Method for manufacturing anamorelin tablets with improved stability

Abstract

A method for reducing the formation of impurities in a final dosage form of anamorelin hydrochloride, including formulations for improving said stability and analytical techniques for controlling impurity formation.

Description

Technical Field

[0001] Field of Invention The present disclosure relates to anamorelin hydrochloride, a formulation of anamorelin hydrochloride with improved stability, a method for manufacturing such a formulation, a treatment method using such a formulation, and a method for reducing and controlling impurity formation.

Background Art

[0002] Background of the Invention Anamorelin is a synthetic orally active compound first synthesized in the 1990s as a growth hormone secretagogue currently under 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 ·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]

Chemical Formula

[0004] Commercially available dosage forms are being developed as hydrochloride salts by Ono Pharmaceutical Co., Ltd. (Osaka, Japan) and Helsin Healthcare (Lugano, Switzerland).

[0005] Ankersen et al.'s International Publication No. 01 / 34593 describes a method for preparing anamorelin as fumarate using the hydrochloride produced as an intermediate in step (j) of Example 1. Lorimer et al.'s International Publication No. 2006 / 016995 describes a method for preparing the crystalline form of the free base of anamorelin. Kuwabe et al.'s International Publication No. 2013 / 158874 describes a method for producing anamorelin hydrochloride with controlled chloride content and low residual solvent. Mann et al.'s 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.'s International Publication Nos. 2010 / 099522 and Polvino et al.'s International Publication Nos. 2008 / 100448.

[0006] Despite the aforementioned developments, there is a need for methods to prevent the formation of undesirable degradation products of anamorelin hydrochloride, particularly when anamorelin hydrochloride with excess chloride is formulated into pharmaceutically acceptable dosage forms. Controlling the formation of anamorelin impurity A, an analog and degradation product of anamorelin hydrochloride with an HPLC response coefficient of 1.53 relative to anamorelin, has become particularly important. [Overview of the Initiative]

[0007] Summary of the Invention Unexpectedly, it was discovered that compressing certain tablet-forming excipients with anamorelin hydrochloride into tablets improved the stability of anamorelin hydrochloride, and that these excipients prevented the degradation of anamorelin hydrochloride into impurity A. While we do not wish to be bound by any theory, it is thought that when these excipients are intimately mixed with anamorelin hydrochloride, they physically or chemically segregate the hydrochloride from the free anamorelin base molecule, thereby preventing the degradation of anamorelin into impurity A.

[0008] Accordingly, in a first main embodiment, the present invention provides a method for producing anamorelin hydrochloride tablets and tablets produced by means of, 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 tablets.

[0009] Other embodiments relate to methods for producing anamorelin hydrochloride dosage forms by detecting and controlling impurity A. Thus, in a second main embodiment, the present invention provides a method for producing anamorelin hydrochloride tablets and tablets produced by means of the present invention, the method comprising: (a) mixing 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. Therefore, in a third main embodiment, the present invention provides impurity A isolated from anamorelin hydrochloride.

[0011] Another embodiment relates to the anamorelin hydrochloride tablet itself. Thus, 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.

[0012] In a fifth primary 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] Further embodiments relate to the use of anamorelin hydrochloride for treating cancer cachexia using tablets of the present invention. Thus, in a sixth primary embodiment, the present invention provides a method for improving one or more symptoms of cancer cachexia in a patient requiring improvement of one or more symptoms of cancer cachexia, comprising administering to the patient a therapeutically effective amount of anamorelin hydrochloride in tablets 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 to 28, or a quality of life questionnaire (QOL-ACD) score for cancer patients treated with anticancer drugs of 65 to 80, and (b) the symptoms are selected from the group consisting of lean body mass, appetite, body weight, fatigue and quality of life.

[0014] Further advantages of the present invention are some described below, some evident from that description, and some can be acquired through the practice of the present invention. The advantages of the present invention should be realized and achieved by the components and combinations specifically indicated in the appended claims. It should be understood that both the above general description and the following detailed description are illustrative and descriptive only and do not limit the present invention as described in the claims. [Modes for carrying out the invention]

[0015] Detailed explanation Definitions and Usage of Terms

[0016] As used herein and in the subsequent claims, the following terms have the following meanings and uses:

[0017] The singular articles "a," "an," and "the" also include plural forms unless explicitly indicated by the context.

[0018] The word “comprise” and its variations such as “comprising” and “comprises” mean “comprise but not limited to,” and are not intended to exclude, for example, other additives, components, integers, or processes. When a component is described as containing multiple components, processes, or conditions, it will be understood that the component may also contain any combination of such multiple components, or may be described as “consisting of” or “essentially consisting of” multiple components, processes, conditions, or combinations.

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

[0020] The "Cancer Fatigue Scale" refers to the clinical outcome assessment reported by Toru Okuyama 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, in the Journal of Pain and Symptom Management.

[0021] The "Questionnaire on the Quality of Life of Cancer Patients Treated with Anticancer Drugs" or "QOL-ACD" refers to the clinical outcome evaluation published by T. Matsumoto et al. in "Questionnaire on the Quality of Life of Cancer Patients Treated with Anticancer Drugs (QOL-ACD): Validity and Reliability in Japanese Patients with Advanced Non-Small-Cell Lung Cancer" (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] It will be understood that when a range is given by specifying the lower end of the range away from the upper end thereof, or by specifying a particular numerical value, the range can be defined by selectively combining any of the lower variable, the upper variable, and the particular numerical value that is mathematically possible. Similarly, when a range is defined as extending from one endpoint to another, the range is also understood to encompass the span between the two endpoints and to exclude the two endpoints.

[0023] As used herein, the term "about" is acceptable in the pharmaceutical industry and will compensate for variability inherent in products of this industry, such as manufacturing variations and differences in product strength due to 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% of chloride. The chloride content is preferably less than 6.3% or 6.2% of the molecule, and preferably ranges from 5.7 to 6.3% or 5.8 to 6.2%. Alternatively, there may be a slight molar excess of chloride, in which case the chloride content may range from 6.1% to 6.3% or 6.1% to 6.2%. Anamorelin hydrochloride defined by any of these ranges can be used in the methods and formulations of the present invention.

[0025] "Impurity A" refers to a decomposition product / analogue of anamorelin hydrochloride having an HPLC response coefficient of 1.53 with respect to anamorelin 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] "Pharmaceutically acceptable carrier means for preventing the formation of Impurity A" is completely mixed with anamorelin hydrochloride, produces a pharmaceutically acceptable immediate-release tablet, and is present in a preventive effective amount when compressed into a tablet with an appropriate hardness to meet its listed functions, corresponding to a combination of microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, and calcium hydrogen phosphate anhydrous. Prevention does not require 100% prevention, but requires either 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 achieve stability equivalent to that reported in the examples of this specification for such ratios. "Preventive effective amount" means an amount sufficient to reduce the decomposition rate of anamorelin hydrochloride, particularly to Impurity A, when combined with anamorelin hydrochloride in a complete mixture and compressed into a tablet. In a preferred embodiment, the preventive effective amount is an amount sufficient to prevent the formation of Impurity A exceeding about 0.1% or 0.05% based on the weight of the anamorelin hydrochloride after storage at 40 °C and 75% relative humidity for 6 months.

[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 storage at 40°C and 75% relative humidity for 6 months,” or “a pharmaceutically acceptable carrier means for preventing a 100% increase in the formation of impurity A after storage at 40°C and 75% relative humidity for 6 months,” in which case the means corresponds to a formulation capable of producing such results.

[0028] The terms “excipient” and “carrier” are used synonymously in this specification. Consider

[0029] The present invention may be defined based on several main embodiments, and further embodiments may be created by further defining or modifying based on the considerations herein. In a first main embodiment, the present invention provides a method for producing anamorelin hydrochloride tablets and tablets produced by means of, 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 tablets.

[0030] In a second primary embodiment, the present invention provides a method for producing anamorelin hydrochloride tablets and tablets produced by means of the same, the method comprising: (a) mixing 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 primary 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 primary 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 primary embodiment, the present invention provides a method for improving one or more symptoms of cancer cachexia in a patient requiring improvement of one or more symptoms of cancer cachexia, comprising administering to the patient a therapeutically effective amount of anamorelin hydrochloride in 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 to 28, or a quality of life questionnaire (QOL-ACD) score for cancer patients treated with anticancer drugs of 65 to 80, and (b) the symptoms are selected from the group consisting of lean body mass, appetite, body weight, fatigue and quality of life. Characteristics of tablets

[0035] Preferred carriers known to improve the stability of anamorelin hydrochloride when compressed into tablets are 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 gelatinized corn starch, stearic acid, and sodium stearyl fumarate. The tablets may be formulated and manufactured to produce a pharmaceutically acceptable and pharmaceutically stable product based on the teachings of the present invention and the common general knowledge of pharmaceutical technology.

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

[0037] However, based on the examples provided herein, it is possible to choose to avoid the use of mannitol and HPC or their pharmaceutically equivalents. Thus, in one embodiment, the formulation of the present invention omits sugar alcohols such as mannitol. In another embodiment, the formulation of the present invention omits mannitol, sorbitol, and / or xylitol. In yet another embodiment, the formulation of the present invention omits mannitol. In yet another embodiment, the formulation of the present invention omits HPC and / or HPMC.

[0038] The tablets preferably contain one or a combination of preferred carriers in an amount sufficient to prevent the decomposition of anamorelin hydrochloride into impurity A during storage ("preventive effective amount"). This "preventive effective amount" may be further described in relation to the amount of preferred excipients or combinations 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 1 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 1 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 1 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 parts by weight or more per 1 part by weight of anamorelin hydrochloride.

[0039] The preventive dose may also be determined based on the amount of preferred excipients present in the formulation in sufficient quantities to perform its conventional tableting function, in addition to its stabilizing function, as diluents, disintegrants, flow enhancers, or lubricants. Thus, in various embodiments, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, lactose monohydrate, D-mannitol, or corn starch are present independently (i.e., only one of the carriers is present) or in combination in amounts of about 1 to about 10 parts by weight per 1 part by weight of anamorelin hydrochloride. In other embodiments, croscarmellose sodium is present in amounts of about 0.1 to about 2 parts by weight per 1 part by weight of anamorelin hydrochloride. In other embodiments, silicon dioxide is present in amounts of about 0.01 to about 0.2 parts by weight per 1 part by weight of anamorelin hydrochloride. In other embodiments, magnesium stearate is present in amounts of about 0.01 to about 0.2 parts by weight per 1 part by weight of anamorelin hydrochloride. In other embodiments, low-substituted hydroxypropyl cellulose is present in an amount of about 0.01 to about 0.2 parts by weight per 1 part by weight of anamorelin hydrochloride. In other embodiments, sodium starch glycolate is present in an amount of about 0.01 to about 0.2 parts by weight per 1 part by weight of anamorelin hydrochloride. In other embodiments, carmellose calcium is present in an amount of about 0.01 to about 0.2 parts by weight per 1 part by weight of anamorelin hydrochloride. In other embodiments, carmellose is present in an amount of about 0.01 to about 0.2 parts by weight per 1 part by weight of anamorelin hydrochloride. In other embodiments, crospovidone is present in an amount of about 0.01 to about 0.2 parts by weight per 1 part by weight of anamorelin hydrochloride. In other embodiments, partially gelatinized corn starch is present in an amount of about 0.01 to about 0.2 parts by weight per 1 part by weight of anamorelin hydrochloride. In other embodiments, stearic acid is present in an amount of about 0.01 to about 0.2 parts by weight per 1 part by weight of anamorelin hydrochloride. In other embodiments, sodium stearyl fumarate is present in an amount of about 0.01 to about 0.2 parts by weight per 1 part by weight of anamorelin hydrochloride. It will be understood that any of these preferred excipients may be present alone or in combination with another preferred excipient in amounts thereof.

[0040] In other embodiments, the preventive dose is based on the total weight of the combination of preferred carriers in the tablet relative to anamorelin hydrochloride. Thus, in one embodiment, the total amount of preferred carriers in the tablet is about 0.01 to about 20 parts by weight per 1 part by weight of anamorelin hydrochloride. In an alternative embodiment, the total amount of preferred carriers in the tablet is about 0.5 to about 10 parts by weight per 1 part by weight of anamorelin hydrochloride. In yet another alternative embodiment, the total amount of preferred carriers in the tablet is about 1 to about 6 parts by weight per 1 part by weight of anamorelin hydrochloride. Here again, the tablet does not need to contain all of the preferred excipients, but it is preferable that the sum of the excipients present satisfies the aforementioned amounts by weight.

[0041] In another sub-embodiment, the tablets are defined by their stability. Thus, in various sub-embodiments, the tablets of the present invention are defined as tablets in which impurity A is substantially not generated, or in which the amount of impurity A generated after storage at 40°C and 75% relative humidity for 2 to 6 months is about 0.3% or 0.05%, preferably less than 0.1% or 0.05%, based on the weight of anamorelin hydrochloride.

[0042] The tablets may be further defined in terms of their hardness. Therefore, in any embodiment of the present invention, the tablets may have a hardness of about 40 to about 200 Newtons. Alternatively, or in addition, in any embodiment of the present invention, a plurality of pharmaceutically acceptable carriers may be compressed together with the anamorelin hydrochloride with a compressive force of about 0.5 to about 15 kN.

[0043] In any embodiment of the present invention, anamorelin hydrochloride and the preferred carrier are completely mixed. That is, anamorelin hydrochloride and the preferred carrier are uniformly dispersed throughout the tablet.

[0044] The tablets may or may not be coated, but in a preferred embodiment, the tablets are coated using a conventional coating excipient.

[0045] In yet another embodiment, the tablet comprises a tablet manufactured by any of the methods described herein, characterized by a method for manufacturing the tablet. Carrier means

[0046] The tablets of the present invention may also be described in relation to means used to achieve remarkable stability. These means are referred to herein as “pharmaceutically acceptable carrier means for preventing the formation of impurity A” or simply “carrier means.” Tablets described in any embodiment of the present invention contain anamorelin hydrochloride and such carrier means in a preventive effective amount. As described in the sections on the characteristics and manufacturing methods of tablets herein, these preferred excipients are most effective when fully mixed with anamorelin hydrochloride and compressed into tablets. Specific compressive forces are about 0.5 to about 15 kN. Specific tablet hardnesses are about 40 to about 200 Newtons.

[0047] Therefore, in one embodiment, the pharmaceutically acceptable carrier means is in a complete mixture with the anamorelin hydrochloride and is compressed together with the anamorelin hydrochloride with a compressive force of about 0.5 to about 15 kN.

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

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

[0050] As described above, these preferred excipients are thought to prevent the formation of impurity A by chemically or physically isolating the hydrochloride from the anamorelin moiety. Therefore, 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. Formulations of the drugs are discussed, for example, in *Remington's Pharmaceutical Sciences*, Mack Publishing Co., Easton, Pennsylvania, 1975; *Pharmaceutical Dosage Forms*, edited by Liberman et al., Marcel Decker, New York, New York, 1980; and *Handbook of Pharmaceutical Excipients (3rd Edition)*, edited by Kibbe et al., 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, a complete mixture of anamorelin hydrochloride, preferably in any of the weight ratios discussed in the section on tablet features, and one or a combination of the preferred carriers discussed herein, is compressed into a tablet at a preventive effective amount, preferably with a compressive force of about 0.5 to about 15 kN. In another embodiment, a complete mixture of anamorelin hydrochloride, preferably in any weight ratio discussed in the section on tablet features, and a carrier means discussed in the section on carrier means, is compressed into a tablet at a preventive effective amount, preferably with a compressive force of about 0.5 to about 15 kN. Conventional excipients other than the preferred carriers discussed herein may also be used according to known pharmaceutical manufacturing techniques. Tablets may also be coated with one or more coating excipients according to methods well known in the art.

[0053] Therefore, in various sub-embodiments, the manufacturing method is carried out by mixing anamorelin hydrochloride with two or more, three or more, or four or more preferred carriers. In other sub-embodiments, the pharmaceutically acceptable carrier means comprises two or more, three or more, or four or more preferred carriers.

[0054] Similarly, the manufacturing method can be carried out by mixing one part by weight of anamorelin hydrochloride with one or a combination of preferred carriers in proportions 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. Conversely, a pharmaceutically acceptable carrier means may contain one or a combination of preferred carriers in proportions 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 one part by weight of anamorelin hydrochloride.

[0055] In any case, the preferred carrier or pharmaceutically acceptable carrier means is preferably present in an amount sufficient to prevent the formation of impurity A. Appropriate percentages with respect to the amount of impurity A generated after storage at 40°C and 75% relative humidity for 6 months are in the ranges of 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, preferred 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 the dosage form can be measured in relation to the increase in impurity A generated after storage at 40°C and 75% relative humidity for 6 months. Therefore, in the alternative embodiment, the proportion of impurity A generated after storage at 40°C and 75% relative humidity for 6 months 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] Upon production, impurity A is preferably isolated from anamorelin hydrochloride by the HPLC method described herein, and the tablets are preferably analyzed for impurity A by the method described herein. Therefore, when separating impurity A in the method of the present invention, it is preferable 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 largely due to the discovery of impurity A, the isolation of impurity A from anamorelin by HPLC, and the method of measuring the amount of impurity A in a given tablet using HPLC. Therefore, in one embodiment, the present invention provides a method for 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 nonpolar organic solvent. In another embodiment, impurity A is present in a solution containing water, trifluoroacetic acid, and acetonitrile.

[0058] In further embodiments, the present invention provides a method for analyzing impurity A during and after the manufacture of anamorelin hydrochloride tablets in a predetermined stability program. For example, tablets from a given batch may be analyzed for impurity A six months or one year after the batch was manufactured. Impurity A is an analog or degradation product of anamorelin hydrochloride having a response coefficient of 1.53 to anamorelin hydrochloride in high-performance liquid chromatography. The conditions under which impurity A exhibits a response coefficient of 1.53 in HPLC are described in more detail in Example 3 of this specification. Treatment method

[0059] As described above, the present invention further includes a method of treatment using the tablets of the present invention. In various sub-embodiments, 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 the QOL-ACD score for items 7-11 ("Physical Condition"), item 8 ("Was your appetite good?"), item 9 ("Did you enjoy your meals?"), and item 11 ("Did you lose weight?"). In other sub-embodiments, the patient has stage III or IV non-small cell lung cancer (NSCLC) or advanced gastrointestinal (colorectal, gastric, or pancreatic) cancer. [Examples]

[0060] In the following embodiments, efforts have been made to ensure accuracy with respect to numbers (e.g., quantity, temperature, etc.), but some errors and deviations should be taken into consideration. The following embodiments are provided to those skilled in the art to provide a complete disclosure and explanation of how the methods claimed in the claims herein are made and evaluated, and are intended purely as concrete examples of the invention, and not to limit the scope of what the inventors consider to be the invention.

[0061] Example 1 Evaluation of the stability of tablets containing anamorelin hydrochloride and a single pharmaceutically acceptable carrier. Anamorelin hydrochloride (Lots A and B) was mixed with different excipients in a weight ratio of 1:10 or 1:1 (anamorelin hydrochloride:excipient) 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 storage in a sealed bottle under accelerated temperature and relative humidity conditions as described in ICH Q1A(R2) for two months, and compared to the stability of a tablet (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 tests are reported in Tables 3 and 4.

[0065] [Table 3]

[0066] [Table 4]

[0067] Example 2 Evaluation of the stability of tablets containing anamorelin hydrochloride and a pharmaceutically acceptable carrier. In the same experiment as in Example 1, pharmaceutically acceptable carrier combinations 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 mixture), 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 storage in sealed bottles under accelerated temperature and relative humidity conditions as described in ICH Q1A(R2) for two months, and compared with 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 tests 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 mobile phase A / mobile phase B mixture (17:3) described below to prepare each 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 samples was measured by automatic integration. The concentrations of anamorelin hydrochloride and impurity A were calculated using the following formulas. ·Analog concentration (%)=At / Aa×RRF×100 • At: Peak area of ​​each test sample • Aa: Total peak area • RRF: Relative reaction coefficient (Impure A: 1.53)

[0077] [Table 12]

[0078] Throughout this application, various publications are referenced. The disclosures of these publications are incorporated into this application in their entirety by reference to provide a more complete explanation of the latest technology relating to the present invention. It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the scope or spirit of the invention. Other embodiments of the present invention should be apparent to those skilled in the art from the discussion herein and the practices of the present invention disclosed herein. This specification and the examples are for illustrative purposes only, and the true scope and spirit of the invention are shown by the following claims.

Claims

1. A method for manufacturing tablets containing anamorelin hydrochloride, a) Mixing anamorelin hydrochloride with one or a combination thereof of pharmaceutically acceptable carriers selected from microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, anhydrous calcium hydrogen phosphate, lactose monohydrate, D-mannitol, corn starch, sodium starch glycolate, carmellose calcium, carmellose, crospovidone, partially gelatinized corn starch, and stearic acid to form a mixture, and b) Compressing the mixture into tablets. A method comprising the above, wherein the mixing ratio of the pharmaceutically acceptable carrier is 0.33 to 20 parts by weight per 1 part by weight of anamorelin hydrochloride.

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

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

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

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

6. The method according to claim 5, comprising mixing 1 to 6 parts by weight of one or a combination thereof of the pharmaceutically acceptable carriers with 1 part by weight of anamorelin hydrochloride.

7. The method according to any one of claims 1 to 6, wherein the mixture is compressed into a tablet with a compressive force of 0.5 to 15 kN.

8. The method according to any one of claims 1 to 7, wherein the mixture is compressed to a hardness of 40 to 200 Newtons.

9. The method according to any one of claims 1 to 8, wherein one or a combination thereof of the pharmaceutically acceptable carriers is present in an amount sufficient to prevent the formation of impurity A, which has an HPLC relative retention time of 0.34 when measured according to the high-performance liquid chromatography (HPLC) conditions described in Example 3, with a retention time of 1 minute for anamorelin hydrochloride.

10. The method according to claim 9, wherein the amount of impurity A generated after storage at 40°C and 75% relative humidity for 2 to 6 months is less than 0.1% of the weight of the anamorelin hydrochloride.

11. The method according to claim 10, wherein the amount of impurity A generated after storage at 40°C and 75% relative humidity for two months is less than 0.05% of the weight of anamorelin hydrochloride.

12. A tablet comprising anamorelin hydrochloride manufactured by the method described in any one of claims 1 to 11.

13. A tablet comprising anamorelin hydrochloride as an active ingredient, further comprising one or a combination thereof from among pharmaceutically acceptable carriers selected from the group consisting of microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, anhydrous calcium hydrogen phosphate, lactose monohydrate, D-mannitol, corn starch, sodium starch glycolate, carmellose calcium, carmellose, crospovidone, partially gelatinized corn starch, and stearic acid, wherein the mixing ratio of the pharmaceutically acceptable carriers is 0.33 to 20 parts by weight per 1 part by weight of anamorelin hydrochloride.

14. The tablet according to claim 13, comprising two or more of the aforementioned pharmaceutically acceptable carriers.

15. The tablet according to claim 14, comprising three or more of the aforementioned pharmaceutically acceptable carriers.

16. The tablet according to claim 15, comprising four or more of the aforementioned pharmaceutically acceptable carriers.

17. The tablet according to claim 13, comprising 0.5 to 10 parts by weight of one or a combination thereof of the pharmaceutically acceptable carriers per 1 part by weight of anamorelin hydrochloride.

18. The tablet according to claim 17, comprising 1 to 6 parts by weight of one or a combination thereof of the pharmaceutically acceptable carriers per 1 part by weight of anamorelin hydrochloride.

19. A tablet according to any one of claims 13 to 18, wherein the tablet substantially does not contain impurity A, which has an HPLC relative retention time of 0.34 when the retention time of anamorelin hydrochloride is 1 minute, as measured according to the high-performance liquid chromatography (HPLC) conditions of Example 3, or the amount of impurity A after storage at 40°C and 75% relative humidity for 2 to 6 months is less than 0.1% of the weight of anamorelin hydrochloride.

20. The tablet according to claim 19, wherein it substantially does not contain impurity A, or the amount of impurity A after storage at 40°C and 75% relative humidity for two months is less than 0.05% of the weight of anamorelin hydrochloride.

21. A tablet comprising anamorelin hydrochloride as an active ingredient and a composition comprising a pharmaceutically acceptable carrier for preventing the formation of impurity A, the HPLC relative retention time of which is 0.34 when the retention time of anamorelin hydrochloride is 1 minute as measured according to the high-performance liquid chromatography (HPLC) conditions described in Example 3, wherein the carrier is selected from one or a combination of microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, anhydrous calcium hydrogen phosphate, lactose monohydrate, D-mannitol, corn starch, sodium starch glycolate, carmellose calcium, carmellose, crospovidone, partially gelatinized corn starch, and stearic acid, and the mixing ratio of the pharmaceutically acceptable carrier is 0.33 to 20 parts by weight per 1 part by weight of anamorelin hydrochloride.

22. The tablet according to claim 21, wherein the pharmaceutically acceptable carrier is compressed together with the anamorelin hydrochloride with a compressive force of 0.5 to 15 kN.

23. The tablet according to claim 21 or 22, wherein the pharmaceutically acceptable carrier acts as an HCl scavenger in a complete mixture with the anamorelin hydrochloride compressed to a hardness of 40 to 200 Newtons.

24. The tablet according to claim 21, comprising 0.5 to 10 parts by weight of the pharmaceutically acceptable carrier per 1 part by weight of anamorelin hydrochloride.

25. The tablet according to claim 24, comprising 1 to 6 parts by weight of the pharmaceutically acceptable carrier per 1 part by weight of anamorelin hydrochloride.

26. A tablet according to any one of claims 21 to 25, wherein the tablet substantially does not contain impurity A, which has an HPLC relative retention time of 0.34 when the retention time of anamorelin hydrochloride is 1 minute, as measured according to the high-performance liquid chromatography (HPLC) conditions described in Example 3, or the amount of impurity A after storage at 40°C and 75% relative humidity for 2 to 6 months is less than 0.1% of the weight of anamorelin hydrochloride.

27. The tablet according to claim 26, wherein it substantially does not contain impurity A, or the amount of impurity A after storage at 40°C and 75% relative humidity for two months is less than 0.05% of the weight of anamorelin hydrochloride.

28. A tablet according to any one of claims 12 to 27 for improving one or more symptoms of cancer cachexia in a patient who requires improvement of one or more symptoms of cancer cachexia, wherein a therapeutically effective amount of anamorelin hydrochloride in the tablet is administered to the patient. (a) The patient is characterized by having a body mass index of less than 25, a cancer fatigue scale score of 20 to 28, or a quality of life questionnaire (QOL-ACD) score of 65 to 80 for cancer patients treated with anticancer drugs, (b) A tablet wherein the symptoms described above are selected from the group consisting of lean body mass, appetite, body weight, fatigue, and quality of life.

29. The tablet according to claim 28, 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 a QOL-ACD score for items 7-11 ("Physical condition"), item 8 ("Was your appetite good?"), item 9 ("Did you enjoy your meals?"), and item 11 ("Did you lose weight?").

30. The tablet according to claim 28 or 29, wherein the patient has stage III or IV non-small cell lung cancer (NSCLC) or advanced gastrointestinal (colorectal, stomach, or pancreatic) cancer.

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