Method of making anamorelin tablets with improved stability

Abstract

To provide a method for preventing the formation of undesirable degradants of Anamorelin Hydrochloride when Anamorelin Hydrochloride having excess chloride is formulated into a pharmaceutically acceptable dosage form.SOLUTION: A method for reducing impurity formation in a final dosage form of Anamorelin Hydrochloride, comprising the aforementioned stability-improving formulations and analytical techniques for controlling impurity formation.SELECTED DRAWING: None

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present disclosure relates to anamorelin hydrochloride, formulations of anamorelin hydrochloride with improved stability, methods of making such formulations, methods of treatment using such formulations, and methods of reducing and controlling impurity formation. [Background technology]

[0002] Background of the Invention Anamorelin is a synthetic, orally active compound first synthesized in the 1990s as a growth hormone secretagogue currently in development for the treatment of cancer-related cachexia. The free base of anamorelin is (3R) 1-(2-methylalanyl-D-tryptophyl)-3-(phenylmethyl)-3-piperidinecarboxylic acid 1,2,2-trimethylhydrazide, 3-{(2R)-3-{(3R)-3-benzyl-3-[(trimethylhydrazino)carbonyl]piperidin-1-yl}-2-[(2-methylalanyl)amino]-3-oxopropyl}-1H-indole, or It is chemically defined as 2-amino-N-[(1R)-2-[(3R)-3-benzyl-3-(N,N',N'-trimethylhydrazinocarbonyl)piperidin-1-yl]-1-(1H-indol-3-ylmethyl)-2-oxoethyl]-2-methylpropionamide and has the following chemical structure:

[0003] [ka]

[0004] A commercial dosage form has been developed as the hydrochloride salt by Ono Pharmaceutical Co., Ltd. (Osaka, Japan) and Helsin Healthcare (Lugano, Switzerland).

[0005] Ankersen et al., International Publication No. 01 / 34593, describes a method for preparing anamorelin as the fumarate salt using the hydrochloride salt prepared as an intermediate in step (j) of Example 1. Lorimer et al., International Publication No. 2006 / 016995, describes a method for preparing a crystalline form of the free base of anamorelin. Kuwabe et al., International Publication No. 2013 / 158874, describes a method for producing anamorelin hydrochloride with controlled chloride content and low residual solvents. Mann et al., International Publication No. 2016 / 036598, describes a method for using anamorelin hydrochloride for the treatment of cancer cachexia. Other methods for using anamorelin are described in Polvino et al., International Publication No. 2010 / 099522 and Polvino et al., International Publication No. 2008 / 100448.

[0006] Despite the foregoing developments, there remains a need for methods to prevent the formation of undesired degradants of anamorelin hydrochloride, particularly when anamorelin hydrochloride with excess chloride is formulated into pharmaceutically acceptable dosage forms. It has become particularly important to control the formation of anamorelin impurity A, an analog and degradant of anamorelin hydrochloride that has an HPLC response factor of 1.53 relative to anamorelin. Summary of the Invention

[0007] Summary of the Invention It has been unexpectedly discovered that certain tableting excipients, when compressed with anamorelin hydrochloride into tablets, improve the stability of anamorelin hydrochloride, and that these excipients prevent the degradation of anamorelin hydrochloride to impurity A. Without wishing to be bound by any theory, it is believed that these excipients, when intimately mixed with anamorelin hydrochloride, physically or chemically separate the hydrochloride from the anamorelin free base molecule, thereby preventing the degradation of anamorelin to impurity A.

[0008] Accordingly, in a first principal embodiment, the present invention provides a method for making an anamorelin hydrochloride tablet, and the tablet made thereby, the method comprising: (a) mixing anamorelin hydrochloride with one or a combination of pharmaceutically acceptable carriers selected from microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, and anhydrous calcium hydrogen phosphate to form a mixture; and (b) compressing the mixture into a tablet.

[0009] Other embodiments relate to methods of producing anamorelin hydrochloride dosage forms by identifying and controlling impurity A. Accordingly, in a second main embodiment, the present invention provides a method of producing anamorelin hydrochloride tablets, and tablets produced thereby, the method comprising: (a) combining anamorelin hydrochloride with a pharmaceutically acceptable carrier means for preventing the formation of impurity A to form a mixture; (b) compressing the mixture into tablets; (c) isolating impurity A from anamorelin hydrochloride in one or more of the tablets; (d) quantifying the amount of impurity A in the one or more tablets; and (e) optionally repeating steps (c) and (d) six months or one year after step (b).

[0010] Other embodiments relate to impurity A itself. Thus, in a third main embodiment, the present invention provides impurity A isolated from anamorelin hydrochloride.

[0011] Yet another embodiment relates to anamorelin hydrochloride tablets themselves. Accordingly, in a fourth main embodiment, the present invention provides tablets comprising anamorelin hydrochloride as an active ingredient, further comprising a pharmaceutically acceptable carrier selected from microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, and anhydrous calcium hydrogen phosphate.

[0012] In a fifth principal embodiment, the present invention provides a tablet comprising anamorelin hydrochloride as an active ingredient and a pharmaceutically acceptable carrier means for preventing the formation of impurity A.

[0013] A still further embodiment relates to the use of anamorelin hydrochloride for treating cancer cachexia using the tablet of the invention. Accordingly, in a sixth main embodiment, the present invention provides a method of ameliorating one or more symptoms of cancer cachexia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of anamorelin hydrochloride in a tablet according to the invention, wherein (a) the patient is characterized by a body mass index of less than 25, a Cancer Fatigue Scale score of 20-28, or an Anti-Cancer Drug-Treated Cancer Patient Quality of Life Questionnaire (QOL-ACD) score of 65-80, and (b) the symptom is selected from the group consisting of lean body mass, appetite, weight, fatigue, and quality of life.

[0014] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed. DETAILED DESCRIPTION OF THE INVENTION

[0015] Detailed Description Definitions and usage of terms

[0016] As used in this specification and the claims that follow, the following terms have the following meanings and uses:

[0017] The singular articles "a", "an" and "the" include the plural forms as well, unless the context clearly dictates otherwise.

[0018] The word "comprise" and variations of this word, such as "comprising" and "comprises," mean "including, but not limited to," and are not intended to exclude, for example, other additives, ingredients, integers, or steps. Where an element is described as comprising a plurality of ingredients, steps, or conditions, it will be understood that the element may also include any combination of such plurality, or be described as "consisting of" or "consisting essentially of" a plurality of ingredients, steps, or conditions or combinations.

[0019] Where a test method is performed by reference to a standard setting body, such as the International Conference on Harmonization ("ICH"), or a test methodology, such as the Cancer Fatigue Scale, it will be understood that the method will be performed in accordance with the method in effect as of the earliest priority date of the relevant subject matter. When a pharmaceutical test is called for herein, it will be understood that the test will be performed in accordance with an ICH guidance document in effect as of the earliest priority date of the relevant subject matter, a United States Pharmacopeia (USP) method in effect as of the earliest priority date of the relevant subject matter, or an American Society for Testing and Materials (ASTM) method in effect as of the earliest priority date of the relevant subject matter.

[0020] The "Cancer Fatigue Scale" refers to a clinical outcome assessment reported by Okuyama Toru et al. in "Development and Validation of the Cancer Fatigue Scale: A Brief, Three-Dimensional, Self-Rating Scale for Assessment of Fatigue in Cancer Patients," Vol. 19, No. 1, January 2000, Journal of Pain and Symptom Management.

[0021] "Quality of Life Questionnaire for Cancer Patients Treated with Anticancer Drugs" or "QOL-ACD" refers to the clinical outcome assessment published by T. Matsumoto et al. in "The quality of life questionnaire for cancer patients treated with anticancer drugs (QOL-ACD): validity and reliability in Japanese patients with advanced non-small-cell lung cancer." Quality of Life Research: an International Journal of Quality of Life Aspects of Treatment, Care and Rehabilitation, July 31, 2002, 11(5):483-493.

[0022] When a range is given by specifying a lower end of the range apart from the upper end of the range, or by specifying specific numerical values, it will be understood that the range can be defined by combining the lower end variable, the upper end variable, and any of the specific numerical values ​​that are mathematically possible. Similarly, when a range is stated to extend from one endpoint to another, the range will also be understood to encompass the span between the two endpoints, and to exclude the two endpoints.

[0023] As used herein, the term "about" is intended to account for variability accepted in the pharmaceutical industry and inherent in products, such as differences in product strength due to manufacturing variations and time-induced product degradation.

[0024] "Anamorelin hydrochloride" refers to a salt of anamorelin and hydrochloric acid in an approximately 1:1 ratio, corresponding to 6.08% chloride. The chloride content is preferably less than 6.3% or 6.2% of the molecule, preferably in the range of 5.7-6.3% or 5.8-6.2%. Alternatively, a slight molar excess of chloride may be present, in which case the chloride content may be in the range of 6.1%-6.3% or 6.1%-6.2%. Anamorelin hydrochloride salts defined by any of these ranges may be used in the methods and formulations of the present invention.

[0025] "Impurity A" refers to a degradant / analog of anamorelin hydrochloride that has an HPLC response factor relative to anamorelin of 1.53 when measured according to the conditions described in Example 3. Alternatively, "Impurity A" has an HPLC relative retention time of 0.34 when the retention time of anamorelin hydrochloride is 1 minute when measured according to the conditions described in Example 3.

[0026] "A pharmaceutically acceptable carrier means for preventing the formation of impurity A" corresponds to a combination of microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, and anhydrous calcium hydrogen phosphate present in a prophylactically effective amount when thoroughly mixed with anamorelin hydrochloride to produce a pharmaceutically acceptable immediate-release tablet and compressed into a tablet of a hardness appropriate to fulfill its recited function. Prevention does not require 100% prevention, but rather requires a weight ratio of carrier means:anamorelin hydrochloride of 0.5:1 to 10:1, or any of the more specific ratios described herein that can achieve stability comparable to that reported in the Examples herein for such ratios. "Prophylactically effective amount" means an amount sufficient to reduce the rate of decomposition of anamorelin hydrochloride, particularly to impurity A, when combined with anamorelin hydrochloride in an intimate mixture and compressed into a tablet. In preferred embodiments, a prophylactically effective amount is an amount sufficient to prevent the formation of impurity A at greater than about 0.1% or 0.05% by weight of the anamorelin hydrochloride after storage for 6 months at 40°C and 75% relative humidity.

[0027] Alternatively, "a pharmaceutically acceptable carrier means for preventing the formation of impurity A" may be expressed as "a pharmaceutically acceptable carrier means for preventing a 200% increase in the formation of impurity A after 6 months of storage at 40°C and 75% relative humidity" or as "a pharmaceutically acceptable carrier means for preventing a 100% increase in the formation of impurity A after 6 months of storage at 40°C and 75% relative humidity", where said means corresponds to a formulation capable of producing such a result.

[0028] The terms "excipient" and "carrier" are used interchangeably herein. Consider

[0029] The present invention can be defined based on several main embodiments, and additional embodiments can be created by further defining or modifying based on the discussion herein. In a first main embodiment, the present invention provides a method for making anamorelin hydrochloride tablets, and the tablets made thereby, the method comprising: (a) mixing anamorelin hydrochloride with one or a combination of pharmaceutically acceptable carriers selected from microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, and anhydrous calcium hydrogen phosphate to form a mixture; and (b) compressing the mixture into a tablet.

[0030] In a second principal embodiment, the present invention provides a method for producing anamorelin hydrochloride tablets, and tablets produced thereby, the method comprising: (a) combining anamorelin hydrochloride with a pharmaceutically acceptable carrier means for preventing the formation of impurity A to form a mixture; (b) compressing the mixture into tablets; (c) isolating impurity A from anamorelin hydrochloride in one or more of the tablets; (d) quantifying the amount of impurity A in the one or more tablets; and (e) optionally repeating steps (c) and (d) six months or one year after step (b).

[0031] In a third principal embodiment, the present invention provides impurity A isolated from anamorelin hydrochloride.

[0032] In a fourth main embodiment, the present invention provides a tablet comprising anamorelin hydrochloride as an active ingredient, further comprising a pharmaceutically acceptable carrier selected from microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, and anhydrous calcium hydrogen phosphate.

[0033] In a fifth principal embodiment, the present invention provides a tablet comprising anamorelin hydrochloride as an active ingredient and a pharmaceutically acceptable carrier means for preventing the formation of impurity A.

[0034] In a sixth main embodiment, the present invention provides a method of ameliorating one or more symptoms of cancer cachexia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of anamorelin hydrochloride in a tablet form according to the present invention, wherein (a) the patient is characterized by a body mass index of less than 25, a Cancer Fatigue Scale score of 20-28, or an Anti-Cancer Drug-Treated Cancer Patient Quality of Life Questionnaire (QOL-ACD) score of 65-80, and (b) the symptoms are selected from the group consisting of lean body mass, appetite, weight, fatigue, and quality of life. Tablet characteristics

[0035] Preferred carriers that have been shown to improve the stability of anamorelin hydrochloride when compressed into tablets with anamorelin hydrochloride are selected from microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, calcium hydrogen phosphate anhydrous, lactose monohydrate, D-mannitol, corn starch, low-substituted hydroxypropyl cellulose, sodium starch glycolate, carmellose calcium, carmellose, crospovidone, partially pregelatinized corn starch, stearic acid, and sodium stearyl fumarate. Tablets can be formulated and manufactured to produce pharmaceutically acceptable and pharmaceutically stable products based on the teachings of the present invention and the common general knowledge of the pharmaceutical arts.

[0036] The tablet may contain only one of these preferred carriers or any combination of these preferred carriers. Thus, in one subembodiment, the tablet contains two or more of these preferred carriers. In another subembodiment, the tablet contains three or more of these preferred carriers. In another subembodiment, the tablet contains four or more of these preferred carriers.

[0037] However, based on the examples provided herein, one may choose to avoid the use of mannitol and HPC or their pharmaceutical equivalents. Thus, in one embodiment, the formulations of the present invention omit sugar alcohols such as mannitol. In another embodiment, the formulations of the present invention omit mannitol, sorbitol, and / or xylitol. In yet another embodiment, the formulations of the present invention omit mannitol. In other embodiments, the formulations of the present invention omit HPC and / or HPMC.

[0038] The tablets preferably contain one or a combination of preferred carriers in an amount sufficient to prevent the degradation of anamorelin hydrochloride into impurity A during storage (a "prophylactically effective amount"). This "prophylactically effective amount" may be further described in terms of the amount of a preferred excipient or combination of preferred excipients in the formulation relative to anamorelin hydrochloride. Thus, any of the preferred excipients may be used in an amount of about 0.01 to about 20 parts by weight per part by weight of anamorelin hydrochloride. Alternatively, any of the preferred excipients may be used in an amount of about 0.5 to about 10 parts by weight per part by weight of anamorelin hydrochloride. As another alternative, any of the preferred excipients may be used in an amount of about 1 to about 6 parts by weight per part by weight of anamorelin hydrochloride. As another alternative, any of the preferred excipients may be used in an amount of about 0.01, 0.1, 1, 5, 10, or 20 or more parts by weight per part by weight of anamorelin hydrochloride.

[0039] A prophylactically effective amount can also be determined based on the amount of a preferred excipient present in the formulation sufficient to perform its traditional tableting function as a diluent, disintegrant, glidant, or lubricant in addition to its stabilizing function. Thus, in various embodiments, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, lactose monohydrate, D-mannitol, or cornstarch, either individually (i.e., only one of the carriers is present) or in combination, are present in an amount of about 1 to about 10 parts by weight per part by weight of anamorelin hydrochloride. In other embodiments, croscarmellose sodium is present in an amount of about 0.1 to about 2 parts by weight per part by weight of anamorelin hydrochloride. In other embodiments, silicon dioxide is present in an amount of about 0.01 to about 0.2 parts by weight per part by weight of anamorelin hydrochloride. In other embodiments, magnesium stearate is present in an amount of about 0.01 to about 0.2 parts by weight per part by weight of anamorelin hydrochloride. In another embodiment, the low-substituted hydroxypropyl cellulose is present in an amount of about 0.01 to about 0.2 parts by weight per part by weight of anamorelin hydrochloride. In another embodiment, the sodium starch glycolate is present in an amount of about 0.01 to about 0.2 parts by weight per part by weight of anamorelin hydrochloride. In another embodiment, the carmellose calcium is present in an amount of about 0.01 to about 0.2 parts by weight per part by weight of anamorelin hydrochloride. In another embodiment, the carmellose is present in an amount of about 0.01 to about 0.2 parts by weight per part by weight of anamorelin hydrochloride. In another embodiment, the crospovidone is present in an amount of about 0.01 to about 0.2 parts by weight per part by weight of anamorelin hydrochloride. In another embodiment, the partially pregelatinized corn starch is present in an amount of about 0.01 to about 0.2 parts by weight per part by weight of anamorelin hydrochloride. In another embodiment, stearic acid is present in an amount of about 0.01 to about 0.2 parts by weight per part by weight of anamorelin hydrochloride. In another embodiment, sodium stearyl fumarate is present in an amount of about 0.01 to about 0.2 parts by weight per part by weight of anamorelin hydrochloride. It will be understood that any of these preferred excipients can be present alone or in combination with another preferred excipient in these parts by weight.

[0040] In other embodiments, the prophylactically effective amount is based on the weight of the total combination of preferred carriers in the tablet relative to anamorelin hydrochloride. Thus, in one embodiment, the total preferred carriers in the tablet is about 0.01 to about 20 parts by weight per part by weight of anamorelin hydrochloride. In an alternative embodiment, the total preferred carriers in the tablet is about 0.5 to about 10 parts by weight per part by weight of anamorelin hydrochloride. In another alternative embodiment, the total preferred carriers in the tablet is about 1 to about 6 parts by weight per part by weight of anamorelin hydrochloride. Again, the tablet need not contain all of the preferred excipients, but it is preferred that the total of the excipients present satisfy the aforementioned weight parts.

[0041] In another subembodiment, the tablet is defined by its stability. Thus, in various subembodiments, the tablet of the present invention is defined as a tablet in which substantially no impurity A is produced, or in which the amount of impurity A produced after storage at 40° C. and 75% relative humidity for 2-6 months is less than about 0.3% or 0.05%, preferably less than 0.1% or 0.05%, based on the weight of the anamorelin hydrochloride.

[0042] Tablets may be further specified with respect to their hardness. Thus, in any of the embodiments of the present invention, the tablet may have a hardness of about 40 to about 200 Newtons. Alternatively, or in addition, in any of the embodiments of the present invention, a pharmaceutically acceptable carrier, which may be more than one, may be compressed with the anamorelin hydrochloride at a compression force of about 0.5 to about 15 kN.

[0043] In any of the embodiments of the present invention, the anamorelin hydrochloride and the preferred carrier are thoroughly mixed, i.e., the anamorelin hydrochloride and the preferred carrier are uniformly dispersed throughout the tablet.

[0044] The tablets may be coated or uncoated, however, in a preferred embodiment, the tablets are coated using conventional coating excipients.

[0045] In yet another embodiment, the tablet is characterized by its method of manufacture, including tablets manufactured by any of the methods described herein. Carrier means

[0046] The tablets of the present invention can also be described in terms of the means used to achieve their surprising stability. This means is referred to herein as a "pharmaceutically acceptable carrier means for preventing the formation of impurity A" or simply as a "carrier means." The tablets described in any of the embodiments of the present invention comprise anamorelin hydrochloride and such a carrier means in a prophylactically effective amount. As described in the tablet characteristics and manufacturing method sections herein, these preferred excipients are most effective when thoroughly mixed with anamorelin hydrochloride and compressed into tablets. Exemplary compression forces are about 0.5 to about 15 kN. Exemplary tablet hardnesses are about 40 to about 200 Newtons.

[0047] Thus, in one embodiment, the pharmaceutically acceptable carrier means is in intimate admixture with said anamorelin hydrochloride and compressed with said anamorelin hydrochloride at a compression force of about 0.5 to about 15 kN.

[0048] In another embodiment, the pharmaceutically acceptable carrier is in intimate admixture with the anamorelin hydrochloride and compressed to a hardness of about 40 to about 200 Newtons.

[0049] In yet another embodiment, the tablet comprises from about 0.01 to about 20, from about 0.5 to about 10, or from about 1 to about 6 parts by weight of said pharmaceutically acceptable carrier means or one or a combination of said pharmaceutically acceptable carriers, based on 1 part by weight of anamorelin hydrochloride.

[0050] As discussed above, these preferred excipients are believed to prevent the formation of impurity A by chemically or physically segregating the hydrochloride salt from the anamorelin moiety. Thus, in one embodiment, the pharmaceutically acceptable carrier means acts as an HCl scavenger. Manufacturing method

[0051] The disclosed pharmaceutical tablets can be prepared by any of the well-known techniques of pharmacy. Drug formulations are discussed, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, New York, 1980; and Kibbe et al., eds., Handbook of Pharmaceutical Excipients (3rd ed.), American Pharmaceutical Association, Washington, 1999. However, in a preferred embodiment, the tablets are manufactured according to one of the main embodiments of the present invention.

[0052] In one embodiment, an intimate mixture of anamorelin hydrochloride, preferably in any of the weight ratios discussed in the Tablet Features section herein, with one or a combination of the preferred carriers discussed herein, in a prophylactically effective amount, is compressed into a tablet, preferably at a compression force of about 0.5 to about 15 kN. In another embodiment, an intimate mixture of anamorelin hydrochloride, preferably in any of the weight ratios discussed in the Tablet Features section herein, with a carrier means discussed in the Carrier Means section herein, in a prophylactically effective amount, is compressed into a tablet, preferably at a compression force of about 0.5 to about 15 kN. Conventional excipients other than the preferred carriers discussed herein can also be used in accordance with known pharmaceutical manufacturing techniques. Tablets can also be coated with one or more coating excipients in accordance with methods well known in the art.

[0053] Thus, in various subembodiments, the manufacturing method is carried out by combining anamorelin hydrochloride with two or more, three or more, or four or more of the preferred carriers. In other subembodiments, the pharmaceutically acceptable carrier means comprises two or more, three or more, or four or more of the preferred carriers.

[0054] Similarly, the manufacturing method can be carried out by mixing one or a combination of preferred carriers in a ratio of about 0.01 to about 20 parts by weight, about 0.5 to about 10 parts by weight, or about 1 to about 6 parts by weight, based on 1 part by weight of anamorelin hydrochloride. Conversely, the pharmaceutically acceptable carrier means can include one or a combination of preferred carriers in a ratio of about 0.01 to about 20 parts by weight, about 0.5 to about 10 parts by weight, or about 1 to about 6 parts by weight, based on 1 part by weight of anamorelin hydrochloride.

[0055] In either case, the preferred carrier or pharmaceutically acceptable carrier means is preferably present in an amount sufficient to prevent the formation of impurity A. With respect to the amount of impurity A formed after six months of storage at 40° C. and 75% relative humidity, suitable percentages range from 0.5% to 0.001%, 0.2% to 0.001%, and 0.1% to 0.001%, based on the weight of the anamorelin hydrochloride. However, suitable percentages are preferably in the ranges of 0.15% to 0.001%, 0.10% to 0.001%, or 0.07% to 0.001%. Alternatively, the stability of a dosage form can be measured in terms of the increase in the amount of impurity A formed after six months of storage at 40° C. and 75% relative humidity. Thus, in alternative embodiments, the proportion of impurity A formed after 6 months of storage at 40° C. and 75% relative humidity is less than 3 times the proportion of impurity A at t0, less than 2 times the proportion of impurity A at t0, or less than 1.5 times the proportion of impurity A at t0.

[0056] Once produced, impurity A is preferably isolated from anamorelin hydrochloride, preferably according to the HPLC methods described herein, and the tablets will preferably be analyzed for impurity A according to the methods described herein. Thus, when separating impurity A in the methods of the present invention, it is preferred to isolate impurity A by dissolving one or more tablets in an organic solvent and separating anamorelin hydrochloride from impurity A by high performance liquid chromatography. Analysis method

[0057] The unexpected stability and purity of the tablets of the present invention are due in large part to the discovery of impurity A, its isolation from anamorelin by HPLC, and the method of measuring the amount of impurity A in a given tablet using HPLC. Thus, in one embodiment, the present invention provides a method of controlling the formation of impurities in anamorelin tablets by measuring the concentration of impurity A by HPLC. In another embodiment, the present invention provides impurity A isolated from anamorelin hydrochloride. In one embodiment, impurity A is present in a non-polar organic solvent. In another embodiment, impurity A is present in a solution comprising water, trifluoroacetic acid, and acetonitrile.

[0058] In yet a further embodiment, the present invention provides a method for analyzing impurity A in a defined stability program during and after the manufacture of anamorelin hydrochloride tablets. For example, tablets from a given batch can be analyzed for impurity A six months or one year after the batch is manufactured. Impurity A is an analog or degradant of anamorelin hydrochloride that has a response factor of 1.53 relative to anamorelin hydrochloride during high performance liquid chromatography. The conditions under which impurity A exhibits a response factor of 1.53 during HPLC are more specifically detailed in Example 3 herein. Treatment method

[0059] As noted above, the present invention further includes methods of treatment using the tablets of the present invention. In various subembodiments, lean body mass is estimated by dual-energy x-ray absorptiometry (DEXA), fatigue is measured by the Cancer Fatigue Scale, and quality of life is measured by QOL-ACD scores for items 7-11 ("Physical Status"), item 8 ("Was your appetite good?"), item 9 ("Did you enjoy your food?"), and item 11 ("Have you lost weight?"). In other subembodiments, the patient has stage III or IV non-small cell lung cancer (NSCLC) or advanced gastrointestinal (colorectal, gastric, or pancreatic) cancer. [Example]

[0060] In the following examples, efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperatures, etc.), but some errors and deviations should be accounted for. The following examples are put forth to provide those of ordinary skill in the art with a complete disclosure and description of how the methods claimed herein are made and evaluated, and are intended to be purely illustrative of the invention and are not intended to limit the scope of what the inventors regard as their invention.

[0061] Example 1 Evaluation of the stability of tablets containing anamorelin hydrochloride and a single pharmaceutically acceptable carrier Anamorelin hydrochloride (Lot A and Lot B) was mixed with different excipients in a weight ratio of 1:10 or 1:1 (anamorelin hydrochloride:excipients) and compressed into tablets containing 50 mg of anamorelin hydrochloride, as reported in Tables 1 and 2.

[0062] [Table 1]

[0063] [Table 2]

[0064] The stability of these tablets was measured after 2 months of storage in closed bottles under accelerated conditions of temperature and relative humidity as described in ICH Q1A(R2) and compared to the stability of tablets (50 mg) containing 100% anamorelin monohydrochloride. Stability was determined by measuring the content of impurity A under the HPLC conditions reported in Example 3. The results of the stability study are reported in Tables 3 and 4.

[0065] [Table 3]

[0066] [Table 4]

[0067] Example 2 Evaluation of the stability of tablets containing a combination of anamorelin hydrochloride and a pharmaceutically acceptable carrier In the same experiment as in Example 1, combinations of pharmaceutically acceptable carriers were mixed with anamorelin hydrochloride in three different weight ratios (1:1, 1:3, and 1:6) or (1:1, 3:2, and 3:1) (anamorelin:excipient mixtures), and the mixtures were compressed to produce tablets containing 50 mg or 150 mg of anamorelin hydrochloride, as recorded in Tables 5, 6, and 7.

[0068] [Table 5]

[0069] [Table 6]

[0070] [Table 7]

[0071] The stability of these tablets was measured after 2 months of storage in closed bottles under accelerated conditions of temperature and relative humidity as described in ICH Q1A(R2) and compared to the stability of the comparative formulation described in Example 1. Stability was determined by measuring the concentration of impurity A under the HPLC conditions reported in Example 3. The results of the stability studies are reported in Tables 8, 9, 10 and 11.

[0072] [Table 8]

[0073] [Table 9]

[0074] [Table 10]

[0075] [Table 11]

[0076] Example 3 HPLC analysis method for impurity A Each sample was dissolved in the following mobile phase A / mobile phase B mixture (17:3) to prepare a test sample. Then, 10 μg of each test sample was tested by HPLC under the conditions described in Table 5. The peak area (At) of the test sample was measured by automatic integration. The concentrations of anamorelin hydrochloride and impurity A were calculated using the following formula. ·Analog concentration (%)=At / Aa×RRF×100 At: each peak area of ​​the test sample Aa: Sum of all peak areas RRF: Relative Reaction Factor (Impurity A: 1.53)

[0077] [Table 12]

[0078] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the invention being indicated by the following claims.

Claims

1. 1. A method for producing anamorelin hydrochloride tablets, comprising: a) mixing anamorelin hydrochloride with one or a combination of pharmaceutically acceptable carriers selected from microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, anhydrous calcium hydrogen phosphate, lactose monohydrate, D-mannitol, corn starch, low-substituted hydroxypropyl cellulose, sodium starch glycolate, carmellose calcium, carmellose, crospovidone, partially pregelatinized corn starch, stearic acid, and sodium stearyl fumarate to form a mixture; and b) compressing said mixture into tablets. A method comprising:

2. 10. The method of claim 1, comprising mixing anamorelin hydrochloride with two or more of the pharmaceutically acceptable carriers.

3. 3. The method of claim 2, comprising mixing anamorelin hydrochloride with three or more of the pharmaceutically acceptable carriers.

4. 4. The method of claim 3, comprising mixing anamorelin hydrochloride with four or more of the pharmaceutically acceptable carriers.

5. 5. The method of any one of claims 1 to 4, comprising mixing about 0.01 to about 20 parts by weight of one or a combination of said pharmaceutically acceptable carriers with 1 part by weight of anamorelin hydrochloride.

6. 6. The method of claim 5, comprising mixing about 0.5 to about 10 parts by weight of one or a combination of said pharmaceutically acceptable carriers with 1 part by weight of anamorelin hydrochloride.

7. 7. The method of claim 6, comprising mixing about 1 to about 6 parts by weight of one or a combination of said pharmaceutically acceptable carriers with 1 part by weight of anamorelin hydrochloride.

8. 8. The method of any one of claims 1 to 7, wherein the mixture is compressed into tablets at a compression force of about 0.5 to about 15 kN.

9. The method of any one of claims 1 to 8, wherein the mixture is compressed to a hardness of about 40 to about 200 Newtons.

10. 10. The method of any one of claims 1 to 9, wherein the one or combination of pharmaceutically acceptable carriers is present in an amount sufficient to prevent the formation of impurity A.

11. 11. The method of claim 10, wherein the amount of impurity A produced after storage at 40° C. and 75% relative humidity for 2 to 6 months is less than about 0.1% by weight of the anamorelin hydrochloride.

12. 12. The method of claim 11, wherein the amount of impurity A produced after storage for 2 months at 40°C and 75% relative humidity is less than about 0.05% by weight of the anamorelin hydrochloride.

13. 13. The method of any one of claims 10 to 12, wherein impurity A has a response factor of 1.53 to anamorelin hydrochloride in high performance liquid chromatography.

14. 13. The method of any one of claims 10 to 12, wherein impurity A has a response factor of 1.53 relative to anamorelin hydrochloride in high performance liquid chromatography as described in Example 3.

15. 1. A method for producing anamorelin hydrochloride tablets, comprising: (a) combining anamorelin hydrochloride with a pharmaceutically acceptable carrier means for preventing the formation of impurity A to form a mixture; (b) compressing the mixture into tablets; (c) isolating impurity A from anamorelin hydrochloride in one or more of said tablets; (d) quantifying the amount of impurity A in said one or more tablets; and (e) optionally repeating steps (c) and (d) six months or one year after step (b); A method comprising:

16. 16. The method of claim 15, wherein the isolating step (c) comprises dissolving one or more of the tablets in an organic solvent and separating the anamorelin hydrochloride from the impurity A by high performance liquid chromatography.

17. 17. The method of claim 15 or 16, wherein said pharmaceutically acceptable carrier means acts as an HCl scavenger in intimate mixture with said anamorelin hydrochloride.

18. 17. The method of claim 15 or 16, wherein the carrier means comprises one or a combination of carriers selected from microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, calcium hydrogen phosphate anhydrous, lactose monohydrate, D-mannitol, corn starch, low-substituted hydroxypropyl cellulose, sodium starch glycolate, carmellose calcium, carmellose, crospovidone, partially pregelatinized corn starch, stearic acid, and sodium stearyl fumarate in a prophylactically effective amount to prevent the formation of Impurity A.

19. 20. The method of claim 18, wherein said carrier means comprises two or more of said pharmaceutically acceptable carriers.

20. 20. The method of claim 19, wherein said carrier means comprises three or more of said pharmaceutically acceptable carriers.

21. 21. The method of claim 20, wherein said carrier means comprises four or more of said pharmaceutically acceptable carriers.

22. 21. The method of any one of claims 15 to 20, comprising mixing about 0.01 to about 20 parts by weight of said carrier means with 1 part by weight of anamorelin hydrochloride.

23. 23. The method of claim 22, comprising mixing about 0.5 to about 10 parts by weight of said carrier means with 1 part by weight of anamorelin hydrochloride.

24. 24. The method of claim 23, comprising mixing about 1 to about 6 parts by weight of said carrier means with 1 part by weight of anamorelin hydrochloride.

25. 25. The method of any one of claims 15 to 24, wherein the mixture is compressed into a tablet at a compression force of about 0.5 to about 15 kN.

26. 26. The method of any one of claims 15 to 25, wherein the mixture is compressed to a hardness of about 40 to about 200 Newtons.

27. 27. The method of any one of claims 15 to 26, wherein the one or combination of pharmaceutically acceptable carriers is present in an amount sufficient to prevent the formation of impurity A.

28. 28. The method of claim 27, wherein the amount of impurity A produced after storage at 40° C. and 75% relative humidity for 2 to 6 months is less than about 0.1% by weight of the anamorelin hydrochloride.

29. 29. The method of claim 28, wherein the amount of impurity A produced after storage for 2 months at 40°C and 75% relative humidity is less than about 0.05% by weight of the anamorelin hydrochloride.

30. Impurity A isolated from anamorelin hydrochloride.

31. 31. Impurity A according to claim 30, having a response factor to anamorelin hydrochloride in high performance liquid chromatography of 1.

53.

32. 32. Impurity A according to claim 31, having a response factor to anamorelin hydrochloride in high performance liquid chromatography of 1.53 as measured in Example 3.

33. The impurity A according to any one of claims 30 to 32 in a non-polar organic solvent.

34. The impurity A according to any one of claims 30 to 32, in a solution comprising water, trifluoroacetic acid and acetonitrile.

35. An anamorelin hydrochloride tablet produced by the method according to any one of claims 1 to 29.

36. A tablet comprising anamorelin hydrochloride as an active ingredient, further comprising a pharmaceutically acceptable carrier selected from microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, anhydrous calcium hydrogen phosphate, lactose monohydrate, D-mannitol, corn starch, low-substituted hydroxypropyl cellulose, sodium starch glycolate, carmellose calcium, carmellose, crospovidone, partially pregelatinized corn starch, stearic acid, and sodium stearyl fumarate.

37. 37. The tablet of claim 36, comprising two or more of said pharmaceutically acceptable carriers.

38. 38. The tablet of claim 37, comprising three or more of said pharmaceutically acceptable carriers.

39. 39. The tablet of claim 38, comprising four or more of said pharmaceutically acceptable carriers.

40. 40. The tablet of any one of claims 36 to 39, comprising about 0.01 to about 20 parts by weight of one or a combination of said pharmaceutically acceptable carriers per 1 part by weight of anamorelin hydrochloride.

41. 41. The tablet of claim 40, comprising about 0.5 to about 10 parts by weight of one or a combination of said pharmaceutically acceptable carriers per part by weight of anamorelin hydrochloride.

42. 42. The tablet of claim 41, comprising about 1 to about 6 parts by weight of one or a combination of said pharmaceutically acceptable carriers per part by weight of anamorelin hydrochloride.

43. 43. The tablet of any one of claims 36 to 42, wherein impurity A is not substantially produced, or the amount of impurity A produced after storage at 40°C and 75% relative humidity for 2 to 6 months is less than about 0.1% by weight of the anamorelin hydrochloride.

44. 44. The tablet of claim 43, wherein substantially no impurity A is produced, or the amount of impurity A produced after storage for 2 months at 40°C and 75% relative humidity is less than about 0.05% by weight of the anamorelin hydrochloride.

45. 45. The tablet of claim 43 or 44, wherein impurity A has a response factor of 1.53 to anamorelin hydrochloride in high performance liquid chromatography.

46. 46. ​​The tablet of claim 45, wherein impurity A has a response factor of 1.53 relative to anamorelin hydrochloride in high performance liquid chromatography as described in Example 3.

47. A tablet comprising anamorelin hydrochloride as an active ingredient and a pharmaceutically acceptable carrier means for preventing the formation of impurity A.

48. 42. The tablet of claim 41, wherein said carrier means comprises a pharmaceutically acceptable carrier selected from one or a combination of microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, calcium hydrogen phosphate anhydrous, lactose monohydrate, D-mannitol, corn starch, low-substituted hydroxypropyl cellulose, sodium starch glycolate, carmellose calcium, carmellose, crospovidone, partially pregelatinized maize starch, stearic acid, and sodium stearyl fumarate.

49. 48. The tablet of claim 47, wherein the pharmaceutically acceptable carrier means acts as an HCl scavenger in intimate mixture with the anamorelin hydrochloride and is compressed with the anamorelin hydrochloride at a compression force of about 0.5 to about 15 kN.

50. 50. The tablet of any one of claims 47 to 49, wherein said pharmaceutically acceptable carrier means acts as an HCl scavenger in intimate admixture with said anamorelin hydrochloride compressed to a hardness of about 40 to about 200 Newtons.

51. 48. The tablet of claim 47, wherein the pharmaceutically acceptable carrier means comprises one or a combination of carriers selected from microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, anhydrous calcium hydrogen phosphate, lactose monohydrate, D-mannitol, corn starch, low-substituted hydroxypropyl cellulose, sodium starch glycolate, carmellose calcium, carmellose, crospovidone, partially pregelatinized corn starch, stearic acid, and sodium stearyl fumarate in intimate admixture with the anamorelin hydrochloride and compressed with the anamorelin hydrochloride at a compression force of about 0.5 to about 15 kN.

52. 52. The tablet of claim 47 or 51, wherein the pharmaceutically acceptable carrier means comprises one or a combination of carriers selected from microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, calcium hydrogen phosphate anhydrous, lactose monohydrate, D-mannitol, corn starch, low-substituted hydroxypropyl cellulose, sodium starch glycolate, carmellose calcium, carmellose, crospovidone, partially pregelatinized corn starch, stearic acid, and sodium stearyl fumarate in intimate admixture with the anamorelin hydrochloride and compressed to a hardness of about 40 to about 200 Newtons.

53. 53. The tablet of any one of claims 47 to 52, comprising about 0.01 to about 20 parts by weight of said pharmaceutically acceptable carrier means per part by weight of anamorelin hydrochloride.

54. 54. The tablet of claim 53, comprising about 0.5 to about 10 parts by weight of said pharmaceutically acceptable carrier means per 1 part by weight of anamorelin hydrochloride.

55. 55. The tablet of claim 54, comprising about 1 to about 6 parts by weight of said pharmaceutically acceptable carrier means per part by weight of anamorelin hydrochloride.

56. 56. The tablet of any one of claims 47 to 55, wherein impurity A is not substantially produced, or the amount of impurity A produced after storage at 40°C and 75% relative humidity for 2 to 6 months is less than about 0.1% by weight of the anamorelin hydrochloride.

57. 57. The tablet of claim 56, wherein substantially no impurity A is produced, or the amount of impurity A produced after storage for 2 months at 40°C and 75% relative humidity is less than about 0.05% by weight of the anamorelin hydrochloride.

58. 58. The tablet of any one of claims 47 to 57, wherein impurity A has a response factor of 1.53 to anamorelin hydrochloride in high performance liquid chromatography.

59. 59. The tablet of claim 58, wherein impurity A has a response factor of 1.53 relative to anamorelin hydrochloride in high performance liquid chromatography as described in Example 3.

60. 60. A method of ameliorating one or more symptoms of cancer cachexia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of anamorelin hydrochloride in a tablet according to any one of claims 35 to 59; (a) the patient is characterized by a body mass index of less than 25, a Cancer Fatigue Scale score of 20 to 28, or an Anti-cancer Drug-Treated Cancer Patient Quality of Life Questionnaire (QOL-ACD) score of 65 to 80; (b) the symptom is selected from the group consisting of lean body mass, appetite, weight, fatigue and quality of life.

61. 61. The method of claim 60, wherein the lean body mass is estimated by dual-energy x-ray absorptiometry (DEXA), the fatigue is measured by the Cancer Fatigue Scale, and the quality of life is measured by QOL-ACD scores for items 7-11 ("Physical status"), item 8 ("Was your appetite good?"), item 9 ("Did you enjoy your meals?"), and item 11 ("Did you lose weight?").

62. 62. The method of claim 60 or 61, wherein the patient has stage III or IV non-small cell lung cancer (NSCLC) or advanced gastrointestinal (colorectal, gastric, or pancreatic) cancer.

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