NZ750367B2 - Sustained-release buprenorphine formulations - Google Patents

Abstract

injectable pharmaceutical composition includes a solution of 3-acyl-buprenorphine, or a pharmaceutically acceptable salt thereof, in a biocompatible organic solvent, wherein the injectable pharmaceutical composition exhibits a steady release profile lasting over one week when injected into a patient. The acyl group is an alkylcarbonyl group, and an alkyl portion of the alkylcarbonyl group is a straight-chain, branched-chain, having 1-20 carbon atoms. The biocompatible organic solvent is N-methyl-2-pyrrolidone, ethyl acetate, ethanol, butanol, 2-butanol, isobutanol, ispropanol, glycerin, benzyl benzoate, dimethyl sulfoxide, N, N-dimethylacetamide, propylene glycol, dimethyl glycol, benzyl alcohol, or a combination of two or more thereof. ent. The acyl group is an alkylcarbonyl group, and an alkyl portion of the alkylcarbonyl group is a straight-chain, branched-chain, having 1-20 carbon atoms. The biocompatible organic solvent is N-methyl-2-pyrrolidone, ethyl acetate, ethanol, butanol, 2-butanol, isobutanol, ispropanol, glycerin, benzyl benzoate, dimethyl sulfoxide, N, N-dimethylacetamide, propylene glycol, dimethyl glycol, benzyl alcohol, or a combination of two or more thereof.

Description

/101327 SUSTAINED-RELEASE ORPHINE FORMULATIONS BACKGROUND OF INVENTION Field of the Invention The invention relates generally to a buprenorphine drug ry . In particular, the invention relates to an able composition sing buprenorphine, a prodrug, or a metabolite thereof for the treatment of opioid dependence, pain, and depression.

Background Art Buprenorphine, (50L,70t(s))—17—cyclopropy1methy1)—0t—(1,1—dimethylethy1)—4,5—epoxy— 18,19—dihydro—3—hydroxy—6—methoxy—0t—methy1—6,14—ethenomorphinan—7—methanol, is a derivative of thebaine, which belongs to the family of opioid alkaloids. The ure of buprenorphine is shown as the following formula (Formula I) with a molecular weight of 467.64: Formula I (buprenorphine) As a partial and potent u—receptor agonist, buprenorphine has a higher affinity to compete with other fu11 agonists, such as morphine, methadone, etc. With 25~40 times higher potency than that of ne, buprenorphine is indicated for the treatment of moderate to severe chronic pain, and pre—operative analgesia in several dosage forms, 6.g. Buprenex® (intramuscular or intravenous injection), Norspan®, Butrans® (transdermal patch), Temgesic® (sublingual tablet), and Belbuca® (buccal film). The therapeutic concentrations (Cmax) of Butrans in healthy subjects range from 0.1 to 0.5 ng/mL, ponding to a dose of 5—20 ug/hour. In addition, various products of buprenorphine hydrochloride are approved for treating opioid addiction in higher dosages, e.g. Subutex® (sublingual tablet), and some are combination products of buprenorphine hydrochloride and naloxone hydrochloride 6.g.

Suboxone® (sublingual film, in 4:1 ratio of buprenorphine hloride and naloxone hydrochloride), Zubsolv® (sublingual tablet), and Bunavail® (buccal film). The therapeutic trations (CmaX) of Suboxone range from 1 to 6 ng/mL, corresponding to a dose of 2—16 mg sublingual films. Furthermore, buprenorphine is also a potent antagonist of K—opioid receptor, and this feature could result in the reduction of tolerance and antidepressant effect.

Recently, buprenorphine is utilized to form a combination product, ALK—5461, which consists of buprenorphine (K—receptor antagonist) and rphan (u—receptor agonist) and has been announced for epressant effect.

In previous studies, s buprenorphine derivatives were disclosed. Among them, modifications of the phenol group by forming ester bond linkages are more common.

These ester derivatives are synthesized and compared with buprenorphine and hydrochloride salt thereof. In 1995, Stinchcomb et al. published an article about 3—alkyl ester derivatives of buprenorphine in Pharm. Res (1995), 12, 1526-1529 (Formula II, R = acetyl, propanoyl, butanoyl, pentanoyl, yl, heptanoyl). These derivatives were viewed as gs and purported to improve the physiochemical characteristics of the parent compound to increase the relative permeability through skin in the ing articles: Biol. Pharm. Bull. (1996), 19, 7 and Pharm. Res. , 13, 1519-1523.

Formula II Thereafter, several C3—esterfied buprenorphine derivatives and the applications thereof have been disclosed in various patents. For example, US. Patent No. 7,084,150, issued to Euro—Celtique S.A., describes a huge family of buprenorphine prodrugs and analogs, which include ester bonds or ether bond ed derivatives. EP Patent No. 1422230, issued to Jhi—Joung Wang, discloses dimerized derivatives of buprenorphine and similar alkylcarbonyl derivatives. Prodrug strategy and oil carrier were introduced by an intramuscular or subcutaneous injection, which displays g analgesia actions from 5 hours to 96 hours.

WO 50043 A series of buprenorphine ester tives also described in U.S. Patent No. 7,964,610, issued to Reckitt Benckiser Healthcare (UK) Limited. Buprenorphine was modified with dicarboxylic acids or esters. Then, these derivatives were used for the treatment of opiate abuse/dependence and for the treatment of moderate to severe pain.

There are a variety of sustained release s for buprenorphine indicated for the treatment of opioid dependence and chronic pain. For example, Titan pharmaceuticals, Inc. developed a subcutaneous implant product of buprenorphine hydrochloride, hine®, using their novel drug delivery system, ProNeuraTM, which is made from a mixture of ethylene vinyl acetate (EVA) and drug substance. Probuphine® is administrated once every six month through al implantation and removed from patients after treatment by surgical procedures.

Camurus established a novel technology for drug delivery systems, FluidCrystal®, which is based on lipid liquid crystals that are composed of phosphatidyl choline and glycerol dioleate. The formulation disclosed in US Publication No. 2013/0190341 is designed as a long—acting buprenorphine product to treat opioid dependence and chronic pain, and is administrated by aneous injection weekly or monthly.

US. Patent Application Publication No. 2003/0152638, by Brookwood Pharmaceuticals, Inc., discloses an injectable slow—release microsphere ation that comprises buprenorphine and poly(D,L—lactide). This formulation is able to treat heroin and alcohol abuse for a period of at least 28 days in a .

US. Patent Application Publication No. 2014/0271869 (Oakwood Laboratories LLC) disclosed a biodegradable formulation, which utilized their proprietary logy, Chronij ectTM. The platform is a polymer—based injectable microspheres system for drug delivery. The buprenorphine microspheres could be generated in higher drug load and d to achieve sustained release for at least one month to several months.

Indivior PLC (WO 201 1/154724) developed a monthly depot, which employed Atrigel system to produce an injectable flowable ation for the treatment of opioid dependency. The composition es orphine free base, biodegradable polymer, and a biocompatible t. The dissolved liquid could be injected and transformed in situ into a solid implant, providing 1—month and 3—month release profiles. In addition, a suspension and solution designs are sed in WC 201 1/154725 and WC 2015/136253, respectively. The suspension is composed of buprenorphine and polyethylene glycol polymer in aqueous conditions, providing a therapeutic period of between 7 and 30 days in dogs after a single intramuscular or subcutaneous injection. As for the disclosed solution, the composition consists of buprenorphine or a salt form thereof and a biocompatible c solvent without a biodegradable polymer. After a single subcutaneous injection in beagle dogs, the formulation is able to provide at least one—month therapeutic period.

According to the description above, these prior art systems are able to perform sustained releases. However, there is still a need to p a formulation with better characteristics, such as a simpler cturing s, an accessible administration ure, a smoother releasing profile without severe initial burst, or a longer therapeutically effective duration after a single injection.

SUMMARY OF INVENTION Embodiments of the present invention relate to a sustained—release pharmaceutical composition of buprenorphine, a prodrug or a metabolite thereof, forming a depot in situ for a therapeutically effective duration of at least one week to several months.

One aspect of the invention relates to injectable pharmaceutical compositions. An injectable pharmaceutical ition in accordance with one embodiment of the invention es a solution of 3—acyl—buprenorphine, or a ceutically acceptable salt thereof, in a biocompatible organic solvent, n the injectable pharmaceutical ition ts a steady release profile lasting over one week when injected into a patient or an animal.

In accordance with ments of the invention, the acyl group is an alkylcarbonyl group or an arylcarbonyl group. An alkyl portion of the arbonyl group is a straight—chain, branched—chain, having 1—20 carbon atoms. An aryl group in the rbonyl group contains an aromatic ring having 6—18 carbons.

In accordance with embodiments of the invention, the biocompatible organic solvent is N—methyl—2—pyrrolidone, ethyl acetate, ethanol, butanol, nol, isobutanol, ispropanol, glycerin, benzyl benzoate, dimethyl sulfoxide, N,N—dimethylacetamide, propylene glycol, dimethyl glycol, benzyl alcohol, an ester, an ether, an amide, a carbonate, a lactam, a sulfonyl, or any combination thereof.

In accordance with embodiments of the invention, the 3—acyl buprenorphine, or a pharmaceutically acceptable salt thereof, is present at a concentration of l—99% w/v, preferably 5—90% w/v, more preferably 10—80% w/v, most preferably 10—60% w/v.

In accordance with embodiments of the invention, an able pharmaceutical composition may further comprise a vative. In accordance with ments of the invention, the preservative is selected from the group ting of methylparaben, propylparaben and benzylalcohol.

In accordance with embodiments of the invention, an injectable pharmaceutical composition is formulated for subcutaneous, intramuscular or intradermal injection.

Another aspect of the invention relates to methods for treating opioid ion, pain, or depression. A method in accordance with one embodiment of the invention comprises administering to a t in need thereof a therapeutically effective amount of the injectable pharmaceutical composition according to any embodiment described above.

In accordance with embodiments of the invention, the administering is performed at a ncy of once per week, once per month, preferably once every three months, and more preferably once every six months.

Other aspects of the invention will become apparent with the attached drawings and the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS shows in vitro dissolution profiles of formulations containing various buprenorphine derivatives, in ance with ments of the invention. shows in vitro dissolution profiles of formulations containing buprenorphine decanoate in various weight ratio and solvents combinations, in accordance with embodiments of the invention. shows in vitro dissolution profiles of formulations containing orphine hexanoate and dodecanoate in s solvents, in accordance with ments of the invention. shows mean plasma levels of buprenorphine after subcutaneous injection of SL006 at the dose of 30, 60, and 90 mg buprenorphine/kg in rats, in accordance with embodiments of the invention. shows mean plasma levels of buprenorphine after subcutaneous injection of SL031 at the dose of 60 mg buprenorphine/kg in rats, in accordance with embodiments of the invention. shows mean plasma levels of buprenorphine after subcutaneous injection of SL035 at the dose of 60 mg buprenorphine/kg in rats, in accordance with embodiments of the invention.

DETAILED DESCRIPTION Embodiments of the invention relate to formulations of buprenorphine derivatives that exhibit no or minimal initial bursts and have long—lasting release es after a single dose administration into a subject in need of treatments. The treatments may e treatments for opioid addiction, pain, or depression. In accordance with embodiments of the invention, the buprenorphine derivatives are l ester derivatives, i.e., esters formed between the 3—hydroxy (phenol) group of buprenorphine and alkylcarbonylation or arylcarbonylation (acylation) reagents.

In accordance with embodiments of the invention, an alkylcarbonyl or arylcarbonyl (i.e., acyl) reagent (R—CO—X), wherein R is an alkyl or aryl residue, may be an acyl chloride, an acyl anhydride, or an acyl active ester. The alkyl portion of an alkylcarbonyl group may be a straight—chain or branched alkyl group. The alkyl portion may contain any suitable number of carbons, such as l—20(C1-C20), l—18(C1—C18), l—l6(C1—C16), 1—12(C1—C12), l—lO(C1—C10), 1—5 (C1—C5), or 1—3 (C1—C3). Examples of arbonyl (acyl) groups may include acetyl, propionyl butyryl, l, and palmityl. The aryl in the arylcarbonyl group is used herein in a broad sense to include not only an aryl group, but also an aryl—alkyl group, wherein the alkyl portion is as defined above. The aryl n of the arylcarbonyl group may be a C6—C18 aromatic ring, such as a phenyl or naphthyl.

In accordance with embodiments of the invention, the orphine derivatives may be synthesized using conventional methods. Buprenorphine or its salt can be purchased from several commercial sources, such as Sigma—Aldrich. To prepare a buprenorphine derivative, buprenorphine (or its salt) may be reacted with an acyl chloride in the presence of a non—nucleophilic base (e.g., triethylamine) to form the ester bond. The product (3—acyl—byprenorphine or 3—alkylcarbonyl—buprenorphine) may be purified with conventional s (e.g., column chromatography).

As used in this description, a buprenorphine derivative refers to 3—acyl—buprenorphine (3—alkylcarbonyl—buprenorphine or 3—arylcarbonyl—buprenorphine) or a salt thereof. A buprenorphine derivative of the invention may on as a prodrug, which may be ted into the parent compound, buprenorphine.

A formulation of the invention may comprise a buprenorphine derivative dissolved in one or more suitable biocompatible ts. The buprenorphine derivative may be in the form of a free base or a pharmaceutically acceptable salt thereof, such as a salt of HCL, formate, acetate, or the like. The biocompatible solvents may be organic solvents, such as N—methyl—2—pyrrolidone (NMP), ethyl acetate (EtOAc), ethanol (EtOH), butanol, 2—butanol, isobutanol, glycerin, benzyl benzoate (BnBzO), dimethyl sulfoxide, propylene glycol, dimethyl glycol, and benzyl l.

The formulations of the invention may contain the buprenorphine derivative or a salt thereof in any suitable concentration, such as 1—99 % w/v, preferably l—90% w/v, more preferably 5—90% w/v, more preferably 5—80% w/v, more preferably 10—70% w/v, more preferably 10—60% w/v. Please note that when a numerical range is disclosed in this description, it is intended to include all numbers within the ranges, as if each of these numbers have been individually disclosed.

A formulation of the invention may further comprise another pharmaceutically acceptable excipient, carrier, t, or preservative. In accordance with embodiments of the invention, a preservative is preferably ed from the group consisting of methylparaben, propylparaben and benzylalcohol.

Formulations of the invention do not have undesirable initial bursts. However, due to the unique combination of the orphine derivatives and the biocompatible solvents, these formulations can form depots at the administration sites to maintain long—term steady releases of the buprenorphine derivative, buprenorphine, or a lite of buprenorphine.

Therefore, a formulation of the invention can e low or no initial burst ing the rable e effects) and yet can maintain therapeutically effective levels of orphine over a long duration. A long duration (or a steady release profile) in accordance with embodiments of the invention may last over 1 week, preferably over 2 weeks, more preferably over 1 month, and most preferably over 2 months (e.g., 3 months, 4 months, 5 months, 6 months, or longer).

Because these formulations do not have appreciable initial bursts, they can be given at higher doses, such as up to 800 mg/Kg body weight, preferable 120 mg/Kg, more preferably 60 mg/Kg, most preferably 40 mg/kg. A therapeutically ive dose is a dose that will achieve the ed therapeutic effects. One skilled in the art would appreciate that a therapeutically effective dose would depend on many factors, such as patient conditions, WO 50043 2017/101327 age, sex, weight, route of administration, etc. One skilled in the art would be able to determine a therapeutically effective dose without inventive efforts.

Due to the unique combination of buprenorphine derivatives and the biocompatible ts, the formulations of the invention have the advantages that less frequent injections are required and patient compliance would be improved.

Embodiments of the invention will be further illustrated with the following specific es. However, one skilled in the art would appreciate that these examples are for illustration only and that other modifications and variations are possible without departing from the scope of the invention.

Example 1- Preparation of buprenorphine derivatives The buprenorphine derivatives were synthesized using typical methods outlined in the ing description. To a 3—necked round—bottom flask, buprenorphine HCl and dichloromethane were added to form a sion, which was then placed in an ice bath for cooling. After that, triethylamine was added slowly with stirring. Acyl chloride was then added dropwise into the flask. Any suitable acyl chloride of a fatty acid may be used, such as C1—C20 acyl chloride, preferably C2—C18 acyl chloride, more preferably C2—C12 acyl chloride.

Removed the ice bath, the esterified reaction was carried out under nitrogen here at ambient temperature. The reaction mixture was neutralized with saturated sodium bicarbonate aqueous solution. The organic layer was washed with brine and then dried with sodium e. After concentration under reduced pressure, the crude orphine derivative was purified with silica gel column chromatography.

Example 2- ation of formulations Buprenorphine derivative (10 wt%— 60 wt%) was added into a glass vial and dissolved with one or a combination of two or more biocompatible organic solvent (e.g.

N—methyl—2—pyrrolidone (NMP), ethyl e (EtOAc), ethanol (EtOH), butanol, 2—butanol, isobutanol, glycerin, benzyl benzoate (BnBzO), yl sulfoxide, N,N—dimethylacetamide, propylene glycol, dimethyl glycol, benzyl alcohol). The mixture was stirred constantly at ambient ature or heated slightly until all the ingredients were dissolved. Exemplary formulation compositions are listed in Table l.

Table l Formulation API, wt% Solvent 1, wt% Solvent 2, wt% SL001 Buprenorphine free base, 30% NMP, 70% — SL002 Buprenorphine acetate, 30% NMP, 70% — SL003 Buprenorphine pentanoate, 30% NMP, 70% — SL004 Buprenorphine hexanoate, 30% NMP, 70% — SL005 Buprenorphine pivalate, 30% NMP, 70% — SL006 Buprenorphine decanoate, 30% NMP, 70% — SL007 Buprenorphine dodecanoate, 30% NMP, 70% — SL008 Buprenorphine palmitate, 30% NMP, 70% — SL009 orphine stearate, 30% NMP, 70% — SL010 Buprenorphine benzonate, 15% NMP, 85% — SL011 Buprenorphine decanoate, 15% NMP, 85% — SL012 Buprenorphine ate, 20% NMP, 80% — SL013 Buprenorphine decanoate, 25% NMP, 75% — SL014 Buprenorphine ate, 30% EtOAC, 40% EtOH, 30% SL015 Buprenorphine decanoate, 50% EtOAC, 50% — SL016 Buprenorphine decanoate, 45% EtOAC, 55% — SL017 Buprenorphine decanoate, 50% EtOAC, 40% EtOH, 10% SL018 Buprenorphine decanoate, 50% EtOAC, 45% EtOH, 5% SL019 Buprenorphine decanoate, 35% EtOAC, 58.5% EtOH, 6.5% SL020 Buprenorphine decanoate, 35% EtOAC, 52% EtOH,13% SL021 Buprenorphine decanoate, 40% EtOAC, 54% EtOH, 6% SL022 orphine decanoate, 40% EtOAC, 48% EtOH,12% SL023 Buprenorphine decanoate, 45% EtOAC, 49.5% EtOH, 5.5% SL024 Buprenorphine decanoate, 45% EtOAC, 44% EtOH,11% SL025 Buprenorphine ate, 40% BnBzO, 60% — SL026 Buprenorphine decanoate, 80% BnBzO, 20% — SL027 Buprenorphine decanoate, 90% BnBzO, 10% — SL028 Buprenorphine hexanoate, 50% NMP, 50% — SL029 Buprenorphine hexanoate, 50% EtOAC, 50% — SL030 Buprenorphine hexanoate, 50% EtOAC, 45% EtOH, 5% SL031 Buprenorphine hexanoate, 50% EtOAc, 40% EtOH, 10% SL032 Buprenorphine dodecanoate, 50% EtOAc, 50% SL033 Buprenorphine dodecanoate, 30% EtOAc, 63% EtOH, 7% SL034 Buprenorphine dodecanoate, 30% EtOAc, 56% EtOH, 14% SL035 Buprenorphine dodecanoate, 35% NMP, 65% Example 3- In vitro dissolution test of the formulations The formulations in example 2 were assessed for their in vitro dissolution profiles.

The dissolution medium comprises 1% sodium dodecyl sulfate and 0.02% sodium azide in phosphate buffered saline. The dissolution medium for formulation SL028 and SO32 comprise 0.2% sodium dodecyl e and 0.02% sodium azide in phosphate buffered saline.

The tubes were incubated in a reciprocal shaker at the rate of 60 rpm in a 55°C water bath.

The tubes were pulled, samples of 1 mL on were d, and the tubes were refilled with 1 mL fresh medium at specified times. The removed s were analyzed with HPLC for buprenorphine derivatives and their parent compound, buprenorphine free base. The dissolution profiles are shown in Figure 1—3 and Table 2—4.

Table 2 Time % Release ((13318) SL002 SL005 SL004 SL006 SL007 SL010 0 0.0 0.0 0.0 0.0 0.0 0.0 0.042 29.4 42.9 8.2 4.3 7.4 62.4 0.083 34.3 42.9 9.0 5.6 7.6 64.4 0.167 41.4 46.3 10.3 7.6 8.8 65.6 1 73.6 51.3 17.7 8.9 8.6 64.9 2 94.4 57.8 24.9 10.5 10.7 69.3 3 102.4 — 32.0 12.9 10.7 4 14.7 — — 68.1 — 16.6 — 71.0 6 — 69.7 44.5 18.6 11.9 79.2 7 — 71.6 48.6 20.0 11.8 89.7 8 — 72.0 52.4 — 12.2 90.9 9 — 73.8 55.1 — 12.4 90.8 — — 57.9 — 12.7 12 — 77.2 — 27.3 — 92.0 WO 50043 13 65.1 79.7 30.7 16 73.7 19 82.5 35.6 22 38.6 23 84.9 26 88.4 41.8 29 48.4 33 51.5 36 52.5 40 54.1 43 53.4 47 56.0 54 58.6 61 62.1 68 64.1 75 64.9 82 69.6 90 72.9 96 74.6 103 78.0 110 79.3 117 81.5 124 83.5 WO 50043 145 — — — 100.8 — — 146 — — — — 47.2 — 152 — — — — — — 154 — — — — 58.3 — 162 — — — — 59.9 — 188 — — — — 64.5 — Table 3 Time % Release (days) SL011 SL015 SL017 SL018 SL026 0 0.0 0.0 0.0 0.0 0.0 0.042 16.6 0.4 0.3 0.7 8.2 0.083 18.8 0.2 0.1 0.6 8.3 0.167 21.8 1.6 0.2 0.7 5.4 1 25.2 12.3 0.9 2.2 8.7 2 24.8 10.7 2.5 4.2 9.1 3 26.0 10.2 3.7 6.5 6.0 4 26.7 — — — — 28.3 10.5 6.3 — 6.9 6 — 11.8 7.3 — — 7 28.3 12.8 7.5 15.8 7.5 8 — 14.3 8.7 17.9 — 9 — — — — 7.4 — — — 24.4 — 11 31.2 — — — — 12 — 18.5 12.5 — — 13 — 20.6 13.3 29.9 9.3 14 32.6 21.9 14.3 — — — 22.8 14.9 — 11.7 17 — — — 35.5 — 18 35.0 — — — — 19 — 25.9 17.7 — 17.5 — — — 38.8 — 36.2 — — — — WO 50043 27 32.6 24.4 45.2 30.6 32 36.3 33 37.8 31.6 47 41.5 53 43.7 70 69.7 74 50.6 76 65.8 81 53.7 83 67.0 89 53.8 90 58.8 51.9 70.7 95 53.7 96 54.2 49.0 103 55.5 53.2 105 73.0 110 61.8 64.4 55.1 2017/101327 113 71.9 116 55.9 118 69.8 123 56.9 125 72.5 60.9 126 83.7 130 62.9 133 65.6 63.1 72.6 137 65.6 138 62.9 60.9 145 66.7 146 67.2 78.1 153 66.8 81.6 68.4 158 63.4 159 82.9 83.1 166 78.7 173 67.4 179 81.1 Table 4 % Release Time (days) SL028 SL032 SL035 0.0 0.0 0.0 0.042 0.0 1.3 0.6. 0.083 0.0 1.3 0.6 0.167 0.0 — 0.0 1.7 1.5 0.0 2.1 2.0 14.1 2.8 2.4 — 3.3 .5 — 23.8 5.4 4.2 WO 50043 6.2 4.5 27.1 6.6 4.9 6.8 5.2 11 7.3 13 38.6 6.2 14 8.4 46.9 17 9.3 21 10.5 24 12.3 29 14.4 14.7 41 12.0 42 16.1 48 14.4 50 21.1 55 17.0 63 21.8 19.3 70 25.1 71 21.2 76 22.6 77 28.3 84 25.5 85 32.6 91 27.5 93 36.0 97 28.9 98 — 37.1 — 106 — 41.1 — 113 — 44.1 — 119 — 45.7 — Example 4- Pharmacokinetic profiles of the formulations in Rats The formulations from Example 2 were injected subcutaneously into CD® (SD) IGS male rats at a dose of 30—90 mg buprenorphine/kg. Blood samples were collected from tail veins at specific time points. Plasma samples were separated by centrifuge and stored in frozen ions for later analysis. LC—MS/MS was used to analyze the concentrations of buprenorphine in the plasma samples. The results are shown in Table 5—7 and Figure 4—6.

Table 5 SL006 Time (days) 30 mg/kg 60 mg/kg 90 mg/kg Mean (ng/mL) S.D.(n = 3) Mean ) S.D.(n = 3) Mean (ng/mL) S.D.(n = 3) pre 0.00 0.00 0.00 0.00 0.00 0.00 0.021 0.00 0.00 3.06 1.61 0.35 0.44 0.042 0.17 0.15 4.78 2.16 1.38 1.13 0.083 0.73 0.42 3.35 2.22 2.29 0.79 0.17 1.32 0.63 3.71 2.03 3.93 0.42 0.25 1.66 0.49 3.25 1.47 4.42 0.74 1 0.93 0.21 3.11 0.60 3.38 0.45 3 0.55 0.24 1.96 0.22 3.24 0.9 7 0.85 0.14 2.5 0.88 3.92 0.71 1.06 0.6 3.7 0.99 6.23 0.82 14 0.74 0.22 5.55 3.67 6.43 0.29 21 1.34 0.56 4.87 3.16 8.79 1.86 28 0.58 0.41 2.05 0.93 6.07 1.05 0.25 0.29 6.43 4.57 5.39 1.31 42 0.18 0.28 2.67 0.67 4.21 0.65 49 — — 1.96 0.65 5.39 0.24 56 — — 1.92 0.48 4.08 0.13 2017/101327 63 — 1.75 0.28 4.51 0.48 70 — 1.73 0.48 4.16 0.50 77 — 1.40 0.65 4.02 0.35 84 — 0.72 0.16 3.61 0.46 91 — 1.25 0.76 3.36 0.22 98 — 0.62 0.57 3.01 0.25 105 — 1.09 0.05 3.05 1.21 112 — 1.06 0.19 119 — 1.06 0.15 126 — 0.91 0.14 133 — 0.86 0.06 Table 6 SL031 (60 mg/kg) Time (days) Mean (ng/mL) S.D.(n = 3) 0 0.95 1.9 0.042 6.5 4.87 0.083 14.7 8.3 0.25 28.08 21.56 1 13.5 5.31 3 16.5 6.03 7 20.5 7.48 16.43 5.34 14 11.59 3.52 21 8.02 3.44 28 5.12 2.54 4.38 2.02 42 3.7 2.43 49 2.41 1.37 56 2.84 1.78 63 4.11 1.97 70 3.85 1.94 77 2.98 1.42 84 2.09 1.43 Table 7 SL035 (60 mg/kg) Time (days) Mean (ng/mL) S.D.(n = 3) 0 0 0 0.042 0.23 0.25 0.083 0.39 0.43 0.25 1.12 0.79 1 1.18 0.82 3 1.06 0.78 7 3.81 1.55 4.64 1.77 14 5.93 3.11 17 — — 21 4.42 2.28 24 — — 28 3.50 1.45 3.18 1.29 42 2.37 0.94 49 2.18 0.89 56 1.91 0.78 63 1.88 0.70 70 1.59 0.38 77 1.45 0.38 84 1.45 0.46 98 1.21 0.34 115 0.91 0.06 126 0.85 0.13 140 0.97 0.23 154 0.73 0.17 168 1.04 0.18 Surprisingly, the ations of present invention using prodrug strategy and in situ depot formation display zero—order—release curves Without initial bursts, See Figures 4—6.

Conversely, the prior art formulations lly exhibit significant l bursts, followed by gradually decreasing drug release/uptakes. The initial bursts limit the highest doses that can be used in a single administration; otherwise, adverse effects may occur due to the unacceptable high dose during the initial burst phase.

In contrast, without the initial bursts, formulations of the invention may be given at a higher dose in a single administration without inducing the adverse effects. A higher dose in each administration would allow a single dose to last longer, which is desirable for slow—release formulations. rmore, the zero—order release profiles of the formulations of the invention guarantees that an effective dose will be ed over a long duration, expanding the therapeutically effective durations to several months. These highly desirable properties of the formations of the present invention may be due to the use of prodrugs (C3—acyl—buprenorphines, i.e., acyl esters formation with the phenol of buprenorphine) as well as the formulations for the depot formation in situ.

While the invention has been bed with respect to a limited number of embodiments, those skilled in the art, having the benefit of this sure, will appreciate that other embodiments can be d which do not depart from the scope of the invention as disclosed . Accordingly, the scope of the invention should be limited only by the attached claims.

Claims (7)

CLAIMS What is claimed is:

1. An injectable pharmaceutical composition, comprising: a solution of -buprenorphine, or a pharmaceutically acceptable salt thereof, in a patible organic solvent, wherein the injectable pharmaceutical composition exhibits a steady release profile lasting over one week when injected into a patient or an animal, wherein the acyl group consists of an arbonyl group, and wherein the alkyl portion of the alkylcarbonyl group is a straight-chain or branched-chain, having 5-12 carbon atoms, wherein the biocompatible organic solvent is N-methylpyrrolidone; and n the 3-acyl buprenorphine, or the pharmaceutically acceptable salt thereof, is present at a concentration of 30% to 60% w/v.

2. An injectable pharmaceutical composition, comprising: a solution of 3-acyl-buprenorphine, or a pharmaceutically acceptable salt thereof, in a biocompatible c solvent, n the injectable pharmaceutical composition exhibits a steady release profile lasting over one week when injected into a patient or an animal, wherein the acyl group consists of an arylcarbonyl group, wherein an aryl portion of the arylcarbonyl group is an aromatic group having 6-18 s, wherein the biocompatible organic solvent is ylpyrrolidone; and wherein the 3-acyl buprenorphine, or the pharmaceutically able salt thereof, is present at a concentration of 30% to 60% w/v.

3. The injectable pharmaceutical composition according to claim 1, further comprising a preservative selected from the group consisting of methylparaben, propylparaben and benzylalcohol.

4. The injectable pharmaceutical composition according to claim 1, wherein the injectable pharmaceutical composition is formulated for subcutaneous, intramuscular or intradermal injection.

5. Use of the injectable pharmaceutical composition ing to any one of claims 1-4 for the manufacture of a ment for treating opioid addiction, pain, or depression, wherein the injectable pharmaceutical composition is formulated to be administered to a subject in need thereof in a therapeutically effective amount.

6. The use according to claim 5, wherein the stration is once every week or once every two weeks.

7. The use according to claim 5, wherein the administration is once every month, once every three , or once every six months.