this purpose, although advances have been made in the area to control and treat acute emesis, the treatment for the adequate control of delayed emesis until now is not available.

SUMMARY OF THE INVENTION Therefore, an objective of the present invention is to provide a method for the treatment of delayed emesis using a dosage form of the MCP that avoids or reduces the incidence of non-compliance of patients. Therefore, another objective of the present invention is to provide a method for the treatment of delayed emesis using nasal spray with MCP that prevents or reduces the incidence of side effects experienced by patients. Therefore, another objective of the present invention is to provide a method for the treatment of delayed emesis using MCP nasal spray administered intranasally. Therefore, still another objective of the present invention is to provide a method for the treatment of delayed emesis induced by chemotherapy using a dosage form of the MCP that avoids or reduces the problem of discontinuity in the patient. Still another objective of the present invention is to provide a method for the treatment of delayed emesis induced by cisplatin chemotherapy using a dosage form of MCP that avoids or reduces the problem of non-compliance of the patient. Yet another objective of the present invention is to provide a method for the sufficient treatment of delayed emesis induced by chemotherapy using a dosage form of the MCP that prevents or reduces the incidence of side effects experienced by patients. Still yet another objective of the present invention is to provide a method for the sufficient treatment of delayed emesis induced by cisplatin chemotherapy using nasal spray with MCP that avoids or reduces the severity of the side effects experienced by patients. Another objective of the present invention is to provide a method for the control of delayed emesis induced by chemotherapy using nasal spray with MCP administered intranasally after the first 24 hours of completing chemotherapy. Yet another objective of the present invention is to provide a method for efficiently controlling the delayed emesis induced by cisplatin chemotherapy using MCP nasal spray which avoids or reduces the problems with non-compliance of the patient. Yet another object of the present invention is to provide a method for the prophylaxis of delayed emesis by administering intranasally a nasal spray dosage form of pharmaceutically acceptable MCP at a therapeutic dosage level of between about 1.95 mg / kg to about 3.9 mg / kg during days 1-7 wherein the chemotherapy was administered on day 0. Yet another objective of the present invention is to provide a method for the prophylaxis of delayed emesis by intranasally administering a pharmaceutically acceptable MCP nasal spray dosage form to a therapeutic dosage level of between approximately 1.95 mg / kg to approximately 3.9 mg / kg during days 1-6 where cisplatin was administered. Yet another objective of the present invention is to provide a method for the prophylaxis of delayed emesis by intranasally administering a pharmaceutically acceptable MCP nasal spray dosage form at a therapeutic dosage level of between about 0.8 mg / mk to about 1.0 mg / kg on days 1-5 where cisplatin was administered. Yet another objective of the present invention is to provide a method for the prophylaxis of delayed emesis by intranasally administering a pharmaceutically acceptable MCP nasal spray dosage form at a therapeutic dosage level of between about 0.9 mg / mk to about 1.1 mg / kg on days 1-4 where cisplatin was administered. Still another object of the present invention is to provide a, method for the prophylaxis of delayed emesis by administering intranasally a dosage form of pharmaceutically acceptable MCP nasal spray at a therapeutic dosage level of between about 40 mg / mk to about 120 mg / kg on days 1-7 where Chemotherapy was administered at 0. Yet another objective of the present invention is to provide a method for the prophylaxis of delayed emesis by intranasally administering a pharmaceutically acceptable MCP nasal spray at a therapeutic dosage level of between about 40 mg / day - 120 mg / day on days 1-6 where cisplatin was administered on day 0. Yet another objective of the present invention is to provide a method for the prophylaxis of delayed emesis by intranasally administering a pharmaceutically acceptable MCP nasal spray at a level of therapeutic dosage of approximately 60 mg / day on days 1-6 where chemotherapy was administered Otherapy on day 0. Yet another objective of the present invention is to provide a method for the prophylaxis of delayed emesis by intranasally administering a pharmaceutically acceptable MCP nasal spray at a therapeutic dosage level of approximately 60 mg / day on days 1- 5 where cisplatin was administered on day 0. Still another objective of the present invention is to provide a method for the prophylaxis of delayed emesis by administering intranasally a pharmacologically acceptable MCP nasal spray at a therapeutic dosage level of approximately 60 mg / day. days 1-4 where cisplatin was administered on day 0. These and other objects of the present invention are achieved by administering intranasally in patients experiencing delayed emesis a therapeutically effective dose of MCP nasal spray in a pharmaceutically acceptable dosage form that is Therapeutically and medically acceptable.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The presently described invention relates to a method for the treatment and control of delayed emesis using a dosage formulation for MCP nasal spray. The nasal spray dosage form of the MCP is formulated to contain a therapeutically effective amount of MCP such that upon administration by the intranasal route, a therapeutically amount of MCP is administered to the patient. In addition, the therapeutically effective amount of MCP is chosen to minimize the severity and incidence of unpleasant side effects and drug interactions found with the MCP. The MCP nasal spray formulation administered to deliver a dose of 20 mg three times a day is indicated below (formulation for 0.1 ml of MCP nasal spray (MCP rn = dosage form in metoclopramide nasal spray)): 10 mg / 0.1 ml metoclopramide hydrochloride 1.5 mg benzyl alcohol 0.8 mg NaCl 0.320 mg glacial acetic acid 0.077 mg sodium acetate 6.425 mg sorbitol 0.1 ml purified water (when for 0.1 ml) The nasal spray formulation of MCP was administered (to the patients indicated in Figures 1 (a) and 1 (b)) as one breath per nostril (ie, 2 breaths at 10 mg / breath (10 mg / 0.1 ml and 0.1 ml / breath)) three times in a day (2 breaths TID for 6 days). The previous formulation was sterile with a bacterial count of 10 below the level allowed by the U.S.P per milliliter. In addition, it did not contain pathogens. The pH of the previous formulation was approximately 4.0 The common MCP nasal spray dosage forms sol solutions or suspensions that can be administered as a nasal spray. However, it is also possible to use nasal drops. The formulation of the nasal spray dosage of the MCP contains the active ingredient in any suitable form, for example, in salt, as hydrochloride, etc. The nasal spray dosage formulation of MCP usually also contains pH adjusters, emulsifiers or dispersing agents, buffers, preservatives and wetting agents as are known to those skilled in the art. See, REMINGTON'S PHARMACEUTICAL SCIENCES, 14th edition, 1970. ' In general, the dosage formulation for nasal spray of the MCP is isotonic. A common MCP nasal spray formulation is in the form of a solution that has a light amber color and is not turbid to the naked eye with a pH of between about 3.0-5.0. The common formulation may contain benzyl alcohol of at least about 13.5 mg / ml with a content of virtually no impurity determined by high performance liquid chromatography (HPLC) and with a bacterial count of less than 250 cfu / ml and sufficient pathogen-free to form an acceptable pharmaceutical nasal spray dosage form. The solvent is usually purified water suitable for use in dosage forms in nasal spray or any equivalent water (e.g., water for injections) allowed for use in these nasal dosage forms. See REMINGTON 'S PH? RMACEUTICAL SCIENCES, any edition from 1980-1996. For adequate and / or sufficient treatment and control of delayed emesis (eg, induced by chemotherapy, induced by cisplatin or induced by other causes), a normal dose is that dose which is therapeutically effective and which minimizes the effects collaterals and drug interactions, for example, in patients receiving chemotherapy. A common dosage of the nasal spray with MCP for the treatment and control of delayed attack emesis experienced by a common patient (for example, delayed emesis induced by chemotherapy). The dosage of the MCP nasal spray can vary from about 40 mg / day to about 120 mg / day. Above about 120 mg / day, the dose may be undesirable due to the unpleasant side effects experienced by patients receiving more than about 120 mg / day of the nasal spray dosage form of MCP. A preferred dose of MCP nasal spray is 60 mg / day, commonly administered as 20 mg three times a day (ie, two puffs of 10 mg / 0.1 ml of the MCP nasal spray, one breath per fossa). The weight of the patient can also affect the dosage to be administered. Typically, a dose of between about 1.95 mg / kg to about 3.90 mg / kg is given to a patient who experiences delayed emesis, (ie, delayed emesis induced by chemotherapy). A preferred dosage is about 0.8 mg / kg. The aforementioned doses for the treatment and control of delayed emesis are given after 24 hours of the time when the cycle of the chemotherapeutic regimen has been administered. Thus, for example, if the cycle of the chemotherapeutic regimen is given between 2.00 to 4.00 pm on day 0, then the nasal spray of MCP is administered starting at approximately 4:00 pm on day 1-7, usually at three or four equal dosages in three or four equal time intervals, respectively. However, the dose can be given during waking hours so as not to awaken the patient. Note that the nasal spray dosage form of MCP is administered intranasally and is given in addition to the medications administered for the treatment and control of acute emesis. All references mentioned in this patent application are incorporated herein by reference in their entireties and for all purposes. Having described the invention, the following examples are included to illustrate the benefits of the present invention. The examples are illustrative only and are not intended to unduly limit the scope of the present invention.

EXAMPLES Example 1 Table I indicates the characteristics of patients who received metoclopramide nasal spray alone or nasal spray of metoclopramide (MCP rn) and dexamethasone (DXM) to control the delayed emesis induced by chemotherapy. The main site of the disease indicates the main location of the cancer.

TABLE I - PATIENT CHARACTERISTICS Table II indicates the chemotherapy regimen that each of the patients received on day 0.

TABLE II - CHEMOTHERAPY REGIME (administered on day 0) Example 2 Table III indicates the vomiting, tonnage and nausea reported in each patient during days 1 to 6 after chemotherapy on day 0. Note that the MCP nasal spray (60 mg / day) indicates administration of a formulation of MCP nasal spray per 0.1 ml of: mg / 0.1 ml metoclopramide hydrochloride 1.5 mg benzyl alcohol 0.8 mg NaCl 0.320 mg glacial acetic acid 0.077 mg sodium acetate 6.425 mg sorbitol 0.1 ml purified water (vC for 0.1 ml) The MCP nasal spray formulation was given as a pit-blowing (ie, 2 breaths at 10 -ag / breath (10 mg / 0.1 ml and 0.1 ml / breath)) three times a day (2 breaths TID for 6 hours). days) . The previous formulation was sterile for bacteria. In addition, the pathogens were absent. The pH of the above formulation was about 4.0.

TABLE III VOMIT, ARCHAE AND NAUSEA REPORTED IN EACH PATIENT DURING DAYS 1 TO 6 AFTER CHEMOTHERAPY (Chemotherapy administered on day 0) 1 = mild, 2 = moderate, 3 = severe Patient No, 2 was not included because he received fractionated chemotherapy, was treated with MPS rn and did not experience vomiting, bowing or nausea (complete response) i9 Example 3 The results of the therapy with the MCP nasal spray (given on day 1-6) for the treatment and control (partial or complete prophylaxis) of delayed emesis is indicated in Table IV.

TABLE IV (a) - COMPLETE ANSWER (without emetic episodes) BY DAY OF STUDY Thus, on day 1, 5 of 5 patients who received MCP rn did not present emetic episodes (complete response) while only 3 of 6 patients who received MCP rn + DXM did not show emetic episodes.

TABLE IV (b) - MAIN RESPONSE (1-2 emetic episodes) t = complete response = 0 emetic episodes F = main response = 1-2 emetic episodes * = on days 5 and 6 all patients received only MCP rn (60 mg / day); y = 0. In the same way, on day 1, no patient who received MCP rn had an emetic episode (main response) while 2 of 6 patients who received MCP rn + DXM had 1-2 emetic episodes.

Claims (9)

1. A method for the prophylaxis of delayed emesis comprises the steps of: administering a pharmaceutically acceptable metoclopramide nasal spray formulation via the route. intranasal to deliver a therapeutically effective and medically acceptable daily dose for prophylaxis.

2. The process of claim 1, wherein the daily dosage is between about 40 mg / day to about 120 mg / day. ,

3. The process of claim 2, wherein the daily dosage is between 40 mg / day to 120 mg / day.

4. The process of claim 2, wherein the daily dosage is about 60 mg / day.

5. The process of claim 4, wherein the daily dosage is 60 mg / day. The process of claim 1, wherein the daily dosage is divided into 3 or 4 equal smaller doses and administered at equally spaced intervals within 24 hours. The process of claim 6, wherein the smallest doses are 20 mg and are administered every 8 hours. The process of claim 1, wherein the daily dosage is between about 1.95 mg / kg to about 3.90 mg / kg. 9, The process of claim 8, wherein the daily dosage is between 1-95 mg / kg to 3.90 mg / kg. The process of claim 9, wherein the daily dosage is about 0.8 mg / kg. 11. The process of claim 10, wherein the daily dosage is 0.8 mg / kg. The process of claim 11, wherein the daily dosage is divided into 3 or 4 equal smaller doses and administered at equally spaced intervals within 24 hours. The process of claim 12, wherein the daily dosage is divided into 3 equal smaller doses and administered at equally spaced intervals within 24 hours. The process of claim 12, wherein the daily dosage is divided into 4 equal smaller doses and administered at equally spaced intervals within 24 hours. The process of claim 1, wherein the dosage is administered for the prophylaxis of delayed emesis induced by chemotherapy. The process of claim 15, wherein the dosage is induced by chemotherapeutic agents selected from the group consisting of cisplatin, cyclophosphamide, adriamycin, vinblastine, methotrexate, etoposide, bleomycin, vincristine, and combinations thereof. The process of claim 16, wherein the daily dosage is administered for 24-168 hours after the end of chemotherapy. 18. The process of claim 16, wherein the daily dosage is administered 24-144 hours after the end of chemotherapy. The process of claim 16, wherein the daily dosage is administered for 24-120 hours after the end of chemotherapy. The process of claim 16, wherein the daily dosage is administered for 24-96 hours after the end of chemotherapy.