Stable formulations of buprenorphine

Abstract

Methods of providing pain relief to animals, such as cats, by administering a formulation comprising buprenorphine or a salt thereof are described. Also provided are formulations comprising buprenorphine or a salt thereof and an additive selected from butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and combinations thereof, as well as methods of storing and using such formulations.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This patent application is an international patent application claiming priority to U.S. Provisional Application No. 63 / 250,723, filed September 30, 2021, and U.S. Provisional Application No. 63 / 348,962, filed June 3, 2022, the disclosures of which are incorporated herein in their entireties.

[0002] The present disclosure relates to formulations, methods, uses, and devices containing buprenorphine or its salts. The present disclosure provides a method for providing pain relief to animals, such as cats. The present disclosure relates to stable formulations of buprenorphine or its salts. The present disclosure further provides a method for storing and shipping the stable formulations of buprenorphine or its salts, and related methods of use for treating or controlling pain, such as post-operative pain associated with surgical procedures in cats. [Background technology]

[0003] Buprenorphine is a potent partial agonist of the μ-opioid receptor that has been shown to be effective in controlling pain in a wide range of patients when delivered by a number of different routes of administration, including transdermal, intravenous, intramuscular, subcutaneous, epidural, intrathecal, or sublingual.

[0004] ZORBIUM (buprenorphine transdermal solution) is a long-acting transdermal formulation of buprenorphine useful, for example, for controlling post-operative pain associated with surgical procedures in cats. Early formulations of ZORBIUM required refrigerated storage (5° C.) to prevent degradation of the active ingredient (buprenorphine hydrochloride). Even with refrigerated storage, the shelf life is limited to about six months. Cold chain storage and distribution of pharmaceutical products is not only inconvenient and costly, but can also limit the scope of distribution of the product to locations that have appropriate storage equipment and sufficient storage space for the product. Thus, there is a need for a formulation containing buprenorphine that does not require refrigeration for distribution and storage. Additionally, there remains a need for a stable formulation containing buprenorphine that exhibits an improved shelf life (e.g., six months or more) even under room temperature and / or elevated temperature storage conditions. Summary of the Invention

[0005] One aspect of the invention is a formulation comprising buprenorphine or a salt thereof and at least one additive selected from the group including butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and combinations thereof.

[0006] Another aspect of the invention is a method for storing a formulation comprising storing the formulation at a temperature above 5°C.

[0007] Yet another aspect of the invention is a method for shipping a formulation comprising shipping the formulation at a temperature above 5°C.

[0008] A further aspect of the invention is a method for reducing pain in a mammalian subject in need thereof comprising administering to the subject the formulation. [Brief description of the drawings]

[0009] [Figure 1] UPLC (ultra performance liquid chromatography) and MS (mass spectrometry) parameters are shown. [Diagram 2]1 shows a UPLC chromatogram of a buprenorphine formulation under temperature stress, including its degradation products as peaks A and B. [Diagram 3] 1 shows a UPLC chromatogram of a buprenorphine formulation under temperature stress, including its degradation products as peaks A and B. [Figure 4A] The MS spectrum of peak A is shown. [Figure 4B] The MS spectrum of peak A is shown. [Figure 4C] The MS spectrum of peak A is shown, with the ion at m / z 933 extracted at lower intensity. [Diagram 5] The MS spectrum of peak B is shown. [Figure 6] Figure 2 shows the change in total degradation over 24 months at 25°C and 30°C for formulation K. [Figure 7] For formulation K, the long-term stability of the excipients at 25°C and 30°C is shown. [Figure 8] Figure 1 shows the change in potency adjusted for weight loss over 24 months at 25°C and 30°C for formulation K. [Figure 9] 1 shows the predicted change in potency over 36 months at 25° C. versus coded levels of the amounts of BHA and BHT used in formulations AP. [Figure 10] 1 shows predicted changes in potency versus total target amount (wt / wt%) of BHA and BHT for formulations A to P. [Figure 11] For each tube type (PF113 or PF413), the predicted change in potency versus the total target amount (wt / wt%) of BHA and BHT in formulations A to P is shown. [Figure 12] The predicted change in potency versus nitrogen (yes (Y) or no (N)) is shown for formulations A, B, N and O, overlaid with tube type (PF113 or PF413). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The present disclosure relates to formulations, methods, uses, and devices containing buprenorphine or salts thereof. The present disclosure provides a method for providing pain relief to animals, such as cats. The present disclosure relates to stable formulations of buprenorphine. The present disclosure further provides a method for storing and shipping the stable formulations of buprenorphine, and related methods of use for treating or controlling pain, such as post-operative pain associated with surgical procedures in cats.

[0011] Various methods of use relate to the treatment, control, and / or prevention of pain in animals (especially cats) in need thereof. These methods may include administering to the animal a pharmaceutical composition comprising a therapeutically effective amount of buprenorphine or a salt thereof. The pharmaceutical composition may be formulated as a liquid formulation (and, for example, is preferably not in the form of a patch). Administration may be transdermal (e.g., applied to the dorsal neck of the animal) as described herein. Additionally, the pain to be treated, controlled, and / or prevented may be post-operative pain associated with a surgical procedure (e.g., in cats).

[0012] Applicants have unexpectedly and surprisingly discovered that formulating buprenorphine with low concentrations of certain additives (e.g., butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), or combinations thereof) advantageously reduces or eliminates degradation of the active ingredient and provides long-term formulation stability of at least 6 months, at least 9 months, at least 12 months, at least 18 months, or at least 24 months. It has further unexpectedly been found that combinations of these additives provide long-term formulation stability even when stored unrefrigerated at room temperature (about 25° C.) conditions. Thus, the present invention provides improved formulations of buprenorphine that have significantly improved shelf life and do not require cold chain storage and shipping. Formulations of the present disclosure containing buprenorphine have been shown to be stable at ambient and higher temperatures for extended periods of time.

[0013] The formulation may contain any suitable amount of buprenorphine or a salt thereof. For example, the concentration of buprenorphine or a salt thereof may be about 5 mg / mL or more, about 10 mg / mL or more, about 15 mg / mL or more, about 20 mg / mL or more, about 25 mg / mL or more, about 30 mg / mL or more, about 35 mg / mL or more, or about 40 mg / mL or more. In some embodiments, the concentration of buprenorphine or a salt thereof is about 5 mg / mL to about 40 mg / mL, about 10 mg / mL to about 35 mg / mL, or about 10 mg / mL to about 30 mg / mL. In further embodiments, the concentration of buprenorphine or a salt thereof is about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, about 20 mg / mL, about 21 mg / mL, about 22 mg / mL, about 23 mg / mL, about 24 mg / mL, about 25 mg / mL, about 26 mg / mL, about 27 mg / mL, about 28 mg / mL, about 29 mg / mL, or about 30 mg / mL. In some embodiments, the buprenorphine is present as a salt, e.g., as buprenorphine hydrochloride.

[0014] Buprenorphine formulations, particularly those intended for transdermal administration, may optionally include penetration enhancers that may exert their effect by disrupting the skin lipid packing and thus altering the barrier function of the stratum corneum, modifying the partitioning of the drug at the stratum corneum-epidermal interface, and / or altering the thermodynamic properties of the drug.

[0015] The penetration enhancer may be present in any suitable amount. For example, the concentration of the penetration enhancer may be about 20 mg / mL or more, about 30 mg / mL or more, about 40 mg / mL or more, about 50 mg / mL or more, or about 60 mg / mL or more. In some embodiments, the concentration of the penetration enhancer is about 20 mg / mL to about 70 mg / mL, about 30 mg / mL to about 60 mg / mL, or about 40 mg / mL to about 60 mg / mL. In other embodiments, the concentration of the penetration enhancer is about 40 mg / mL, about 41 mg / mL, about 42 mg / mL, about 43 mg / mL, about 44 mg / mL, about 45 mg / mL, about 46 mg / mL, about 47 mg / mL, about 48 mg / mL, about 49 mg / mL, about 50 mg / mL, about 51 mg / mL, about 52 mg / mL, about 53 mg / mL, about 54 mg / mL, about 55 mg / mL, about 56 mg / mL, about 57 mg / mL, about 58 mg / mL, about 59 mg / mL, or about 60 mg / mL. An example of a suitable penetration enhancer can include padimate O.

[0016] In some embodiments, the buprenorphine formulation is a liquid at standard room temperature and pressure, which is useful for transdermal administration of the formulation to the skin of a subject, as well as other routes of administration.

[0017] Liquid formulations typically contain a solvent. For example, volatile solvents may be used to aid application and absorption of the formulation during transdermal administration. Suitable volatile solvents include alcohols such as isopropanol, ethanol, and combinations thereof. In some embodiments, the solvent is ethanol (dehydrated alcohol).

[0018] In accordance with the present invention, the buprenorphine formulation comprises at least one of the specific additives selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and combinations thereof. The addition of one or more of these additives has been found to improve long-term storage stability and / or eliminate the need for refrigerated storage to maintain stability. In some embodiments, the formulation contains a combination of BHA and BHT. In some embodiments, the antioxidant in the formulation consists of or consists essentially of BHA and BHT (i.e., comprises more than 90% by weight, or even more than 95% by weight, of the total amount of antioxidants). This combination of additives provides excellent formulation stability over a wide range of temperatures and storage conditions.

[0019] The concentration of the at least one additive (BHA and / or BHT) can be about 0.1 mg / mL or more, about 0.2 mg / mL or more, about 0.3 mg / mL or more, about 0.4 mg / mL or more, about 0.5 mg / mL or more, about 0.6 mg / mL or more, about 0.8 mg / mL or more, about 0.9 mg / mL or more, about 1.0 mg / mL or more, about 1.1 mg / mL or more, about 1.2 mg / mL or more, about 1.3 mg / mL or more, about 1.4 mg / mL or more, or about 1.5 mg / mL or more. In some embodiments, the concentration of the at least one additive is from about 0.1 mg / mL to about 1.5 mg / mL, from about 0.1 mg / mL to about 1.0 mg / mL, from about 0.2 mg / mL to about 1.0 mg / mL, from about 0.2 mg / mL to about 0.9 mg / mL, from about 0.3 mg / mL to about 0.9 mg / mL, from about 0.4 mg / mL to about 0.9 mg / mL, from about 0.5 mg / mL to about 0.9 mg / mL, or from about 0.6 mg / mL to about 0.8 mg / mL.

[0020] The concentration of BHA is typically 0.04 mg / mL or more, about 0.1 mg / mL or more, about 0.2 mg / mL or more, about 0.3 mg / mL or more, about 0.4 mg / mL or more, about 0.5 mg / mL or more, about 0.7 mg / mL or more, or about 1.0 mg / mL or more. For example, in some embodiments, the concentration of BHA is about 0.04 mg / mL to about 1.0 mg / mL, about 0.1 mg / mL to about 1.0 mg / mL, about 0.2 mg / mL to about 1.0 mg / mL, about 0.2 mg / mL to about 0.7 mg / mL, about 0.3 mg / mL to about 0.7 mg / mL, about 0.3 mg / mL to about 0.6 mg / mL, about 0.3 mg / mL to about 0.5 mg / mL, or about 0.3 mg / mL to about 0.4 mg / mL of BHA.

[0021] The concentration of BHT is typically about 0.1 mg / mL or more, about 0.2 mg / mL or more, about 0.3 mg / mL or more, about 0.4 mg / mL or more, about 0.5 mg / mL or more, about 0.7 mg / mL or more, or about 1.0 mg / mL or more. For example, in some embodiments, the concentration of BHT is about 0.1 mg / mL to about 1.0 mg / mL, about 0.2 mg / mL to about 1.0 mg / mL, about 0.2 mg / mL to about 0.7 mg / mL, about 0.3 mg / mL to about 0.7 mg / mL, about 0.3 mg / mL to about 0.6 mg / mL, about 0.3 mg / mL to about 0.5 mg / mL, or about 0.3 mg / mL to about 0.4 mg / mL.

[0022] In formulations containing both BHA and BHT additives, the weight ratio of BHT to BHA can be about 1.1:1 or more, about 2:1 or more, about 5:1 or more, or about 10:1 or more. As detailed in Example 1, the presence of both BHA and BHT reduces the rate of depletion of both of these compounds, especially when BHT is present in an amount at least equal to BHA, providing superior formulation stability. In some embodiments, the weight ratio of BHT to BHA is about 1:1.

[0023] In some embodiments, the formulation comprises a combination of buprenorphine HCl, Padimate O, ethanol, and BHA and BHT additives. In such embodiments, the concentration of buprenorphine HCl is from about 10 mg / mL to about 30 mg / mL, the concentration of Padimate O is from about 40 mg / mL to about 60 mg / mL, the concentration of the combined BHA and BHT is from about 0.5 mg / mL to about 0.9 mg / mL, the weight ratio of BHT to BHA is about 1:1 or greater, and the solvent comprises ethanol.

[0024] The stability of buprenorphine in the formulations of the present invention can be assessed by determining the relative decrease in the concentration of buprenorphine degradation products. These buprenorphine degradation products have been identified and are further described in Example 1. Specifically, the buprenorphine degradation products are pseudobuprenorphine (a dimer of buprenorphine) and / or positional isomers thereof.

[0025] In some embodiments, the formulations are stable such that after storage at 25° C. and higher for up to 3 months, 6 months, 9 months, 12 months, or 24 months, the concentration of buprenorphine degradation products in the formulation is lower than the concentration of buprenorphine degradation products in an otherwise identical formulation that does not contain BHA and / or BHT.

[0026] In various such embodiments, the concentration of buprenorphine degradation products in the formulation after storage for 3 months at 25° C. can be about 0.05 mg / mL or less, about 0.04 mg / mL or less, about 0.03 mg / mL or less, about 0.02 mg / mL or less, about 0.01 mg / mL or less, about 0.009 mg / mL or less, about 0.008 mg / mL or less, about 0.007 mg / mL or less, about 0.006 mg / mL or less, about 0.005 mg / mL or less, about 0.004 mg / mL or less, about 0.003 mg / mL or less, about 0.002 mg / mL or less, or about 0.001 mg / mL or less. In this and other embodiments, the concentration of buprenorphine degradation products in the formulation after storage for 3 months at 30° C. can be about 0.08 mg / mL or less, about 0.07 mg / mL or less, about 0.06 mg / mL or less, about 0.05 mg / mL or less, about 0.04 mg / mL or less, about 0.03 mg / mL or less, about 0.02 mg / mL or less, about 0.01 mg / mL or less, about 0.009 mg / mL or less, about 0.008 mg / mL or less, about 0.007 mg / mL or less, about 0.006 mg / mL or less, about 0.005 mg / mL or less, about 0.004 mg / mL or less, about 0.003 mg / mL or less, about 0.002 mg / mL or less, or about 0.001 mg / mL or less. In further embodiments, the concentration of buprenorphine degradation products in the formulation after storage at 40° C. for 3 months is about 3 mg / mL or less, about 2.5 mg / mL or less, about 2 mg / mL or less, about 1.5 mg / mL or less, about 1 mg / mL or less, about 0.90 mg / mL or less, about 0.80 mg / mL or less, about 0.70 mg / mL or less, about 0.60 mg / mL or less, about 0.50 mg / mL or less, about 0.40 mg / mL or less, or about 0.50 mg / mL or less. The concentration may be about 0.30 mg / mL or less, about 0.20 mg / mL or less, about 0.10 mg / mL or less, about 0.09 mg / mL or less, about 0.08 mg / mL or less, about 0.07 mg / mL or less, about 0.06 mg / mL or less, about 0.05 mg / mL or less, about 0.04 mg / mL or less, about 0.03 mg / mL or less, about 0.02 mg / mL or less, or about 0.01 mg / mL or less.In yet another embodiment, the concentration of buprenorphine degradation products in the formulation after storage for 12 months at 25° C. is about 0.20 mg / mL or less, about 0.15 mg / mL or less, about 0.10 mg / mL or less, about 0.09 mg / mL or less, about 0.08 mg / mL or less, about 0.07 mg / mL or less, about 0.06 mg / mL or less, about 0.05 mg / mL or less, about 0.04 mg / mL or less, about 0. The concentration may be about 0.03 mg / mL or less, about 0.02 mg / mL or less, about 0.01 mg / mL or less, about 0.009 mg / mL or less, about 0.008 mg / mL or less, about 0.007 mg / mL or less, about 0.006 mg / mL or less, about 0.005 mg / mL or less, about 0.004 mg / mL or less, about 0.003 mg / mL or less, about 0.002 mg / mL or less, or about 0.001 mg / mL or less.

[0027] The formulation of the present invention can be packaged as a unit dose. The unit dose can be any volume. For example, the unit dose can be about 0.5 mL to about 1.0 mL. In some embodiments, the unit dose is about 0.7 mL. In other embodiments, the unit dose is about 1.0 mL.

[0028] The unit dose may be contained in any suitable container. In some embodiments, the container is a tube. In some embodiments, the tube is an aluminum and polymer laminate tube, such as PF113 tube from Neopac US, Inc. (Wilson, North Carolina).

[0029] The dosage of buprenorphine can be in the range of about 1 mg / kg to about 10 mg / kg, about 2 mg / kg to about 8 mg / kg, or about 2.5 mg / kg to about 7 mg / kg.

[0030] The present disclosure is also directed to methods for storing the formulations described herein, including storing the formulations at a temperature above 5° C. The formulations may be advantageously stored at a temperature of about 5° C. to about 25° C. The formulations may be stored for up to 6 months, 9 months, 12 months, 24 months, 36 months, or longer.

[0031] Another aspect of the present disclosure is a method for shipping a formulation described herein, comprising shipping the formulation at a temperature above 5° C. The formulation may be shipped at a temperature of about 5° C. to about 25° C. By providing a formulation that maintains stability and efficacy during extended storage and shipping operations, even in the absence of refrigeration, handling and administration of the formulation is simplified.

[0032] The present disclosure is further directed to a method for alleviating pain in a mammalian subject in need thereof, comprising administering to the subject a formulation described herein. The pain may be post-operative pain associated with a surgical procedure. The mammalian subject may be any mammal. In some embodiments, the mammalian subject is a companion animal, such as a cat or a dog.

[0033] The formulation is typically administered at a temperature similar to or about the same as the temperature at which it is stored, e.g., about 5°C to about 25°C, about 10°C to about 25°C, or about 15°C to about 25°C. For example, the formulation may be administered at a temperature within 5°C of the temperature at which the formulation is stored prior to administration. The formulations described herein are stable over a wide range of temperatures and do not require refrigeration, thus eliminating the need to heat the formulation prior to administration. The present invention provides improved formulations of buprenorphine that have a longer shelf life of 9 months, 12 months, 24 months, 36 months, or more, and do not require cold chain storage and shipping (e.g., can be stored at about 25°C).

[0034] The formulation may be administered transdermally, intravenously, intramuscularly, subcutaneously, epidurally, intrathecally, or sublingually. In some embodiments, the formulation is administered transdermally.

[0035] The formulations of the present invention may be packaged in an applicator comprising a reservoir for containing the formulation and an applicator tip for applying the formulation to a subject. The applicator tip may be designed to facilitate the product reaching the skin through the hair without the need to shave the application site. The formulations of the present invention may be packaged in a unit dose pack. The package preferably contains a single dose of the formulation. The package may be any suitable material, such as an aluminum polymer laminate tube, that prevents solvent evaporation or oxygen ingress. The present disclosure provides a device for use in a method for treating pain in a companion animal. The device comprises a reservoir for storing the TBS formulation described herein at room temperature and an applicator for administering the formulation to the skin of the animal. The applicator is preferably adapted to apply the formulation through the fur of the companion animal.

[0036] The therapeutic agent may be administered locally to the dorsal neck (base of the skull). For example, the tip of the applicator tube can be placed directly on the skin at the application site, by brushing aside the hair if necessary, and the entire dose volume is administered at a single location. Alternatively, the dose volume may be distributed over two or more sites. The formulation may be applied by gently holding the subject (e.g., a cat) to prevent shaking or rubbing during application. The applicator is brought into contact with the skin and the contents are dispensed. The applicator is removed from the application site, avoiding contact with the hair. Contact with the application site should be avoided while the formulation dries (approximately 30 minutes after administration).

[0037] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. In case of conflict, the present specification, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and are not intended to be limiting.

[0038] The term "about," when used in connection with a measurable numerical variable, refers to the stated value of the variable, and all values ​​of the variable that are within the experimental error of the stated value or within ±10 percent of the stated value, whichever is greater.

[0039] The term "effective amount" refers to an amount that provides a desired benefit to a subject, and includes both therapeutic and regulatory administration. This amount may vary from subject to subject, and depends on several factors, including the subject's overall physical condition and the severity of the underlying cause of the condition being treated, concurrent treatments, and the amount of the disclosed compound used to maintain the desired response at a beneficial level.

[0040] The effective amount can be readily determined by the attending physician as one of ordinary skill in the art by the use of known techniques and by observing results obtained under similar circumstances. In determining the effective amount, dose, several factors are considered by the attending physician, including, but not limited to, the species of the patient, its size, age, and general health, the particular condition, disorder, infection, or disease involved, the extent or involvement or severity of the condition, disorder, or disease, the response of the individual patient, the particular compound administered, the mode of administration, the bioavailability characteristics of the preparation administered, the dose regimen selected, the use of concomitant medications, and other relevant circumstances. The effective amount, therapeutic dose of the active ingredient of the present disclosure may be in the range of, for example, 0.5 mg to 100 mg. The specific amount can be determined by one of ordinary skill in the art. These dosage amounts are based on a subject having a mass of about 1 kg to about 20 kg, although a diagnostician would be able to determine the appropriate dose for a subject whose mass falls outside this weight range. The effective amount, therapeutic dose of the active ingredient of the present disclosure may be in the range of, for example, 0.1 mg to 10 mg / kg of the subject. Dosing regimens are expected to be once daily, once weekly, or once monthly administration.

[0041] The terms "subject" and "patient" refer to and include non-human mammalian animals, such as dogs, cats, mice, rats, guinea pigs, rabbits, ferrets, cows, horses, sheep, goats, and pigs. More specific subjects are pet or companion mammalian animals, such as dogs and cats, as well as mice, rats, guinea pigs, ferrets, and rabbits.

[0042] The terms "treating," "to treat," "treated," or "treatment" include, but are not limited to, inhibiting, slowing, halting, alleviating, ameliorating, reversing the progression or severity of existing symptoms, or preventing a disorder, condition, or disease. A therapeutic agent may be applied or administered therapeutically.

[0043] Those skilled in the art will understand that certain compounds of the present disclosure exist as isomers. All stereoisomers of the compounds of the present disclosure, including geometric isomers, enantiomers, and diastereomers, in any ratio, are contemplated to be within the scope of the present disclosure. Those skilled in the art will also understand that certain compounds of the present disclosure exist as tautomers. All tautomeric forms of the compounds of the present disclosure are contemplated to be within the scope of the present disclosure.

[0044] For the recitation of numerical ranges herein, each intervening number is expressly contemplated to the same degree of precision. For example, for the range 6 to 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0 to 7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are expressly contemplated.

[0045] In certain embodiments, the formulation can include buprenorphine or a salt thereof and at least one additive selected from the group including butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and combinations thereof.

[0046] The concentration of buprenorphine or a salt thereof may be about 5 mg / mL or more, about 10 mg / mL or more, about 15 mg / mL or more, about 20 mg / mL or more, about 25 mg / mL or more, about 30 mg / mL or more, about 35 mg / mL or more, or about 40 mg / mL or more. The concentration of buprenorphine or a salt thereof may be about 5 mg / mL to about 40 mg / mL, about 10 mg / mL to about 35 mg / mL, or about 10 mg / mL to about 30 mg / mL. The concentration of buprenorphine or a salt thereof can be about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, about 20 mg / mL, about 21 mg / mL, about 22 mg / mL, about 23 mg / mL, about 24 mg / mL, about 25 mg / mL, about 26 mg / mL, about 27 mg / mL, about 28 mg / mL, about 29 mg / mL, or about 30 mg / mL.

[0047] The buprenorphine or salts thereof can include buprenorphine hydrochloride.

[0048] The formulation may further comprise a penetration enhancer. The concentration of the penetration enhancer may be about 20 mg / mL or more, about 30 mg / mL or more, about 40 mg / mL or more, about 50 mg / mL or more, or about 60 mg / mL or more. The concentration of the penetration enhancer may be about 20 mg / mL to about 70 mg / mL, about 30 mg / mL to about 60 mg / mL, or about 40 mg / mL to about 60 mg / mL. The concentration of the penetration enhancer can be about 40 mg / mL, about 41 mg / mL, about 42 mg / mL, about 43 mg / mL, about 44 mg / mL, about 45 mg / mL, about 46 mg / mL, about 47 mg / mL, about 48 mg / mL, about 49 mg / mL, about 50 mg / mL, about 51 mg / mL, about 52 mg / mL, about 53 mg / mL, about 54 mg / mL, about 55 mg / mL, about 56 mg / mL, about 57 mg / mL, about 58 mg / mL, about 59 mg / mL, or about 60 mg / mL. The penetration enhancer can include padimate O.

[0049] The formulation may further comprise a solvent. The solvent may be a volatile solvent. The solvent may be selected from the group consisting of isopropanol, ethanol, and combinations thereof. The solvent may comprise ethanol.

[0050] The formulations may be stable such that after storage at 25° C. for up to 3 months, 6 months, 9 months, 12 months, or 24 months, the concentration of buprenorphine degradation products in the formulation is less than the concentration of buprenorphine degradation products in an otherwise identical formulation that does not contain BHA and / or BHT.

[0051] The concentration of buprenorphine degradation products in the formulation after storage for 3 months at 25° C. can be about 0.05 mg / mL or less, about 0.04 mg / mL or less, about 0.03 mg / mL or less, about 0.02 mg / mL or less, about 0.01 mg / mL or less, about 0.009 mg / mL or less, about 0.008 mg / mL or less, about 0.007 mg / mL or less, about 0.006 mg / mL or less, about 0.005 mg / mL or less, about 0.004 mg / mL or less, about 0.003 mg / mL or less, about 0.002 mg / mL or less, or about 0.001 mg / mL or less.

[0052] The concentration of buprenorphine degradation products in the formulation after storage for 3 months at 30° C. can be about 0.08 mg / mL or less, about 0.07 mg / mL or less, about 0.06 mg / mL or less, about 0.05 mg / mL or less, about 0.04 mg / mL or less, about 0.03 mg / mL or less, about 0.02 mg / mL or less, about 0.01 mg / mL or less, about 0.009 mg / mL or less, about 0.008 mg / mL or less, about 0.007 mg / mL or less, about 0.006 mg / mL or less, about 0.005 mg / mL or less, about 0.004 mg / mL or less, about 0.003 mg / mL or less, about 0.002 mg / mL or less, or about 0.001 mg / mL or less.

[0053] The concentration of buprenorphine degradation products in the formulation after storage for 3 months at 40° C. can be about 3 mg / mL or less, about 2.5 mg / mL or less, about 2 mg / mL or less, about 1.5 mg / mL or less, about 1 mg / mL or less, about 0.90 mg / mL or less, about 0.80 mg / mL or less, about 0.70 mg / mL or less, about 0.60 mg / mL or less, about 0.50 mg / mL or less, about 0.40 mg / mL or less, about 0.30 mg / mL or less, about 0.20 mg / mL or less, about 0.10 mg / mL or less, about 0.09 mg / mL or less, about 0.08 mg / mL or less, about 0.07 mg / mL or less, about 0.06 mg / mL or less, about 0.05 mg / mL or less, about 0.04 mg / mL or less, about 0.03 mg / mL or less, about 0.02 mg / mL or less, or about 0.01 mg / mL or less.

[0054] The concentration of buprenorphine degradation products in the formulation after storage for 12 months at 25° C. can be about 0.20 mg / mL or less, about 0.15 mg / mL or less, about 0.10 mg / mL or less, about 0.09 mg / mL or less, about 0.08 mg / mL or less, about 0.07 mg / mL or less, about 0.06 mg / mL or less, about 0.05 mg / mL or less, about 0.04 mg / mL or less, about 0.03 mg / mL or less, about 0.02 mg / mL or less, about 0.01 mg / mL or less, about 0.009 mg / mL or less, about 0.008 mg / mL or less, about 0.007 mg / mL or less, about 0.006 mg / mL or less, about 0.005 mg / mL or less, about 0.004 mg / mL or less, about 0.003 mg / mL or less, about 0.002 mg / mL or less, or about 0.001 mg / mL or less.

[0055] Buprenorphine degradation products can include polymers of buprenorphine.

[0056] Buprenorphine degradation products can include dimers of buprenorphine and / or positional isomers thereof.

[0057] The concentration of the at least one additive can be about 0.1 mg / mL or more, about 0.2 mg / mL or more, about 0.3 mg / mL or more, about 0.4 mg / mL or more, about 0.5 mg / mL or more, about 0.6 mg / mL or more, about 0.8 mg / mL or more, about 0.9 mg / mL or more, about 1.0 mg / mL or more, about 1.1 mg / mL or more, about 1.2 mg / mL or more, about 1.3 mg / mL or more, about 1.4 mg / mL or more, or about 1.5 mg / mL or more.

[0058] The concentration of the at least one additive can be from about 0.1 mg / mL to about 1.5 mg / mL, from about 0.1 mg / mL to about 1.0 mg / mL, from about 0.2 mg / mL to about 1.0 mg / mL, from about 0.2 mg / mL to about 0.9 mg / mL, from about 0.3 mg / mL to about 0.9 mg / mL, from about 0.4 mg / mL to about 0.9 mg / mL, from about 0.5 mg / mL to about 0.9 mg / mL, or from about 0.6 mg / mL to about 0.8 mg / mL.

[0059] The formulation can include BHA. The formulation can include BHT. The formulation can include BHA and BHT, or the antioxidants in the formulation consist or consist essentially of BHA and BHT (i.e., constitute more than 90% by weight, or even more than 95% by weight, of the total amount of antioxidants). The concentration of BHA can be 0.04 mg / mL or more, about 0.1 mg / mL or more, about 0.2 mg / mL or more, about 0.3 mg / mL or more, about 0.4 mg / mL or more, about 0.5 mg / mL or more, about 0.7 mg / mL or more, or about 1.0 mg / mL or more. The concentration of BHA may be about 0.04 mg / mL to about 1.0 mg / mL, about 0.1 mg / mL to about 1.0 mg / mL, about 0.2 mg / mL to about 1.0 mg / mL, about 0.2 mg / mL to about 0.7 mg / mL, about 0.3 mg / mL to about 0.7 mg / mL, about 0.3 mg / mL to about 0.6 mg / mL, about 0.3 mg / mL to about 0.5 mg / mL, or about 0.3 mg / mL to about 0.4 mg / mL of BHA. The concentration of BHT may be about 0.1 mg / mL or more, about 0.2 mg / mL or more, about 0.3 mg / mL or more, about 0.4 mg / mL or more, about 0.5 mg / mL or more, about 0.7 mg / mL or more, or about 1.0 mg / mL or more. The concentration of BHT can be about 0.1 mg / mL to about 1.0 mg / mL, about 0.2 mg / mL to about 1.0 mg / mL, about 0.2 mg / mL to about 0.7 mg / mL, about 0.3 mg / mL to about 0.7 mg / mL, about 0.3 mg / mL to about 0.6 mg / mL, about 0.3 mg / mL to about 0.5 mg / mL, or about 0.3 mg / mL to about 0.4 mg / mL.

[0060] The weight ratio of BHT to BHA can be about 1.1:1 or greater, about 2:1 or greater, about 5:1 or greater, or about 10:1 or greater.

[0061] The formulation is About 10 mg / mL to about 30 mg / mL of buprenorphine hydrochloride; About 40mg / mL to about 60mg / mL of Padimate O, a combination of BHA and BHT from about 0.5 mg / mL to about 0.9 mg / mL, the weight ratio of BHT to BHA being about 1:1 or greater; and a solvent comprising ethanol.

[0062] The formulation can be packaged as a unit dose. The unit dose can be contained in an aluminum and polymer laminate tube. The unit dose can be about 0.5 ml to about 1.0 ml. The unit dose can be about 1.0 ml.

[0063] In certain embodiments, the methods for storing the formulations described herein may include storing the formulation at a temperature above 5° C. The formulations may be stored at a temperature of about 5° C. to about 25° C. The formulations may be stored for up to 12 months, 24 months, or 36 months. The formulations may be stored at about 25° C.

[0064] In certain embodiments, the methods for shipping the formulations described herein can include shipping the formulation at a temperature greater than 5° C. The formulation can be shipped at a temperature of about 5° C. to about 25° C. The formulation can be shipped at about 25° C.

[0065] In certain embodiments, a method for reducing pain in a mammalian subject in need thereof may include administering to the subject a formulation described herein. The formulation may be administered transdermally, intravenously, intramuscularly, subcutaneously, epidurally, intrathecally, or sublingually. The formulation may be administered transdermally.

[0066] The pain may be post-operative pain associated with a surgical procedure.

[0067] The subject may be a cat.

[0068] The formulation may be administered at a temperature of about 5°C to about 25°C, about 10°C to about 25°C, or about 15°C to about 25°C.

[0069] The formulation may be administered at a temperature within 5° C. of the temperature at which the formulation may be stored prior to administration.

[0070] The formulation may be administered at approximately the same temperature at which the formulation may be stored prior to administration.

[0071] The formulation cannot be heated prior to administration. EXAMPLES

[0072] The present invention has multiple aspects, illustrated by the following non-limiting examples.

[0073] Example 1 Sixteen formulation batches of buprenorphine HCl (20 mg / mL buprenorphine, 8 mg / 0.4 mL per tube) containing various amounts of additives BHA and BHT were prepared according to the Design of Experiments (DOE) described below in Tables 1 and 2. Each formulation also contained 50 mg / mL Padimate O (a permeation enhancer) and anhydrous ethanol solvent (qs). [Table 1] [Table 2] The prepared formulation batches were evaluated for stability according to the test plan shown in Table 3 below. [Table 3]

[0074] At each time point, the properties shown in Table 4 were collected and used for evaluation. The 0 month data were collected initially after packaging and the results are used as general initial time results for all temperature / relative humidity storage conditions. [Table 4]

[0075] The related substances measured (as described in Table 4) are the two most prominent peaks ("Degradation Product 1" and "Degradation Product 2") that are shown to increase over time when the product is exposed to oxidative conditions. As explained further below, these peaks correspond to pseudobuprenorphine and two degradation products consistent with positional isomers of pseudobuprenorphine. The total related substances used in the analysis in this example is the sum of these two individual related substances.

[0076] "Degradation product 1" and "degradation product 2" were identified by UPLC-MS methodology (Figure 1). A control formulation containing buprenorphine but no BHA or BHT was stressed for 3 days at 50 °C. Samples were prepared for analysis by diluting 50 μL of the formulation with 950 μL of 50 / 50 water / acetonitrile for UPLC and Aligent TOF MS. Peaks A and B in the UPLC chromatogram correspond to "degradation product 1" and "degradation product 2," respectively (Figures 2-3). The MS spectrum of peak A was a doubly charged ion at m / z 467 and an ion at m / z 933 (Figures 4A-4B). To obtain a more accurate mass value, the ion at m / z 933 was extracted at lower intensity (Figure 4C).

[0077] After analysis, the best fitted empirical formula was C 58 H 80 Peak A was C 58 H 80 This is consistent with pseudobuprenorphine, a dimer of buprenorphine with a chemical formula of N2O8 and an exact mass of 932.5915. The structure of pseudobuprenorphine is shown below. [ka]

[0078] Peak B is believed to be an isomer of peak A based on its MS spectrum (Figure 5). Peak B is consistent with a positional isomer of pseudobuprenorphine.

[0079] For comparison, buprenorphine has an exact mass of 467.3036 C 29 H 41 It has the chemical formula NO4 and its structure is shown below: [ka]

[0080] Forty tubes per batch of the buprenorphine formulations listed in Table 2 were placed in the chamber (10 tubes per storage condition) and monitored for stability over time and analyzed for potency (i.e., concentration of buprenorphine) and degradation products according to the analytical method and stability study plan (Table 3). The stability data are presented in Tables 5-8 below. [Table 5-1] [Table 5-2] [Table 5-3] [Table 6-1] [Table 6-2] [Table 6-3] [Table 7-1] [Table 7-2] [Table 7-3] [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4]

[0081] Long-term stability analysis of targeted formulations Data over 24 months for Formulation K from Tables 5-8 are shown in Figures 6-8. This portion of the analysis focuses on this formulation (Formulation Batch K, containing 0.5% / 0.5% wt / wt BHA / BHT). An unexpected upward trend in the titer results was observed, but the total degradation product results are within acceptable limits for good product quality at both 25°C and 30°C (Figure 6). Although BHT is preferentially oxidized and consumed faster than BHA, the total amount of BHA and BHT remains well above 10% of the starting BHA and BHT levels (Figure 7).

[0082] To further understand the potential causes of the observed titer increase, the tube weight data was examined (see Table 8). The data shows a weight trend that correlates with the titer increase. Specifically, the weight trend shows that there is some evidence of a weight loss in the PF113 tubes and a weight increase in the PF413 tubes.

[0083] No significant liquid leakage from the PF113 tubes was observed. Although all tubes were filled and sealed manually for this study, one potential cause of the decline trend in the PF113 packaging material is that the caps on the tubes did not have a tight or lasting seal, causing the formulation to slowly lose volume and mass due to evaporation of ethanol vapor. Another possibility is that ethanol solvent leaked from the sealed end of the tube due to a non-optimized manual seal. Assuming that the weight loss of formulation batch K was due to evaporation loss of ethanol, the adjusted potency (corrected for the volume of EtOH loss) is shown in Figure 8. No significant trend is observed in the adjusted potency results.

[0084] The starting potency was significantly above the target potency of 20 mg / mL, so the adjusted results are considered to be very close to the currently approved upper regulatory tolerance limit of 21.0 mg / mL. This may be due to the manual filling of these formulation batches, which may have resulted in some evaporative loss of ethanol (EtOH) prior to filling into the tubes, so commercial production of this material would use an automated filling line under more controlled conditions.

[0085] Potential improvements in stability due to packing in a nitrogen atmosphere, as well as differences between the two tube types, were also evaluated, but neither was found to be a significant factor affecting stability.

[0086] Discussion of results A summary of the relevant data from Table 5 is provided below in Table 9. All formulations in Table 9 did not use nitrogen blanketing during filling and used tubing type PF113. In Table 9, "0" indicates 0 mg / mL BHA and / or BHT, "L" indicates 0.0404 mg / mL for BHA and 0.162 mg / mL for BHT, "M" indicates 0.162 mg / mL for BHA and 0.404 mg / mL for BHT, and "H" indicates 0.404 mg / mL for BHA and 0.727 mg / mL for BHT. The total active (buprenorphine hydrochloride) degradation product values ​​reported in Table 9 were calculated by subtracting the initial (0 month) total degradation products from the total degradation products measured at 3 or 12 months at a given storage temperature (25° C., 30° C., or 40° C.) and relative humidity. [Table 9]

[0087] When the tubes were stored at 25°C and 60% relative humidity for 12 months, the total buprenorphine hydrochloride degradation products of the test formulations containing BHA alone (Formulation I), BHT alone (Formulation D), or both BHA and BHT (Formulations G, H, K, L, and M) ranged from 0.0018 to 0.1322 mg / mL. In contrast, formulation N (containing no BHA or BHT) contained 2.1901 mg / mL of total degradation products immediately after 3 months at 25°C. Thus, at room temperature, formulations containing at least one of BHA or BHT unexpectedly exhibited significantly lower concentrations of degradation products (i.e., demonstrated greater buprenorphine hydrochloride stability) even after 1 year of storage compared to formulation N without BHA or BHT after only one-quarter (3 months) of storage time at room temperature.

[0088] This surprising improvement in formulation stability was also observed at higher storage temperatures and relative humidity, both of which can adversely affect stability. After 3 months at 30° C. and 65% relative humidity, the concentrations of total buprenorphine hydrochloride degradation products for test formulations D, G, H, I, K, L, and M, which contain at least one of BHA and BHT, ranged from 0.0013 to 0.06 mg / mL. In contrast, formulation N contained 4.3268 mg / mL of total buprenorphine hydrochloride degradation products. Similarly, after 3 months at 40° C. and 75% relative humidity, the concentrations of total degradation products for test formulations D, G, H, I, K, L, and M ranged from 0.0188 to 1.9905 mg / mL, while formulation N contained 8.1993 mg / mL of total degradation products. Thus, after 3 months at elevated storage temperatures of 30° C. or 40° C., formulations containing at least one of BHA or BHT surprisingly exhibited significantly lower concentrations of buprenorphine hydrochloride degradation products compared to formulation N, which did not contain BHA or BHT.

[0089] Furthermore, formulations containing high (H) or medium (M) levels of both BHA and BHT (formulations H, K, and L) were more stable compared to formulations containing only one of BHA and BHT (formulations D and I) and formulations containing low (L) levels of BHA or BHT (formulations G and M). Formulations H, K, and L accumulated the least total degradation products after 12 months at 25° C. and after 3 months at 25° C., 30° C., and 40° C.

[0090] The BHA / BHT stability data in Table 7 further highlight these unexpected results. For example, after 12 months at 25° C., the residual concentration of BHA is lower in formulation I containing no BHT (77.97% of original BHA) compared to the residual concentration of BHA in formulation L containing a high (H) amount of BHT (99.27% ​​of original BHA). Similarly, after 12 months at 25° C., the residual concentration of BHT is lower in formulation D containing no BHA (62.73% of original BHT) compared to the residual concentration of BHT in formulation L containing a high (H) amount of BHA (86.95% of original BHT). When examining formulation K containing a high (H) level of BHA and a medium (M) level of BHT after 12 months at 25° C., the BHT level is further reduced (79.37% of original BHA) compared to the BHA level (98.81% of original BHT). Similarly, when examining formulation L containing high (H) levels of both BHA and BHT after 12 months at 25° C., the BHT levels are reduced further (86.95% of original BHT) than the BHA levels (99.27% ​​of original BHA). Thus, although the BHT levels generally decrease at a higher rate than the BHA levels, the presence of both BHA and BHT reduces the rate of decrease of both of these compounds, providing for superior formulation stability.

[0091] In summary, these results show that relatively low concentrations of the additives BHA and / or BHT, even more preferably BHA and BHT, unexpectedly provide significantly enhanced long-term storage stability. Furthermore, the results show that enhanced long-term storage stability can be achieved without refrigeration, even when the formulation is stored at high temperatures and relative humidities.

[0092] Example 2 36-month stability analysis The study design provided for the assessment and modeling of the rate of change over time as a function of temperature. The Arrhenius Time-Scaled Least Squares (ATLS) methodology was applied to this data to estimate the expected rate of change at the desired commercial storage conditions (reference temperature = 25°C) and the expected total rate of change over the desired commercial shelf life (36 months). See Rauk et al., "Arrhenius Time-Scaled Least Squares: A Simple, Robust Approach to Accelerated Stability Data Analysis for Bioproducts," Journal of Pharmaceutical Sciences, 103:2278-2286, 2014, DOI 10.1002 / jps.24063. The models used to fit the data in this analysis are either linear trend models or quadratic trend models. Y batch (t ref )=θ batch +α batch t ref (1) or Y batch (t ref )=θ batch +α batch t ref +β batch t 2 ref (2) During the ceremony,

number

[0093] This model uses an Arrhenius kinetic model for the time scale t refThe effect of accelerating the rate of change with increasing temperature is captured by varying . The model that best fits the data is selected (either linear (1) or quadratic (2) on the Arrhenius time scale). The key parameter estimated in the model is the activation energy E a , which is chosen by finding the value that minimizes the sum of squared errors for the model predictions. Each batch is assigned an estimated intercept, θ batch , linear slope, α batch and if a quadratic model is chosen, the curvature term β batch This model makes it possible to make a prediction of the evolution over time of each batch at a selected reference temperature and a given storage time. The calculations were carried out using the JMP Accelerated Stability Analysis Tool (Elanco R&D version 1.0) running on JMP Version 14.1.0.

[0094] The predicted change in potency over 36 months at 25° C. storage conditions was determined for each formulation batch (see Table 10 below). Formulation batches that showed significant predicted changes (>15%) were identified (formulation batches F, C, N, A, B, and O). As a result of this initial screening analysis, formulation batches F, C, N, A, B, and O were excluded from further analysis for stability. [Table 10]

[0095] The predicted quality attributes from the ATLS accelerated predictive stability modeling based on 9 months of accelerated stability data are shown in the table below. The reference temperature was set at 25° C. and the target shelf life was selected to be 36 months. [Table 11]

[0096] Plotting the predicted change over 36 months at 25°C against the coded levels of the amounts of BHA and BHT used in each formulation batch (Figure 9) shows a strong correlation in the amounts of additives used. Plotting the predicted change against the total amount of BHA and BHT in the formulation (wt / wt%) (Figure 10) also shows a strong relationship, with a combined amount of at least 0.05% wt / wt of additives resulting in very little predicted change over time. Separate plots of this relationship by tube type are shown in Figure 11, showing very little difference in the rate of change depending on the type of tube used.

[0097] To compare the impact of using a nitrogen blanketed environment for filling, sub-designs (Batch, A, B, N, and O) of the overall experimental design were considered. All four batches were produced without the use of BHA and / or BHT additives. Figure 12 shows the predicted change for nitrogen (Y or N) overlaid with tube type. There is no indication of a statistically significant effect of nitrogen or tube type. In addition, all of these formulations were identified as having very low stability. Therefore, the use of only filling under nitrogen does not appear to provide adequate protection against degradation. There are apparent differences between tube types, but the differences were not statistically significant. However, the PF113 tubes have better apparent stability (less change over time).

[0098] Example 3 A transdermal buprenorphine solution was formulated as shown in Table 12 below. The formulation contains 20 mg / mL of buprenorphine (as the hydrochloride salt) solubilized in dehydrated alcohol (ethanol). The solution also contains the excipient Padimate O (50 mg / mL), as well as BHA (0.39 mg / mL) and BHT (0.39 mg / mL) as skin penetration enhancers. The formulation can be packaged using unit-dose aluminum and polymer laminate tubes with a dosage volume of 0.4 mL or 1.0 mL. This allows a single dose of the formulation to be applied directly to the skin of a cat. [Table 12]

[0099] Example 4 To evaluate pharmacokinetics (PK), transdermal buprenorphine solution (TBS) was formulated to contain 25 mg / mL buprenorphine (calculated as free base), 5% w / v (50 mg / mL) padimate O as a permeation enhancer, and ethanol. To prepare the formulation, buprenorphine HCl (Spectrum Chemical Mfg. Corp., New Brunswick, NJ, USA) was dissolved in a small amount of ethanol (Sigma-Aldrich, St. Louis, MO, USA), padimate O (Sigma-Aldrich) was added and mixed. The formulation was brought to volume with ethanol and aliquoted into 10 mL amber glass vials sealed with rubber stoppers and aluminum crimp tops until use. For the bioavailability phase of the study, the formulation was prepared in the same manner, but the final buprenorphine concentration was 20 mg / mL. The control article for the bioavailability portion of the study was buprenorphine hydrochloride injection (Buprenex, Reckitt Benckiser Pharmaceuticals, Inc., Richmond, VA, USA).

[0100] The first, PK phase of the study used 12 adult, habituated short-haired cats (7 neutered males and 5 intact females) ranging in age from 1 to 4 years and weighing 2.35 to 6.35 kg. The second, bioavailability phase of the study used 12 adult, habituated short-haired cats (6 neutered and 6 intact) ranging in age from 9 to 13 months and weighing 4.20 to 6.35 kg.

[0101] Animals were randomized to receive a single dose of TBS at 10, 30, or 50 mg (n=4 / group). Randomization was blocked by body weight to maintain balance between dose groups. Animals were not fasted prior to treatment administration. TBS was administered locally to the unshaven skin of the dorsal neck (base of the skull) using the tip of a needleless syringe. The tip of the syringe was placed directly on the skin at the application site, and the entire dose volume was administered in a single location without moving the syringe. The volume of TBS administered was 0.4, 1.2, and 2 mL for the 10, 30, or 50 mg dose groups, respectively. Cats were gently restrained for 2 minutes after dosing to prevent them from shivering or grooming while the solution dried. Blood samples (approximately 1 mL / sample) for plasma buprenorphine assays were collected from all cats pre-dose and at 2, 4, 12, 24, 48, 72, and 168 hours post-dose. Samples were collected by jugular vein puncture using a syringe and needle, immediately transferred to K2EDTA tubes and placed on ice until plasma processing by centrifugation at 1500 g for 15 min at 4° C. Plasma samples were stored frozen at −20° C. or below until analysis. Animals were assessed for behavioral effects and mydriasis (0=absent, 1=present) and rectal body temperature was measured before and 2, 4, 12, 24, 48, 72, and 168 hours after dose administration. Behavior was scored on a 5-point scale as follows: 0: normal; 1: sedated (docile and docile. Signs include sleeping, tail tucked under the ventral side, and purring; not very responsive to human interaction); 2: euphoric (exaggerated sociable and playful behavior. Signs include meowing, rolling, kneading with front paws, biting, and rubbing head and body against cage); 3: mildly uncomfortable (restless and disorganized. Signs include blank stare, irritability, rocking, and / or vocalization and may be accompanied by increased spontaneous activity. No obvious signs of fear or confusion and no signs of aggression. May appear sedated at first but suddenly startles or shows irritability); 4-disturbing (anxious or excited state. Signs include staring at non-existent objects, irritability, sudden movements, and / or vocalization and may be accompanied by increased spontaneous activity. Cat appears visibly confused or frightened and may become aggressive).

[0102] To assess bioavailability, cats were randomized to receive a single dose of 20 mg TBS (1 mL) or 0.05 mg IV buprenorphine (n=6 / group). Randomization was blocked by body weight to maintain balance between dose groups. Animals were not fasted prior to treatment administration. Transdermal buprenorphine solution was administered in the same manner as in Phase 1 of the study, i.e., topically on the dorsal neck. Injectable buprenorphine was administered IV as a bolus. To ensure IV drug delivery, a temporary cephalic venous catheter was placed in each cat under sedation with 40 μg / kg intramuscular dexmedetomidine hydrochloride (Dexdomitor, Zoetis Inc., Florham Park, NJ, USA). Sedation was reversed by administration of 0.2 mg / kg intramuscular atipamezole (Antisedan, Zoetis Inc.) after catheter placement and prior to buprenorphine injection. After IV administration of buprenorphine, the catheters were flushed with sterile saline and removed from the animals. Blood samples (approximately 2 mL / sample) for plasma buprenorphine assays were collected from cats treated with TBS pre-dose and 1, 2, 4, 12, 24, 48, 96, 168, and 240 hours post-dose, and from cats administered IV buprenorphine pre-dose and 5 and 15 minutes, 1, 2, 4, 12, and 24 hours post-dose. Samples were collected and stored as described in Phase 1 of this study.

[0103] In the first PK phase of the study, plasma samples were analyzed for buprenorphine concentrations using a validated liquid chromatography tandem mass spectrometry (LC-MS / MS) method. A 100 μg / mL stock solution of buprenorphine HCl (Cerilliant®, Round Rock, TX, USA) was diluted in 50:50 methanol (Honeywell Burdick & Jackson, Morristown, NJ, USA):water to create working standard solutions ranging from 0.500 to 1250 ng / mL, as well as quality control (QC) working solutions of 3.00, 375, and 1000 ng / mL. Similarly, a 100 μg / mL stock solution of internal standard (IS) buprenorphine-d4 (Cerilliant®, Round Rock, TX, USA) was diluted in acetonitrile to create a working IS solution of 10 ng / mL. Calibration and QC standards were then prepared by adding 10.0 μL of the appropriate working standard or QC working solution to 50.0 μL of blank feline plasma control. Similarly, 10.0 μL of 50:50 methanol:water was added to 50.0 μL of all test samples, blanks, and zero controls. Subsequently, 250 μL of IS working solution was added to all calibration standard, QC, test, and zero control samples, and 250 μL of acetonitrile was added to all blanks. Samples were vortex mixed for 2 minutes and then centrifuged for 10 minutes. 50 (50.0) μL of the supernatant was transferred to a 96-well elution plate containing 250 μL of reverse osmosis water and vortex mixed for 2 minutes. Water-diluted samples were quantified using an API 5000™ triple quadrupole mass spectrometer equipped with a TurboIonSpray™ interface (AB SCIEX, Framingham, MA, USA) with peak area integration performed using Analyst Software v1.5.1 (AB SCIEX) data acquisition system. HPLC separation was achieved using a Phenomenex Gemini C18 (50 × 3 mm, 5 μm particle size) column (Phenomenex, Torrence, CA, USA) with the flow rate set at 0.700 mL / min and column temperature at 30 μC. Mobile phase A consisted of 0.1% formic acid in water and mobile phase B consisted of 0.11% formic acid in acetonitrile.The mobile phase gradient started with 10% mobile phase B from 0.0 to 0.5 min, switched from 10% to 80% mobile phase B from 0.5 to 2.0 min, and returned from 80% to 10% mobile phase B from 3.0 to 3.1 min. The injection volume was 5 μL, and mass spectrometer detection was performed by monitoring the transition from 468.5 m / z to 396.3 m / z for buprenorphine and from 472.5 m / z to 400.3 m / z for IS buprenorphine-d4 using positive ionization mode. Both analytes typically eluted from the column at 1.82 min. Standard curves were determined using linear regression with 1 / x2 weighting, where x was the nominal sample concentration, with typical squared correlation coefficient (R2) values ​​of 0.9977 to 0.9993, using Excel (Version 11, Microsoft Corporation, Redmond, WA, USA). All concentration calculations were based on the peak area ratio of buprenorpine to IS. The calibrated concentration range for buprenorphine was 0.100-250 ng / mL, with a lower limit of quantification (LLOQ) of 0.100 ng / mL. Intra- and interassay precision (i.e., coefficient of variation) was ≤5.95%, and accuracy (i.e., relative error) ranged from 0.00% to 2.67%. A similar validated LC-MS / MS method was used for the second bioavailability phase of the study, with modifications. The calibrated concentration range for buprenorphine was 0.200-100 ng / mL, with a lower limit of quantification (LLOQ) of 0.200 ng / mL. It was demonstrated that the buprenorphine metabolite norbuprenorphine did not interfere with the quantification of plasma buprenorphine. Intra- and interassay precision (i.e., coefficient of variation) was ≤8.2%, and accuracy (i.e., relative error) ranged from -4.3% to 7.5%.

[0104] Plasma buprenorphine concentrations below the LLOQ were excluded from the calculation of summary statistics. PK parameters were calculated for each subject using the non-compartmental PK analysis method with Phoenix (registered trademark) WinNonlin (registered trademark) Version 6.2 (Build 6.2.0.495, Pharsight (registered trademark) - A Certara Company, St. Louis, MO, USA). The linear trapezoidal rule was used for the calculation of the area under the plasma concentration-time curve (AUC). The absolute bioavailability (F) of TBS was calculated as the ratio of the geometric mean of the AUC with dose adjusted according to body weight.

[0105] In the first phase of the study, the ranges of the doses administered on a body weight basis in the 10, 30, and 50 mg groups were 1.57 - 4.35, 4.72 - 13.03, and 7.87 - 21.73 mg / kg, respectively. Three plasma buprenorphine concentrations were considered outliers. Two concentrations were excluded from the 30 mg group: the 12-hour sample was 54.6 ng / mL and the 48-hour sample was 72.6 ng / mL. The single concentration excluded from the 24-hour time point in the 10 mg treatment group was 24.8 ng / mL. The reasons for these outliers were not determined by the study monitoring, but the measured concentrations were confirmed by re-assay. Subsequently, a sensitivity analysis was performed for plasma buprenorphine concentrations by removing these three observations and recalculating the summary statistics and PK analysis of plasma concentrations. There was no difference from the removed outliers, and thus the samples remained excluded from the following analysis. In the first phase of the study, plasma buprenorphine reached the peak mean concentration at 2 - 4 hours after dosing, and all samples remained above the LLOQ for 168 hours after dosing. The mean plasma buprenorphine concentration in the 50 mg TBS group was sometimes slightly higher or the same as compared to the concentration in the 30 mg dose group. The mean (range) C max values were 10.5 (3.02 - 18.1), 18.6 (10.6 - 27.6), and 22.5 (19.5 - 29.0) ng / mL, respectively, after administration of 10, 30, and 50 mg of TBS. C max Onset period (t maxThe mean terminal half-life (t 1 / 2 ) ranged from 78.3 to 91.2 hours. The mean percentage of extrapolated AUC ranged from 21.8% to 24.9% across dose groups. The mean (range) areas under the curve from time 0 to infinity (AUC0-∞) were 578 (218-967), 1590 (658-3310), and 2070 (1500-2710) hr·ng / mL after the 10, 30, and 50 mg doses, respectively. The AUC 0-∞ A 2.8-fold and 3.6-fold increase in body temperature was observed. Transient sedation and euphoria were observed beginning within 2 hours after dosing. In the 10 mg group, sedation was observed in 25-50% of cats for 24 hours (behavioral score = 1). In the 30 and 50 mg groups, sedation was observed in 25-50% of cats over 48 hours, with no effects observed after 72 hours. Euphoria (behavioral score = 2) was observed in 25-75% of cats in all dose groups over 24 hours, with no euphoria observed beyond 72 hours. Neither mild discomfort (behavioral score = 3) nor malaise (behavioral score = 4) were observed at any time point during the study. Mean rectal temperatures peaked 12 hours after dosing and were higher in the 30 and 50 mg TBS dose groups (38.9 and 39.1°C, respectively) than the 10 mg dose group (38.5°C). Mean temperatures remained 0.6-0.9°C above baseline (37.4-37.8°C) for 168 hours after dosing. Mydriasis was observed in 75%-100% of cats in each dose group 4-12 hours after dosing. No mydriasis was observed beyond 48 hours after dosing in any cat in the 10 and 30 mg TBS dose groups. Mydriasis was observed in at least 50% of cats receiving 50 mg TBS for 72 hours after dosing. No mydriasis was observed in any cat beyond the 72 hour observation period. In the second phase of the study, on a weight basis, the mean (range) buprenorphine doses following IV and TBS dosing were 0.00972 (0.00787-0.0112) and 3.95 (3.33-4.76) mg / kg, respectively.

[0106] Plasma buprenorphine concentrations from the IV group declined rapidly from a mean of 13.6 ng / mL at 5 min post-dose to 0.231 ng / mL by 4 h post-dose, and were at the LLOQ beyond 4 h. In contrast, mean plasma buprenorphine concentrations from the TBS group peaked at 1 h and gradually declined; mean concentrations were 11.6, 7.11, 1.86, and 0.513 ng / mL at 1, 24, 96, and 240 h post-dose, respectively. max and t max were 15.1 (4.82-25.6) ng / mL and 7.33 (1-24) hours, respectively, and the initial concentration (C0) after IV administration was 18.4 (14.2-27.5) ng / mL. The clearance (Cl) after IV administration was 16.7 (12.4-23.2) mL / min kg. The t1 / 2 after IV and TBS administration was 0.82 (0.59-0.97) and 64.9 (39.1-85.7) hours, respectively. The extrapolated percent AUC was <20% in all subjects. The estimated absolute bioavailability (F) of TBS was 16.0% (90% CI: [11.8%-21.7%]).

[0107] Following topical application of the various TBS doses in this study, mean plasma buprenorphine concentrations exceeded 2.3 ng / mL at the 2-hour sampling period for all three doses, suggesting a rapid onset of action. Mean terminal half-lives across the 10, 30, and 50 mg TBS doses ranged from 78.3 to 91.2 hours, supporting extended duration. Mean buprenorphine concentrations exceeded 2.3 ng / mL for 168 hours at the 30 and 50 mg doses and exceeded 2.3 ng / mL for 72 hours at the 10 mg dose, except for the 48-hour sampling point. Further supporting a pharmacological effect, plasma buprenorphine concentrations were temporally associated with behavioral and physiological effects consistent with opioid exposure, including transient sedation, euphoria, mydriasis, and elevated rectal temperature.

[0108] Mean plasma buprenorphine concentrations at sampling points 2-72 h ranged from 1.63-8.3, 4.61-17.1, and 7.90-22.3 ng / mL after 10, 30, and 50 mg TBS administration, respectively. Bioavailability was 16% (12.4-23.5%), which is close to the estimated target and similar to estimates of buprenorphine bioavailability from the patch in cats.

[0109] These results indicate that a single dose of TBS resulted in plasma buprenorphine concentrations likely to provide multiple days of analgesia at all doses tested, although further testing of TBS across a range of doses is warranted to determine its analgesic efficacy. TBS product attributes have the potential to overcome limitations of other approved or formulated buprenorphine products used in cats, including limited duration of action, need for repeated dosing, controlled substance dispensing, breakthrough pain between doses, and provide in-office, worry-free, stress-free administration, and extended duration of action. In addition, TBS can be easily included in preventive pain management analgesia protocols in the clinic.

[0110] Example 5 A prospective, double-masked, placebo-controlled, multicenter, phase 2 clinical trial was conducted to select a dose of transdermal buprenorphine solution (TBS) for the control of postoperative pain in cats. TBS was formulated in two strengths, containing 16 and 20 mg / mL buprenorphine (calculated as the free base), 5% w / v (50 mg / mL) padimate O, and ethanol. The negative control veterinary product was a placebo transdermal solution containing 5% w / v (50 mg / mL) padimate O and ethanol. The transdermal solution was packaged in 10 ml amber glass serum vials sealed with rubber stoppers and aluminum crimp tops until use.

[0111] One hundred fifteen (115) cats were randomized to receive a single topical dose of placebo solution, low TBS dose (1.91-2.07 mg / kg), or high TBS dose (4.27-4.88 mg / kg) prior to surgical sterilization with forelimb declawing. The dose administered was based on the unit dose for cats matched to the weight range. For cats assigned to the low TBS dose, smaller cats (1.2-3 kg) received 4 mg and larger cats (>3-7.5 kg) received 10 mg. A 16 mg / mL TBS formulation was used in the low TBS group, with dose volumes of 0.25 and 0.625 mL for smaller and larger cats, respectively. For cats assigned to the high TBS dose, smaller cats (1.2-3 kg) received 8 mg and larger cats (>3-7.5 kg) received 20 mg. A 20 mg / mL solution was used in the high TBS group, with dose volumes of 0.4 and 1 mL in the smaller and larger cats, respectively. Transdermal buprenorphine solution was administered 2-4 hours before surgery for those assigned to the low TBS dose and 1-2 hours before surgery for those assigned to the high TBS dose. To maintain masking, a transdermal placebo solution was administered 1-2 hours or 2-4 hours before surgery, according to randomization. A single person assigned to administer the treatment administered the treatment locally to the dorsal neck (base of the skull) using a needleless syringe. The tip of the syringe was placed directly on the skin at the application site, by brushing aside the hair as necessary, and the entire dose volume was administered in a single location without moving the syringe.

[0112] Interactive pain assessments and physiological variables were quantified throughout the 96 h after anesthesia recovery, and rescue analgesia was administered whenever analgesia was deemed inadequate. Overall treatment success rates estimated from generalized linear mixed-effects model analysis were 0.10 (95% CI: [0.02-0.36]), 0.56 (95% CI: [0.25-0.83]), and 0.71 (95% CI: [0.38-0.91]) for the placebo, low TBS, and high TBS dose groups, respectively. Success rates in both TBS treatment groups were superior to placebo. Adverse events were rare in all treatment groups, but postoperative body temperatures during the study period were on average 0.31 (95% CI: [0.08-0.55]) °C and 0.30 (95% CI: [0.05-0.53]) °C higher in cats receiving the low and high TBS doses, respectively, compared with placebo. Both low and high TBS doses were found to be safe and effective.

[0113] Example 6 To evaluate the safety and efficacy of the transdermal buprenorphine solution (TBS) used in Example 5 for the control of postoperative pain in cats, a prospective, double-masked, placebo-controlled, multi-site Phase 3 clinical trial was conducted. A total of 228 cats from 12 trial sites in the United States met the enrollment criteria, and 107 cats treated with placebo and 112 cats treated with TBS were included in the per-protocol efficacy analysis. The dose of TBS was 8 mg (0.4 ml) for cats weighing 1.2 - 3 kilograms and 20 mg (1 ml) for cats weighing > 3 - 7.5 kilograms, and it was applied topically to the dorsal, unshaved neck skin 1 - 2 hours prior to undergoing elective surgical sterilization combined with onychectomy. Interactive pain assessment and physiological variables were quantified over 96 hours after recovery from anesthesia, and rescue analgesia was administered whenever pain control was deemed inadequate. The treatment success rates were 0.40 (95% confidence interval [CI]: [0.28 - 0.53]) in the placebo group and 0.81 (95% CI: [0.70 - 0.89]) in the TBS group, and the difference was significant (< p.05). Adverse events occurred with similar frequencies and were not clinically significant in either treatment group. The postoperative body temperature during this study period was on average 0.35 (95% CI: [0.20 - 0.50]) °C higher than the baseline in cats treated with TBS, which was not clinically significant and was a typical observation for opioids in cats. These results serve as substantial evidence that TBS is safe and effective for the control of postoperative pain in feline orthopedic and soft tissue surgeries when applied as a single topical dose 1 - 2 hours prior to surgery.

[0114] Example 7 Transdermal buprenorphine solution (TBS) was administered as an 8 mg unit dose to cats weighing 1.2-3 kg and as a 20 mg unit dose to cats weighing 3-7.5 kg. This corresponds to a dose of 2.7-6.7 mg / kg on a body weight basis. In this safety study, a 1X dose was defined as 6.7 mg / kg. Thirty-two cats (16 males, 16 females) were randomly assigned to placebo and 1, 2, and 3X TBS administered topically to the dorsal neck skin in three doses every 4 days. Clinical observations, behavioral scores, mydriasis scores (yes / no), and physiological variables were assessed or measured prior to each dose administration (0 hours), and at 1, 2, 4, 8, 12, 24, 36, 48, and 72 hours after each treatment, and prior to euthanasia on days 12 or 13. Blood samples for clinical pathology were collected on days 1, 4, 8, and prior to euthanasia. Little evidence of respiratory, cardiovascular, or gastrointestinal effects was seen. Respiratory rates were above the reference range in all groups and were 10 breaths / min lower in the 3X group compared to placebo during the third dosing interval. Heart rate was not different. Constipation was observed transiently in approximately equal numbers in placebo- and TBS-treated cats. Behavioral scores indicated that sedation or euphoria was transient during the first dosing interval, but became more prolonged with each dosing interval. Mydriasis was prolonged during the first dosing interval and decreased by the third dosing interval, consistent with accommodation. Mean body temperature in TBS-treated cats was up to 0.6°C (1.8°F) higher than placebo-treated cats. There were no clinically relevant changes in serum chemistry, hematology, or urinalysis results, and no gross or microscopic observations attributable to TBS. These data demonstrate that TBS is safe and well tolerated when administered to 16-week-old cats at multiples of the approved dose and duration, supporting clinical safety in the event of delayed buprenorphine metabolism, dosing errors, or changes in dosing regimen.

[0115] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations on the scope of the invention, which is defined solely by the appended claims and their equivalents.

[0116] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including but not limited to those with respect to the chemical structure, substituents, derivatives, intermediates, compounds, compositions, formulations, or methods of use of the invention, may be made without departing from the spirit and scope thereof.

[0117] Although reference is made herein to particular examples, aspects, embodiments, etc., it is within the scope of the disclosure to combine various elements of such examples, aspects, embodiments, etc. with one another.

Claims

1. A liquid pharmaceutical composition for treating postoperative pain associated with at least one surgical procedure in a mammal in need of treatment for postoperative pain associated with at least one surgical procedure, comprising a therapeutically effective amount of buprenorphine or a salt thereof, said composition being administered transdermally to the dorsal neck of said mammal.

2. A liquid pharmaceutical composition for treating pain in a mammal in need thereof, comprising a therapeutically effective amount of buprenorphine or a salt thereof, said composition being administered transdermally to said mammal.

3. A liquid pharmaceutical composition for treating pain in a mammal in need thereof, comprising a therapeutically effective amount of buprenorphine or a salt thereof, said composition being administered locally to the dorsal neck of said mammal.

4. The composition described in claim 3, wherein the pain is postoperative pain associated with at least one surgical procedure.

5. A composition described in any of claims 1 to 4, wherein the liquid pharmaceutical composition constitutes a formulation containing buprenorphine or a salt thereof and at least one additive selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and combinations thereof.

6. A composition described in any one of claims 1 to 4, wherein the concentration of buprenorphine or a salt thereof is about 5 mg / mL or more, about 10 mg / mL or more, about 15 mg / mL or more, about 20 mg / mL or more, about 25 mg / mL or more, about 30 mg / mL or more, about 35 mg / mL or more, or about 40 mg / mL or more.

7. A composition described in any one of claims 1 to 4, wherein the buprenorphine or a salt thereof comprises buprenorphine hydrochloride.

8. The composition of claim 1, further comprising a penetration enhancer.

9. The composition described in claim 8, wherein the concentration of the penetration enhancer is about 20 mg / mL or more, about 30 mg / mL or more, about 40 mg / mL or more, about 50 mg / mL or more, or about 60 mg / mL or more.

10. The composition of claim 8, wherein the penetration enhancer comprises Padimate O.

11. The composition of claim 1, wherein the composition further comprises a solvent, optionally a volatile solvent.

12. The composition of claim 11, wherein the solvent is selected from the group consisting of isopropanol, ethanol, and combinations thereof, and optionally the solvent comprises ethanol.

13. The composition of any one of claims 1 to 4, wherein the composition is stable such that after storage at 25°C for up to 3 months, 6 months, 9 months, 12 months, or 24 months, the concentration of buprenorphine degradation products in the composition is lower than the concentration of buprenorphine degradation products in an otherwise identical composition that does not contain BHA and / or BHT.

14. The composition after storage for 3 months at 25°C has a concentration of buprenorphine degradation products of about 0.05 mg / mL or less, about 0.04 mg / mL or less, about 0.03 mg / mL or less, about 0.02 mg / mL or less, about 0.01 mg / mL or less, about 0.009 mg / mL or less, about 0.008 mg / mL or less, about 0.007 mg / mL or less, about 0.006 mg / mL or less, about 0.005 mg / mL or less, about 0.004 mg / mL or less, about 0.003 mg / mL or less, about 0.002 mg / mL or less, or about 0.001 mg / mL or less; or the concentration of buprenorphine degradation products in the composition after storage at 30° C. for 3 months is about 0.08 mg / mL or less, about 0.07 mg / mL or less, about 0.06 mg / mL or less, about 0.05 mg / mL or less, about 0.04 mg / mL or less, about 0.03 mg / mL or less, about 0.02 mg / mL or less, about 0.01 mg / mL or less, about 0.009 mg / mL or less, about 0.008 mg / mL or less, about 0.007 mg / mL or less, about 0.006 mg / mL or less, about 0.005 mg / mL or less, about 0.004 mg / mL or less, about 0.003 mg / mL or less, about 0.002 mg / mL or less, or about 0.001 mg / mL or less; or and wherein the concentration of buprenorphine degradation products in the composition after storage at 40°C for 3 months is about 3 mg / mL or less, about 2.5 mg / mL or less, about 2 mg / mL or less, about 1.5 mg / mL or less, about 1 mg / mL or less, about 0.90 mg / mL or less, about 0.80 mg / mL or less, about 0.70 mg / mL or less, about 0.60 mg / mL or less, about 0.50 mg / mL or less, about 0.40 mg / mL or less, about 0.80 mg / mL or less, about 0.70 mg / mL or less, about 0.60 mg / mL or less, about 0.50 mg / mL or less, about 0.40 mg / mL or less, about 0.9 ...

14. The composition of claim 13, wherein the α-glutamyltransferase concentration is less than about 30 mg / mL, less than about 0.20 mg / mL, less than about 0.10 mg / mL, less than about 0.09 mg / mL, less than about 0.08 mg / mL, less than about 0.07 mg / mL, less than about 0.06 mg / mL, less than about 0.05 mg / mL, less than about 0.04 mg / mL, less than about 0.03 mg / mL, less than about 0.02 mg / mL, or less than about 0.01 mg / mL.

15. After storage at 25°C for 12 months, the concentration of buprenorphine degradation products in the composition is about 0.20 mg / mL or less, about 0.15 mg / mL or less, about 0.10 mg / mL or less, about 0.09 mg / mL or less, about 0.08 mg / mL or less, about 0.07 mg / mL or less, about 0.06 mg / mL or less, about 0.05 mg / mL or less, about 0.04 mg / mL or less, about 0.03 mg / mL or less, 14. The composition of claim 13, wherein the concentration is about 0.02 mg / mL or less, about 0.01 mg / mL or less, about 0.009 mg / mL or less, about 0.008 mg / mL or less, about 0.007 mg / mL or less, about 0.006 mg / mL or less, about 0.005 mg / mL or less, about 0.004 mg / mL or less, about 0.003 mg / mL or less, about 0.002 mg / mL or less, or about 0.001 mg / mL or less.

16. The composition of claim 13, wherein the buprenorphine degradation products include buprenorphine polymers, buprenorphine dimers and / or positional isomers thereof.

17. The composition of claim 5, wherein the concentration of the at least one additive is about 0.1 mg / mL or more, about 0.2 mg / mL or more, about 0.3 mg / mL or more, about 0.4 mg / mL or more, about 0.5 mg / mL or more, about 0.6 mg / mL or more, about 0.8 mg / mL or more, about 0.9 mg / mL or more, about 1.0 mg / mL or more, about 1.1 mg / mL or more, about 1.2 mg / mL or more, about 1.3 mg / mL or more, about 1.4 mg / mL or more, or about 1.5 mg / mL or more.

18. The composition of claim 5, wherein the formulation comprises BHA.

19. The composition of claim 5, wherein the formulation contains BHT.

20. The composition described in claim 5, wherein the composition comprises BHA and BHT, or the antioxidants in the formulation consist of or essentially consist of BHA and BHT (i.e., constitute more than 90% by weight of the total amount of antioxidants).

21. The composition of claim 5, wherein the concentration of BHA is 0.04 mg / mL or more, about 0.1 mg / mL or more, about 0.2 mg / mL or more, about 0.3 mg / mL or more, about 0.4 mg / mL or more, about 0.5 mg / mL or more, about 0.7 mg / mL or more, or about 1.0 mg / mL or more.

22. The composition of claim 5, wherein the concentration of BHT is greater than or equal to about 0.1 mg / mL, greater than or equal to about 0.2 mg / mL, greater than or equal to about 0.3 mg / mL, greater than or equal to about 0.4 mg / mL, greater than or equal to about 0.5 mg / mL, greater than or equal to about 0.7 mg / mL, or greater than or equal to about 1.0 mg / mL.

23. The composition described in claim 20, wherein the weight ratio of BHT to BHA is about 1.1:1 or more, about 2:1 or more, about 5:1 or more, or about 10:1 or more.

24. The formulation, about 10 mg / mL to about 30 mg / mL of buprenorphine hydrochloride; about 40 mg / mL to about 60 mg / mL of Padimate O; a combination of BHA and BHT from about 0.5 mg / mL to about 0.9 mg / mL, wherein the weight ratio of BHT to BHA is about 1:1 or greater; The composition according to any one of claims 1 to 4, comprising: a solvent comprising ethanol.

25. The composition of any one of claims 1 to 4, wherein the composition is packaged as a unit dose.

26. The composition of claim 25, wherein the unit dose is from about 0.4 ml to about 1.0 ml, optionally 0.4 ml, optionally 1.0 ml.

27. The composition of claim 25, wherein the unit dose is from about 8 mg to about 20 mg, optionally 8 mg, optionally 20 mg.

28. A formulation comprising buprenorphine or a salt thereof and at least one additive selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and combinations thereof.

29. The formulation of claim 28, wherein the concentration of buprenorphine or a salt thereof is greater than or equal to about 5 mg / mL, greater than or equal to about 10 mg / mL, greater than or equal to about 15 mg / mL, greater than or equal to about 20 mg / mL, greater than or equal to about 25 mg / mL, greater than or equal to about 30 mg / mL, greater than or equal to about 35 mg / mL, or greater than or equal to about 40 mg / mL.

30. The formulation of claim 28 or 29, wherein the buprenorphine or salt thereof comprises buprenorphine hydrochloride.

31. The formulation of claim 28, wherein the formulation further comprises a penetration enhancer.

32. The formulation of claim 31, wherein the concentration of the penetration enhancer is greater than or equal to about 20 mg / mL, greater than or equal to about 30 mg / mL, greater than or equal to about 40 mg / mL, greater than or equal to about 50 mg / mL, or greater than or equal to about 60 mg / mL.

33. The formulation of claim 31 or 32, wherein the penetration enhancer comprises Padimate O.

34. The formulation of claim 28, wherein the composition further comprises a solvent, optionally a volatile solvent.

35. The formulation of claim 34, wherein the solvent is selected from the group consisting of isopropanol, ethanol, and combinations thereof, and optionally the solvent comprises ethanol.

36. The formulation of claim 28, wherein the formulation is stable such that after storage at 25°C for up to 3 months, 6 months, 9 months, 12 months, or 24 months, the concentration of buprenorphine degradation products in the formulation is less than the concentration of buprenorphine degradation products in an otherwise identical formulation that does not contain BHA and / or BHT.

37. The concentration of buprenorphine degradation products in the formulation after storage at 25°C for 3 months is about 0.05 mg / mL or less, about 0.04 mg / mL or less, about 0.03 mg / mL or less, about 0.02 mg / mL or less, about 0.01 mg / mL or less, about 0.009 mg / mL or less, about 0.008 mg / mL or less, about 0.007 mg / mL or less, about 0.006 mg / mL or less, about 0.005 mg / mL or less, about 0.004 mg / mL or less, about 0.003 mg / mL or less, about 0.002 mg / mL or less, or about 0.001 mg / mL or less; or the concentration of buprenorphine degradation products in the formulation after storage at 30° C. for 3 months is about 0.08 mg / mL or less, about 0.07 mg / mL or less, about 0.06 mg / mL or less, about 0.05 mg / mL or less, about 0.04 mg / mL or less, about 0.03 mg / mL or less, about 0.02 mg / mL or less, about 0.01 mg / mL or less, about 0.009 mg / mL or less, about 0.008 mg / mL or less, about 0.007 mg / mL or less, about 0.006 mg / mL or less, about 0.005 mg / mL or less, about 0.004 mg / mL or less, about 0.003 mg / mL or less, about 0.002 mg / mL or less, or about 0.001 mg / mL or less; or and wherein the concentration of buprenorphine degradation products in the formulation after storage at 40°C for 3 months is about 3 mg / mL or less, about 2.5 mg / mL or less, about 2 mg / mL or less, about 1.5 mg / mL or less, about 1 mg / mL or less, about 0.90 mg / mL or less, about 0.80 mg / mL or less, about 0.70 mg / mL or less, about 0.60 mg / mL or less, about 0.50 mg / mL or less, about 0.40 mg / mL or less, about 0.80 mg / mL or less, about 0.70 mg / mL or less, about 0.60 mg / mL or less, about 0.50 mg / mL or less, about 0.40 mg / mL or less, about 0.9 ...

37. The formulation of claim 36, wherein the solubility is less than about 30 mg / mL, less than about 0.20 mg / mL, less than about 0.10 mg / mL, less than about 0.09 mg / mL, less than about 0.08 mg / mL, less than about 0.07 mg / mL, less than about 0.06 mg / mL, less than about 0.05 mg / mL, less than about 0.04 mg / mL, less than about 0.03 mg / mL, less than about 0.02 mg / mL, or less than about 0.01 mg / mL.

38. After storage at 25°C for 12 months, the concentration of buprenorphine degradation products in the formulation is about 0.20 mg / mL or less, about 0.15 mg / mL or less, about 0.10 mg / mL or less, about 0.09 mg / mL or less, about 0.08 mg / mL or less, about 0.07 mg / mL or less, about 0.06 mg / mL or less, about 0.05 mg / mL or less, about 0.04 mg / mL or less, about 0.03 mg / mL or less, 37. The formulation of claim 36, wherein the concentration is about 0.02 mg / mL or less, about 0.01 mg / mL or less, about 0.009 mg / mL or less, about 0.008 mg / mL or less, about 0.007 mg / mL or less, about 0.006 mg / mL or less, about 0.005 mg / mL or less, about 0.004 mg / mL or less, about 0.003 mg / mL or less, about 0.002 mg / mL or less, or about 0.001 mg / mL or less.

39. The formulation of claim 36, wherein the buprenorphine degradation products include polymers of buprenorphine, dimers of buprenorphine and / or positional isomers thereof.

40. The formulation of claim 36, wherein the concentration of the at least one additive is about 0.1 mg / mL or more, about 0.2 mg / mL or more, about 0.3 mg / mL or more, about 0.4 mg / mL or more, about 0.5 mg / mL or more, about 0.6 mg / mL or more, about 0.8 mg / mL or more, about 0.9 mg / mL or more, about 1.0 mg / mL or more, about 1.1 mg / mL or more, about 1.2 mg / mL or more, about 1.3 mg / mL or more, about 1.4 mg / mL or more, or about 1.5 mg / mL or more.

41. The formulation of claim 36, wherein the formulation comprises BHA, BHT, or a combination thereof.

42. The formulation of claim 36, wherein the formulation comprises BHA and BHT, or the antioxidants in the formulation consist of or essentially consist of BHA and BHT (i.e., constitute more than 90% by weight of the total amount of antioxidants).

43. The formulation of any one of claims 36 to 42, wherein the concentration of BHA is 0.04 mg / mL or more, about 0.1 mg / mL or more, about 0.2 mg / mL or more, about 0.3 mg / mL or more, about 0.4 mg / mL or more, about 0.5 mg / mL or more, about 0.7 mg / mL or more, or about 1.0 mg / mL or more.

44. The formulation of any one of claims 36 to 42, wherein the concentration of BHT is about 0.1 mg / mL or more, about 0.2 mg / mL or more, about 0.3 mg / mL or more, about 0.4 mg / mL or more, about 0.5 mg / mL or more, about 0.7 mg / mL or more, or about 1.0 mg / mL or more.

45. The formulation of any one of claims 36 to 42, wherein the weight ratio of BHT to BHA is about 1.1:1 or more, about 2:1 or more, about 5:1 or more, or about 10:1 or more.

46. ​​The formulation, about 10 mg / mL to about 30 mg / mL of buprenorphine hydrochloride; about 40 mg / mL to about 60 mg / mL of Padimate O; a combination of BHA and BHT from about 0.5 mg / mL to about 0.9 mg / mL, wherein the weight ratio of BHT to BHA is about 1:1 or greater; and a solvent comprising ethanol.

47. The formulation of claim 28, wherein the formulation is packaged as a unit dose.

48. The formulation of claim 28, wherein the unit dose is contained in an aluminum and polymer laminate tube.

49. The formulation of claim 28, wherein the unit dose is from about 0.4 ml to about 1.0 ml.

50. The formulation of claim 28, wherein the unit dose is from about 8 mg to about 20 mg.

51. A composition described in any one of claims 1 to 4, wherein the mammal is a cat.

Images