Stable pharmaceutical composition of buprenorphine, preparation method and application thereof

Abstract

The present disclosure provides 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), Formula (IIB), or Formula (IIC) wherein R1 is hydrogen, C1-C20 alkylcarbonyl, or C6-C18 arylcarbonyl, and wherein within the shelf life of the pharmaceutical composition, R1 is hydrogen, C1-C20 alkylcarbonyl, or C6-C18 arylcarbonyl, R2 is hydrogen, C1-C20 alkylcarbonyl, or C6-C18 arylcarbonyl, and R3 is hydrogen, C1-C20 alkylcarbonyl, or C6-C18 arylcarbonyl. The amounts of the compounds of formula (IIA), formula (IB), and formula (IIC) are each less than 1% w / w based on the total weight of the pharmaceutical composition. The disclosure also provides a method of making the pharmaceutical composition and a method of administering the pharmaceutical composition to a subject in need thereof to treat opioid addiction, pain, and / or depression. # imgabs0 #

Description

Technical Field

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

[0002] Buprenorphine is used to treat pain and opioid dependence in a variety of dosage forms, such as BUVIDAL (subcutaneous injection), BUPRENEX (intravenous or intramuscular injection), BUTRANS (transdermal film), SUBLOCADE (subcutaneous injection), SUBOXONE (sublingual lozenge or sublingual film), and SUBUTEX (sublingual lozenge).

[0003] It is known in the art that buprenorphine can degrade and produce impurities through oxidation, dehydration, ring opening, rearrangement and other pathways. Den Herder et al. (J. Am. Assoc. Lab. Anim. Sci. (2017) 56 (4): 457-461) disclosed a chemical stability test of buprenorphine injection diluted with saline, which showed that the concentration of buprenorphine stored in a glass bottle decreased significantly, with 95.7% remaining after refrigeration for 30 days and 94.2% remaining after 60 days at room temperature. The reduction of buprenorphine may be caused by degradation, so it is necessary to develop a buprenorphine composition with better stability.

[0004] In previous studies, a method for enhancing the stability of buprenorphine through an antioxidant pathway has been proposed. However, buprenorphine can be degraded into impurities via a non-oxidative pathway. For example, Hotha et al. (Am. J. Analyt. Chem. (2016) 7, 107-140) disclosed the degradation pathway of buprenorphine and pointed out that according to the European Pharmacopoeia (Ph. Eur.) monograph, buprenorphine is degraded into impurity I due to the dehydration cyclization of buprenorphine to form a furan ring.

[0005]

[0006] According to the European Pharmacopoeia monograph, buprenorphine hydrochloride has 10 different impurities and the related substances are monitored. For example, impurities A, B, F and J are limited to a content of no more than 0.2%; impurity G is limited to a content of no more than 0.15%; and impurity H is limited to a content of no more than 0.25%. Among these impurities, impurities A, B, F, G, H and J are formed through non-oxidative pathways. Similarly, according to the British Pharmacopoeia, buprenorphine preparations will produce impurities A, B, F and G, and excessive amounts of impurities may cause unknown health hazards to the human body.

[0007] Furthermore, the appearance of conventional pharmaceutical compositions containing buprenorphine may change color during the shelf life, thereby significantly affecting the product acceptability and commercial value of buprenorphine in the market.

[0008] Therefore, there is still an unmet and urgent need in the art to provide a stable pharmaceutical composition of buprenorphine or its derivatives or pharmaceutically acceptable salts thereof, wherein the impurities formed by non-oxidative pathways are reduced and discoloration can be prevented during the shelf life at room temperature. Summary of the invention

[0009] In view of the above, the present disclosure provides a stable pharmaceutical composition of buprenorphine, which comprises buprenorphine, its derivatives and pharmaceutically acceptable salts thereof as an active pharmaceutical ingredient and a relatively low content of impurities.

[0010] In at least one embodiment of the present disclosure, the pharmaceutical composition comprises an active pharmaceutical ingredient and at least one compound represented by the following formula (IIA), formula (IIB) or formula (IIC):

[0011]

[0012] Wherein R1 is hydrogen, C1-C 20 Alkylcarbonyl or C6-C 18 Arylcarbonyl.

[0013] 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, the buprenorphine and the buprenorphine derivatives can be represented by the following formula (I):

[0014]

[0015] wherein R1 is as defined above.

[0016] 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 valerate, buprenorphine hexanoate, buprenorphine trimethyl ethyl ester, buprenorphine decanoate, buprenorphine stearate, buprenorphine benzoate or buprenorphine hydrochloride.

[0017] 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 has a lower limit selected from 5%, 10%, 15%, 20%, 25%, 30%, 35% and 40% by weight of the pharmaceutical composition, and an upper limit selected from 80%, 75%, 70%, 65%, 60%, 55%, 50% and 45% by weight of the pharmaceutical composition. In some embodiments, the amount of buprenorphine, its derivatives and pharmaceutically acceptable salts thereof as the active pharmaceutical ingredient may range from 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.

[0018] In at least one embodiment of the present disclosure, the compound of formula (IIA), formula (IIB) and formula (IIC) is each present in the pharmaceutical composition in an amount of less than 1% w / w, based on the total weight of the pharmaceutical composition. For example, the amount of each compound of formula (IIA), formula (IIB) and formula (IIC) is 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.

[0019] In at least one embodiment of the present disclosure, the total amount of the compound of formula (IIA), formula (IIB), and formula (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 the compound of formula (IIA), formula (IIB), and formula (IIC) in the pharmaceutical composition is not 0% at the same time. For example, in the pharmaceutical composition, 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% at the same time.

[0020] In at least one embodiment of the present disclosure, when the compound of formula (IIA), formula (IIB) or formula (IIC) is present in the pharmaceutical composition during the shelf life of the pharmaceutical composition, the amount of each compound is 0% to 1%, based on the total weight of the pharmaceutical composition, 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. In some embodiments, the compounds of formula (IIA), formula (IIB) and formula (IIC) are each present in an amount of 0% to 1% w / w during the shelf life of the pharmaceutical composition.

[0021] In at least one embodiment of the present disclosure, the shelf life of the pharmaceutical composition at ambient temperature or below ambient temperature 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. In some embodiments, the ambient temperature may be within a certain temperature range, for example, 20°C to 25°C, 22°C to 28°C and 20°C to 28°C. In some other 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.

[0022] In at least one embodiment of the present disclosure, the pharmaceutical composition may further include a stabilizer. In some embodiments, the stabilizer is selected from the group consisting of vitamin E (vitamin E, VitE) or its derivatives, ascorbic acid (ascorbic acid, VitC), butylated hydroxyanisole (butylated hydroxyanisole, BHA) and combinations thereof. In some embodiments, the vitamin E or its derivatives 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 (D-α-tocopherolpolyethylene glycol 1000succinate, TPGS).

[0023] 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 can be 0.05% to 5%, 0.1% to 5%, 0.2% to 5%, 0.5% to 5%, 0.05% to 3%, 0.1% to 3%, 0.2% to 3%, 0.5% to 3%, 0.05% to 2%, 0.1% to 2%, 0.2% to 2%, 0.5% to 2%, 0.05% to 1%, 0.1% to 1%, 0.2% to 1%, or 0.5% to 1%, by weight of the pharmaceutical composition.

[0024] In at least one embodiment of the present disclosure, the pharmaceutical composition may further include 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, glycerol, benzylbenzoate (BnBzO), dimethyl sulfoxide, N,N-dimethylacetamide (DMA), propylene glycol, dimethyl glycol, benzyl alcohol, and any combination thereof.

[0025] 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% to 95%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, 20% to 50%, 30% to 95%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, or 30% to 50% by weight of the pharmaceutical composition.

[0026] In at least one embodiment, the present disclosure also provides a method for preparing the above-mentioned stable pharmaceutical composition. The method for preparing the pharmaceutical composition comprises 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, a derivative thereof, and a pharmaceutically acceptable salt thereof.

[0027] In at least one embodiment, the present disclosure also provides a method for treating opioid addiction, pain and / or depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the above-mentioned pharmaceutical composition.

[0028] In some specific embodiments, the stable pharmaceutical composition of the present disclosure includes buprenorphine, its derivatives or pharmaceutically acceptable salts thereof as an active pharmaceutical ingredient and a stabilizer, which can reduce impurities formed by the active pharmaceutical ingredient, for example, impurities formed via non-oxidative pathways. Therefore, the pharmaceutical composition of the present disclosure can improve the stability of the active pharmaceutical ingredient, thereby exhibiting a longer shelf life and preventing the pharmaceutical composition from discoloring. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] The present disclosure may be more fully understood by reading the following description of specific embodiments and referring to the accompanying drawings.

[0030] Figure 1 The various degradation pathways of buprenorphine compounds and the impurity structures formed by different degradation pathways are shown.

[0031] Figure 2 Shown is a profile of the formation of impurity A1 in formulations F28 and F29 according to specific examples of the present disclosure, wherein formulations F28 and F29 were stored at 25°C; USL: upper specification limit.

[0032] Figure 3 Shown is a profile of the formation of impurity A1 in formulations F28 and F29 according to specific examples of the present disclosure, wherein formulations F28 and F29 were stored at 40°C; USL: upper specification limit.

[0033] Figure 4 The appearance of formulations F28 and F29 according to specific examples of the present disclosure are shown, wherein formulations F28 and F29 are stored at 25° C.; M: month.

[0034] Figure 5 The appearance of formulations F28 and F29 according to specific examples of the present disclosure are shown, wherein formulations F28 and F29 are stored at 40° C.; M: month. DETAILED DESCRIPTION

[0035] 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 description of the present disclosure. The present disclosure can also be implemented or applied as described in different embodiments. For different aspects and applications, the following embodiments can be modified and / or changed to implement the present disclosure without violating the scope of the present disclosure.

[0036] It should also be noted that, as used in this disclosure, the singular forms "a," "an," and "the" include plural referents unless expressly and unequivocally limited to one referent. The term "or" can be used interchangeably with the term "and / or," unless the context clearly indicates otherwise.

[0037] As used herein, the terms "include", "comprising", "having", "containing" and any other variations thereof are intended to cover non-exclusive inclusions. For example, when describing an object "comprising" a limitation, other ingredients, components, compositions, structures, regions, parts, devices, systems, steps or connections, etc. may be additionally included unless otherwise stated, and other limitations should not be excluded.

[0038] As used herein, the terms "at least one" and "one or more" may have the same meaning and include one, two, three or more.

[0039] Throughout this disclosure, ordinals (e.g., first, second, third, etc.) may be used as adjectives of components (i.e., any noun in this disclosure). The use of ordinals does not imply or create an ordering of components, nor does it limit any component to only a single component, unless otherwise expressly indicated, for example, by the use of the terms "before," "after," "single," and other such terms. Rather, ordinals are used to distinguish components. For example, a first component is different from a second component, and a first component may encompass more than one component and may be ranked after (or before) a second component in the ordering of components.

[0040] As used herein, the term "about" generally means a variation of ±20%, ±10%, ±5%, ±1%, ±0.5% or ±0.1% within a given value or range. The variation of the numerical value may occur due to experimental errors, typical errors in the measurement or processing flow for preparing compounds, compositions, concentrates or preparations, differences in the source, manufacture or purity of the starting materials or ingredients used in the present disclosure, or similar reasons. Alternatively, the term "about" means within the acceptable standard error of the mean value as considered by those skilled in the art. Unless otherwise expressly indicated, all numerical ranges, quantities, values ​​and percentages disclosed herein, for example, numerical ranges, quantities, values ​​and percentages for material quantities, durations, temperatures, operating conditions, quantity ratios, etc., should be understood to be modified by the term "about" in all cases.

[0041] The numerical range used herein is inclusive and combinable. Any numerical value falling within the numerical range herein can be regarded as a maximum or minimum value to derive a sub-range therefrom. For example, it should be understood that the numerical range "1% to 99%" includes any sub-range between the minimum value 1% and the maximum value 99%, for example, from 1% to 90%, from 20% to 80%, from 40% to 60%, etc. The sub-range. In addition, multiple numerical values ​​used herein can be selected as maximum and minimum values ​​to derive numerical ranges as needed. For example, the 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%.

[0042] As used herein, the term "treatment" (treat, treating or treatment) covers partial or complete prevention, improvement, alleviation and / or control of symptoms, disorders or states associated with a disease. The term "treatment" used herein means the application or administration of one or more therapeutic agents or surgery to a subject with symptoms, disorders or states associated with a disease, with the purpose of achieving partial or complete relief, improvement, alleviation, postponement of onset, inhibition of progression, reduction of severity and / or reduction of incidence for one or more symptoms, disorders or states associated with the disease. The treatment may be administered to a subject who only exhibits early signs of such symptoms, disorders and / or states to reduce the risk of developing symptoms, disorders and / or states associated with the disease.

[0043] As used herein, the terms "subject", "individual" and "patient" are used interchangeably and refer to animals, e.g., mammals. Unless a gender is specifically indicated, the term "subject" refers to both male and female. 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.

[0044] As used herein, the term "therapeutically effective amount" means an amount of an active agent or composition sufficient to treat or prevent a particular condition, state or disease in a subject in need thereof. As will be appreciated by those skilled in the art, the effective dose will vary depending on the route of administration, the excipient used, the possibility of co-use with other therapies, and the condition to be treated.

[0045] 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), formula (IIB) or formula (IIC):

[0046]

[0047] Wherein R1 is hydrogen, C1-C 20 Alkylcarbonyl or C6-C 18 Arylcarbonyl.

[0048] As used herein, the term "impurity" means a chemical substance formed by degradation 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 its pharmaceutically acceptable salts, which can be degraded into impurities through oxidation or non-oxidation pathways (e.g., dehydration, ring opening, and rearrangement pathways). Therefore, the impurities may be oxidized impurities, non-oxidized impurities, and individual unknown impurities.

[0049] As used herein, the compounds of formula (IIA), formula (IIB) and formula (IIC) are also referred to as impurity A, impurity B and impurity C, respectively, which are non-oxidized impurities formed by degradation of the active pharmaceutical ingredient via a non-oxidative pathway. Therefore, the structures of the compounds of formula (IIA), formula (IIB) and formula (IIC) are related to the structures of the active pharmaceutical ingredients that form the compounds.

[0050] For example, buprenorphine or its derivatives in the pharmaceutical composition can be represented by the following formula (I):

[0051]

[0052] Wherein R1 is hydrogen, C1-C 20 Alkylcarbonyl or C6-C 18 The arylcarbonyl group, and the compounds of formula (IIA), formula (IIB) and formula (IIC) may have the same R1 group as the active pharmaceutical ingredient of formula (I).

[0053] In at least one embodiment of the present disclosure, the compounds of formula (IIA), formula (IIB) and formula (IIC) formed by buprenorphine hexanoate as an active pharmaceutical ingredient can be further represented by the following impurities A1, B1 and C1, respectively:

[0054]

[0055]

[0056] In at least one embodiment of the present disclosure, the compounds of formula (IIA), formula (IIB) and formula (IIC) formed by buprenorphine decanoate as an active pharmaceutical ingredient can be further represented by the following impurities A2, B2 and C2, respectively:

[0057]

[0058] In at least one embodiment of the present disclosure, the compounds of formula (IIA), formula (IIB) and formula (IIC) formed by buprenorphine acetate as an active pharmaceutical ingredient can be further represented by the following impurities A3, B3 and C3, respectively:

[0059]

[0060] In at least one embodiment of the present disclosure, the total amount of the compounds of formula (IIA), formula (IIB) and formula (IIC) in the pharmaceutical composition is less than 1% based on the total weight of the pharmaceutical composition. In some embodiments, the amount of the compounds of formula (IIA), formula (IIB) and formula (IIC) in the pharmaceutical composition is individually 0% to 1% w / w based on the total weight of the pharmaceutical composition. In some embodiments, the amount of total impurities in the pharmaceutical composition may be less than 1% based on the total weight of the pharmaceutical composition. In some embodiments, the total amount of impurities in the pharmaceutical composition is less than 1% w / w during the shelf life of the pharmaceutical composition.

[0061] In at least one embodiment of the present disclosure, the amount of buprenorphine, its derivatives or pharmaceutically acceptable salts thereof is 1% to 99% w / w based on the total weight of the pharmaceutical composition. In some embodiments, the amount of buprenorphine, its derivatives or pharmaceutically acceptable salts thereof is 5% to 80% based on the total weight of the pharmaceutical composition. For example, the amount of buprenorphine, its derivative or its pharmaceutically acceptable salt may be 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.

[0062] In at least one embodiment of the present disclosure, the amount of the stabilizer is 0.01% to 10% w / w based on the total weight of the pharmaceutical composition. In some embodiments, the amount of the stabilizer is 0.1% to 2% based on the total weight of the pharmaceutical composition. For example, the amount of the stabilizer may be 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, and is not limited thereto.

[0063] In at least one embodiment of the present disclosure, the amount of the biocompatible solvent is 20% to 95% w / w, based on the total weight of the pharmaceutical composition. In some embodiments, the amount of the biocompatible solvent is 30% to 95% w / w, for example, about 25% w / w, about 30% w / w, about 35% w / w, about 38% w / w, 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, about 94.5% w / w, or about 95% w / w, based on the total weight of the pharmaceutical composition, and is not limited thereto.

[0064] In at least one embodiment of the present disclosure, a method for preparing the above-mentioned pharmaceutical composition is provided, wherein the method comprises adding an active pharmaceutical ingredient and a stabilizer into a biocompatible solvent to form a mixture of the pharmaceutical composition.

[0065] In at least one embodiment of the present disclosure, the method further comprises stirring the mixture to form a homogeneous solution. In some embodiments, the stirring can be performed for any time period, for example, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes or longer, and is not limited thereto. In some specific embodiments, the stirring may be performed at 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.

[0066] 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, without limitation. In some embodiments, the homogeneous solution can be prepared at 0°C to 200°C with or without heating.

[0067] In at least one embodiment of the present disclosure, the method further includes filtering the homogeneous solution to obtain a filtered homogeneous solution. In some specific embodiments, the filtration is carried out at a temperature from 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. For example, the filtration may be performed with or without heating and at a temperature ranging from 20°C to 200°C.

[0068] In at least one embodiment of the present disclosure, the method further includes sterilizing the homogeneous solution or the filtered homogeneous solution to obtain a sterilized pharmaceutical composition. In some embodiments, the sterilization may be heat sterilization, filtration sterilization, radiation sterilization, or any combination thereof. In some embodiments, the homogeneous solution may be sterilized at 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, and is not limited thereto. In some embodiments, the homogenous solution is 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, and is not limited thereto. In some embodiments, when sterilization is performed by filtration sterilization, the step of filtering the homogenous solution can be performed together with the process of filtration sterilization.

[0069] In at least one embodiment of the present disclosure, the active pharmaceutical ingredient may be buprenorphine free base, buprenorphine compounds or pharmaceutically acceptable salts thereof. In some embodiments, buprenorphine compounds may be used interchangeably with buprenorphine derivatives, meaning 3-acyl-buprenorphine. In some embodiments, the acyl group of 3-acyl-buprenorphine is an alkylcarbonyl or arylcarbonyl group. In some further embodiments, the alkyl portion of the alkylcarbonyl group is a straight-chain alkyl or branched-chain alkyl group having 1 to 20 carbon atoms, and the aryl portion of the arylcarbonyl group is an aromatic ring having 6 to 18 carbon atoms.

[0070] In at least one embodiment of the present disclosure, the pharmaceutically acceptable salt of 3-acyl-buprenorphine may be, for example, hydrochloride, formate, acetate, etc., but is not limited thereto.

[0071] As used herein, the term "biocompatible solvent" means any solvent known in the art that is substantially non-toxic or harmless to living tissues or organisms. For example, the biocompatible solvent 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, glycerol, benzyl benzoate (BnBzO), dimethyl sulfoxide, N,N-dimethylacetamide (DMA), propylene glycol, dimethyl glycol, benzyl alcohol, and any combination thereof, and is not limited thereto.

[0072] In at least one embodiment of the present disclosure, the stabilizer is selected from at least one of 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 derivatives may be α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocopherol with double bonds, β-tocopherol with double bonds, γ-tocopherol with double bonds, δ-tocopherol with double bonds, D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), or any combination thereof.

[0073] In at least one embodiment of the present disclosure, the pharmaceutical composition comprises a reduced amount of impurities formed by 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 via non-oxidative pathways is reduced.

[0074] In at least one embodiment of the present disclosure, the stabilizer prevents the pharmaceutical composition from discoloration. In some embodiments, the amount of impurities formed by degradation of buprenorphine, its derivatives, or pharmaceutically acceptable salts thereof in the pharmaceutical composition is reduced by the presence of the stabilizer. In some embodiments of the present disclosure, the amount of impurities formed via non-oxidative pathways in the pharmaceutical composition is significantly reduced by the presence of the stabilizer.

[0075] In some embodiments of the present disclosure, the pharmaceutical composition is formulated into at least one preparation selected from the group consisting of subcutaneous administration, intravenous administration, intramuscular administration, intradermal administration, transdermal administration, sublingual administration, topical administration, intraperitoneal administration, intraarticular administration, transmucosal administration, intraorgan administration, intraosseous administration and oral administration.

[0076] The present disclosure also provides a method for treating opioid addiction, pain and / or depression in a subject in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition of the present disclosure.

[0077] In at least one embodiment of the method for treating opioid addiction, pain and / or depression disclosed herein, 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 period of administration can vary according to actual needs and is not limited to the above period.

[0078] As used herein, the term "administering" or "administration" means placing the active ingredient in the body of a subject by a method or route that positions the active ingredient at least partially at a desired site to produce a desired effect. The active ingredients described herein can be administered by any appropriate route known in the art, including but not limited to oral or parenteral routes.

[0079] 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 via subcutaneous administration, intravenous administration, intramuscular administration, intradermal administration, transdermal administration, sublingual administration, topical administration, intraperitoneal administration, intraarticular administration, transmucosal administration, intra-organ administration, intraosseous administration or oral administration.

[0080] Discoloration of pharmaceutical compositions affects product acceptability and commercial value in the market. The appearance of conventional pharmaceutical compositions of buprenorphine changes color during the shelf life. For example, the color of SUBLOCADE changes from colorless to yellow, and further changes to an amber solution through degradation, while BUVIDAL is originally a light yellow solution and changes color to a yellow solution. Acceptable buprenorphine solutions should be colorless, ivory, beige, vanilla, wheat, light yellow, corn silk yellow, or yellow in appearance, while undesirable degradation may result in dark yellow, greenish yellow, light orange, orange, dark orange, amber, bronze, chocolate, khaki, camel, olive, brown, or even black. The color is determined by the naked eye and the Gardner color scale, with SUBLOCADE having a Gardner color scale of at least 8 and BUVIDAL having a Gardner color scale of at least 6.

[0081] According to the manufacturer's instructions, SUBLOCADE should be stored at 2°C to 8°C and has a shelf life of 18 months. If it is left at room temperature for more than 7 days, it should be discarded. Therefore, SUBLOCADE is limited to refrigerated storage conditions and its shelf life is relatively shorter than other products.

[0082] In at least one embodiment of the present disclosure, the pharmaceutical composition provided herein can maintain its appearance color by adding a suitable stabilizer, which can reduce impurities formed by degradation of buprenorphine, its derivatives or pharmaceutically acceptable salts thereof, such as non-oxidative impurities. In some embodiments, the pharmaceutical composition has a Gardner chroma of less than 5, for example, a Gardner chroma of less than 4, a Gardner chroma of less than 3 or a Gardner chroma of less than 2.

[0083] The present disclosure also provides a pharmaceutical composition for the preparation of a drug for treating opioid addiction, pain and / or depression, wherein the pharmaceutical composition comprises buprenorphine, a derivative thereof or a pharmaceutically acceptable salt thereof, a stabilizer, a biocompatible solvent and a low level of impurities. The present disclosure further provides a pharmaceutical composition for the treatment of opioid addiction, pain and / or depression, wherein the pharmaceutical composition comprises buprenorphine, a derivative thereof or a pharmaceutically acceptable salt thereof, a stabilizer, a biocompatible solvent and a low level of impurities. The present disclosure further provides a pharmaceutical composition for the treatment of opioid addiction, pain and / or depression, wherein the pharmaceutical composition comprises buprenorphine, a derivative thereof or a pharmaceutically acceptable salt thereof, a stabilizer, a biocompatible solvent and a low level of impurities.

[0084] The following specific examples further illustrate the efficacy of the present disclosure, but should not be construed as limiting the scope of the present disclosure.

[0085] Example

[0086] The present disclosure will be further described by the following examples. However, the embodiments are only used to illustrate the present disclosure and do not limit the scope and significance of the present disclosure. After reading this specification, those skilled in the art will understand the various modifications and variations of the present disclosure, and the modifications and variations can be carried out without departing from the scope of the present disclosure.

[0087] Generally speaking, buprenorphine, its derivatives or pharmaceutically acceptable salts thereof contained in the preparation will be degraded into impurities, wherein the degradation pathways include oxidation, dehydration, ring opening and rearrangement pathways. In the stability test described herein, the main impurities of the buprenorphine preparation are formed by non-oxidative pathways, and the examples are described below.

[0088] The properties of impurities A to C have been confirmed by nuclear magnetic resonance (NMR) spectra. The structures of impurities A to C are as follows: Figure 1 As shown, R1 represents H, alkylcarbonyl or arylcarbonyl. In some specific embodiments, R1 is alkylcarbonyl, and the alkyl portion may be a straight chain alkyl or branched chain alkyl having 1 to 20 carbons. In some specific embodiments, R1 is arylcarbonyl, and the aryl portion may be an aromatic ring having 6 to 18 carbons.

[0089] like Figure 1 As shown in the table, impurities A to C are formed by alkyl shift rearrangement, dehydration and O-ring opening, respectively. According to the European Pharmacopoeia monograph, the degradation pathways of impurities A and B are the same as those of impurities I and F of buprenorphine hydrochloride. In addition, 10-oxo impurities and N-oxide impurities formed by buprenorphine or its derivatives via oxidation pathways are also shown in the table. Figure 1 However, the 10-keto impurity and the N-oxide impurity were not the major impurities in the stability testing described herein.

[0090] Example 1: Preparation of buprenorphine formulation

[0091] Buprenorphine, its derivatives or pharmaceutically acceptable salts thereof and stabilizers are added to a glass vial containing a biocompatible solvent to form a mixture, wherein the buprenorphine, its derivatives or pharmaceutically acceptable salts thereof are used as active pharmaceutical ingredients (API). In addition, the mixture is ultrasonically shaken or stirred at ambient temperature until the API and stabilizer are dissolved in the biocompatible solvent to obtain a uniform solution. Then, the uniform solution is sterilized by filtration sterilization at ambient temperature or heat sterilization at 121° C. for 15 minutes. Exemplary compositions such as preparations F01 to F40 are listed in Table 1 below, wherein preparations F01, F03, F05, F07, F15, F20, F23, F24, F29, F30 and F39 do not contain stabilizers as comparative examples.

[0092] Table 1. Buprenorphine preparations prepared in Example 1

[0093]

[0094]

[0095]

[0096] NMP: N-methyl-2-pyrrolidone; DMA: N,N-dimethylacetamide; VitE: Vitamin E; VitC: Vitamin C; BHA: Butylated hydroxyanisole; TPGS: D-α-tocopheryl polyethylene glycol 1000 succinate.

[0097] Example 2: Stability Study

[0098] For stability study, the preparations F01 to F27 prepared in Example 1 were stored at 60°C for 1 day, and the preparations F05, F06, F14, F20, F21, F22, F24, F25, F26 and F27 were also tested by storing them at 40°C for 1 month. In addition, to test the preparations F28 to F40 prepared in Example 1, they were stored at 25°C or 40°C for a specified period of time. It should be noted that the storage conditions of 40°C or 60°C used here are accelerated storage conditions.

[0099] In order to measure the impurity content in the preparation after storage, high performance liquid chromatography (HPLC) was used to analyze the buprenorphine derivatives, buprenorphine free base, impurities A to C and other impurities in each sample, and the analysis conditions were as follows:

[0100] HPLC: 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 (diode array detector (DAD)) 210 nm; column temperature: 30°C; injection volume: 10 μL.

[0101] To evaluate the appearance of the formulations after storage, each sample was diluted 3 times with acetonitrile and the color of the sample was recorded using a Lovibond EC 2000 Gardner. The Gardner color is a one-dimensional color scale that is used to measure the yellowness of transparent liquids. Gardner color 1 is light yellow, while Gardner color 18 is dark brown.

[0102] The results of the stability study of formulations F28 and F29 are shown in Tables 2 and 3. The formulations of buprenorphine hexanoate were assayed using HPLC and found to contain impurity A1.

[0103] Table 2. Stability test results of preparations containing buprenorphine hexanoate (R1 = hexanoyl) stored at 25°C for 1 to 6 months

[0104]

[0105] M: month; VitE: vitamin E; ND: not detected.

[0106] Table 3. Stability test results of preparations containing buprenorphine hexanoate (R1 = hexanoyl) stored at 40°C for 1 to 6 months

[0107]

[0108]

[0109] M: month; VitE: vitamin E; ND: not detected.

[0110] In the stability test of buprenorphine hexanoate formulation, impurity A1 was associated with an impurity with a retention time of 17.5 minutes. These results indicate that the addition of 0.2% VitE to formulation F28 significantly inhibited the formation of total impurities and impurity A1 at temperatures of 25°C and 40°C. For example, Figure 2 and Figure 3As shown, by adding a stabilizer, the impurity A1 generated is less than 0.15%. It is worth noting that after 6 months of storage at 25°C, the formulation F28 with the addition of a stabilizer significantly reduced the formation of impurity A1 by about 51.9% compared to the formulation F29 without a stabilizer (i.e., 0.13% for formulation F28 and 0.27% for formulation F29). Similarly, after 6 months of storage at 40°C, the formulation F28 with the addition of a stabilizer even reduced the formation of impurity A1 by about 65.5% compared to the formulation F29 without a stabilizer (i.e., 0.1% for formulation F28 and 0.29% for formulation F29).

[0111] In addition, the appearance of the preparation is Figure 4 and Figure 5 As shown in FIG. 1 , it is shown that the preparation F29 shows a serious discoloration compared with the preparation 28. In addition, the formation profiles of the impurity A1 stored at 25°C and 40°C are respectively as shown in FIG. Figure 2 and Figure 3 As shown, USL stands for the upper specification limit, indicating that the impurities in the new drug product specifications should be less than 0.2% according to the ICH guideline Q3B (R2).

[0112] These results show that compared with formulation F29 without any stabilizer, formulation F28 with 0.2% VitE added as a stabilizer significantly inhibits the formation of impurity A1 at 25°C and 40°C, and the amount of impurity A1 can be maintained below USL for at least 6 months. It is also noted that the proportion of impurity A1 in formulation F29 decreased due to the gradual formation of buprenorphine free base and individual unknown impurities within 6 months, while no buprenorphine free base was observed in formulation F28.

[0113] In addition, the stability study results of formulations F30 to F40 are shown in Tables 4 and 5 below.

[0114] Table 4. Stability test results of preparations containing buprenorphine decanoate (R1 = decanoyl) stored at 40°C for a specified time

[0115]

[0116] VitE: vitamin E; ND: not detected.

[0117] Table 5. Stability test results of preparations containing buprenorphine hexanoate (R1 = hexanoyl) stored at 40°C for a specified time

[0118]

[0119]

[0120] VitE: vitamin E; VitC: vitamin C; BHA: butylated hydroxyanisole; TPGS: D-α-tocopheryl polyethylene glycol 1000 succinate; ND: not detected.

[0121] The buprenorphine derivative preparation was determined by HPLC, and impurities A1, A2, and C1 were found. In the stability test of buprenorphine hexanoate preparation, impurities A1 and C1 were associated with impurities with retention times of 17.5 minutes and 18.9 minutes, respectively. In the stability test of buprenorphine decanoate preparation, impurity A2 was associated with an impurity with a retention time of 30.1 minutes.

[0122] The above results show that the addition of stabilizers to the formulations containing buprenorphine derivatives significantly reduces the formation of total impurities. For example, Table 4 shows that compared with the formulation F30 without stabilizer, the formulation F31 with the addition of 0.5% VitE significantly reduces the formation of total impurities and impurity A2. Specifically, formulation F30 produces up to 1.23% of non-oxidized impurities (i.e., impurity A2) after 14 days, while formulation F31 produces less than 0.50% of non-oxidized impurities after 14 days, i.e., a reduction of about 61% of impurity A2.

[0123] Furthermore, as shown in Table 5, formulations F33 and F40, each with 2% VitE added, produced relatively small amounts of total impurities (0.23% and 0.08%) after 14 days, and non-oxidized impurities (ie, impurity A1) therein were observed to be less than 0.25%.

[0124] In addition, after 14 days, the impurities A1 and C1 formed in the preparations with added BHA or TPGS (i.e., preparations F34 and F38) were also significantly reduced. Specifically, the total amount of impurities A1 and C1 in preparations F34 and F38 was observed to be less than 0.60% after 14 days.

[0125] The results of the stability studies of Formulations F01 to F27 are shown in Tables 6 to 12 below.

[0126] Table 6. Stability test results of preparations containing buprenorphine free base (R1=H) stored at 60℃ for 1 day

[0127]

[0128] VitE: Vitamin E.

[0129] From the results in Table 6, it can be seen that the addition of VitE did not significantly reduce the impurity formation in the formulation containing buprenorphine free base, which means that although VitE is considered an antioxidant, it may not inhibit the oxidation of buprenorphine free base.

[0130] Table 7. Stability test results of preparations containing buprenorphine acetate (R1 = acetyl) stored at 60°C for 1 day

[0131]

[0132] VitE: vitamin E; ND: not detected.

[0133] Table 8. Stability test results of preparations containing buprenorphine hexanoate (R1 = hexanoyl) stored at 60°C for 1 day

[0134]

[0135] VitE: vitamin E; VitC: vitamin C; BHA: butylated hydroxyanisole; TPGS: D-α-tocopheryl polyethylene glycol 1000 succinate; ND: not detected; N / A: not applicable.

[0136] Table 9. Stability test results of preparations containing buprenorphine decanoate (R1 = decanoyl) stored at 60°C for 1 day

[0137]

[0138] VitE: vitamin E; ND: not detected.

[0139] Further, Tables 7 to 9 show that the addition of stabilizers to formulations containing different buprenorphine derivatives significantly reduces the formation of total impurities and non-oxidized impurities after storage at 60°C for 1 day. For example, the amount of various non-oxidized impurities (i.e., A1 to A3, B1 to B3, and C1) produced in formulations containing stabilizers (e.g., VitE and BHA) can be less than about 0.5%, and the amount of total impurities can be less than about 1%. In contrast, formulations without any stabilizer (i.e., formulations F05, F07, F15, F20, F23, and F24) not only show higher chromaticity, but also produce higher levels of total impurities, which are as high as about 1.7% to 5.6%.

[0140] Table 10. Stability test results of preparations containing buprenorphine acetate (R1 = acetyl) stored at 40°C for 1 month

[0141]

[0142] VitE: vitamin E; ND: not detected.

[0143] Table 11. Stability test results of preparations containing buprenorphine hexanoate (R1 = hexanoyl) stored at 40°C for 1 month

[0144]

[0145]

[0146] VitE: vitamin E; ND: not detected.

[0147] Table 12. Stability test results of preparations containing buprenorphine decanoate (R1 = decanoyl) stored at 40°C for 1 month

[0148]

[0149] VitE: Vitamin E.

[0150] Likewise, Tables 10 to 12 show that the addition of stabilizers to formulations containing different buprenorphine derivatives still has the ability to reduce the formation of total impurities and non-oxidative impurities and prevent discoloration during long-term storage after storage at 40°C for 1 month.

[0151] From the above results, it can be seen that in the stability test, the addition of stabilizers (e.g., VitE, VitC, BHA) can effectively inhibit the formation of non-oxidative impurities. The stabilizers used herein are generally considered to be antioxidants in previous knowledge. However, the present disclosure confirms that the stabilizers also unexpectedly reduce impurities formed by non-oxidative pathways.

[0152] Although the present disclosure has been described with a limited number of specific embodiments, those skilled in the art who benefit from the present disclosure will appreciate that other specific embodiments can be designed without departing from the scope of the present disclosure as disclosed herein. Therefore, the scope of the present disclosure should be limited only by the scope of the attached 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), formula (IIB) or formula (IIC): in, R1 is hydrogen, C1-C 20 Alkylcarbonyl or C6-C 18 Arylcarbonyl; wherein the active pharmaceutical ingredient is at least one of buprenorphine, its derivatives and pharmaceutically acceptable salts thereof; and Wherein, within the shelf life of the pharmaceutical composition, based on the total weight of the pharmaceutical composition, the amount of the compounds of formula (IIA), formula (IIB) and formula (IIC) is each less than 1% w / w.

2. The pharmaceutical composition according to claim 1, characterized in that During the shelf life, the amount of the compound of formula (IIA), formula (IIB) and formula (IIC) is each less than 0.5% w / w based on the total weight of the pharmaceutical composition.

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

4. The pharmaceutical composition according to claim 1, wherein The buprenorphine or its derivatives are represented by the following formula (I): wherein R1 is as defined in 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-tocopherol with double bonds, β-tocopherol with double bonds, γ-tocopherol with double bonds, δ-tocopherol with double bonds 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, glycerol, benzyl benzoate, dimethyl sulfoxide, N,N-dimethylacetamide, propylene glycol, dimethyl glycol, benzyl alcohol and any combination thereof.

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

11. A method for preparing the pharmaceutical composition of 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 of claim 11, further comprising stirring the pharmaceutical composition to form a homogenous solution.

13. The method according to claim 12, characterized in that The stirring is performed under heating.

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

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

16. The method according to claim 15, characterized in that The sterilization is selected from the group consisting of heat sterilization, filtration sterilization, radiation sterilization and any combination thereof.

17. The method according to claim 11, characterized in that The compounds represented by formula (IIA), formula (IIB) and formula (IIC) are formed by degradation of the active pharmaceutical ingredient.

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

19. The method according to claim 18, characterized in that The pharmaceutical composition is administered to the subject 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.

20. The method of claim 18, wherein: The pharmaceutical composition is administered to the subject via subcutaneous administration, intravenous administration, intramuscular administration, intradermal administration, transdermal administration, sublingual administration, topical administration, intraperitoneal administration, intraarticular administration, transmucosal administration, intraorgan administration, intraosseous administration or oral administration.

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