WO2007064845A1

WO2007064845A1 - Sustained release butorphanol drug delivery compositions for analgesia

Info

Publication number: WO2007064845A1
Application number: PCT/US2006/045932
Authority: WO
Inventors: James E. Matsuura; Ehud Zeigerson
Original assignee: Pr Pharmaceuticals, Inc.
Priority date: 2005-11-29
Filing date: 2006-11-29
Publication date: 2007-06-07

Abstract

The invention is directed to a composition comprising a water-insoluble form of butorphanol for non-vascular administration whereby an analgesic effect from the composition lasts at least one day. The invention is further directed to methods of making a water insoluble butorphanol composition and producing butorphanol particles with a defined particle size.

Description

DRUG DELIVERY COMPOSITIONS

FOR ANALGESIA

FIELD OF THE INVENTION

The present invention relates to sustained release compositions of butorphanol and methods of producing the same.

BACKGROUND OF THE INVENTION Butorphanol is a synthetic opioid agonist-antagonist analgesic with a well- characterized pharmacological and therapeutic profile. The relatively new introduction of a transnasal formulation represents a new and noninvasive delivery method for moderate to severe pain with an administration route that effectively bypasses the gastrointestinal tract. The onset of action and systemic bioavailability of butorphanol following transnasal delivery are similar to those observed with parenteral administration.

Currently marketed formulations of butorphanol are based on a water-soluble form, butorphanol tartrate. Due to its high water solubility, (>35 mg/ml) when administered in salt form, rapid absorption occurs resulting in a rapid delivery profile over several hours. Therefore, multiple administrations to patients in need of long- term pain relief is required. Both the parenteral and the transnasal formulation require administration of butorphanol every 3 to 4 hours for effective analgesia. For the long-term control of pain that lasts for greater than four hours, both of these formulations need to be administered multiple times. Currently, there is an unmet clinical need for long-term pain relief via the administration of analgesia in a single administration.

SUMMARY OF THE INVENTION In one embodiment, the invention relates to a composition comprising a water- insoluble form of butorphanol for non-vascular administration whereby an analgesic effect from said composition lasts at least one day.

In another embodiment, the invention relates to a composition comprising butorphanol tartrate and a poloxamer and/or a hyaluronic acid for non-vascular administration.

In a further embodiment, the invention relates to a method of producing a water-insoluble butorphanol composition comprising dissolving the butorphanol in an " If o Itr "ganic ''^■έ'olvenF'td pTδdύc'e"'^'^ oil phase; emulsifying the oil phase in water; and extracting the organic solvent to produce butorphanol particles.

In another embodiment, the invention relates to a method of producing butorphanol particles with a defined particle size comprising combining immiscible liquid phases employing a packed bed emulsifier operated in laminar flow to produce an emulsion of a discontinuous phase, comprising a solvent and butorphanol, suspended in a continuous phase; and removing the solvent from the emulsion to form the butorphanol particles.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

Fig. 1 illustrates a plot of the in vitro release of butorphanol tartrate (BT) (35 mg/mL) gel comprising pluronic F127 (350, 450, 550 or 650 mg/mL) according to an embodiment of the invention.

Fig. 2 illustrates a plot of the in vitro release of butorphanol tartrate (30 mg/mL) gel comprising Pluronic F127 (350, 450, 550 or 650 mg/mL) according to an embodiment of the invention.

Fig. 3 illustrates a plot of the in vitro release of butorphanol tartrate (25 mg/mL) gel comprising Pluronic F127 (250, 350, 450, 550 or 650 mg/mL) according to an embodiment of the invention. Fig. 4 illustrates a plot of the in vitro release of butorphanol tartrate (averaged over 25, 30 or 35 mg/mL) gel comprising Pluronic F 127 (250, 350, 450, 550 or 650 mg/mL) according to an embodiment of the invention.

Fig. 5 illustrates a representative scanning electron micrograph of free-base particles produced from a benzyl alcohol emulsion and collected in water according to an embodiment of the invention.

Fig. 6 illustrates a representative scanning electron micrograph of free-base particles produced by an emulsification process from a benzyl alcohol oil phase and a 1% solution of polyvinyl alcohol in water solvent extraction phase according to an embodiment of the invention. Fig. 7 illustrates a plot of the in vitro release rate profiles for free-base (FB) amorphous particles in aqueous solution according to an embodiment of the present invention. Similar release rates were obtained using free-base crystals •^>fy[^:»8llMstr^'afdS"^"β'fep'ri§sentative scanning electron micrograph of free-base crystal formation from an N-methyl pyrrolidone vortexed emulsion according to an embodiment of the invention.

Fig. 9 illustrates a representative scanning electron micrograph of free-base crystal formation from a dimethyl sulfoxide vortexed emulsion according to an embodiment of the invention.

Fig. 10 illustrates a representative scanning electron micrograph free-base crystal formation from a N-methyl pyrrolidone solution with very slow addition of water according to an embodiment of the invention. Fig. 11 illustrates a representative scanning electron micrograph free-base crystal formation from a dimethyl sulfoxide solution with slow addition of water according to an embodiment of the invention.

Fig. 12 illustrates a representative scanning electron micrograph free-base crystal formulation from N-methyl pyrrolidone according to an embodiment of the invention.

Fig. 13 illustrates a graph of the amount of drug released in vitro day-one (burst) after incubation at 37 C in water, for the ion-pairs (IP) of butorphanol with xinafoate (Xin), pamoate (Pam) and di(2-ethy!hexyl) sulfosuccinate (AOT) and for the free-base (FB)₁ in two solvents according to an embodiment of the invention. The burst release is minimal for the free-base and di(2-ethylhexyl) sulfosuccinate (AOT) ion-pair in dimethyl sulfoxide.

Fig. 14 is a graph of the in vitro average release rate in concentration per day as a function of formulation according to an embodiment of the present invention.

Fig. 15 illustrates a representative scanning electron micrograph of butorphanol di(2-ethylhexyl) sulfosuccinate drug particle produced from an oil phase of benzyl alcohol:ethyl acetate (1:1) emulsified in water (with 1% polyvinyl alcohol) and extracted in water according to an embodiment of the present invention.

Fig. 16 illustrates a representative scanning electron micrograph of crystals of butorphanol dodecyl sulfate produced from an emulsion of 50 mg/mL butorphanol dodecyl sulfate dissolved in benzyl alcohol:ethyl acetate 1:1; in 1% polyvinyl alcohol and then extracted in water according to an embodiment of the present invention.

Fig. 17 illustrates a plot of the serum concentrations of butorphanol as a function of time upon subcutaneous injection of formulation A, B, C, D, E or F to dogs according to an embodiment of the present invention. •^■Fi|l^{ι ;}W41liastrd%PΦ|>l<sraf an expanded scale version of Figure 17 according to an embodiment of the present invention.

Fig. 19 illustrates a plot of the Formulation D pharmacokinetic profile for 5 days according to an embodiment of the present invention. Fig. 20 illustrates a plot of the pharmacokinetics of three Butorphanol

Formulations in NMP after subcutaneous injection in dogs according to an embodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION In one embodiment of the present invention, compositions including butorphanol tartrate are provided. In a particular embodiment, the release of butorphanol tartrate from the site of injection is slowed by the use of an aqueous thermosetting gel to control the delivery of butorphanol from the depot site. This aspect of the invention is based on the formation of compositions including a water- soluble form of butorphanol with poloxamers or hyaluronic acid for long-term pain relief. The poloxamers and hyaluronic acids are well known in the art to be both biocompatible and non-toxic. The viscosity conferred by the poloxamers or hyaluronic acid allows for an in vivo pharmacokinetic profile and an analgesic effect lasting for at least one day and up to multiple days. In one embodiment of the invention, compositions of butorphanol free-base in solvents are provided. This aspect of the invention is based on (a) the low aqueous solubility of butorphanol free-base and (b) the high solubility of the butorphanol free- base in solvents, and (c) the ability of the solvent to leave the site of injection rapidly to leave behind a depot of butorphanol free-base. Formation of a butorphanol free- base dramatically decreases its water solubility, producing a composition suitable for sustained release formulations. The free-base itself has a very low solubility in water (~200 ug/ml in phosphate buffered saline (PBS) pH 7.4, and below detection at pH 10).

Butorphanol free-base is soluble in one or more of N-methyl pyrrolidone, dimethyl sulfoxide, ethyl acetate, methylene chloride, propylene carbonate, and alcohols, such as benzyl alcohol, and mixtures of two or more thereof, to high concentrations (>50 mg/ml), but has minimal solubility in water. This low water solubility is utilized to the advantage of compositions of the invention by preparing particulate formulations of the free-base from benzyl alcohol to produce amorphous i ^rtibles^rr^lMrhotiV^l^ ifrsWutions of N-methy! pyrrolidone to produce crystalline formulations. In Fig. 7 there is shown a plot of the in vitro release rate profiles for free-base amorphous particles. Similar release rates were obtained using free-base crystals. These particulate formulations can then be isolated via conventional means and suspended in an aqueous vehicle for parenteral administration.

In another embodiment, the solution itself can be used as the delivery system. When the free-base is dissolved in N-methyl pyrrolidone, dimethyl sulfoxide, propylene carbonate or benzyl alcohol, the drug will precipitate or crystallize in situ after administration within the tissue space due to the low solubility of the free-base in aqueous environments.

In another embodiment of the invention, compositions of butorphanol hydrophobic ion-pairs are disclosed. This aspect of the invention is based on the formation of ion-pairs of butorphanol with various ion-pair agents that render the ion- pair water-insoluble. Without limitation, appropriate ion-pair agents include pamoate, cholate, xinafoate, dodecyl sulfate, di(2-ethylhexyl) sulfosuccinate, and the like, and combinations thereof.

These hydrophobic ion-pairs can be made into three different types of dosage forms. In one embodiment, the dosage form comprises a solution injection whereby the low water solubility drug is dissolved in an organic solvent and injected as a solution. As the organic solvent dissipates the drug will precipitate and form a depot, producing a sustained release. In one embodiment, the dosage form comprises a microsphere in which the drug is dissolved in an organic solvent with a polymer to increase encapsulation efficiency and core load for sustained delivery from a microsphere. In another embodiment, the dosage form comprises a particle in which the drug is dissolved in an organic solvent, an emulsion is formed and the drug particle size distribution, after organic solvent is extracted, is determined by the size distribution of the initial emulsion.

In a particular embodiment, a solution dosage form is presented as the butorphanol dodecyl sulfate dissolved in propylene carbonate and injected to give sustained release over 1 -2 days. Examples of other injectable solvents are N-methyl pyrrolidone, dimethyl sulfoxide, and ethanol. The release rates of various ion pair formulations in N-methyl pyrrolidone and dimethylsulfoxide are illustrated in Figs. 13 and 14. ^•■''dbWetftib'h'aliy', microparticles are routinely produced from a process where the active agent and a polymer are co-solubilized in an organic solvent, and an oil in water emulsion is formed. The organic solvent is then removed from the emulsion droplets to form hardened microparticles. The solvent removal may be by evaporation or exposure to a bath in which the solvent is partially soluble. In Fig. 15 there is illustrated a representative scanning electron micrograph of butorphanol di(2-ethylhexyl) sulfosuccinate drug particle produced from an oil phase of benzyl alcohol.ethyl acetate (1:1) emulsified in water (with 1% polyvinyl alcohol) and extracted in water. Fig. 16 illustrates a representative scanning electron micrograph of crystals of butorphanol dodecyl sulfate produced from an emulsion of 50 mg/mL butorphanol dodecyl sulfate dissolved in benzyl alcohol:ethyl acetate 1:1; in 1% polyvinyl alcohol and then extracted in water.

Owing to the altered solubility of the butorphanol compositions of the invention, drug particles of butorphanol can be produced, in one embodiment, by dissolving the drug in an organic solvent and producing an oil in water emulsion, without the use of a polymer. Such organic solvents include, but are not limited to, propylene carbonate, benzyl alcohol, N-methy! pyrrolidone, dimethyl sulfoxide, ethyl acetate, methylene chloride, and the like, and mixtures of two or more thereof. This "oil phase" comprising drug and solvent is then emulsified in water (o/w emulsion). The size of the oil droplets in the water phase and the concentration of the active in the oil phase determine the size of the resulting particles or crystals (and to some extent their morphology). The organic solvent is extracted into the water phase, just as it is extracted to produce microspheres. The rate of solvent extraction into the water phase is controlled by altering the amount of solvent in the water phase used to make the emulsion, volume of extraction medium, rate of addition of final extract volume, and the like. Controlling the rate of solvent extraction assists with controlling the type of particles produced. Slow extraction facilitates crystal or semi-crystalline particles (e.g. butorphanol dodecyl sulfate), as shown in Figures 8-12, while fast extraction freezes the conformation and result in more amorphous particles (e.g. butorphanol di(2-ethylhexyl) sulfosuccinate), as shown in Figures 5 and 6.

In another embodiment of the invention, a process for production of particles with a well-defined and narrow particle size distribution is disclosed. In a particular embodiment the invention employs a packed bed emulsifier operated in laminar flow combining immiscible liquid phases to produce an emulsion of a discontinuous lφ^!ha^^'dyii3|)tⁱisϊ%''a"'S'o^6m"aι^ti€i an active agent, suspended in a continuous phase.

The solvent is then removed from the emulsion to form the active agent particles or crystals, which are later collected and dried. In another embodiment a water soluble active agent is combined with a hydrophobic ion to form a water insoluble complex. The complex is dissolved in a suitable organic solvent or solvent mixture and introduced into a packed bed emulsifier along with a water phase. The resulting emulsion undergoes solvent removal to produce crystals of the insoluble complex where the crystals have a narrow, well-defined particle size distribution. The crystals are collected and dried by conventional means and used as an injectable controlled release drug delivery preparation.

The rate of drug delivery for these low water solubility butorphanol compositions is controlled by solubility and the surface area presented by the drug particles. Thus the size of the particles/crystals is one of the controlling factors in the rate of drug delivery. Size is also important since the particles need to pass through a small gauge needle for parenteral administration. Drug particles of different sizes can be produced by a number of technologies, including spray drying, jet milling, milling, grinding, etc.

Release of butorphanol from compositions of the present invention may take a prolonged period of time. In one embodiment, such release may take from at least one day up to five days as demonstrated by pharmacokinetics. In one embodiment, such release may take from at least one day up to three days.

In another embodiment, the compositions provide an effective drug delivery system for pain control.

The formulations of the present invention may be administered as a solution, as particles with an aqueous suspending phase, as a gel, as a hydrogel, and the like.

The compounds of the present invention may be administered to animals, including mammals, fish, reptiles, and avians. Mammals include humans, horses, livestock, cattle; poultry; and household pets including cats and dogs, and the like.

The compositions of the present invention may be processed in accordance with conventional methods to produce medicinal agents for administration to any animal, including humans.

The compounds of this invention can be employed in admixture with conventional excipients, such as pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral administration which do not deleteriously '»^;;l<§act v/ifh^!it^^^»&Wιve"¹i3ϊ)FinfJθιin€JS. The term "admixing" is defined as mixing thefδvo⁹³² components together so that there is no chemical reaction or physical interaction. The term "admixing" also includes the chemical reaction or physical interaction between the composition of the present invention and the pharmaceutically- acceptable carrier. Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatine, carbohydrates such as lactose, amylose, or starch, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethyl cellulose, polyvinyl pyrrolidone, and the like, merely to name a few.

The compositions of the present invention may be sterilized and/or mixed with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds. They can also be combined where desired with other active agents, such as vitamins, antiinflammatories, antimicrobials, antibacterials, anti-virals, antifungals, antiproliferatives, antibiotics, steroids, and the like.

For parenteral application, particularly suitable are injectable, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants including suppositories.

For topical application, formulations include non-sprayable forms, viscous to semi-solid or solid forms including a carrier compatible with topical application and having a dynamic viscosity that may be greater than water. Suitable formulations include but are not limited to solutions, gels, suspensions, emulsions, creams, ointments, powders, liniments, salves, aerosols and the like, which are, if desired, sterilized or mixed with auxiliary agents, such as, preservatives, stabilizers, wetting agents, buffers, or salts for influencing osmotic pressure, and the like. Topical administration may also include ophthalmic, vaginal, rectal, intranasal, and the like, administration. It may further include administration into a body cavity during or after surgery, such as the peritoneal cavity, and the like.

It will be appreciated that the actual amount of active agent in a specified case will vary according to the specific compound being utilized, the particular compositions formulated, the mode of application, and the particular situs and animal being treated. Dosages for a given animal can be determined using conventional ^!!'e^'©nsfderati©?isf §^'tιe;h"¹iS'"-b'yⁱⁱβCis.t&mary comparison of the differential activities of the subject compounds and of a known agent, by means of an appropriate convention pharmacological protocol and the like. One of skill in the art will realize how to formulate the compounds of the present invention with a sufficient concentration of active agent within them.

EXAMPLES

The invention is more particularly described in the examples that follow, which are intended to be illustrative only, since numerous modifications and variations therein will be apparent to those skilled in the art.

EXAMPLE 1: BUTORPHANOL GEL DRUG DELIVERY SYSTEM

Example 1 illustrates the production of sustained delivery formulations of butorphanol according to an embodiment of the present invention. Butorphanol tartrate is water soluble (>35 mg/ml) and results in rapid absorption when used in a salt form.

Illustrative formulations including butorphanol tartrate at concentrations of 25, 30 or 35 mg/mL and pluronic F127 at concentrations of 250, 350, 450, 550, or 650 mg/mL in water were prepared. The formulations formed gels and appeared viscous upon visual observation. The formulations were then incubated at 37 C for up to 8 days, and the amount of butorphanol tartrate released from each gels was measured. Figures 1 through 3 illustrate the effect of varying the butorphanol tartrate concentration over the range 25 through 35 mg/mL and of varying the pluronic F 127 concentration over the range 250 through 650 mg/mL according to particular embodiments of the present invention. It appeared that at any given concentration of butorphanol tartrate, the rate of release was slower as the concentration of pluronic F127 was increased. Figure 4 illustrates the effect of increasing the concentration of pluronic F127 on in vitro release rate as it shows the kinetic profiles averaged over the butorphanol tartrate concentration range according to a particular embodiment of the present invention.

OF BUTORPHANOL DRUG DELIVERY

SYSTEMS IN DOGS

The analgesic effect of the butorphanol compositions of the present invention in a dog model are illustrated in Table 1. The butorphanol composition of the invention demonstrated control of pain for at least 3 days. Formulations A, B, C, D,

E, and F are as follows:

A: Butorphanol.AOT 36 mg/ml butorphanol tartrate (BT) equiv/ml in N-methyl

Pyrrolidone (NMP) B: Butorphanol Free Base 36 mg/ml BT equiv/ml in NMP

C: Butorphanol Free Base 36 mg/ml BT equiv/mL in dimethyl sulfoxide (DMSO)

D: Butorphanol SDS crystal formulation in aqueous suspension

E: Butorhphanol Free Base Crystal formulation in aqueous suspension

F: Butorphanol Tartrate in Pluronic F 127 aqueous thermosetting gel

Table 1: ANALGESIC EFFECT OF BUTORPHANOL DRUG DELIVERY SYSTEMS IN DOGS

Table 1 Cont'd

2006/045932

EXAMPLE 3: PHARMACOKINETICS OF BUTORPHANOL DRUG DELIVERY SYSTEMS

This example illustrates the pharmacokinetics of butorphanol drug delivery systems (A, B, C, D, E and F) upon subcutaneous injection in a dog model. Formulations A, B, C, D, E and F correspond to:

A: Butorphanol:AOT 36 mg/ml butorphanol tartrate (BT) equiv/ml in NMP B: Butorphanol Free Base 36 mg/ml BT equiv/ml in NMP C: Butorphanol Free Base 36 mg/ml BT Equiv in DMSO D: Butorphanol SDS crystal formulation in aqueous suspension

E: Butorhphanol Free Base Crystal formulation in aqueous suspension F: Butorphanol Tartrate in Pluronic F127 aqueous thermosetting gel

Each formulation was administered to a treatment group comprising six (6) laboratory beagle dogs per group. The dose was given by subcutaneous injection in the back near the neck. The dose per dog was 3.6 mg/kg, i.e. a customized volume of injection for each dog depending on its weight. Blood was drawn from each dog after butorphanol injection at 0.5, 1 , 2, 4, 6, 9, 12, 18, 24, 30, 36, 48, 60, and 72 hrs.

The blood was processed to obtain the serum and frozen. Serum butorphanol levels were determined by a HPLC procedure. The serum concentrations as a function of time after injection are shown in Figure 17. Circulating levels of butorphanol were detectable for at least 72 hours for several formulations, as seen in Figure 18. The formulation D pharmacokinetic profile is illustrated in Fig. 19 and demonstrates that circulating levels of butorphanol were detectable for a time of up to 120 hours.

EXAMPLE 4: PHARMACOKINETICS OF BUTORPHANOL DRUG DELIVERY SYSTEMS

In this example, the pharmacokinetics of butorphanol drug delivery systems (A, B, and G) were determined upon subcutaneous injection in a dog model. Formulations A₁ B, and G correspond to:

A: Butorphanol:AOT 36 mg/ml butorphanol tartrate (BT) equiv/ml in NMP B: Butorphanol Free Base 36 mg/ml BT equiv/ml in NMP

G. A mixture of 50% A and 50% B by volume. Each formulation was administered to a treatment group comprising six (6) dogs per group. The dose was given by subcutaneous injection in the back near the neck. The dose per dog was 3.6 mg/kg, i.e. a customized volume of injection for each dog depending on its weight. Blood was drawn from each dog after butorphanol injection at 0.5, 1 , 2, 4, 6, 9, 12, 18, 24, 30, 36, 48, 60, and 72 hrs.

The blood was processed to obtain the serum and frozen. Serum butorphanol levels were determined by a HPLC procedure.

The serum concentrations as a function of time after injection are shown in Figure 20. Circulating levels of butorphanol were detectable for at least 72 hours for each formulation.

While the invention has been explained in relation to specific embodiments, it is to be understood that various modifications thereof will become apparent to those skilled in the art upon reading the specification. Therefore, it is to be understood that the invention disclosed herein is intended to cover such modifications as fall within the scope of the appended claims.

Claims

What is claimed is:

1. A composition comprising a water-insoluble form of butorphanol for nonvascular administration whereby an analgesic effect from the composition lasts at least one day.

2. The composition of claim 1, wherein the water-insoluble form of butorphanol comprises one or more of a solution of butorphanol free-base in a solvent and/or a hydrophobic ion-pair.

3. The composition of claim 2, wherein the solvent comprises one or more of N-methyl pyrrolidone, dimethyl sulfoxide, benzyl alcohol, ethyl acetate, methylene chloride, propylene carbonate, an alcohol, or a mixture of two or more thereof.

4. The composition of claim 1, wherein the hydrophobic ion-pair is formed from interaction with an agent comprising one or more of pamoate, cholate, xinafoate, di(2-ethylhexyl) sulfosuccinate, dodecylsulfate, and combinations thereof.

5. The composition of claim 1 , further including an excipient, an auxiliary agent, and/or an active agent.

6. The composition of claim 1, wherein the composition comprises an aqueous suspension and/or an emulsion.

7. The composition of claim 1 , wherein the composition comprises a crystalline particle and/or an amorphous particle.

8. The composition of claim 1 , wherein the analgesic effect lasts from at least one day up to five days.

9. The composition of claim 8, wherein the composition comprises a gel and/or a hydrogel.

10. The composition of claim 1, wherein the composition is applied parenterally and/or topically.

11. A composition comprising butorphanol tartrate and a poloxamer and/or a hyaluronic acid for non-vascular administration.

12. The composition of claim 11 , wherein the composition provides an analgesic effect for at least one day up to five days.

13. The composition of claim 12, wherein the composition comprises a gel and/or a hydrogel.

14. A method of producing a water-insoluble butorphanol composition comprising:

(a) dissolving the butorphanol in an organic solvent to produce an oil phase;

(b) emulsifying the oil phase in water; and (c) extracting the organic solvent to produce butorphanol particles.

15. The method of claim 14, wherein the organic solvent comprises propylene carbonate, benzyl alcohol, N-methyl pyrrolidone, dimethyl sulfuxide, ethyl acetate, methylene chloride or mixtures of two or more thereof.

16. The method of claim 14, wherein the particles comprise amorphous particles and/or crystalline particles.

17. A method of producing butorphanol particles with a defined particle size comprising: (a) combining immiscible liquid phases employing a packed bed emulsifier operated in laminar flow to produce an emulsion of a discontinuous phase, comprising an organic solvent and butorphanol, suspended in a continuous phase; and

(b) removing the solvent from the emulsion to form the butorphanol particles.

18. The method of claim 17, wherein the particles comprise a crystal and/or an amorphous particle.

19. The method of claim 17, further including combining the butorphanol with a hydrophobic ion to form a water insoluble complex.

20. A drug delivery system comprising a sustained release composition of butorphanol for non-vascular administration.