Stable pharmaceutical composition of buprenorphine, method for preparing the same, and use thereof

Abstract

A pharmaceutical composition comprising buprenorphine, a derivative thereof, or a pharmaceutically acceptable salt thereof, a stabilizer, a biocompatible solvent, and at least one compound represented by formula (IIA), (IIB) or (IIC), wherein R1 is hydrogen, C1-C 20 an alkylcarbonyl group, or C6-C 18 an arylcarbonyl group, and the compounds of formula (IIA), (IIB) and (IIC) each have an amount of less than 1% w / w based on the total weight of the pharmaceutical composition during the shelf life of the pharmaceutical composition, to provide a pharmaceutical composition. Also provided are a method for preparing the pharmaceutical composition, and a method for using it in a subject in need of treatment for opioid dependence, pain, and / or depression by administering the pharmaceutical composition to the subject. [Chemical 1] JPEG2025520773000029.jpg41170

Description

Technical Field

[0001] The present disclosure relates to a stable formulation of buprenorphine, in particular, a pharmaceutical composition for the treatment of opioid dependence, pain, and depression, comprising buprenorphine or a derivative or pharmaceutically acceptable salt thereof, a biocompatible solvent, and a stabilizer.

Background Art

[0002] Buprenorphine is indicated for the treatment of pain and opioid dependence in several dosage forms, such as BUVIDAL (subcutaneous injection), BUPRENEX (intravenous or intramuscular injection), BUTRANS (transdermal film), SUBLOCADE (subcutaneous injection), SUBOXONE (sublingual tablet or sublingual film), and SUBUTEX (sublingual tablet).

[0003] It is well known in the art that buprenorphine decomposes through oxidation, dehydration, ring-opening, rearrangement pathways, etc. to produce impurities. DenHerder et al. (J. Am. Assoc. Lab. Anim. Sci. (2017) 56(4):457 - 461) disclosed a chemical stability test of buprenorphine injection diluted with physiological saline, showing that the concentration of buprenorphine stored in a glass vial decreased significantly, with 95.7% remaining after 30 days when refrigerated and 94.2% remaining after 60 days at room temperature. The decrease in buprenorphine may be due to decomposition. Therefore, it would be necessary to develop a buprenorphine composition with better stability.

[0004] In previous studies, one method of enhancing the stability of buprenorphine through an antioxidant pathway was proposed. However, buprenorphine can be decomposed into impurities through non-oxidative pathways. For example, Hotha et al. (Am. J. Analyt. Chem. (2016) 7, 107 - 140) disclosed the buprenorphine degradation pathway and showed that according to the European Pharmacopoeia (Ph.Eur.), buprenorphine is decomposed into impurity I by dehydration cyclization of buprenorphine to form a furanyl ring. [Chemistry]

[0005] According to the monograph of Ph.Eur., buprenorphine hydrochloride has 10 different impurities and related substances are monitored. For example, impurities A, B, F, and J are limited not to exceed 0.2%, impurity G is limited not to exceed 0.15%, and impurity H is limited not to exceed 0.25%. Among these impurities, impurities A, B, F, G, H, and J are formed from non-oxidative pathways. Similarly, according to the British Pharmacopoeia, buprenorphine preparations are reported to produce impurities A, B, F, and G, and excessive impurities may cause unknown health hazards to humans.

[0006] Furthermore, the appearance of conventional pharmaceutical compositions containing buprenorphine may show discoloration during the shelf life, which significantly affects the product acceptability and commercial value of buprenorphine in the market.

[0007] Therefore, there is still an urgent need in the art to provide a stable pharmaceutical composition of buprenorphine, its derivatives, or pharmaceutically acceptable salts that reduces impurities formed by non-oxidative pathways and prevents discoloration during storage at room temperature. [Summary of the Invention]

[0008] In view of the foregoing, the present disclosure provides a stable pharmaceutical composition of buprenorphine, its derivatives, and pharmaceutically acceptable salts thereof, containing buprenorphine as an active pharmaceutical ingredient, relatively low amounts of impurities, and.

[0009] In at least one embodiment of the present disclosure, the pharmaceutical composition includes an active pharmaceutical ingredient and at least one compound represented by the following formula (IIA), (IIB), or (IIC), [Chemistry] In the formula, R1 is hydrogen, C1-C 20 alkylcarbonyl group, or C6-C 18 arylcarbonyl group.

[0010] In at least one embodiment of the present disclosure, the active pharmaceutical ingredient in the pharmaceutical composition is at least one of buprenorphine, its derivatives, and pharmaceutically acceptable salts thereof. In some embodiments, buprenorphine and buprenorphine derivatives may be represented by the following formula (I), [Chemical formula] In the formula, R1 is as defined herein.

[0011] In at least one embodiment of the present disclosure, the active pharmaceutical ingredient in the pharmaceutical composition may be a buprenorphine derivative and / or a pharmaceutically acceptable salt of buprenorphine. In some embodiments, the active pharmaceutical ingredient in the pharmaceutical composition may be buprenorphine acetate, buprenorphine pentanoate, buprenorphine hexanoate, buprenorphine pivalate, buprenorphine decanoate, buprenorphine stearate, buprenorphine benzoate, or buprenorphine hydrochloride.

[0012] In at least one embodiment of the present disclosure, the active pharmaceutical ingredient in the pharmaceutical composition is present in an amount of 1% to 99% w / w, based on the total weight of the pharmaceutical composition. In some embodiments, the amount of buprenorphine, its derivatives, and pharmaceutically acceptable salts thereof in the pharmaceutical composition is selected from a lower limit of 5 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, and 40 wt% of the pharmaceutical composition and an upper limit selected from 80 wt%, 75 wt%, 70 wt%, 65 wt%, 60 wt%, 55 wt%, 50 wt%, and 45 wt% of the pharmaceutical composition. In some embodiments, buprenorphine, its derivatives, and pharmaceutically acceptable salts thereof as the active pharmaceutical ingredient may be present in an amount in the range of 5% to 80%, for example, 5% to 80%, 5% to 70%, 5% to 60%, 10% to 80%, 10% to 70%, 10% to 60%, 20% to 80%, 20% to 70%, and 20% to 60%, based on the total weight of the pharmaceutical composition.

[0013] In at least one embodiment of the present disclosure, each of the compounds of formula (IIA), (IIB), and (IIC) in the pharmaceutical composition is present in an amount of less than 1% w / w, based on the total weight of the pharmaceutical composition. For example, the compounds of formula (IIA), (IIB), and (IIC) each have an amount of less than 1% w / w, less than 0.95% w / w, less than 0.9% w / w, less than 0.85% w / w, less than 0.8% w / w, less than 0.75% w / w, less than 0.7% w / w, less than 0.65% w / w, less than 0.6% w / w, less than 0.55% w / w, less than 0.5% w / w, less than 0.45% w / w, or less than 0.4% w / w.

[0014] In at least one embodiment of the present disclosure, the total amount of the compounds of formula (IIA), (IIB), and (IIC) is less than 1% w / w, for example, less than 0.9% w / w, less than 0.8% w / w, less than 0.7% w / w, less than 0.6% w / w, or less than 0.5% w / w during the shelf life of the pharmaceutical composition. In some embodiments, the amount of each of the compounds of formula (IIA), (IIB), and (IIC) is not 0% simultaneously in the pharmaceutical composition. For example, the amount of the compound of formula (IIA), the amount of the compound of formula (IIB), and the amount of the compound of formula (IIC) are not 0% simultaneously in the pharmaceutical composition.

[0015] In at least one embodiment of the present disclosure, when a compound of formula (IIA), (IIB), or (IIC) is present in a pharmaceutical composition during the shelf life of the pharmaceutical composition, the compound, respectively, is 0% to 1%, for example, less than 0.9% w / w, less than 0.8% w / w, less than 0.7% w / w, less than 0.6% w / w, less than 0.5% w / w, less than 0.4% w / w, less than 0.3% w / w, less than 0.2% w / w, or less than 0.1% w / w, based on the total weight of the pharmaceutical composition. In some embodiments, the compounds of formula (IIA), (IIB), and (IIC) are each present in an amount of 0% to 1% w / w during the shelf life of the pharmaceutical composition.

[0016] In at least one embodiment of the present disclosure, the shelf life of the pharmaceutical composition is at least 1 month, for example, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 20 months, 24 months, 30 months, 36 months, 40 months, 42 months, 4 years, 4.5 years, and 5 years, at or below ambient temperature. In some embodiments, the ambient temperature may be in a temperature range such as 20°C to 25°C, 22°C to 28°C, and 20°C to 28°C. In still some embodiments, the temperature below ambient temperature may be a temperature below 28°C, for example, 2°C to 8°C, 22°C to 25°C, 20°C to 22°C, 2°C to 25°C, 2°C to 15°C, 2°C to 10°C, 1°C to 20°C, or 1°C to 10°C.

[0017] In at least one embodiment of the present disclosure, the pharmaceutical composition may further contain a stabilizer. In some embodiments, the stabilizer is selected from the group consisting of vitamin E (VitE) or its derivatives, ascorbic acid (VitC), butylated hydroxyanisole (BHA), and combinations thereof. In some embodiments, vitamin E or its derivative may be α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, or D-α-tocopherol polyethylene glycol 1000 succinate (TPGS).

[0018] In at least one embodiment of the present disclosure, the stabilizer in the pharmaceutical composition is present in an amount of 0.01% w / w to 10% w / w based on the total weight of the pharmaceutical composition. For example, the amount of the stabilizer may be 0.05% by weight to 5% by weight, 0.1% by weight to 5% by weight, 0.2% by weight to 5% by weight, 0.5% by weight to 5% by weight, 0.05% by weight to 3% by weight, 0.1% by weight to 3% by weight, 0.2% by weight to 3% by weight, 0.5% by weight to 3% by weight, 0.05% by weight to 2% by weight, 0.1% by weight to 2% by weight, 0.2% by weight to 2% by weight, 0.5% by weight to 2% by weight, 0.05% by weight to 1% by weight, 0.1% by weight to 1% by weight, 0.2% by weight to 1% by weight, or 0.5% by weight to 1% by weight of the pharmaceutical composition.

[0019] In at least one embodiment of the present disclosure, the pharmaceutical composition may further comprise a biocompatible solvent. In some embodiments, the biocompatible solvent is selected from the group consisting of water, N-methyl-2-pyrrolidone (NMP), polyethylene glycol 400 (PEG400), polyethylene glycol 4000 (PEG4000), ethyl acetate, ethanol, butanol, 2-butanol, isobutanol, isopropanol, glycerin, benzyl benzoate (BnBzO), dimethyl sulfoxide, N,N-dimethylacetamide (DMA), propylene glycol, dimethyl glycol, benzyl alcohol, and any combination thereof.

[0020] In at least one embodiment of the present disclosure, the biocompatible solvent in the pharmaceutical composition is present in an amount of 20% w / w to 95% w / w based on the total weight of the pharmaceutical composition. For example, the amount of the biocompatible solvent may be 20% by weight to 95% by weight, 20% by weight to 90% by weight, 20% by weight to 80% by weight, 20% by weight to 70% by weight, 20% by weight to 60% by weight, 20% by weight to 50% by weight, 30% by weight to 95% by weight, 30% by weight to 90% by weight, 30% by weight to 80% by weight, 30% by weight to 70% by weight, 30% by weight to 60% by weight, or 30% by weight to 50% by weight of the pharmaceutical composition.

[0021] In at least one embodiment, the present disclosure also provides a method for preparing the stable pharmaceutical composition described above. The method for preparing the pharmaceutical composition includes adding an active pharmaceutical ingredient and a stabilizer in a biocompatible solvent to form the pharmaceutical composition, wherein the active pharmaceutical ingredient is at least one of buprenorphine, its derivatives, and pharmaceutically acceptable salts thereof.

[0022] In at least one embodiment, the present disclosure also provides a method for performing it in a subject in need of treatment for opioid addiction, pain, and / or depression, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition described above.

[0023] In some embodiments, the stable pharmaceutical composition of the present disclosure comprising buprenorphine, its derivatives, or pharmaceutically acceptable salts thereof as an active pharmaceutical ingredient and a stabilizer can reduce impurities formed by the active pharmaceutical ingredient, for example, impurities formed by non-oxidative pathways. Therefore, the pharmaceutical composition of the present disclosure can improve the stability of the active pharmaceutical ingredient, and thus exhibit a longer shelf life and prevent discoloration of the pharmaceutical composition.

[0024] The present disclosure can be more fully understood by reading the following description of embodiments with reference to the accompanying drawings.

Brief Description of the Drawings

[0025]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Mode for Carrying Out the Invention

[0026] The following examples are used to illustrate the present disclosure. Those skilled in the art can understand other advantages of the present disclosure based on the specification of the present disclosure. The present disclosure can also be implemented or applied as described in different examples. It is possible to modify and / or change the following examples for implementing the present disclosure without violating its scope for different aspects and applications.

[0027] It should be noted that when used in the present disclosure, the singular forms "a", "an", and "the" include plural referents unless explicitly and specifically limited to one referent. The term "or" is used interchangeably with the term "and / or" unless the context clearly indicates otherwise.

[0028] As used herein, the terms "comprising", "including", "having", "containing", and any other variations thereof are intended to cover non-exclusive inclusion. For example, when an object is described as "including" a limitation, it may additionally include other components, elements, components, structures, regions, parts, devices, systems, steps, or connections, etc., unless otherwise specified, and other limitations should not be excluded.

[0029] As used herein, the terms "at least one" and "one or more" may have the same meaning and include one, two, three, or more.

[0030] Throughout this disclosure, ordinal numbers (e.g., first, second, third, etc.) may be used as adjectives of elements (i.e., any noun in this disclosure). The use of ordinal numbers does not imply or create an order of elements, nor does it limit any element to only a single element, unless explicitly indicated by the use of terms such as "before," "after," "single," and other such terms. Rather, the use of ordinal numbers is to distinguish between elements. As an example, a first element is different from a second element, the first element includes two or more elements, and may follow (or precede) the second element in the order of elements.

[0031] As used herein, the term "about" generally refers to a numerical value that encompasses a variation of ±20%, ±10%, ±5%, ±1%, ±0.5%, or ±0.1% from a given value or range. Such variations in numerical values can occur, for example, due to experimental error, typical errors in measurement or processing procedures for making compounds, compositions, concentrates, or formulations, differences in the sources, manufacture, or purity of starting materials or components used in this disclosure, or similar considerations. Alternatively, the term "about" means within the range of an acceptable standard error of the mean when considered by one of ordinary skill in the art. Unless otherwise explicitly specified, all numerical ranges, amounts, values, and percentages of amounts, periods, temperatures, operating conditions, ratios of amounts, etc., of materials disclosed herein are to be understood to be modified in all instances by the term "about."

[0032] The numerical ranges used in this specification are inclusive and combinable. Any numerical value falling within the numerical range of this specification can be taken as the maximum or minimum value for deriving a sub-range therefrom. For example, it should be understood that a numerical range of "1% to 99%" includes any sub-range from the minimum value of 1% to the maximum value of 99%, such as sub-ranges of 1% to 90%, 20% to 80%, 40% to 60%, etc. Further, a plurality of numerical values used in this specification can optionally be selected as the maximum and minimum values to derive a numerical range. For example, numerical ranges of 5% to 60%, 10% to 40%, and 20% to 60% can be derived from the numerical values of 5%, 10%, 20%, 40%, and 60%.

[0033] As used herein, the terms "treat", "treating", or "treatment" include partially or completely preventing, ameliorating, alleviating, and / or managing symptoms, disorders, or conditions associated with a disease. The terms "treat", "treating", or "treatment" as used herein refer to the application or administration of one or more therapeutic agents or surgeries to a subject having symptoms, disorders, or conditions associated with a disease, with the aim of partially or completely relieving, ameliorating, alleviating, delaying the onset, inhibiting the progression, reducing the severity, and / or reducing the incidence of one or more symptoms, disorders, or conditions associated with the disease. Treatment may be performed on a subject showing only the initial signs of such symptoms, disorders, and / or conditions for the purpose of reducing the risk of developing symptoms, disorders, and / or conditions associated with the disease.

[0034] As used herein, the terms "subject," "individual," and "patient" may be used interchangeably and refer to an animal, such as a mammal. The term "subject" is intended to refer to both males and females unless a specific gender is indicated. In at least one embodiment of the present disclosure, the subject is selected from the group consisting of rodents, mice, monkeys, guinea pigs, dogs, cats, cows, sheep, pigs, horses, rabbits, and humans. In some embodiments, the subject is a human.

[0035] As used herein, the term "therapeutically effective amount" refers to an amount of an active agent or composition sufficient to effect treatment or prevention of a particular disorder, condition, or disease in a subject in need thereof. The effective dosage will vary depending upon the route of administration, the use of excipients, the possibility of co-administration with other therapies, and the condition being treated, as will be recognized by those skilled in the art.

[0036] The present disclosure relates to a pharmaceutical composition comprising an active pharmaceutical ingredient, a stabilizer, a biocompatible solvent, and at least one compound represented by the following formula (IIA), (IIB), or (IIC), [Chemical Formula] wherein R1 is hydrogen, a C1-C 20 alkylcarbonyl group, or a C6-C 18 arylcarbonyl group.

[0037] As used herein, the term "impurity" refers to a chemical substance formed by the decomposition of an active pharmaceutical ingredient. In at least one embodiment of the present disclosure, the active pharmaceutical ingredient is at least one of buprenorphine, its derivatives, and pharmaceutically acceptable salts thereof, which can be decomposed into impurities through oxidation pathways or non-oxidation pathways (e.g., dehydration, ring-opening, and rearrangement pathways). Thus, impurities can refer to oxidation impurities, non-oxidation impurities, and individual unknown impurities.

[0038] As used herein, the compounds of formulas (IIA), (IIB), and (IIC) are also referred to as impurity A, impurity B, and impurity C, respectively, and these refer to non-oxidative impurities that are decomposed by non-oxidative pathways of the active pharmaceutical ingredient. Accordingly, the structures of the compounds of formulas (IIA), (IIB), and (IIC) correlate with the structure of the active pharmaceutical ingredient from which the compounds are formed.

[0039] For example, buprenorphine or a derivative thereof in a pharmaceutical composition can be represented by the following formula (I),

Chem.

[0040] In at least one embodiment of the present disclosure, the compounds of formulas (IIA), (IIB), and (IIC) formed from buprenorphine hexanoate as the active pharmaceutical ingredient can be further represented by the following impurity A1, impurity B1, and impurity C1, respectively.

Chem.

[0041] In at least one embodiment of the present disclosure, the compounds of formulas (IIA), (IIB), and (IIC) formed from buprenorphine decanoate as the active pharmaceutical ingredient can be further represented by the following impurity A2, impurity B2, and impurity C2, respectively.

Chem.

[0042] In at least one embodiment of the present disclosure, the compounds of formulas (IIA), (IIB), and (IIC) formed from buprenorphine acetate as an active pharmaceutical ingredient may be further represented by the following Impurity A3, Impurity B3, and Impurity C3, respectively.

Chemical formula

[0043] In at least one embodiment of the present disclosure, the total amount of the compounds of formulas (IIA), (IIB), and (IIC) in the pharmaceutical composition is in an amount less than 1% based on the total weight of the pharmaceutical composition. In some embodiments, the compounds of formulas (IIA), (IIB), and (IIC) in the pharmaceutical composition are independently in an amount of 0% to 1% based on the total weight of the pharmaceutical composition. In some embodiments, the total impurities in the pharmaceutical composition may be in an amount less than 1% based on the total weight of the pharmaceutical composition. In some embodiments, the impurities in the pharmaceutical composition have a total amount of less than 1% w / w during the shelf life of the pharmaceutical composition.

[0044] In at least one embodiment of the present disclosure, buprenorphine, its derivatives, or pharmaceutically acceptable salts thereof are in an amount of 1% to 99% w / w based on the total weight of the pharmaceutical composition. In some embodiments, buprenorphine, its derivatives, or pharmaceutically acceptable salts thereof are in an amount of 5% to 80% w / w based on the total weight of the pharmaceutical composition. For example, buprenorphine, its derivatives, or pharmaceutically acceptable salts thereof may be in an amount of about 1% w / w, about 2% w / w, about 5% w / w, about 10% w / w, about 15% w / w, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, about 60% w / w, about 65% w / w, about 70% w / w, about 75% w / w, about 80% w / w, about 85% w / w, about 90% w / w, about 95% w / w, about 96% w / w, about 97% w / w, about 98% w / w, or about 99% w / w based on the total weight of the pharmaceutical composition, and is not limited thereto.

[0045] In at least one embodiment of the present disclosure, the stabilizer is present in an amount of 0.01% to 10% w / w, based on the total weight of the pharmaceutical composition. In some embodiments, the stabilizer is present in an amount of 0.1% to 2% w / w, based on the total weight of the pharmaceutical composition. For example, the stabilizer may be in an amount of about 0.01% w / w, about 0.02% w / w, about 0.04% w / w, about 0.06% w / w, about 0.08% w / w, about 0.1% w / w, about 0.2% w / w, about 0.5% w / w, about 1% w / w, about 1.5% w / w, about 2% w / w, about 4% w / w, about 6% w / w, about 8% w / w, or about 10% w / w, but is not limited thereto.

[0046] In at least one embodiment of the present disclosure, the biocompatible solvent is present in an amount of 20% to 95% w / w, based on the total weight of the pharmaceutical composition. In some embodiments, the biocompatible solvent is present in an amount of 30% to 95%, for example, about 25%, about 30%, about 35%, about 38%, about 39% w / w, about 39.5% w / w, about 40% w / w, about 45% w / w, about 48% w / w, about 49% w / w, about 49.5% w / w, about 50% w / w, about 78% w / w, about 79% w / w, about 79.5% w / w, about 80% w / w, about 85% w / w, about 90% w / w, 94.5% w / w, or about 95% w / w, but is not limited thereto.

[0047] In at least one embodiment of the present disclosure, a method for preparing the above pharmaceutical composition is provided. The method includes adding an active pharmaceutical ingredient and a stabilizer into a biocompatible solvent to form a mixture of the pharmaceutical composition.

[0048] In at least one embodiment of the present disclosure, the method further includes stirring the mixture to form a homogeneous solution. In some embodiments, stirring may be performed for any period, for example, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, or more, and is not limited thereto. In some embodiments, stirring is performed under ambient temperature, for example, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 21°C, about 22°C, about 23°C, about 24°C, about 25°C, about 26°C, about 27°C, about 28°C, about 29°C, about 30°C, about 31°C, about 32°C, about 33°C, about 34°C, about 35°C, about 36°C, about 37°C, about 38°C, about 39°C, about 40°C, about 41°C, about 42°C, about 43°C, about 44°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, or about 80°C, and is not limited thereto.

[0049] In at least one embodiment of the present disclosure, the homogeneous solution is prepared under heating. In some embodiments, the mixture is heated to above ambient temperature to about 200°C, for example, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, about 105°C, about 110°C, about 115°C, about 120°C, about 125°C, about 130°C, about 135°C, about 140°C, about 145°C, about 150°C, about 155°C, about 160°C, about 165°C, about 170°C, about 175°C, about 180°C, about 185°C, about 190°C, about 195°C, or about 200°C, and is not limited thereto. In some embodiments, the homogeneous solution can be prepared at 0°C to 200°C, with or without heating.

[0050] In at least one embodiment of the present disclosure, the method further includes filtering a homogeneous solution to obtain a filtered homogeneous solution. In some embodiments, the filtering is performed at a temperature in the range of ambient temperature to about 200 °C, for example, about 20 °C, about 25 °C, about 30 °C, about 35 °C, about 40 °C, about 45 °C, about 50 °C, about 55 °C, about 60 °C, about 65 °C, about 70 °C, about 75 °C, about 80 °C, about 85 °C, about 90 °C, about 95 °C, about 100 °C, about 105 °C, about 110 °C, about 115 °C, about 120 °C, about 125 °C, about 130 °C, about 135 °C, about 140 °C, about 145 °C, about 150 °C, about 155 °C, about 160 °C, about 165 °C, about 170 °C, about 175 °C, about 180 °C, about 185 °C, about 190 °C, about 195 °C, or about 200 °C, but not limited thereto. For example, the filtering may be performed at a temperature in the range of 20 °C to 200 °C, with or without heating.

[0051] In at least one embodiment of the present disclosure, the method further includes sterilizing a homogeneous solution or a filtered homogeneous solution to obtain a sterilized pharmaceutical composition. In some embodiments, the sterilizing may be heat sterilization, filtration sterilization, irradiation sterilization, or any combination thereof. In further some embodiments, the homogeneous solution may be sterilized at about 100 °C to 200 °C, for example, about 100 °C, about 105 °C, about 110 °C, about 115 °C, about 120 °C, about 125 °C, about 130 °C, about 135 °C, about 140 °C, about 145 °C, about 150 °C, about 155 °C, about 160 °C, about 165 °C, about 170 °C, about 175 °C, about 180 °C, about 185 °C, about 190 °C, about 195 °C, or about 200 °C, but not limited thereto. In some embodiments, the homogeneous solution may be sterilized for 10 to 120 minutes, for example, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 minutes, about 110 minutes, about 115 minutes, or about 120 minutes, but not limited thereto. In some embodiments, when the sterilizing is performed by filtration sterilization, the step of filtering the homogeneous solution may be performed together with the filtration sterilization process.

[0052] In at least one embodiment of the present disclosure, the active pharmaceutical ingredient may be buprenorphine free base, a buprenorphine-based compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the buprenorphine-based compound is used interchangeably to refer to a buprenorphine derivative that may be 3-acyl-buprenorphine. In some embodiments, the acyl group of 3-acyl-buprenorphine is an alkylcarbonyl group or an arylcarbonyl group. In still some embodiments, the alkyl portion of the alkylcarbonyl group is a linear alkyl or branched alkyl having 1 to 20 carbon atoms, and the aryl portion of the arylcarbonyl group is an aromatic ring having 6 to 18 carbon atoms.

[0053] In at least one embodiment of the present disclosure, the pharmaceutically acceptable salt of 3-acyl-buprenorphine may be, for example, a salt of HCl, formate, acetate, etc., and is not limited thereto.

[0054] As used herein, the term "biocompatible solvent" refers to any solvent well known in the art that is substantially non-toxic or harmless to living tissues or organisms. For example, the biocompatible solvents of the present disclosure may be water, N-methyl-2-pyrrolidone (NMP), polyethylene glycol 400 (PEG400), polyethylene glycol 4000 (PEG4000), ethyl acetate, ethanol, butanol, 2-butanol, isobutanol, isopropanol, glycerin, benzyl benzoate (BnBzO), dimethyl sulfoxide, N,N-dimethylacetamide (DMA), propylene glycol, dimethyl glycol, benzyl alcohol, and any combination thereof, and is not limited thereto.

[0055] In at least one embodiment of the present disclosure, the stabilizer is at least one selected from the group consisting of vitamin E (VitE) or its derivatives, ascorbic acid (VitC), butylated hydroxyanisole (BHA), and any combination thereof. In some embodiments, the vitamin E or its derivative may be α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, D-α-tocopherol polyethylene glycol 1000 succinate (TPGS), or any combination thereof.

[0056] In at least one embodiment of the present disclosure, the pharmaceutical composition comprises a reduced amount of impurities formed by the degradation of buprenorphine, its derivatives, or pharmaceutically acceptable salts thereof via non-oxidative or oxidative pathways. In some embodiments of the present disclosure, the amount of impurities formed by the non-oxidative pathway is reduced.

[0057] In at least one embodiment of the present disclosure, the stabilizer prevents discoloration of the pharmaceutical composition. In some embodiments, the amount of impurities formed by the degradation of buprenorphine, its derivatives, or pharmaceutically acceptable salts thereof is reduced by the presence of a stabilizer in the pharmaceutical composition. In some embodiments of the present disclosure, the amount of impurities formed by the non-oxidative pathway is significantly reduced by the presence of a stabilizer in the pharmaceutical composition.

[0058] In at least one embodiment of the present disclosure, the pharmaceutical composition is formulated into a formulation for at least one selected from the group consisting of subcutaneous administration, intravenous administration, intramuscular administration, intradermal administration, transdermal administration, sublingual administration, topical administration, intraperitoneal administration, intra-articular administration, transmucosal administration, intra-organ administration, intraosseous administration, and oral administration.

[0059] The present disclosure further provides a method for performing it in a subject in need of treatment for opioid addiction, pain, and / or depression, the method comprising administering a therapeutically effective amount of the pharmaceutical composition of the present disclosure.

[0060] In at least one embodiment of the method for treating opioid addiction, pain, and / or depression of the present disclosure, the administration is three times a day, twice a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every ten weeks, once every twelve weeks, once every four months, once every five months, or once every six months. It should be understood that the duration of administration can be changed based on actual needs and is not limited to the periods described above.

[0061] As used herein, the terms "administering" or "administration" refer to placing an active ingredient within a subject by a method or route that results in at least partial localization of the active ingredient at a desired site to produce a desired effect. The active ingredients described herein can be administered by any suitable route known in the art, including, but not limited to, oral or parenteral routes.

[0062] In at least one embodiment of the method for treating opioid addiction, pain, and / or depression of the present disclosure, the pharmaceutical composition is administered to a subject in need thereof through subcutaneous administration, intravenous administration, intramuscular administration, intradermal administration, transdermal administration, sublingual administration, topical administration, intraperitoneal administration, intra-articular administration, transmucosal administration, intra-organ administration, intraosseous administration, or oral administration.

[0063] The discoloration of pharmaceutical compositions affects the acceptability and commercial value of products in the market. The appearance of conventional pharmaceutical compositions of buprenorphine shows discoloration during the shelf life. For example, the color of SUBLOCADE changes from colorless to yellow due to decomposition and further to an amber solution, and BUVIDAL is originally a slightly yellow solution and turns into a yellow solution. The acceptable appearance of buprenorphine solutions should be colorless, ivory, beige, vanilla, wheat, light yellow, yellow of corn tassels, or yellow, while undesirable decomposition can result in dark yellow, yellowish green, light orange, orange, dark orange, amber, bronze, chocolate, khaki, camel, olive, brown, or even black. When determining the color with the Gardner color scale by the naked eye, SUBLOCADE has a color score of at least Gardner 8, and BUVIDAL has a color score of at least Gardner 6.

[0064] According to the manufacturer's instructions, SUBLOCADE should be stored at 2°C to 8°C with a shelf life of 18 months and should be discarded if left at room temperature for more than 7 days. Therefore, SUBLOCADE is restricted by refrigerated storage conditions, and it can be seen that its shelf life is relatively shorter than that of other products.

[0065] In at least one embodiment of the present disclosure, the pharmaceutical composition provided herein can maintain its apparent color by adding a suitable stabilizer that can reduce the formation of impurities, such as non-oxidized impurities, from the decomposition of buprenorphine, its derivatives, or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition has a color score of less than Gardner 5, for example, less than Gardner 4, less than Gardner 3, or less than Gardner 2.

[0066] The present disclosure also provides the use of a pharmaceutical composition in the manufacture of a medicament for treating opioid addiction, pain, and / or depression, the pharmaceutical composition comprising buprenorphine, a derivative thereof, or a pharmaceutically acceptable salt thereof, a stabilizer, a biocompatible solvent, and impurities in a low amount. The present disclosure further provides a pharmaceutical composition for use in the treatment of opioid addiction, pain, and / or depression, the pharmaceutical composition comprising buprenorphine, a derivative thereof, or a pharmaceutically acceptable salt thereof, a stabilizer, a biocompatible solvent, and impurities in a low amount. The present disclosure further provides a pharmaceutical composition for use in treating opioid addiction, pain, and / or depression, the pharmaceutical composition comprising buprenorphine, a derivative thereof, or a pharmaceutically acceptable salt thereof, a stabilizer, a biocompatible solvent, and impurities in a low amount.

[0067] The following embodiments further demonstrate the effectiveness of the present disclosure but should not be used to limit the scope of the present disclosure.

Examples

[0068] The present disclosure is further illustrated by the following examples. However, these examples are merely illustrative of the present disclosure and do not limit the scope and meaning of the present disclosure in any way. Many modifications and variations of the present disclosure will be apparent to those skilled in the art upon reading this specification and can be made without departing from its scope.

[0069] Generally, buprenorphine, a derivative thereof, or a pharmaceutically acceptable salt thereof contained in the formulation is decomposed into impurities, and the decomposition pathways include oxidation, dehydration, ring-opening, and rearrangement pathways. In the stability tests described herein, the main impurities in the buprenorphine formulation are formed by non-oxidation pathways. The examples are described as follows.

[0070] The characterization of impurities A to C was confirmed by nuclear magnetic resonance (NMR) spectroscopy. The structures of impurities A to C are shown in Figure 1, where R1 represents H, alkylcarbonyl, or arylcarbonyl. In some embodiments, R1 is alkylcarbonyl, and the alkyl moiety may be a linear alkyl or branched alkyl having 1 to 20 carbons. In some embodiments, R1 is arylcarbonyl, and the aryl moiety may be an aromatic ring having 6 to 18 carbons.

[0071] As shown in Figure 1, impurities A to C were formed by alkyl shift rearrangement, dehydration, and O-ring opening, respectively. The degradation pathways of impurities A and B are the same as those of impurities I and F of buprenorphine hydrochloride according to the Ph.Eur. monograph. Furthermore, the 10-oxo impurities and N-oxide impurities of buprenorphine or its derivatives formed by the oxidation pathway are also shown in Figure 1. However, the 10-oxo impurities and N-oxide impurities were not major impurities in the stability tests described herein.

[0072] Example 1. Preparation of Buprenorphine Formulations Buprenorphine, its derivatives, or its pharmaceutically acceptable salts, and a stabilizer were added to a glass vial containing a biocompatible solvent to form a mixture, and buprenorphine, its derivatives, or its pharmaceutically acceptable salts were used as the active pharmaceutical ingredient (API). Furthermore, the mixture was subjected to sonication or stirring at ambient temperature until the API and the stabilizer were dissolved in the biocompatible solvent, thereby obtaining a homogeneous solution. Thereafter, the homogeneous solution was sterilized by filtration sterilization at ambient temperature or heat sterilization at 121 °C for 15 minutes. Formulations F01 to F40, which are exemplary compositions, are listed in Table 1 below, and formulations F01, F03, F05, F07, F15, F20, F23, F24, F29, F30, and F39, which do not contain a stabilizer, were used as comparative examples.

[0073]

Table 1-1

Table 1-2

Table 1-3

[0074] Example 2. Stability Study For the stability study, the formulations F01 - F27 prepared in Example 1 were stored at 60 °C for 1 day, and the formulations F05, F06, F14, F20, F21, F22, F24, F25, F26, F27 were also tested for storage at 40 °C for 1 month. Further, the formulations F28 - F40 prepared in Example 1 were tested for storage at 25 °C or 40 °C for a given period. Note that the storage conditions at 40 °C or 60 °C used herein serve as accelerated storage conditions.

[0075] To measure the amount of impurities in the formulations after storage, each sample was analyzed by high performance liquid chromatography (HPLC) under the following conditions for buprenorphine derivatives, buprenorphine free base, impurities A - C, and other impurities.

[0076] HPLC instrument: Alliance 1260 Infinity, column: Waters Xterra C18, 4.6 mm × 250 mm, 5 μm, mobile phase A: 0.1% trifluoroacetic acid in water, mobile phase B: methanol, flow rate: 1 mL / min, UV detection (DAD) 210 nm, column temperature: 30 °C, injection volume: 10 μL.

[0077] To evaluate the appearance of the formulations after storage, each sample was diluted 3-fold with acetonitrile, and then the color scale of the sample was recorded using a Lovibond EC2000 Gardner. The Gardner color scale is a one-dimensional scale used to measure the yellow color of a transparent liquid. The color score of Gardner 1 is light yellow, and the color score of Gardner 18 is dark brown.

[0078] The results of the stability studies of Formulations F28 and F29 are shown in Tables 2 and 3 below. Impurity A1 was found in the formulation of buprenorphine hexanoate using HPLC.

Table 2-1

Table 2-2

Table 3

[0079] Impurity A1 was correlated with the impurity having a retention time of 17.5 minutes in the stability test of buprenorphine hexanoate formulation. The results showed that formulation F28 with 0.2% VitE added significantly inhibited the formation of total impurities and Impurity A1 at temperatures of 25 °C and 40 °C. For example, as shown in Figures 2 and 3, by adding a stabilizer, less than 0.15% of Impurity A1 was generated. It should be noted that compared with formulation F29 without a stabilizer, after storage at 25 °C for 6 months, formulation F28 with a stabilizer added significantly reduced the formation of Impurity A1 by about 51.9% (i.e., 0.13% for formulation F28 and 0.27% for formulation F29). Similarly, compared with formulation F29 without a stabilizer, after storage at 40 °C for 6 months, formulation F28 with a stabilizer added also reduced the formation of Impurity A1 by about 65.5% (i.e., 0.1% for formulation F28 and 0.29% for formulation F29).

[0080] Furthermore, the appearance of the formulations is shown in Figures 4 and 5, indicating that formulation F29 showed severe discoloration compared to formulation 28. Furthermore, the formation profiles of Impurity A1 stored at 25 °C and 40 °C are also shown in Figures 2 and 3 respectively, where USL in the figures represents the upper specification limit, indicating that according to ICH guidance Q3B(R2), the impurities should each be less than 0.2% in the new drug product specification.

[0081] These results showed that by adding 0.2% VitE as a stabilizer to formulation F28 compared with formulation F29 without adding any stabilizer, the formation of Impurity A1 at 25 °C and 40 °C was significantly inhibited, and the amount of Impurity A1 could remain lower than the USL for at least 6 months. It was also shown that the proportion of Impurity A1 in formulation F29 decreased because buprenorphine free base and individual unknown impurities were gradually formed within 6 months, but no buprenorphine free base was observed in formulation F28.

[0082] Furthermore, the results of the stability studies of formulations F30 - F40 are shown in Table 4 below.

Table 4

Table 5-1

Table 5-2

[0083] Impurities A1, A2 and C1 were found in the formulations of buprenorphine derivatives by using HPLC. In the stability test of buprenorphine hexanoate formulation, impurities A1 and C1 were correlated with the impurities having retention times of 17.5 minutes and 18.9 minutes, respectively. Impurity A2 was correlated with the impurity having a retention time of 30.1 minutes in the stability test of buprenorphine decanoate formulation.

[0084] The above results indicate that the formation of total impurities was significantly reduced by adding a stabilizer to the formulation containing a buprenorphine derivative. For example, Table 4 shows that formulation F31 with 0.5% VitE added significantly reduced the formation of total impurities and impurity A2 compared to formulation F30 without a stabilizer. Specifically, up to 1.23% of non-oxidized impurities (i.e., impurity A2) were generated in formulation F30 after 14 days, while less than 0.50% of non-oxidized impurities were generated in formulation F31 after 14 days, and impurity A2 decreased by about 61%.

[0085] Furthermore, as shown in Table 5, formulations F33 and F40, each with 2% VitE added, produced relatively low amounts of total impurities (0.23% and 0.08%) after 14 days, and less than 0.25% of non-oxidized impurities (i.e., impurity A1) were observed therein.

[0086] Also, after 14 days, the formation of impurity A1 and impurity C1 in the formulations with BHA or TPGS added (i.e., formulations F34 and F38) was also clearly reduced. Specifically, after 14 days, in formulations F34 and F38, it was observed that the total amount of impurity A1 and C1 was less than 0.60%.

[0087] The results of the stability studies of formulations F01 - F27 are shown in Tables 6 - 12 below.

Table 6

[0088] From the results in Table 6, it can be seen that the addition of VitE does not significantly reduce the formation of impurities in the formulations containing buprenorphine free base, suggesting that although VitE is regarded as an antioxidant, it may not inhibit the oxidation of buprenorphine free base.

Table 7

Table 8 - 1

Table 8 - 2

Table 9

[0089] Furthermore, Tables 7 - 9 show that by adding stabilizers to formulations containing different buprenorphine derivatives, the formation of total impurities and non-oxidized impurities after storage at 60°C for 1 day was significantly reduced. For example, each of the non-oxidized impurities (i.e., A1 - A3, B1 - B3, and C1) generated in formulations containing stabilizers (e.g., VitE and BHA) can be in an amount of less than about 0.5%, and the total impurities can be in an amount of less than about 1%. In contrast, formulations without stabilizers (i.e., Formulations F05, F07, F15, F20, F23, and F24) not only showed a higher color scale but also generated higher amounts of total impurities, up to about 1.7% - 5.6%.

Table 10

Table 11

Table 12

[0090] Similarly, Tables 10 to 12 show that adding a stabilizer to formulations containing different buprenorphine derivatives after storage at 40°C for one month has the ability to reduce the formation of total impurities and non-oxidized impurities, and prevent discoloration during long-term storage.

[0091] From the above results, it was observed that the addition of stabilizers (e.g., VitE, VitC, and BHA) can effectively inhibit the formation of non-oxidized impurities in the stability test. The stabilizers used herein were generally regarded as antioxidants from prior knowledge. However, the present disclosure has demonstrated that the stabilizers unexpectedly reduced the impurities formed also through non-oxidative pathways.

[0092] Although the present disclosure has been described with respect to a limited number of embodiments, those skilled in the art who benefit from the present disclosure will understand that other embodiments can be devised without departing from the scope of the present disclosure disclosed herein. Therefore, the scope of the present disclosure should be defined only by the appended claims.

Claims

1. A pharmaceutical composition comprising an active pharmaceutical ingredient, a stabilizer, a biocompatible solvent, and at least one compound represented by the following formula (IIA), (IIB), or (IIC), wherein 【Chemical 1】 wherein, R 1 is hydrogen, C 1 -C 20 an alkylcarbonyl group, or C 6 -C 18 an arylcarbonyl group, and the active pharmaceutical ingredient is at least one of buprenorphine, its derivatives, and pharmaceutically acceptable salts thereof, the compounds of formula (IIA), (IIB), and (IIC) each have an amount of less than 1% w / w based on the total weight of the pharmaceutical composition during the shelf life of the pharmaceutical composition. A pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the compounds of formula (IIA), (IIB), and (IIC) each have an amount of less than 0.5% w / w based on the total weight of the pharmaceutical composition during the shelf life.

3. The pharmaceutical composition according to claim 1, wherein the shelf life is at least 20 months at ambient temperature or a temperature below ambient temperature.

4. The buprenorphine or its derivative is represented by the following formula (I), 【Chemical Formula 2】 wherein R 1 is as defined in claim 1, the pharmaceutical composition according to claim 1.

5. The pharmaceutical composition according to claim 1, wherein the active pharmaceutical ingredient is present in an amount of 5% w / w to 80% w / w based on the total weight of the pharmaceutical composition.

6. The pharmaceutical composition according to claim 1, wherein the stabilizer is present in an amount of 0.01% w / w to 10% w / w based on the total weight of the pharmaceutical composition.

7. The pharmaceutical composition according to claim 1, wherein the stabilizer is selected from the group consisting of vitamin E or its derivatives, ascorbic acid, butylated hydroxyanisole, and combinations thereof.

8. The pharmaceutical composition according to claim 7, wherein the vitamin E or its derivative is α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, or D-α-tocopherol polyethylene glycol 1000 succinate.

9. The pharmaceutical composition according to claim 1, wherein the biocompatible solvent is selected from the group consisting of N-methyl-2-pyrrolidone, polyethylene glycol 400, polyethylene glycol 4000, ethyl acetate, ethanol, butanol, 2-butanol, isobutanol, isopropanol, glycerin, benzyl benzoate, dimethyl sulfoxide, N,N-dimethylacetamide, propylene glycol, dimethyl glycol, benzyl alcohol, and any combination thereof.

10. The pharmaceutical composition according to claim 1, having a color score of less than Gardner 4.

11. A method for preparing the pharmaceutical composition according to claim 1, comprising adding an active pharmaceutical ingredient and a stabilizer to a biocompatible solvent to form the pharmaceutical composition, wherein the active pharmaceutical ingredient is at least one of buprenorphine, its derivatives, and pharmaceutically acceptable salts thereof.

12. The method according to claim 11, further comprising stirring the pharmaceutical composition to form a homogeneous solution.

13. The method according to claim 12, wherein the stirring is carried out under heating.

14. The method according to claim 12, further comprising filtering the homogeneous solution to obtain a filtered homogeneous solution.

15. The method according to claim 12, further comprising sterilizing the homogeneous solution to obtain a sterilized pharmaceutical composition.

16. The method according to claim 15, wherein the sterilizing is selected from the group consisting of heat sterilization, filtration sterilization, irradiation sterilization, and any combination thereof.

17. The method according to claim 11, wherein the compounds represented by formulas (IIA), (IIB), and (IIC) are formed by the decomposition of the active pharmaceutical ingredient.

18. A method for performing it in a subject in need of treatment for opioid addiction, pain, and / or depression, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 1.

19. The method according to claim 18, wherein the pharmaceutical composition is administered to the subject once every three days, once every two days, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every ten weeks, once every twelve weeks, once every four months, once every five months, or once every six months.

20. The method according to claim 18, wherein the pharmaceutical composition is administered to the subject through subcutaneous administration, intravenous administration, intramuscular administration, intradermal administration, transdermal administration, sublingual administration, topical administration, intraperitoneal administration, intra-articular administration, transmucosal administration, intra-organ administration, intraosseous administration, or oral administration.

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