RU2795099C2 - Pharmaceutical compositions containing an opioid receptor agonist as active ingredient, methods of their production and their therapeutic use - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions discloses a ready-to-use pharmaceutical composition in the form of an aqueous solution for sublingual and buccal administration, the said composition containing: 0.0075 wt./vol.% buprenorphine hydrochloride based on the base, 1.5 wt./vol.% about. hydroxyethylcellulose or 6.0 wt./vol.% sodium carboxymethyl cellulose, 0.12 wt./vol.% anhydrous citric acid, 1.13 wt./vol.% anhydrous sodium citrate, water for injection. The group of inventions also relates to a method for preparing a composition ready for use, to a syringe pre-filled with the composition, and to a package containing the composition.

EFFECT: safety and effectiveness of the composition for sublingual administration to newborns, which has a sufficient shelf life for storage and use. However, the composition has sufficient viscosity to hold it under the tongue of a newborn or an individual in need of treatment, and in close contact with the mucous membrane, avoiding ingestion and absorption through the gastrointestinal tract.

12 cl, 5 tbl, 2 dwg, 5 ex

Description

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions containing an opioid receptor agonist as an active ingredient, to processes for their preparation and their therapeutic uses.

More specifically, the invention relates to a buccal/sublingual formulation of buprenorphine providing a therapeutically effective dosage for the treatment of neonatal withdrawal symptoms.

STATE OF THE ART TO which THE INVENTION RELATES

Neonatal withdrawal syndrome (NAS) is a set of postnatal signs and symptoms associated with sudden withdrawal of maternally transmitted opioids.

The main manifestations include increased muscle tone, autonomic nervous system disorder, irritability, low sucking reflex, and reduced body weight gain.

In epidemiological studies, maternal opioid addiction is common, with toxicological signs of use in approximately 1% of children born (Vega WA et al. N Engl J Med 1993, 16:329(12), 850-854).

In addition, according to the Committee on Drugs of the American Academy of Pediatrics, NAS occurs in 55%-94% of children born to mothers with opioid dependence.

The optimal treatment for NAS has not yet been developed.

Specific opioids that are used include morphine sulfate, morphine in opium solution for newborns, deodorized opium tincture, and methadone.

The administration of the morphine-based compositions is described to last from 8 to 79 days, with a total duration of approximately 30 days.

The indicated duration of hospitalization is suboptimal due to obstruction of maternal attachment, possible nosocomial infection, and resource use.

Thus, there is a need for improved therapeutic agents that can safely reduce the duration of hospitalization.

Buprenorphine is a partial opioid μ-receptor agonist that is increasingly being used to treat high-dose opioid dependence, to control moderate acute pain in individuals with low-dose opioid intolerance, and to control moderate chronic pain at even lower doses.

This drug has significant first pass metabolism in adults and is therefore administered by the sublingual and buccal route.

Buprenorphine has a number of characteristics that may make it an attractive treatment for NAS. For example, its long half-life and duration of action prevent a rapid change in receptor occupancy, which can reverse withdrawal symptoms.

However, experience with the use of buprenorphine in neonates or pediatric populations is limited and there is limited information on the use of a sublingual formulation in neonates.

Moreover, the therapeutically effective dosage in neonates depends on their body weight and the severity of maternal abuse; thus, fixed dose film formulations for sublingual and buccal administration, such as those commercially available or described in EP 2461795, may not be suitable because it is not possible to precisely adjust the amount of drug required.

Kraft W et al. described the results of open clinical trials in neonates for the treatment of opiate withdrawal (Pediatrics 2008, 122(3), e601-607; Addiction 2010, 106, 574-580; N Engl. J Med 2017, 376:2341-2348).

The authors concluded that sublingual buprenorphine was safe with a significant advantage in terms of efficacy over standard oral morphine therapy.

However, a solution formulation was used to prepare just before use by mixing buprenorphine hydrochloride for injection in 30% ethanol and sucrose simple syrup. The final concentration was 0.075 mg/ml as buprenorphine free base.

Due to the presence of ethanol, this formulation may not be suitable for repeated administration to neonates.

Moreover, without proper viscosity, sublingual/buccal solution dosage forms can deliver varying amounts of drug because they have low retention at the site of application.

In particular, given the volumes likely to be administered, the horizontal position of the neonate after dosing, and the use of a pacifier, there is a risk of ingestion of the drug and absorption in the gastrointestinal tract along with the sublingual route.

In other prior art documents, ie. EP 0069600, US 2007/117828, US 2016/175295 and WO 03/080022 describe buprenorphine-based formulations, but lack characteristics that would make them suitable for sublingual administration to neonates.

In view of the foregoing, there is still a need to develop a safer and more effective formulation for sublingual administration to neonates that has a sufficient shelf life for storage and use.

It would be advantageous to provide a composition with sufficient viscosity to hold it under the tongue of the neonate or individual in need of treatment and in close contact with the mucosa, avoiding ingestion and absorption through the gastrointestinal tract.

SUMMARY OF THE INVENTION

In a first aspect, the present invention relates to a ready-to-use pharmaceutical composition in the form of an aqueous solution for sublingual and buccal administration, said composition comprising:

i) from 0.005 to 0.02% w/v. buprenorphine or a pharmaceutically acceptable salt thereof as the sole active ingredient;

ii) from 0.5% to 10% w/v. thickener; And

iii) buffering agent in an amount to provide a pH of 5.0-7.0.

Its viscosity should be between 500 and 2300 mPa s, preferably between 700 and 2100 mPa s at 25±2°C.

In a preferred embodiment, the thickener is a cellulose derivative, more preferably hydroxyethylcellulose (HEC) or sodium carboxymethylcellulose (NaCMC), even more preferably hydroxyethylcellulose.

In a second aspect, the invention relates to the aforementioned ready-to-use pharmaceutical composition for use in the treatment of opioid withdrawal, preferably neonatal opioid withdrawal.

In a third aspect, the invention relates to a ready-to-use pharmaceutical composition as described above for the manufacture of a medicament for the treatment of opioid withdrawal, preferably neonatal opioid withdrawal.

A fourth aspect relates to a method for treating opioid withdrawal in a patient in need thereof by administering a ready-to-use formulation of the invention over a period of 1 to 90 days, preferably 3 to 70 days.

Preferably, the patient is a neonate suffering from neonatal opioid withdrawal syndrome.

The fifth aspect relates to a process for preparing a ready-to-use composition according to the invention.

The sixth aspect relates to a syringe prefilled with a ready-to-use formulation of the invention.

A seventh aspect relates to a package containing a pharmaceutical composition of the invention in the form of either a ready-to-use aqueous solution or a powder for reconstitution in a suitable aqueous vehicle, in combination with a syringe and instructions for oral administration of said pharmaceutical composition to a patient suffering from opioid withdrawal.

DEFINITIONS

In relation to buprenorphine, the terms "drug", "active ingredient" and "active substance" are used interchangeably.

The terms "newborns", "newborns" and "infants" are used interchangeably.

The term "safe" means a pharmaceutical formulation suitable for sublingual administration, well tolerated by neonates, and free from excipients that may be harmful, antigenic or toxic to the specified patient population.

The term "buccal and sublingual administration" embraces mucosal areas, i. a pharmacological route of administration by which substances diffuse into the blood through tissues under the tongue and through the oral mucosa (tissues that line the mouth), which are most commonly used for systemic drug delivery. The buccal/sublingual routes bypass the GI tract and thus drugs absorbed in this manner bypass the liver and first pass metabolism and have direct access to the systemic circulation.

The term "microenvironment pH" refers to the pH of the region of the patient's mouth immediately surrounding the formulation.

For a ready-to-use formulation, "physically stable" refers to a formulation that, under long-term storage conditions (25°C±2°C, 60%±2% relative humidity), exhibits substantially no settling of the active ingredient and/or excipient upon storage in for at least one month.

Due to analytical difficulties regarding the definition of an active ingredient at a low concentration, the expression "chemically stable" refers to a formulation that exhibits a change in buprenorphine content of no more than ± 15% on storage and no drug-related degradation products of more than 5% when stored for at least one month.

The term "bioequivalent" means achieving 80%-125% of the Cmax and AUC values for a given active ingredient in another product.

The term "therapeutically effective amount" means the amount of the active ingredient which, when delivered to neonates, provides the desired biological effect.

The term "treatment" refers to therapeutic use for palliative, curative, symptom-relieving, symptom-reducing, regression-inducing treatment.

The term "essentially consisting of" is used to refer to a formulation containing only a thickener and a buffering agent as main excipients. For example, it may contain a sweetener and/or flavor, but not excipients such as penetration enhancers.

BLUEPRINTS

Figure 1 - PK profile with the introduction of the composition 1 according to example 1 against the reference composition.

Figure 2 - PK profile with the introduction of the composition 2 according to example 1 against the reference composition.

DETAILED DESCRIPTION OF THE INVENTION

Due to its activity on opioid receptors, buprenorphine can be successfully used for the treatment of withdrawal symptoms, in particular neonatal withdrawal syndrome.

Thus, it is an object of the present invention to provide a safe pharmaceutical formulation for effective sublingual treatment in patients suffering from opioid withdrawal syndrome (OWS), preferably neonates suffering from neonatal OWS (hereinafter NOWS).

Said safe formulation contains buprenorphine dissolved in an aqueous vehicle.

The compositions of the invention may be administered to neonates as well as to children or adolescents.

The composition of the invention may be in the form of a dry powder to be dissolved immediately before use, or in the form of a ready-to-use composition.

When issued as a dry powder for reconstitution, it can be prepared by known methods and can be provided as a kit containing a) a pharmaceutical powder formulation; b) a pharmaceutically acceptable aqueous carrier; c) syringe; d) pharmaceutical formulation container, aqueous carrier and syringe.

Preferably, a ready-to-use formulation is used.

Buprenorphine is used in the form of a base or in the form of a pharmaceutically acceptable salt formed with an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid , succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid acid, benzenesulfonic acid and toluenesulfonic acid.

Preferably, buprenorphine is present as the hydrochloric acid salt.

Preferably, the concentration of the active ingredient is from 0.005 to 0.02% w/v, preferably from 0.006 to 0.01% w/v. in terms of free base.

In a specific embodiment of the invention, the concentration of buprenorphine hydrochloride is 0.0075% w/v. in terms of free base.

The thickener concentration is 0.5% to 10% w/v, preferably 0.6% to 8.0% w/v. The type and amount of thickener is appropriately chosen to achieve sufficient viscosity to hold the formulation as far as possible under the patient's tongue to minimize absorption through the gastrointestinal tract.

At the same time, the viscosity should not be too high in order to slow down the release of the active ingredient from the matrix and thus its local absorption.

More preferably, the concentration of the thickener may be from 1.0 to 6.0% w/v.

In specific embodiments, the specified concentration is 1.0% w/v, or 1.5% w/v, or 2.0% w/v, or 6.0% w/v.

Advantageously, the thickener can be selected from water-soluble polysaccharides such as alginates, carrageenans, pectin, water-soluble cellulose derivatives: hydroxyalkylcellulose alkylcelluloses and hydroxyalkylalkylcelluloses such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, cellulose esters and hydroxyalkylcellulose esters such as cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose (HPMC); carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters such as carboxymethylcellulose and their alkali metal salts; water-soluble synthetic polymers such as polyacrylic acids and polyacrylic acid esters, polymethacrylic acids and polymethacrylic acid esters, polyvinyl acetates, polyvinyl alcohols, polyvinyl acetate phthalates (PVAP), polyvinyl pyrrolidone (PVP) and polycrotonic acids; also suitable are phthalated gelatin, gelatin succinate, cross-linked gelatin, shellac, water-soluble chemical starch derivatives, cationically modified acrylates and methacrylates having, for example, a tertiary or quaternary amino group, such as a diethylaminoethyl group, which may be quaternized if desired.

Preferably, the thickener is a water-soluble cellulose derivative selected from the group consisting of hydroxyethylcellulose (HEC) or an alkali metal salt of carboxymethylcellulose (CMC), such as the sodium salt.

In fact, thickeners belonging to these classes can provide a suitable viscosity, while in the case of other agents of the gum class, such as xanthan gum, the viscosity of the composition was found to be too high.

Advantageously, the viscosity of the formulation at 25±2° C. is between 500 and 2300 mPas (1 mPas corresponds to 1 centipoise), preferably between 700 and 2100 mPas. Viscosity can be determined in any way, for example using a rheometer.

Advantageously, the pH of the composition according to the invention may be from 5.0 to 7.0, more preferably from 5.2 to 6.8, preferably from 5.5 to 6.5.

In fact, it has been found that above pH 7.0 the compositions of the invention may exhibit lower chemical and physical stability.

In contrast to what is described in EP 2461795, it was found that the specified pH range, which prevents precipitation of the active ingredient in saliva, promotes its absorption.

Without being bound by theory, this may be due to the fact that there is no shift in the pH of the microenvironment (saliva/mucosal contact surface).

The results of the mucoaghesion test also demonstrated that the compositions of the invention are endowed with an optimal viscosity property to allow it to be held under the patient's tongue without delaying the release of the active ingredient from the matrix, in particular when a water-soluble cellulose derivative is used as a thickening agent.

Moreover, according to in vitro permeation experiments, when a water-soluble cellulose derivative is used, the preferred compositions of the invention have a pH of 5.5 to 6.5 and an amount of thickener of 1.0% to 2.0% by weight. /about., even more preferably 1.5% wt./about. A preferred thickener of this class may be hydroxyethyl cellulose. Said excipient is commercially available from Natrosol 250 HX ^TM .

In vitro permeability tests simulate the passage of a drug through the oral mucosa and allow the release rate to be determined.

Any buffering agent capable of maintaining the aforementioned pH can be used, for example phosphate or citrate buffers such as sodium or potassium salts. One skilled in the art will be able to determine the proper amount.

In a preferred embodiment of the invention, anhydrous citric acid and anhydrous sodium citrate are used as a buffer.

The composition of the invention may also contain other excipients such as flavors and/or sweeteners.

Flavors may be selected from natural and synthetic flavor liquids. An illustrative list of such agents includes volatile oils, synthetic flavor oils, flavorings, oils, liquids, oleoresins, or extracts from plants, leaves, flowers, fruits, stems, and combinations thereof. A representative list of examples includes mint, cocoa and citrus oils such as lemon, orange, grape, lime and grapefruit oils, and fruit essences including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot and other fruits.

Other suitable flavors include aldehydes and esters such as benzaldehyde (cherry, almond), citral, i. alpha citral (lemon, lime), neral, i.e. beta-citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruit), aldehyde C-9 (citrus fruit), aldehyde C-12 (citrus fruit), tolylaldehyde (cherry, almond), 2,6-dimethyloctanol (green fruits) and 2-dodecanal (cirus, mandarin), combinations thereof, etc.

Sweeteners may be selected from the following non-limiting list: glucose (corn syrup), dextrose, invert sugar, fructose, and combinations thereof; saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcon compounds, glycyrrhizin; Stevia rebaudiana (stevioside); sucrose derivatives with chlorine such as sucralose; sugar alcohols such as sorbitol, mannitol, xylitol, and the like. Also provided are hydrogenated starch hydrolysates and the synthetic sweetener 3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide, in particular its potassium salt (acesulfame-K ), and sodium and calcium salts. You can also use other sweeteners.

Typically, one of skill in the art will be able to select a sweetener and/or flavoring agent from among those that are considered safe for administration to neonates.

Although not preferred, the compositions of the invention may also contain absorption enhancers such as propylene glycol and polyoxyl hydrogenated castor oil derivatives, eg polyoxyl 40 hydrogenated castor oil (commercially available as Kolliphor RH 40 ^TM ).

In a preferred embodiment of the invention, the composition has the following composition: 0.05-0.01% wt./about. buprenorphine hydrochloride based on the free base, 1.5% wt./about. hydroxyethylcellulose, 0.12% w/v anhydrous citric acid, 1.13% wt./about. anhydrous sodium citrate, water for injection, and its pH is 6.0±0.3.

In an alternative preferred embodiment of the invention, the composition may have the following composition: 0.05-0.01% wt./about. buprenorphine hydrochloride based on the free base, 6.0% wt./about. sodium carboxymethyl cellulose, 0.12% w/v anhydrous citric acid, 1.13% wt./about. anhydrous sodium citrate, water for injection, and its pH is 6.0 ± 0.3.

As described in more detail in the Examples section below, in a sublingual animal model, aqueous formulations having the aforementioned formulations were found to be bioequivalent to the alcohol formulation described in Kraft et al., Pediatrics 2008, 122(3), e601-607.

Without being limited by theory, this turned out to be rather unexpected, since ethanol usually promotes absorption.

Thus, in accordance with a preferred embodiment of the invention, the composition consists only of the pharmaceutically acceptable salt of buprenorphine as the sole active ingredient, a thickening agent, a buffering agent in an appropriate amount to provide a pH of 5 to 7.0, and optionally a flavoring agent and/or sweetener. .

The composition according to the invention can be obtained by known methods.

In a specific embodiment, the compositions of the invention are prepared through the following steps:

i) dissolving an appropriate amount of buprenorphine or a pharmaceutically acceptable salt thereof, preferably its hydrochloride, in water in an appropriate container to obtain a concentrated clear solution;

ii) optionally sterilizing the solution obtained in step i) by filtration;

iii) parallel dissolving the proper amount of buffer in water in a suitable volumetric container until a clear solution is obtained;

iv) optionally sterilizing the solution obtained in step iii) by heating;

v) adding an appropriate volume of concentrated buprenorphine solution to the buffer solution to obtain the final desired concentration of buprenorphine, preferably 0.05-0.01 mg/ml (as free base), mixing with continuous agitation;

vi) slowly adding the proper amount of thickener to the solution according to step iii) with constant stirring until the thickener is completely dissolved and a clear homogeneous solution is obtained.

Preferably, the water is water for injection (WFI).

In step i) the concentration may vary from 0.1 to 0.5 mg/ml, preferably from 0.2 to 0.4 mg/ml, more preferably 0.324 mg/ml.

Advantageously, the container in steps i) and iii) may be made from any suitable material such as plastic or glass.

The sterilization procedures of steps ii) and iv) can be carried out by methods known in the art.

In particular, the porosity of the filter in step ii) and the heating temperature in step iv) can be appropriately adjusted by a person skilled in the art.

The final formulation can be dispensed under aseptic conditions into suitable containers.

Advantageously, the composition of the invention can be used to treat neonatal withdrawal symptoms of any severity.

Preferably, the composition of the invention can be used to treat patients suffering from opioid withdrawal syndrome (OWS), with or without exposure to other drugs, more preferably for the treatment of neonates suffering from NOWS.

The dose and duration of treatment in any case will be adjusted by the attending physician depending on the body weight of the newborn and the severity of the neonatal withdrawal syndrome.

Typically, when used to treat NOWS, the formulation is poured under the tongue with a syringe and then a pacifier is inserted into the newborn's mouth to reduce swallowing.

Any commercially available syringe having a volume of 0.1 to 2.5 ml, more preferably 0.5 to 2.0 ml, may be used.

Preferably, 0.5 ml or 1.0 ml syringes can be used.

The syringe may be made of plastic, glass, or any suitable material, preferably plastic, more preferably cyclo-olefin polymer (COP).

For example, syringes from Becton Dickinson (New Jersey, USA) may be suitable.

In a preferred embodiment of the invention, the ready-to-use formulation may be provided as a pre-filled syringe, preferably in COP, and without a Luer lock.

For example, suitable prefillable syringes are commercially available from Gerresheimer AG (Dusseldorf, Germany).

When used in neonates, these pre-filled syringes should be without a needle and they should be provided with a suitable cap, preferably large enough to avoid obstruction in the neonate in the event of accidental swallowing.

In an alternative embodiment, a package may be provided containing the pharmaceutical composition of the invention in the form of either a ready-to-use aqueous solution or a powder for reconstitution in a suitable aqueous vehicle, in combination with a suitable syringe.

The invention is illustrated by the following examples.

EXAMPLES

Example 1

The aim of the first set of experiments was to evaluate the feasibility of obtaining buprenorphine aqueous solution formulations with sufficient viscosity and pH to be physically and chemically stable while maintaining a good absorption profile.

Received the following compositions:

Composition 1, pH=6.0 Quantity per ml (mg) Function Buprenorphine HCl 0.075* Active Ingredient Anhydrous citric acid 1.22 Buffer Anhydrous sodium citrate 11.3 Buffer Hydroxyethylcellulose 15.0 Thickener Water for injections 100 ml Solvent Composition 2, pH=6.0 Quantity per ml (mg) Function Buprenorphine HCl 0.075* Active Ingredient Anhydrous citric acid 1.22 Buffer Anhydrous sodium citrate 11.3 Buffer Sodium carboxymethyl cellulose 60.0 Thickener Water for injections 100 ml Solvent Composition 3 pH=7.2 Quantity per ml (mg) Function Buprenorphine HCl 0.075* Active Ingredient Dibasic potassium phosphate 2.28 Buffer Potassium phosphate monobasic 5.79 Buffer Hydroxyethylcellulose 15.0 Thickener Water for injections 100 ml Solvent Composition 4 pH=7.2 Quantity per ml (mg) Function Buprenorphine HCl 0.075* Active Ingredient Dibasic potassium phosphate 2.28 Buffer Potassium phosphate monobasic 5.79 Buffer Sodium carboxymethyl cellulose 60.0 Thickener Water for injections 100 ml Solvent Composition 5 pH=6.0 Quantity per ml (mg) Function Buprenorphine HCI 0.075* Active Ingredient Anhydrous citric acid 1.22 Buffer Anhydrous sodium citrate 11.3 Buffer Hydroxyethylcellulose 15.0 Thickener Polyoxyl 40 hydrogenated castor oil 10.0 Suction booster Water for injections 100 ml Solvent Composition 6 pH=6.0 Quantity per ml (mg) Function Buprenorphine HCl 0.075* Active Ingredient xanthan gum 10.0 Thickener Dibasic potassium phosphate 2.28 Buffer Potassium phosphate monobasic 5.79 Buffer Water for injections 100 ml Solvent

*per base.

Compositions similar to composition 1 were obtained using 0.5%, 1.0% and 2.0% w/v. hydroxyethylcellulose (composition 1', composition 1", composition 1"', respectively).

The respective formulations were prepared at a buprenorphine HCl concentration of 0.01 mg/mL, based on the free base.

Moreover, a reference composition was prepared in ethanol according to the ideas of Kraft W et al. Pediatrics 2008, 122(3), e601-607.

Formulations 1, 2, 3, 4 and 5 show a viscosity at 25±2°C in the range of 700-2100 mPa s (cP), while composition 6 shows a higher viscosity, i. 2500 mPa s (cP). In an aqueous solution, the latter composition forms a kind of "soft gel" that persists provided that the system is left undisturbed.

It was not possible to determine the viscosity of the reference formulation according to Kraft because the rheometer used to determine the viscosity of formulations 1, 2, 3, 4, 5 and 6 is not suitable for a fluid having a viscosity comparable to a Newtonian fluid.

Example 2

Compositions 1, 2, 3 and 4 of example 1 at a concentration of buprenorphine 0.01% wt./about. stored for one month under long-term storage conditions, i.e. 25±2°C and 60% relative humidity, and under accelerated conditions, i.e. at 50±2°C, to evaluate their physical and chemical stability.

Stability was also tested under refrigeration conditions.

Buprenorphine and its impurities were analyzed by HPLC. The following parameters were also tested: pH, viscosity and appearance.

The results under long-term storage conditions are presented in Table 1.

Table 1 - Stability of formulations 1, 2, 3 and 4 according to example 1 under long-term storage conditions.

Composition 1 pH Viscosity
(mPa s) Total degradation products (%) Analysis
% against initial level Appearance Initial (t=0) 6.0 2067 0.63 100 Clear colorless solution t=2 weeks 6.1 1849 1.39 91.4 Clear colorless solution t=1 month 6.0 1607 0.89 92.6 Clear colorless solution Composition 2 Initial (t=0) 5.8 1035 0.50 100 Clear colorless solution t=2 weeks 5.8 1058 1.94 89.6 Clear colorless solution t=1 month 5.8 1011 0.43 92.8 Clear colorless solution Composition 3 Initial (t=0) 7.1 1814 0.66 100 Slightly cloudy colorless solution t=2 weeks 7.3 1798 1.58 92.3 Slightly cloudy colorless solution t=1 month 7.2 1869 1.53 92.1 Slightly cloudy colorless solution Composition 4 Initial (t=0) 6.9 787 0.70 100 Clear, colorless to light yellow solution t=2 weeks 7.0 774 1.35 86.4 Clear, colorless to light yellow solution t=1 month 7.0 715 0.98 86.5 Clear, colorless to light yellow solution

The results at 50±2°C are presented in table 2.

Table 2 - Stability of formulations 1, 2, 3 and 4 according to example 1 at 50±2°C.

Composition 1 pH Viscosity
(mPa s) Total degradation products (%) Analysis of % vs Baseline Appearance Initial (t=0) 6.0 2067 0.63 100 Clear colorless solution t=2 weeks 6.0 1754 1.71 89.7 Clear colorless solution t=1 month 5.9 1671 2.11 92.1 Clear colorless solution Composition 2 Initial (t=0) 5.8 1035 0.50 100 Clear, colorless to light yellow solution t=2 weeks 5.9 814 3.08 87.9 Clear, colorless to light yellow solution t=1 month 5.8 769 1.0 93.5 Clear, colorless to light yellow solution Composition 3 Initial (t=0) 7.1 1814 0.66 100 Slightly cloudy colorless solution t=2 weeks 7.3 1785 1.51 91.3 Slightly cloudy colorless solution t=1 month 7.2 1583 2.03 91.6 Slightly cloudy colorless solution Composition 4 Initial (t=0) 6.9 787 0.70 100 Clear, colorless to light yellow solution t=2 weeks 6.9 444 1.60 99.2 Clear, colorless to light yellow solution t=1 month 6.9 360 3.71 52.6 Clear, colorless to light yellow solution with precipitate

The results shown in Tables 1 and 2 demonstrate that there is no significant increase in the total level of degradation products for formulations 1 and 2 at pH=6.0, and their amount remains well below the 5.0% limit.

Notably, the level of degradation products increases after 4 weeks at 50°C for Formulation 4, while Formulation 3 appears cloudy, indicating that a pH above 7 may not be optimal for chemical and physical stability.

Example 3

Formulations 1 and 2 at a buprenorphine concentration of 0.075 mg/mL based on base and reference formulation were administered to dogs via sublingual administration.

Three male beagle dogs were used and all administration options were administered with a washout period of one week. The formulations were administered by dispensing the dose (maximum 2.5 ml) sublingually into the sublingual area and then keeping the mouth closed for approximately 45 seconds. This procedure was repeated until the full dose volume (0.4 ml/kg) was administered.

Buprenorphine plasma concentrations in dogs were determined using a validated HPLC-MS/MS bioanalytical method and were used to compare systemic exposure for three different formulations.

As shown in Figure 1, Formulation 1 and the Reference Formulation exhibited the maximum concentration at the same time and after normalization of the dose had almost the same maximum concentration and AUC.

Formulation 2 and reference composition are compared in Figure 2: the time of maximum concentration was on average somewhat later for composition 2 (0.75 vs. 0.5 hours), and the maximum concentration and AUC were slightly lower than for the reference composition. The average relative bioavailability of formulations 1 and 2 compared to the reference was 110% and 102%, respectively.

Example 4

This study was designed to screen for in vitro efficacy of Formulations 1, 2, 3, 4 and 5 against the Kraft Reference Formulation.

Experimental technique

Kuprofan (cellulose-based membranes) contains glycerin as a humectant (to prevent drying and cracking). It was removed by soaking in distilled water. The membranes (22 mm diameter pre-cut circles were prepared) were placed in a 500 ml Duran soaking bottle and the contents were mixed by rotation (20 rpm). Two additional total water changes were performed to eliminate glycerin. The total soak/rinse time was ~46 hours before the release test.

Cuprofan membranes were placed as a barrier between halves of individually numbered and lightly lubricated (High Vacuum Grease, Dow Corning, USA) horizontal Franz diffusion cells, with the stratum corneum facing the donor chamber. The area available for diffusion was approximately 1.2 cm ² , with the exact area and volume (~3.4 ml on average) pre-measured for each individual diffusion cell.

The receptor chambers of the diffusion cells were filled with a known temperature-equilibrated volume of 1% (w/v) Brij O20 in pH 7.4 phosphate buffered saline (BPBS) and sealed. The diffusion cells were immersed in a constant temperature water bath while maintaining the receptor chambers at 37.0±0.5°C during the experiment. The contents of the receptor chambers were continuously stirred by means of small PTFE-coated magnetic elements driven by submersible magnetic stirrers. The wells were allowed to equilibrate before dosing (≥75 minutes).

The test formulations were applied to the membrane surface at a dose of 500 μl/cm ² using a Microman M1000 positive displacement pipette. Care was taken to achieve complete coverage of the surface without air bubbles). Donor chambers were covered using Parafilm (Nesco) immediately after dosing. There were three repetitions for each active substance and there were six control cells, each of which was dosed with a separate placebo formulation. The exact time of application was noted, and this time corresponded to the zero time point for this cell. Dosing time monitoring was very thorough due to frequent sampling times.

The doses of formulations applied were equal to 37.5 μg/cm ² buprenorphine HCl for all cells of the active substance.

100 μl samples were taken (using a digital pipette) from each receptor chamber 15 and 30 minutes after dosing. The removed liquid was replaced only by sampling after 30 minutes. 200 μl receptor phase samples were obtained 60 and 120 minutes after dosing. Each sample was placed in a pre-labeled 200 μl conical glass vial (Agilent, Cheadle, UK) and immediately capped (PTFE coated membrane) before vial freezing (-20°C) prior to analysis.

After extracting 200 µl receptor phase samples after 120 minutes, the remaining receptor phase was removed and placed in 20 ml glass vials (Chromacol, UK), which were capped and frozen (-20°C) for assay validation.

Ultra high performance liquid chromatography (UHPLC) analysis with UV detection was used to analyze the samples for buprenorphine content.

Receptor phase samples (in 200 μl vials stored at -20° C.) were prepared for analysis as follows. The vials were allowed to thaw at room temperature before vigorous shaking. The vials were then centrifuged (3 minutes at 10,000 rpm) and transferred to an autosampler.

The yield of buprenorphine in receptor phase samples after 2 hours was evaluated by addition studies. Using the total receptor phase (stored in 20 ml vials), a small aliquot of calibration solution (added concentration 2.00 μg/ml) was added to the samples (one well from each active and control group). After analyzing the spiked and non spiked samples, the yield of buprenorphine was calculated after subtracting the contribution from the recipient phase. The mean addition yield was 100.2% (0.79% RSD, n=17) and a similar value was obtained with BPBS alone.

The results are shown in table 3.

Table 3 - Buprenorphine HCl permeation data (µg/cm ² , mean ± SE, n=3)

Compound 15 minutes 30 min 60 min 120 min Average value SE Average value SE Average value SE Average value SE Reference according to Kraft 0.895 0.034 3.04 0.11 5.47 0.19 9.27 0.10 Composition1 2.16 0.12 4.13 0.02 6.51 0.23 10.3 0.1 Composition 2 0.414 0.036 0.988 0.061 1.90 0.10 3.52 0.15 Composition 3 1.37 0.06 2.85 0.09 5.53 0.34 11.0 0.3 Composition 4 0.000 0.000 0.448 0.025 0.829 0.047 1.70 0.12 Composition 5 0.430 0.020 0.822 0.008 1.44 0.02 2.39 0.04

As can be seen, the release rates were better for formulations 1 and 3 than for formulations 2 and 4 having a pH greater than 7.0.

Release from formulation 1 containing HEC was faster than both formulation 3 containing NaCMC and the Kraft reference formulation.

The inclusion of a suction enhancer significantly reduced the release.

Example 5 Evaluation of Mucoadhesive Properties

The mucoadhesive properties of the formulations of the invention were tested using an "inclined plane" device as described in Pescina, S., et al. Drug Dev Ind Pharm, 2017. 43(9): p. 1472-1479.

For the experiment, compositions 1, 1', 1" and 1"' of example 1 were used.

Approximately 30 mg, accurately weighed, of each composition was applied to the epithelium of the esophagus (1.13 cm ² ), previously glued to a Petri dish (9 cm ² ), tilted at 45°C. The formulation was flushed with salivary fluid (SSF, NaCl 8 g/l, Na2HPO4 2.38 g/l, KH2PO4 0.19 g/l, pH 6.8) at a flow rate of 1 ml/min using a syringe pump.

The temperature was maintained at 25±2°C.

The solution was collected at predetermined time points and injected into HPLC to evaluate the washed off drug.

The results are presented in Table 4, which describes the effect of viscosity (expressed as % thickener) on % buprenorphine flushed from the mucosa.

The viscosity of the formulation appears to be critical only at 0.5% (when after 1 min 60% of the formulation was washed off the mucosa), while formulations containing 1%, 1.5% and 2.0% thickener demonstrated good mucoadhesive properties.

Table 4

Time (min) 0.5% 1% 1.5% 2% 1 62.0 40.1 35.4 40.5 2 15.2 23.5 17.5 24.8 3 4.5 14.9 8.6 7.6 4 2.7 11.9 5.3 7.7 5 1.6 11.9 5.2 6 0.7 9.4 4.0 7 0.4 8.7 2.4 8 0.2 5.7 1.9

Claims (19)

1. A ready-to-use pharmaceutical composition in the form of an aqueous solution for sublingual and buccal administration, said composition comprising: 0.0075% w/v buprenorphine hydrochloride based on the base, 1.5% wt./about. hydroxyethylcellulose or 6.0% wt./about. sodium carboxymethyl cellulose, 0.12% w/v anhydrous citric acid, 1.13% wt./about. anhydrous sodium citrate, water for injection. 2. The composition according to claim 1, where the pH is from 5.2 to 6.8. 3. The composition according to claim 1 or 2, where the pH is from 5.5 to 6.5. 4. Composition according to any one of the preceding claims, further comprising a sweetener and/or flavoring agent. 5. A method for obtaining a ready-to-use composition according to any one of claims 1 to 4, including the steps: i) dissolving an appropriate amount of buprenorphine or its hydrochloride in water in an appropriate container to obtain a concentrated clear solution; iii) in parallel, dissolving the proper amount of buffer in water in a suitable measuring container until a clear solution is obtained; iv) adding an appropriate volume of the concentrated buprenorphine solution to the buffer solution to achieve the final desired concentration of buprenorphine while mixing by continuous agitation; vi) slowly adding the proper amount of thickener to the solution of step iii) with constant stirring until the thickener is completely dissolved and a homogeneous solution is obtained. 6. The method according to claim 5, further comprising the step of: ii) sterilizing the solution obtained in step i) by filtration. 7. The method according to claim 5 or 6, further comprising the steps of: v) sterilizing the solution obtained in step iii) by heating. 8. A composition according to any one of claims 1 to 4 for use in the treatment of opioid withdrawal. 9. The composition of claim 8, wherein the syndrome is neonatal opioid withdrawal syndrome. 10. A syringe pre-filled with a composition according to any one of claims 1 to 4. 11. A package containing a composition according to any one of claims 1 to 4 in the form of a ready-to-use aqueous solution and instructions for oral administration of said pharmaceutical composition to a patient suffering from opioid withdrawal. 12. The package of claim 11 wherein the patient is a neonate suffering from neonatal opioid withdrawal syndrome.

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