UA89505C2 - Sustained local anesthetic composition - Google Patents

Abstract

The present invention relates to novel anesthetic compositions containing a non-polymeric carrier material and an anesthetic, where the compositions are suitable for providing a sustained local anesthesia without an initial burst and having duration for about 24 hours or longer. The compositions contains bupivacaine, sucrose acetate isobutyrate and benzyl alcohol.

Description

36-48 hours after administration, and more preferably at least about 48-72 hours after administration.

In one aspect of the invention, the non-polymeric carrier is sufficient to provide either a controlled first-order anesthetic release profile or a pseudo-zero-order anesthetic release profile. In specific embodiments, the anesthetic is a local anesthetic, such as an amide or ether type local anesthetic. In a preferred embodiment, the anesthetic is bupivacaine, which can additionally be provided in the form of a free base. In other embodiments, the composition is capable of providing a long-term sustained mean plasma anesthetic concentration (CeH) of at least about 20 ng/ml for a period of at least about 24 hours when the composition is administered subcutaneously, preferably at least about 25 ng/ml, or at least about 10 ng/ml, or at least approximately 35 ng/ml.

In another aspect of the invention, the non-polymeric carrier is essentially insoluble in water or in an aqueous biological system. In such compositions, the pharmaceutical preparation may additionally contain a solvent that is dispersible, soluble in water or an aqueous system, or miscible with it. The solvent, therefore, may be an organic solvent capable of dispersing, diffusing, or leaching from the composition when placed in a biological system, whereby the carrier may then coagulate or precipitate to form a solid implant.

In another aspect of the invention, the non-polymeric carrier is a liquid, preferably a high-viscosity liquid carrier material ("NMI SM") having a viscosity of at least about 5000 cSP at 37"C, which, without impurities, does not crystallize under ambient or physiological conditions conditions. Such liquid carrier materials can be combined with a solvent in which the carrier material is soluble. When using NMI CM, it is preferred that the solvent be sufficient to reduce the viscosity of the NMI CM. In a specific embodiment, the diluent may be a second anesthetic agent, such as benzyl alcohol. The compositions can be provided in any suitable form, for example, as an emulsion, paste, gel, suspension, cream, film, spray, solid, particle, microparticle, powder, implant, or liquid. In specific embodiments, the composition additionally contains a material not mixed with a non-polymeric carrier, for example when the composition is an emulsion In these compositions the carrier may be present either in a dispersed or di dispersion phase of the emulsion.

The purpose of the present invention is also to obtain a composition that contains an anesthetic and a pharmaceutically acceptable non-polymeric carrier. The non-polymeric carrier controls the release of the anesthetic to provide an anesthetic effect characterized by prolonged local anesthesia after administration to the subject, wherein the composition is further capable of providing a sustained mean plasma anesthetic concentration (Se) of at least about 200 ng/mL for a period of at least about 24 hours, wherein the composition is administered subcutaneously, preferably at least about 25 ng/ml, or at least about 30 ng/ml, preferably at least about 35 ng/ml.

In one aspect of the invention, the composition is capable of providing a sustained mean plasma concentration (Cv) for a period of at least about 48 hours. In another aspect, the composition is further characterized as having no significant initial release. In other aspects, the non-polymeric carrier is sufficient to provide either a controlled first-order anesthetic release profile or a pseudo-zero-order anesthetic release profile. In specific embodiments, the anesthetic is a local anesthetic, such as an amide or ether type local anesthetic. In a preferred embodiment, the anesthetic is bupivacaine, which can additionally be provided in the form of a free base.

In another aspect of the invention, the non-polymeric carrier is essentially insoluble in water or in an aqueous biological system. In such compositions, the pharmaceutical preparation may additionally contain a solvent that is dispersible, soluble in or miscible with water or an aqueous system. The solvent, therefore, may be an organic solvent capable of dispersing, diffusing, or leaching from the composition when placed in a biological system, whereby the carrier may then coagulate or precipitate to form a solid implant.

In another aspect of the invention, the non-polymeric carrier is a liquid, preferably a high-viscosity liquid carrier material ("NMI SM") having a viscosity of at least about 5000 cSP at 37"C, which, without impurities, does not crystallize under ambient or physiological conditions conditions. Such liquid carrier materials can be combined with a solvent in which the carrier material is soluble. When using NM CM, it is preferable that the solvent is sufficient to reduce the viscosity of the NM CM. In specific embodiments, the solvent can be a second anesthetic agent, such as benzyl alcohol. The compositions may be provided in any suitable form, for example, as an emulsion, paste, gel, suspension, cream, film, spray, solid, particle, microparticle, powder, implant, or liquid. In specific embodiments, the composition further comprises material not mixed with a non-polymeric carrier, for example when the composition is an emulsion In these compositions the carrier may be present either in a dispersed or dispersed seed phase of the emulsion.

A related object of the invention is to obtain a composition that contains a first anesthetic, a second anesthetic and a pharmaceutically acceptable non-polymeric carrier. The second anesthetic in the composition is a solvent for the first anesthetic and provides the initial anesthetic effect when administered to the subject. The non-polymeric carrier controls the release of the first anesthetic to provide a subsequent anesthetic effect characterized by sustained local anesthesia with an onset within about 2 hours of administration to the subject without an initial release and lasting at least about 24 hours after administration, preferably at least about 36-48 hours after administration, and preferably at least about 48-72 hours after administration.

In one aspect of the invention, the non-polymeric carrier is sufficient to provide either a controlled first-order anesthetic release profile or a pseudo-zero-order anesthetic release profile. In other embodiments, the composition is capable of providing a long-term sustained mean plasma anesthetic concentration (Ce) of at least about 200 ng/mL for a period of at least about 24 hours when the composition is administered subcutaneously, preferably at least about 25 ng/mL, or at least about 10 ng/mL, or at least approximately 35 ng/ml. In other specific embodiments, the first anesthetic is a local anesthetic, for example a local anesthetic of the amide or ether type. In other embodiments, the second anesthetic is also a solvent for the non-polymeric carrier. The second anesthetic can be a solvent - an alcohol, an aromatic alcohol, an acid or an acid derivative, or any combination of such solvents.

In a preferred embodiment, the second anesthetic is benzyl alcohol. In another preferred embodiment, the first anesthetic is bupivacaine, which can additionally be provided in the form of a free base.

In another aspect of the invention, the non-polymeric carrier is essentially insoluble in water or in an aqueous biological system. In such compositions, the pharmaceutical preparation may additionally contain a solvent that is suitable for dispersing, soluble in or miscible with water or an aqueous system. The solvent, therefore, may be an organic solvent capable of dispersing, diffusing, or leaching from the composition when placed in a biological system, whereby the carrier may then coagulate or precipitate to form a solid implant.

In another aspect of the invention, the non-polymeric carrier is a liquid, preferably a high-viscosity liquid carrier material ("NMI SM") having a viscosity of at least about 5000 cSP at 37"C, which, without impurities, does not crystallize under ambient or physiological conditions conditions. Such liquid carrier materials can be combined with a solvent in which the carrier material is soluble. When using NM CM, it is preferable that the solvent is sufficient to reduce the viscosity of the NM CM. In specific embodiments, the solvent can be a second anesthetic agent, such as benzyl alcohol. The compositions may be provided in any suitable form, for example, as an emulsion, paste, gel, suspension, cream, film, spray, solid, particle, microparticle, powder, implant, or liquid. In specific embodiments, the composition further comprises material which is immiscible with a non-polymeric carrier, for example when the composition is an emulsion In these compositions the carrier may be present either in dispersed form or in d dispersion phase of the emulsion.

A related object of the invention is also to obtain a composition that contains a non-polymeric, non-water-soluble carrier material with high viscosity ("NMI SM"), having a viscosity of at least approximately 5000 cSP at 37"C, which without impurities does not crystallize under conditions environmental or physiological conditions, a first anesthetic and a second anesthetic. Here again the second anesthetic is a solvent for the first anesthetic and provides the initial anesthetic effect when administered to the subject. The NM SM controls the release of the first anesthetic to provide a subsequent anesthetic effect characterized by prolonged local anesthesia beginning within about 2 hours of administration to a subject without baseline and lasting at least about 24 hours after administration, preferably at least about 36-48 hours after administration, and even more preferably at least about 48-72 hours after administration. in specific variants of implementation, the composition is able to provide a long-lasting stable average concentration of the anesthetic in the pla zmi (Cxx) of at least about 200 ng/ml for a period of at least about 24 hours when the composition is administered subcutaneously, preferably at least about 2500 ng/ml, or at least about 300 ng/ml, or at least about 35 ng/ml.

In one aspect of the invention, the first anesthetic is a local anesthetic, such as an amide or ether type local anesthetic. In other embodiments, the second anesthetic is also a solvent for NMI SM.

The second anesthetic can be a solvent - alcohol, an aromatic alcohol, an acid or an acid derivative, or any combination of such solvents. In a preferred embodiment, the second anesthetic is benzyl alcohol. In another preferred embodiment, the first anesthetic is bupivacaine, which can additionally be provided in free base form. In other preferred embodiments, the NMI SM is an ester, such as a sugar ester, such as sucrose acetate isobutyrate. In such compositions, it may be useful to provide a solvent in which the NUMI CM is soluble.

An additional and related object of the invention is to provide a composition that contains a non-polymeric, non-water-soluble liquid carrier material with a high viscosity ("NMI CM") having a viscosity of at least about

BOOOSP at 37"C, which without impurities does not crystallize under environmental conditions or under physiological conditions, the first anesthetic and the second anesthetic. Here again, the second anesthetic in the composition is a solvent for the first anesthetic and provides the initial anesthetic effect when administered to the subject.

The NMI SM controls the release of the first anesthetic to provide a subsequent anesthetic effect characterized by sustained local anesthesia, wherein the composition is further capable of providing a sustained mean plasma anesthetic concentration (CeH) of at least about 20 ng/ml for a period of at least about 24 hours when the composition is administered subcutaneously, preferably at least about 25 ng/ml, or at least about 300 ng/ml, or at least about 35 ng/ml.

In one aspect of the invention, the composition is capable of providing a sustained mean plasma anesthetic concentration (CeH) for a period of at least about 48 hours. In a second aspect, the composition is further characterized as having no significant initial emission.

In another aspect of the invention, the first anesthetic is a local anesthetic, for example a local anesthetic of the amide or ether type. In other embodiments, the second anesthetic is also a solvent for NMI CM.

The second anesthetic can be a solvent - alcohol, an aromatic alcohol, an acid or an acid derivative, or any combination of such solvents. In a preferred embodiment, the second anesthetic is benzyl alcohol. In another preferred embodiment, the first anesthetic is bupivacaine, which can additionally be provided in the form of a free base. In other preferred embodiments, the NMI SM is an ester, such as a sugar ester, such as sucrose acetate isobutyrate. In such compositions, it may be useful to provide a solvent in which the NUMI CM is soluble.

An additional purpose of the invention is to obtain a method of providing the subject with an anesthetic effect in the area. The method consists in introducing the composition to the site, near the site, in the site or in the vicinity of the site, where the composition contains an anesthetic and a pharmaceutically acceptable non-polymeric carrier. The non-polymeric carrier controls the release of the anesthetic to provide an anesthetic effect characterized by prolonged local anesthesia after administration to the subject without an initial release and lasting at least approximately 24 hours after administration.

In one aspect of the invention, the anesthetic is a local anesthetic, such as an amide or ether type local anesthetic.

A related purpose of the invention is to obtain a method of providing the subject with an anesthetic effect in the area. The method consists in introducing the composition to the site, near the site, in the site or in the vicinity of the site, where the composition contains an anesthetic and a pharmaceutically acceptable non-polymeric carrier. The non-polymeric carrier controls the release of the anesthetic agent to provide an anesthetic effect characterized by prolonged local anesthesia after administration to the subject, wherein the composition is further capable of providing a sustained mean plasma anesthetic concentration (Cx) of at least about 20 ng/ml for a period of at least about 24 hours when the composition administered subcutaneously.

In one aspect of the invention, the anesthetic is a local anesthetic, such as an amide or ether type local anesthetic.

An additional purpose of the invention is to provide a method of providing the subject with an anesthetic effect in the area. The method consists in introducing the composition to the site, near the site, in the site or in the vicinity of the site, where the composition contains an anesthetic and a pharmaceutically acceptable non-polymeric carrier. The second anesthetic is a solvent for the first anesthetic and provides the initial anesthetic effect at the site of injection. The non-polymeric carrier controls the release of the first anesthetic to provide a subsequent anesthetic effect characterized by long-lasting local anesthesia at the site with an onset within about 2 hours of administration without an initial release and lasting at least about 24 hours after administration, preferably at least about 36-48 hours after administration , and preferably at least about 48-72 hours after administration.

In one aspect of the invention, the non-polymeric carrier is a liquid carrier material, preferably a high viscosity carrier material ("NMI CM") that is not soluble in water and has a viscosity of at least about 5000 cSP at 37"C and, in addition, does not crystallize free of impurities under ambient or physiological conditions. Such liquid carrier materials can be combined with a solvent in which the carrier material is soluble. When used

NMISM is better so that the solvent is sufficient to reduce the viscosity of NMISM. In specific embodiments, the solvent may be a second anesthetic agent, such as benzyl alcohol.

In another aspect of the invention, the first anesthetic is a local anesthetic, for example a local anesthetic of the amide or ether type. In other embodiments, the second anesthetic is also a solvent for NMI CM.

The second anesthetic can be a solvent - an alcohol, an aromatic alcohol, an acid or an acid derivative, or any combination of such solvents. In a preferred embodiment, the second anesthetic is benzyl alcohol. In another preferred embodiment, the first anesthetic is bupivacaine, which can additionally be provided in the form of a free base. In other preferred embodiments, the NMI SM is an ester, such as a sugar ester, such as sucrose acetate isobutyrate. In such compositions, it may be useful to provide a solvent in which the NUMI CM is soluble.

In another aspect of the invention, the composition is administered to the site by topical, transdermal, injection, or as an implant. In specific embodiments, the composition is administered to an area that is a surgical wound, and the composition is administered into the wound and/or adjacent to the wound.

An additional purpose of the invention is a method of providing the subject with an anesthetic effect in the area. The method consists in introducing the composition to the site, near the site, in the site or in the vicinity of the site, where the composition contains a first anesthetic, a second anesthetic and a pharmaceutically acceptable non-polymeric carrier.

The second anesthetic is a solvent for the first anesthetic and provides the initial anesthetic effect in the area after injection. The non-polymeric carrier controls the release of the first anesthetic to provide a subsequent anesthetic effect characterized by prolonged local anesthesia at the site, and the composition is further capable of providing a sustained mean plasma anesthetic concentration (CvV) of at least about 200 ng/mL for a period of at least about 24 hours when the composition is administered. subcutaneously

In one aspect of the invention, the non-polymeric carrier is a liquid, preferably a high viscosity liquid carrier material ("NMI CM"), which is not soluble in water and has a viscosity of at least about 5000 cSP at 37"C, and which, in addition , without impurities does not crystallize under environmental conditions or under physiological conditions.

Such liquid carrier materials can be combined with a solvent in which the carrier material is soluble. When using NMGSM, it is better that the solvent is sufficient to reduce the viscosity of NMI SM. IN specific embodiments, the solvent may be a second anesthetic agent, such as benzyl alcohol.

In another aspect of the invention, the first anesthetic is a local anesthetic, for example a local anesthetic of the amide or ether type. In other embodiments, the second anesthetic is also a solvent for NMI CM.

The second anesthetic can be a solvent - an alcohol, an aromatic alcohol, an acid or an acid derivative, or any combination of such solvents. In a preferred embodiment, the second anesthetic is benzyl alcohol. In another preferred embodiment, the first anesthetic is bupivacaine, which can additionally be provided in the form of a free base. In other preferred embodiments, the NMI SM is an ester, such as a sugar ester, such as sucrose acetate isobutyrate. In such compositions, it may be useful to provide a solvent in which the NUMI CM is soluble.

In another aspect of the invention, the composition is administered to the site by topical, transdermal, injection, or as an implant. In specific embodiments, the composition is administered to an area that is a surgical wound, and the composition is administered into the wound and/or adjacent to the wound.

An advantage of the present invention is that the non-polymeric carrier material is capable of controlling the release of the anesthetic agent both to avoid the initial burst of release and to provide a sustained anesthetic effect for at least approximately 24 hours. An additional advantage of the invention is that the compositions are easily designed to provide any number of different pharmaceutical forms and, in addition, to provide a wide variety of different pharmacological release characteristics depending on the intended site of administration and medical use.

These and other objects, aspects and advantages of the present invention will be readily apparent to one skilled in the art upon reading this disclosure and description.

Figure 1 shows the mean plasma levels of bupivacaine over 7 days (pharmacodynamic results) from Example 3, where data from cohort 1 are presented on the lower curve, and data from cohort 2 are presented on the upper curve.

Figure 2 shows mean bupivacaine plasma levels 0-144 hours (pharmacodynamic results) from Example 4, Cohort 1.

Figure 3 shows mean plasma levels of bupivacaine over 0-12 hours (pharmacodynamic results) from Example 4, Cohort 1.

Figure 4 shows mean bupivacaine plasma levels over 0-300 hours (pharmacodynamic results) from Example 4, Cohort 2, where subgroup C data are presented in the lower curve (9), subgroup 2 data are presented in the middle curve (c), and the data of subgroup 1 are presented in the upper curve (A).

Figure 5 shows mean plasma levels of bupivacaine over 0-12 hours (pharmacodynamic results) from Example 4, Cohort 2, where subgroup C data are presented in the lower curve (9), subgroup 2 data are presented in the middle curve (c), and the data of subgroup 1 are presented in the upper curve (A).

Figure 6 shows the average pain scores in the incision site "at rest" recorded using the 0-100mm visual analog scale (MA5) from example 4, cohort 2, where subgroup C data are presented on the upper curve (A), subgroup data 2 are presented on the middle curve (c), and subgroup 1 data are presented on the lower curve (9).

Before describing the present invention in detail, it should be understood that this invention is not limited to the given specific examples of carrier materials or method parameters, as they may, of course, vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments of the invention only and is not intended to be limiting.

The entire contents of all publications, patents and patent applications cited herein, above or below, are incorporated herein by reference.

It should be noted that, as used in this description and the appended claims, the singular forms include plural reference objects unless the context clearly requires otherwise. Thus, for example, the designation "non-polymeric carrier" contains a mixture of two or more such carriers, the designation "solvent" contains a mixture of two or more such solvents, the designation "anesthetic" contains a mixture of two or more such agents, etc. .

It is an object of the present invention to provide a sustained-release controlled delivery system that releases anesthetic over a long period of time sufficient to provide a local anesthetic effect at the site of administration for at least about 24 hours after administration, preferably for at least about 36-48 hours after administration, and further preferably, at least for about 48-72 hours after administration. The purpose of the present invention is also that the release of the active anesthetic agent from the long-acting anesthetic composition occurs without an initial release. It is an additional object of the present invention that the composition releases the active anesthetic agent from the long-acting anesthetic composition to provide a long-term sustained mean plasma anesthetic concentration (CeH) of at least about 2000 ng/ml for a period of at least about 24 hours when the composition is administered subcutaneously, preferably at least about 25 Ong/ml, or at least about 300 Ong/ml, or at least about 35 Ong/ml.

The purpose of the present invention is also to obtain a composition that contains an anesthetic and a pharmaceutically acceptable non-polymeric carrier. The non-polymeric carrier controls the release of the anesthetic to provide an anesthetic effect characterized by prolonged local anesthesia after administration to the subject without an initial release lasting at least about 24 hours after administration, preferably at least about 36-48 hours after administration, and more preferably at least about 48 -72 hours after administration.

The purpose of the present invention is also to obtain a composition that contains an anesthetic and a pharmaceutically acceptable non-polymeric carrier. The non-polymeric carrier controls the release of the anesthetic to provide an anesthetic effect characterized by prolonged local anesthesia after administration to a subject, wherein the composition provides a sustained mean plasma anesthetic concentration (SeH) of at least about 20 ng/ml for a period of at least about 24 hours when the composition is administered subcutaneously , preferably at least about 25 ng/ml, or at least about 35 ng/ml, or at least about 35 ng/ml.

A related object of the invention is to obtain a composition that contains a first anesthetic, a second anesthetic and a pharmaceutically acceptable non-polymeric carrier. The second anesthetic in the composition is a solvent for the first anesthetic and provides the initial anesthetic effect when administered to the subject. The non-polymeric carrier controls the release of the first anesthetic agent to provide a subsequent anesthetic effect characterized by sustained local anesthesia with an onset within about 2 hours of administration to the subject without an initial release and lasting at least about 24 hours after administration, preferably at least about 36-48 hours after administration, and preferably at least about 48-72 hours after administration.

A related object of the invention is also to obtain a composition that contains a non-polymeric, non-water-soluble carrier material with high viscosity ("NMI SM"), having a viscosity of at least approximately 5000 cSP at 37"C, which without impurities does not crystallize under conditions environmental or physiological conditions, a first anesthetic and a second anesthetic. Here again, the second anesthetic is a solvent for the first anesthetic and provides the initial anesthetic effect when administered to the subject. The NM SM controls the release of the first anesthetic to provide a subsequent anesthetic effect characterized by prolonged local anesthesia beginning within about 2 hours of administration to a subject without baseline and lasting at least about 24 hours after administration, preferably at least about 36-48 hours after administration, and even more preferably at least about 48-72 hours after administration.

An additional, related object of the invention is to provide a composition that contains a non-polymeric, non-water-soluble liquid carrier material with a high viscosity ("NMI SM") having a viscosity of at least about

BOOOSP at 37"C, which without impurities does not crystallize under ambient or physiological conditions, the first anesthetic and the second anesthetic. Here again, the second anesthetic is a solvent for the first anesthetic and provides the initial anesthetic effect when administered to the subject. NMI SM controls the release of the first anesthetic to provide a subsequent anesthetic effect characterized by prolonged local anesthesia, and the composition provides a long-term sustained mean plasma anesthetic concentration (CeH) of at least about 20 ng/ml for a period of at least about 24 hours when the composition is administered subcutaneously, preferably at least about 25 ng/ml , or at least about 30 ng/ml, or at least about 35 ng/ml.

An additional goal of the invention is to provide a method for providing the subject with an anesthetic effect in the area. The method consists in introducing the composition to the site, near the site, in the site or in the vicinity of the site, where the composition contains an anesthetic and a pharmaceutically acceptable non-polymeric carrier. The non-polymeric carrier controls the release of the anesthetic to provide an anesthetic effect characterized by prolonged local anesthesia after administration to the subject without an initial release and lasting at least approximately 24 hours after administration.

An additional purpose of the invention is to obtain a method of providing the subject with an anesthetic effect in the area. The method consists in introducing the composition to the site, near the site, in the site or in the vicinity of the site, where the composition contains an anesthetic and a pharmaceutically acceptable non-polymeric carrier. The non-polymeric carrier controls the release of the anesthetic to provide a sustained anesthetic effect characterized by prolonged local anesthesia after administration to the subject, and the composition provides a sustained mean plasma anesthetic concentration (Cx) of at least about 20 ng/ml for a period of at least about 24 hours when the composition is administered subcutaneously

An additional purpose of the invention is to obtain a method of providing the subject with an anesthetic effect in the area. The method consists in introducing the composition to the site, near the site, in the site or in the vicinity of the site, where the composition contains a first anesthetic, a second anesthetic and a pharmaceutically acceptable non-polymeric carrier. The second anesthetic is a solvent for the first anesthetic and provides the initial anesthetic effect at the site of injection. The non-polymeric carrier controls the release of the first anesthetic to provide a subsequent anesthetic effect characterized by long-lasting local anesthesia at the site with an onset within about 2 hours of administration without an initial release and lasting at least about 24 hours after administration, preferably at least about 36-48 hours after administration , and more preferably at least about 48-72 hours after administration.

The purpose of the invention is also to obtain a method of providing the subject with an anesthetic effect in the area.

The method consists in introducing the composition to the site, near the site, in the site or in the vicinity of the site, where the composition contains a first anesthetic, a second anesthetic and a pharmaceutically acceptable non-polymeric carrier.

The second anesthetic is a solvent for the first anesthetic and provides the initial anesthetic effect at the site of injection. The non-polymeric carrier controls the release of the first anesthetic to provide a subsequent anesthetic effect characterized by prolonged local anesthesia at the site, and the composition provides a long-term sustained mean plasma anesthetic concentration (Se) of at least about 200 ng/ml for a period of at least about 24 hours when the composition is administered subcutaneously.

The phrase "no initial release" as used herein means that the particular agent referred to is not released from the composition upon normal administration and becomes pharmacologically available in substantial amounts during a predetermined initial period. A person skilled in the art can readily determine the presence and level of initial release of an agent from this composition using conventional pharmacological testing methods well known in the art. Suitable methods for characterizing the release of ip migo include the blade O5P I method using a commonly accepted buffer, mixing and heating conditions. The release characteristics of the release of this composition can also be readily determined using conventional ip mimo testing, such as monitoring the concentration of the agent of interest in the plasma of an animal subject over this time period. In the compositions of this invention, preferably less than about 40-6095 of the anesthetic agent is released during the first 24 hours, more preferably less than about 30-5095, and even more preferably less than about 200-409 is released during the initial time period. In other particular preferred embodiments, less than about 5-1095 of the anesthetic agent is released during the first hour, more preferably less than about 3-795 is released during this initial time period.

Accordingly, the compositions of the present invention will contain at least one anesthetic agent in a controlled release system that releases the anesthetic agent over a sustained period of time. In specific embodiments, the anesthetic is present in this composition in an amount from about 95 to about 1 percent by weight relative to the total weight of the composition (95 weight), in an amount from about 30 to 195 weight, in an amount from about 25 to 595 weight. or in an amount of approximately 20-1095 mass, depending on the characteristics of the anesthetic and its intended use.

As used herein, the term "anesthetic" refers to any agent that provides reversible local numbness, analgesia, blockade of impulse conduction along nerve axons and other excitable membranes, such as local blockade of nociceptive pathways (afferent and/or efferent), analgesia, and/or or anesthesia. See, for example, Bigisnatl, (3.8. (Ea.) osa! Apevipeiis5, Naparasok oi Ehreptepia! Rpagtasiodu, moiI.81, briipdeg, Vepip/Memzh Mogk, (1987). The term also includes any means which upon local administration provides localized (local) complete or partial inhibition of sensory perception and/or motor function. Examples of commonly accepted agents suitable for use as anesthetics in the implementation of the invention include, but are not limited to, ambucaine, amolanone, amylcaine, benoxynate, benzyl alcohol, benzocaine, bethoxycaine, biphenamine, bupivacaine, butacaine, butamben, butanilicaine, butethamine, butoxycaine, carticaine, chlorprocaine, cocaethylene, cocaine, cyclomethicaine, dibucaine, dimethisoquine, dimethocaine, diperodone, diclonine, ecogonidine, ecogonine, etidocaine, euprocin, phenalcomine, formocaine, hexylcaine, hydroxytetracaine, isoguanine, isobutyl-p-aminobenzoate, leucinecaine, levobupivacaine, levoxadrole, lidocaine, mepivacaine, meprilcaine, metabutoxacaine, methyl chloride, myrtle caine, naepaine, octacaine, orthocaine, oxetazaine, parenthoxaine, phenocaine, phenol, piperocaine, pyridocaine, polidocanol, pramoxine, prilocaine, procaine, propanocaine, proparacaine, propipocaine, propoxycaine, pseudococaine, pyrocaine, ropivacaine, salicylic alcohol, tetracaine, tolicaine, trimecaine , xylocaine, zolamine, their anesthetic active derivatives, analogues and any pharmaceutically acceptable salts and any mixture thereof.

For use here, local anesthetics of the amide or ether type are best. Local anesthetics of the amide type are characterized by the presence of an amide functional group, while local anesthetics of the ether type contain an ether functional group. The best local anesthetics of the amide type include lidocaine, bupivacaine, prilocaine, mepivacaine, etidocaine, ropivacaine, and dibucaine. The best ether-type local anesthetics include tetracaine, procaine, benzocaine, and chlorprocaine. The best local anesthetic is bupivacaine.

The anesthetic agent is provided in the composition in a neutral form, in the form of a free base or in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt", as used herein, means such salts that retain the biological effectiveness and properties of neutral anesthetics and are not otherwise unacceptable for pharmaceutical use. Pharmaceutically acceptable salts include salts of acidic or basic groups that may be present in anesthetic agents. Those anesthetic agents that are basic in nature are able to form a wide range of salts with various inorganic and organic acids. Pharmaceutically acceptable acid addition salts of basic anesthetics suitable for use herein are those which form non-toxic acid addition salts, i.e., salts that contain pharmacologically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate salts. , acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate and pamoate (ie 1,1-methylene-bis-(2-hydroxy-3-naphthoate)). Anesthetic agents that contain an amino group can form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above. Acceptable basic salts can be formed from non-toxic salt-forming bases, such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts. See, for example, Vegodee ei a). (1977) 9U. Rnagt. si. 66:1-19.

The ability of an anesthetic agent to provide a state of long-term local anesthesia refers to the ability of the specified agent to cause a condition that is subject to evaluation, localized (local) total or partial inhibition of sensory perception and/or motor function. Various methods and tools for making such evaluations will be readily apparent to one skilled in the art. For non-human animal subjects, these methods include measuring spontaneous locomotion in test rats (using, for example, commercially available equipment and software from May Avzosiasez Ips., 9. AIrape, MT), where data on total distance traveled, walking rates, stereotypies, rearing, time spent in various movements, and time spent at rest can be collected for test subjects; visualization of the reaction to a pin prick in rats; and a model of rat paw twitching from a hot plate, for example, according to the method described in detail in IASOS

Me9511-2199.

Sensory research in human subjects is also an applicable way of evaluating the local anesthetic effect. Testing is often focused on three main areas: mechanical testing (pin prick, Frey fibers), thermal testing (warm, hot, cold) and tactile testing (touch). Methods of such a test are described in the literature. See, for example, rani, eyi ai. (1993)

Raip 53:43-51; Moipisne, her a)y. (1993) Howls. 9. oi Apaesipezia 71:201-205; My writing, oh! (1993) Nediope! Apepypeuzia 18:300-303; Redegzep, Yei A. (1996) Apezipezioiodu 84(5): 1020-1026; Redegzep, ey a. (1996) Eyelashes. U. oi Apaeziiesia 76(6): 806-810; and Redegwep, ei a). (1998) Raip 74:139-151. For example, the local anesthetic activity of the tested agent can be investigated with respect to the onset, peak value and duration of the effect using specific methods: 1) mechanical sensory test (threshold for recognition of mechanical pain using Frey fibers); 2) over-the-limit (mechanical) test using a separate Frey fiber; 3) thermal sensory test (warm recognition threshold); 4) the threshold for recognizing pain from heat; 5) extreme (hot) test; b) cold recognition threshold; and 7) tactile sensory test (mechanical touch recognition threshold). These data are indicative of the local pain relief, local numbness, and/or local nerve block experienced by the subject in response to the administration of the test anesthetic agent. The pain response can be characterized using a verbal rating scale of 0-10 (eg, where 0 - no pain and 10 is the worst imagined pain) or a visual analog scale from 0 to 100 mm (for example, where 0 is no pain and 100 mm is the worst imagined pain).

With respect to the selection of a candy anesthetic agent, those skilled in the art will also appreciate that the pharmacological properties of each candidate agent will vary, for example, with respect to onset and intensity of anesthetic effect, duration, and the like. Specific agents can provide a moderate anesthetic effect, with a fairly rapid onset of action, but a short duration. Such agents can be used in the compositions of the present invention to provide an "initial anesthetic effect", where they are typically combined with various anesthetic agents to provide "sustained local anesthesia", which is characterized by a more gradual onset of activity, but a stronger effect and a longer duration its duration. An example of an anesthetic that can be used to provide an initial anesthetic effect is benzyl alcohol. An example of an anesthetic that can be used to provide prolonged local anesthesia is bupivacaine. Additional agents that can be used to provide an initial anesthetic effect may include organic substances commonly used as solvents and/or penetration enhancers, such as ethanol, dimethylsulfoxide, M-methylpyrrolidone, polyethylene glycol, and esters of specific fatty acids. These and other similar agents may provide a very mild initial anesthetic effect, eg when applied they may cool or otherwise desensitize/numb an area of tissue, thus partially inhibiting sensory perception in that area. Whenever an agent is used in the practice of the invention to provide an initial anesthetic effect, the agent is provided in a suitable composition in an amount sufficient to provide the specified effect and in such a way that the agent can be rapidly released from the composition to provide the intended effect. Formulation of such suitable compositions (which contain an agent to provide an initial anesthetic effect) is within the competence of one skilled in the art in conjunction with the guidance and explanations provided herein.

In specific embodiments, the invention relates to a composition that contains two anesthetic agents, a first anesthetic agent and a second anesthetic agent, where the second anesthetic agent is a solvent for the first anesthetic agent. In these particular compositions, the second anesthetic agent is typically used to provide an initial anesthetic effect and the first anesthetic agent is used to provide a subsequent anesthetic effect characterized by prolonged local anesthesia with an onset within approximately 2 hours of administration to the subject without an initial release , and lasting at least about 24 hours after administration, or even longer. In particular preferred embodiments, the first anesthetic agent provides prolonged local anesthesia with an onset within about 1 to 2 hours of administration, and in other preferred embodiments, the first anesthetic agent provides prolonged local anesthesia with an onset within approximately 30 minutes to 1 hour of administration . In other specific embodiments, the other anesthetic is also a solvent for the controlled delivery carrier system.

An anesthetic agent will here serve as a solvent for another anesthetic agent when one agent is at least partially dissolved in the other solvent in the preparation of the composition. In addition, the anesthetic solvent is present in the composition in an amount sufficient both to provide the initial anesthetic effect and to at least partially dissolve the other anesthetic agent. In specific embodiments, the second anesthetic is thus present in an amount of from about 95 to about 1 percent by weight relative to the total weight of the composition (90 wt), or in an amount of from about 75 to 1095 wt, or in an amount of from about 50 to 1595 wt.

A number of suitable anesthetic agents, which also serve as solvents for other anesthetic agents, can be used in the practice of the invention. Suitable agents include aromatic alcohols, acids and acid derivatives and their combinations. A particularly preferred anesthetic agent that can be used as a solvent for additional anesthetic is benzyl alcohol.

Controlled delivery carrier systems used in the compositions of this invention are classified as non-polymeric carriers. A pharmaceutically acceptable non-polymeric carrier is generally biocompatible, and preferably biodegradable, biodegradable or bioadsorbable. A substance is biocompatible if it and any of its degradation products do not produce significant, harmful or adverse effects, cause significant tissue irritation or necrosis when injected into living tissue. As used interchangeably herein, the terms "biodegradable" or "biodegradable" mean a specified non-polymeric material that will degrade or break down to smaller chemical compounds where such degradation may occur, for example, by enzymatic, chemical, or physical processes. processes. The term "bioadsorbable" means that this polymeric material can be degraded and adsorbed within the body of an animal subject, such as a cell, tissue, or the like.

The non-polymeric carrier material is used to control the release of at least one anesthetic agent from the compositions of the present invention in such a way as to provide sustained local anesthesia with an onset within about 2 hours of administration and a duration of at least about 24 hours or longer.

In some compositions of the present invention, the non-polymeric carrier material is sufficient to provide at least one anesthetic with either a first-order controlled release profile or a pseudo-zero-order release profile. Accordingly, the non-polymeric carrier will be present in the composition in an amount from about 99.5 to about 1 percent by weight relative to the total weight of the composition (95 weight), or in an amount from about 95 to 1095 weight, or in an amount from about 75 to 2595 weight.

Selection of a suitable non-polymeric support is within the general competence of those skilled in the art using the explanations and guidance provided by this disclosure and description. For example, numerous pharmaceutically acceptable non-polymeric carrier systems are available to one skilled in the art to produce a liquid, spray, cream, lotion, ointment, gel, suspension, oil, emulsion, microemulsion, solid, patch, film, particle, microparticle, powder, or other acceptable forms of pharmaceutical composition. These and other media systems are described, for example, in Vetipdiopye Rpagtaseshiis! Zsiepse5, 16" Eyop, 1980 and 17" Eyop, 1985, both published by Mask Rybiizpd Sotrapu, Easiyop, RA.

Compositions of the present invention may additionally contain one or more additional components, such as pharmaceutically acceptable excipient materials, such as dispersing agents, fillers, binders, carriers, stabilizers, slip promoting agents, antioxidants, pH regulators, barrier agents irritation, etc. One of ordinary skill in the art will appreciate that particular filler materials may perform several of the above functions in any particular formulation. Thus, any number of suitable filler materials can be mixed with or incorporated into the compositions of this invention to provide bulking properties, alter active release rates, increase or complicate water absorption, control pH, provide structural support, facilitate the manufacturing process and other applications known to those skilled in the art. The term "filler" generally refers to an essentially inert material that is non-toxic and does not interact with other components of the composition in a harmful manner. The ratio in which a particular filler may be present in the composition depends on the purpose for which the filler is provided and the type of filler.

For example, acceptable excipients that can also act as stabilizers for active ingredients include glucose, sucrose, lactose, trehalose, mannitol, sorbitol, inositol, dextran, etc. of pharmaceutical grade. Such stabilizers can therefore be a saccharide, such as a monosaccharide, a disaccharide, a polysaccharide or a sugar alcohol. Other acceptable excipients include starch, cellulose, sodium or calcium phosphates, calcium sulfate, citric acid, tartaric acid, glycine, and combinations thereof. Examples of hydrophobic excipients that may be added to slow hydration and dissolution kinetics include fatty acids and their pharmaceutically acceptable salts (eg, magnesium stearate, stearic acid, zinc stearate, palmitic acid, and sodium palmitate).

It may also be useful to use in the compositions of this invention a filler made of a charged lipid and/or a detergent. Suitable charged lipids include, but are not limited to, phosphatidylcholine (lecithin), etc. Detergents will generally be nonionic, anionic, cationic or Examples of suitable surfactants include, for example, TegoyoFf and TpopF surfactants (piop Sagride Spetis!5 apa Riaviis5); polyoxyethylene sorbitans, for example TM/EEMF surfactants (Aitsaz Spetisai! Ipdivipev); polysorbates; polyoxyethylene ethers, for example Lashes); pharmaceutically acceptable esters of fatty acids, for example, lauryl sulfate and its salts; amphiphilic surfactants (glycerides, etc.); and similar materials.

Other bulking materials may be added to modify the porosity, for example materials such as sucrose, glucose, sodium chloride, sorbitol, lactose, polyethylene glycol, mannitol, fructose, polyvinylpyrrolidone, or suitable combinations thereof. Additionally, the anesthetic agent or agents may be dispersed in oils (eg, sesame oil, corn oil, vegetable oil), or in a mixture thereof with a phospholipid (eg, lecithin) or a medium-chain fatty acid triglyceride (eg, Miglyol 812) for obtaining an oil suspension.

In the composition according to this invention, additional filler materials can be introduced, including solvents of different buffer capacity (for example, Tris-HCI, acetate); agents that change pH and ionic strength; additives such as antioxidants (eg, ascorbic acid, glutathione, sodium metabisulfite); preservatives (eg

Tpiteggo!, benzyl alcohol, methylparaben, propylparaben); and dispersing agents such as water-soluble polysaccharides (eg, mannitol, lactose, glucose, starches), hyaluronic acid, glycine, fibrin, collagen, and inorganic salts (eg, sodium chloride).

In specific embodiments of the invention, the non-polymeric carrier is essentially insoluble in water or in an aqueous biological system. Such non-polymeric carrier materials include, but are not limited to: sterols such as cholesterol, stigmasterol, β-sitosterol, and estradiol; cholesterol esters such as cholesterol stearate; C1i2-Cg24 fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, arachinic acid, behenic acid and lignoseric acid; Siv-Szv mono-, di- and triacylglycerides, such as glyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate, glyceryl monodocosanoate, glyceryl monomyristate, glyceryl monodecanoate, glyceryl dipalmitate, glyceryl didocosanoate, glyceryl dimyristate, glyceryl didecanoate, glyceryl tridocosanoate, glyceryl trimyristanoate, glyceryl tridecate, glyceryl tridecanoate; esters of sucrose and fatty acids, such as sucrose distearate and sucrose palmitate; esters of sorbitan and fatty acids, such as sorbitan monostearate, sorbitan monopalmitate and sorbitan tristearate; Sivie-Siv fatty alcohols such as cetyl alcohol, myristyl alcohol, stearyl alcohol and ketostearyl alcohol; esters of complex alcohols and fatty acids, such as cetyl palmitate and cetearyl palmitate; fatty acid anhydrides such as stearic anhydride; phospholipids, including phosphatidylcholine (lecithin), phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol and their lyso derivatives; sphingosine and its derivatives; sphingomyelins such as stearyl, palmitoyl and triclosanyl sphingomyelins; ceramides such as stearyl and palmitoyl ceramides; glycosphingolipids; lanolin and lanolin alcohols; and their combinations and mixtures. Particular preferred non-polymeric carriers include cholesterol, glyceryl monostearate, glycerol tristearate, stearic acid, stearic anhydride, glyceryl monooleate, glyceryl monolinoleate and acetylated monoglycerides.

When one of the aforementioned non-polymeric carrier materials is selected for use in a composition of the present invention, it will generally be combined with a compatible and suitable organic solvent for the carrier material to produce a composition that varies in consistency from watery to viscous to pasty. putty or paste. The consistency of the composition will vary depending on factors such as the solubility of the non-polymeric carrier in the solvent, the concentration of the non-polymeric carrier, the concentration of the anesthetic agent, and/or the presence of additional anesthetic agents, additives and excipients. The solubility of a non-polymeric carrier in a particular solvent will vary depending on factors such as its crystallinity, hydrophilicity, ionic character, and lipophilicity. Accordingly, the ionic nature and concentration of the non-polymeric carrier in the solvent can be adjusted to achieve the desired solubility. The best non-polymer carrier materials are those that have low crystallinity, non-polar properties and are more hydrophobic.

Suitable organic solvents for use in the compositions are generally those that are biocompatible, pharmaceutically acceptable and will at least partially dissolve the non-polymeric carrier. The organic solvent will also have a solubility in water ranging from miscible to soluble to dispersible. In specific embodiments, the solvent is selected such that it is capable of diffusing, dispersing, or leaching from the composition into the aqueous system and fluids encountered at the site of insertion, thus forming a solid implant. Preferably, the solvent has a Hildebrand solubility parameter (NO B) of about 9-13(cal/cm3)!?, Preferably, the degree of polarity of the solvent is capable of providing at least about 595 solubility in water.

Suitable organic solvents thus include, but are not limited to: substituted heterocyclic compounds such as M-methyl-2-pyrrolidone (MMP) and 2-pyrrolidone (2-pyrrole); esters of carbonic acid and alkyl alcohols, such as propylene carbonate, ethylene carbonate and dimethyl carbonate; fatty acids such as acetic acid, lactic acid and heptanoic acid; esters of alkyl and mono-, di- and tricarboxylic acids, such as 2-ethoxyethyl acetate, ethyl acetate, methyl acetate, ethyl lactate, ethyl butyrate, diethyl malonate, diethyl glutonate, tributyl citrate, diethyl succinate, tributyrin, isopropyl myristate, dimethyl adipate, dimethyl succinate, dimethyl oxalate, dimethyl citrate, triethyl citrate, acetyl tributyl citrate , glyceryl triacetate; alkyl ketones such as acetone and methyl ethyl ketone; ether alcohols such as 2-ethoxyethanol, ethylene glycol dimethyl ether, glucofurol, and glycerol formal; alcohols such as ethanol and propanol; polyhydroxyalcohols such as propylene glycol, polyethylene glycol (PES), glycerol (glycerol), 1,3-butylene glycol, and isopropylidene glycol (2,2-dimethyl-1,3-dioxolone-4-methanol); Solketal; dialkylamides such as dimethylformamide, dimethylacetamide; dimethylsulfoxide (OM5O) and dimethylsulfone; tetrahydrofuran; lactones such as ε-caprolactone and butyrolactone; cyclic alkyl amides such as caprolactam; aromatic amides such as N,N-dimethyl-t-toluamide and 1-dodecyl azacycloheptan-2-one; and the like; and their mixtures and combinations. The best solvents include M-methyl-2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, ethyl lactate, propylene carbonate, glucofurol, glycerol formal, and isopropylidene glycol.

The organic solvents will be present in the composition in an amount of from about 99.5 to about 1 percent by weight relative to the total weight of the composition (95 weight), in an amount of from about 95 to 1095 weight, in an amount of from about 75 to 2595 weight, or in an amount of approximately 60 to 4095 wt. depending on the selected non-polymeric carrier, organic solvent, anesthetic agent, additive and/or filler used in the composition. In specific embodiments, the organic solvent diffuses or washes out of the composition in an aqueous medium when placed in a biological system where the non-polymeric carrier material coagulates to form a solid. Preferably, the non-polymeric carrier hardens to a solid within approximately 1-5 days after insertion (implantation), preferably within approximately 1-3 days, preferably within approximately 2 hours.

A number of suitable additives can be included in the composition to impart selected characteristics to the composition. For example, a small amount of a thermoplastic heat-degradable polymer such as polylactide, polycaprolactone, polyglycolide, or a copolymer thereof may be included to provide a more cohesive hard implant or a composition with greater viscosity to hold it in place, in which while it hardens. Such thermoplastic polymers are described in U.S. Patent No. 4,938,763, U.S. Patent No. 4,938,763.

It is not necessary to include a pore-forming agent in the composition. The pore-forming agent can be any organic or inorganic, pharmaceutically acceptable substance that is substantially soluble in water or body fluids and will disperse from the non-polymeric carrier material and/or the solid of the implant into the surrounding body fluid at the site of the implant. The pore-forming agent preferably can be insoluble in an organic solvent to form a homogeneous mixture with the non-polymeric carrier material. The pore-forming agent can also be a water-immiscible substance that quickly breaks down into a water-soluble substance. In specific compositions, the pore-forming agent is combined in a mixture with a non-polymeric carrier and an organic solvent. Suitable blowing agents that can be used in the composition include, for example, sugars such as sucrose and glucose, salts such as sodium chloride and sodium carbonate, polymers such as hydroxypropylcellulose, carboxymethylcellulose, polyethylene glycol and polyvinylrolidone, etc. Solid crystals that provide a certain pore size, such as salt or sugar, are preferred.

Other embodiments of the present invention relate to compositions where the non-polymeric carrier is a liquid. The non-polymeric liquid carrier is preferably a high viscosity liquid carrier material ("NMI SM") that is insoluble in water and has a viscosity of at least 5000 cP (and not necessarily at least 10000, 15000; 20000; 25000 or even 50000 cP) at 37"C, which without impurities does not crystallize under ambient or physiological conditions. The term "insoluble in water" refers to a material that is soluble in water to a ratio of less than one percent by weight under ambient conditions. The term "non-polymeric" refers to esters or mixed esters that have essentially no repeating units in the acidic ester group, as well as esters or mixed esters having acidic groups where the functional units in the acidic group are repeated a small number of times (ie, oligomers). As a general rule, substances having more than five identical and contiguous repeating units or units in an acidic ester group are excluded from the term "non-polymeric" as used herein, however substances which contain dimers, trimers, tetramers or pentameters are included within the scope of this term. When the ester is formed from groups of hydroxyl-containing carboxylic acids that can be further esterified, such as lactic acid or glycolic acid, the number of repeat units is calculated based on the number of lactide or glycolide groups instead of the number of lactic acid or glycolic acid groups where the lactide repeat unit contains two lactic acid groups esterified at their respective hydroxy and carboxyl groups, and wherein the repeating unit of glycolysis comprises two glycolic acid groups esterified at their respective hydroxy and carboxyl groups. Esters having from 1 to about 20 esterified polyols in their alcohol group or from 1 to about 10 glycerol groups in their alcohol group are considered non-polymeric as used herein.

In a candy embodiment, the viscosity of NMI SM is reduced, in some cases significantly, when mixed with a solvent to produce a low viscosity liquid carrier material ("I MI SM") that can be administered using conventional medical devices. A composition with I MI SM is generally easier to place in the body than a composition with NMI SM because it flows more easily in and out of syringes or other implantable devices. it can also be easily formulated as an emulsion. | MGESM can have any desired viscosity, but its viscosity is, as a rule, lower than that of the corresponding NMI SM. As an example, viscosity limits for MI SM of less than about 6000 cP, less than about 4000 cP, less than about 1000 cP or less than 200 cP are generally suitable for IP mimo applications.

The specific NMI SM used in the compositions according to the invention can be one or more of a variety of materials. Suitable materials include non-polymeric esters or mixed esters of one or more carboxylic acids. In a specific embodiment, the ester is formed from carboxylic acids that are esterified with a polyol having from about 2 to about 20 hydroxy groups, and which may contain from 1 to about 20 esterified polyols. Particularly suitable carboxylic acids for the formation of the acidic part of the complex ester of NMI SM include carboxylic acids with one or more hydroxy groups, for example, those obtained by alcoholysis of ring-opening lactones or cyclic carbonates, or alcoholysis of carboxylic acid anhydrides. Amino acids are also suitable for forming complex esters with polyol. In a specific embodiment, the ester or mixed ester contains an alcohol group having one or more terminal hydroxy groups that are esterified with one or more carboxylic acids obtained by alcoholysis of a carboxylic anhydride, such as a cyclic anhydride.

Suitable carboxylic acids that can be esterified to produce NMI SM include, but are not limited to, glycolic acid, lactic acid, ε-hydroxycaproic acid, serine and any related lactones or lactams, trimethylene carbonate, and dioxanone. Hydroxy-containing acids themselves can be further esterified by reaction of their hydroxy groups with an additional carboxylic acid, which may be the same or different from other carboxylic acid groups in the material. Suitable lactones include, but are not limited to, glycolide, lactide, ε-caprolactone, butyrolactone, and valerolactone.

Suitable carbonates include, but are not limited to, trimethylene carbonate and propylene carbonate.

The alcohol group in the ester or mixed ester can be obtained from a polyhydroxy alcohol having from about 2 to about 20 hydroxy groups and, as indicated above, can be obtained by esterification of 1-20 polyol molecules. Suitable alcohol groups include those obtained by removing one or more hydrogen atoms from: monofunctional C1-C0 alcohols, difunctional C1-C0 alcohols, trifunctional alcohols, hydroxy-containing carboxylic acids, hydroxy-containing amino acids, phosphate-containing alcohols, tetrafunctional alcohols, sugar alcohols, monosaccharides and disaccharides, sugar acids and polyester polyols. More specifically, alcohol groups may include one or more of: dodecanol, hexanediol, more specifically, 1,6-hexanediol, glycerin, glycolic acid, lactic acid, hydroxybutyric acid, hydroxyvaleric acid, hydroxycaproic acid, serine, ATP, pentaerythritol , mannitol, sorbitol, glucose, fructose, sucrose, glucuronic acid, polyglycerol esters containing from 1 to about 10 units of glycerol, polyethylene glycols containing from 1 to about 20 units of ethylene glycol.

In specific embodiments of the invention, at least one of the carboxylic acid groups of esters or mixed esters of NMGSM contains at least one oxy group. In a more specific embodiment, each of the carboxylic acid groups contains at least one oxy group.

In another specific embodiment, at least one of the carboxylic acid groups of esters or mixed esters according to the invention contains 2-4 carbon atoms. In a more specific embodiment, each of the carboxylic acid groups of esters or mixed esters according to the invention contains 2-4 carbon atoms.

In another, more specific embodiment of the invention, at least one of the carboxylic acid groups of the ester or mixed ester according to the invention has 2-4 carbon atoms and contains at least one oxy group. In another more specific embodiment of the invention, each of the carboxylic acid groups of the ester or mixed ester of the invention has 2-4 carbon atoms and contains at least one oxy group.

In a specific embodiment, NMI SM can be sucrose isobutyrate acetate (5AIIV) or any other complex ester of a sugar alcohol with one or more alkanoic acid groups.

In a sweet embodiment, the invention relates to compositions where the NM SM has a structure selected from the group consisting of:

I: gy opo 1 o g do-yu k;-O sn o v o o o o-« and p de B", 82, VZ, B, B", Vb, B" and VZ are independently selected from the group consisting of from hydrogen, alkanoyl, hydroxy-substituted alkanoyl and acyloxy-substituted alkanoyl; where at least three of B", B, VU, VU, B", Be, B" and VZ are different from hydrogen; and where, when B", B2, BZ, VU, B", Be, B" and BZ are selected from the group consisting of acetyl and isobutyryl, at least three of B", B2, VU, B", B", Be , B" and B" are acetyl;

I: he y (os soido-ya p de B", B? and BZ are independently selected from the group consisting of hydrogen, alkanoyl, hydroxy-substituted alkanoyl and acyloxy-substituted alkanoyl and where p is between 1 and 20;

I: tk -0-(snu-0-82 where n is an integer from 4 and 8 and B' and B? are independently selected from the group consisting of hydrogen, alkanoyl, hydroxy-substituted alkanoyl and acyloxy-substituted alkanoyl;

IM:

o0-th v-o 1 v' -o sn.-0- v-o

In: k-o-sn, o-it 0. t-o sn.-0-i kE-o where in the formulas IM and M B", B2, VU, B" and B? independently selected from the group consisting of hydrogen, alkanoyl, hydroxy-substituted alkanoyl and acyloxy-substituted alkanoyl;

MI: r o tk -o-sn,-sn-sn-sn Chen -sn;-o0-k ov' ov

E:

Sivash v/-o-son;-sn-sn-sn-sn-sn;-o0-k

And where in the formulas MI and MI! B", B, BZ, VU, B? and B? are independently selected from the group consisting of hydrogen, alkanoyl, hydroxy-substituted alkanoyl and acyloxy-substituted alkanoyl;

MI: sn.-ov k-o-sn,-s-sn.-0-k - I sn.- OK where B", B, BZ and B" are independently selected from the group consisting of hydrogen, alkanoyl, hydroxy -substituted alkanoyl and acyloxy-substituted alkanoyl.

In each of the formulas from | to MI, one or more of the alkanoyl, hydroxy-substituted alkanoyl, and acyloxy-substituted alkanoyl groups may be an alkanoyl group having 2-6 carbon atoms, including the carbonyl carbon. Moreover, in another more specific embodiment of the invention, each of the formulas from | to MI contains at least one hydroxy-substituted or acyloxy-substituted alkanoyl group. In a sweeter embodiment, at least one of these hydroxy-substituted or acyloxy-substituted alkanoyl groups is an alkanoyl group having 2-6 carbon atoms, including the carbonyl carbon.

Acyl groups forming acyloxy substituents of NMI SM can be any group derived from a carboxylic acid according to the generally accepted definition of the term "acyl". More specifically, acyl groups in the composition according to the invention can be present in the form ВЯСО-, where В? is not necessarily oxy-substituted alkyl with 2-6 carbon atoms. This oxy-substitution can take the form of hydroxy-substitution or substitution with additional acyl groups. For example, V? can be an oligomer of oxy-substituted carboxylic acids connected by an ester bond between the hydroxy of one acid and the carboxy of another acid.

In a more specific example B? may contain 1-5 lactide or glycolide units, where the lactide unit contains two lactic acid groups esterified together, and the glycolide unit contains two glycolic acid groups esterified together. Alternatively, V? may contain mixed lactide and glycolide units or may contain mixed lactic acid and glycolic acid with no lactide or glycolide units present.

Concrete materials of NMISM have in their composition components of formulas I or I, where B", B? and BZ are independently lactoyl, polylactoyl, ε-caproyl, hydroxyacetyl or polyhydroxyacetyl, especially polylactoyl and ε-caproyl, or polylactoyl and polyhydroxyacetyl.

The use of oxy-substituted carboxylic acid groups with a relatively short chain (2-6 carbon atoms) in the ester or in the mixed ester according to the invention is preferred. When these acid groups are present in the form of oligomeric esters (that is, the subsequent acid group is linked to the previous acid group by esterification of the next carboxy with the previous oxy), hydrolysis of the material is much easier than for oligomers obtained with more than b carbon atoms, since the material is more hydrophilic. As a rule, for the delivery of the drug, it is desirable that the NMI SM is not soluble in water, but it can be somewhat hydrophilic. Generally, SM NMIs synthesized with more hydrophilic units (as defined by a higher O:C ratio) are expected to absorb water more quickly and degrade more quickly.

For example, NMI SM prepared by covalently bonding 4 mol of glycolide with one mol of glycerol is expected to absorb water faster and degrade faster than NMI SM prepared by covalently bonding 2 mol of glycolide and 2 mol of lactide with one mol of glycerol. A similar increase can be expected for more flexible molecules and for more branched, spherical molecules based on free volume arguments. The use of flexible and branched molecules may also have the advantage of reducing the viscosity of I MI SM.

The use of carboxylic acids and/or polyols with different chain lengths and the use of carboxylic acids having an oxy-substitution allows precise control of the degree of hydrophilicity and solubility of the resulting ester. These materials are significantly resistant to the dissolution of ip mimo, so that they are able to provide a controlled release of the transferred anesthetic agent in the body, which is accompanied by or has a subsequent hydrolysis of the oxy-bonds of ip mimo.

In a more specific embodiment, sucrose acetate isobutyrate ester, which has a ratio of acetate to acid isobutyrate groups of 2:6, is excluded from NMI SM. Meanwhile, sucrose acetate isobutyrate ester, having a ratio of acetate groups to isobutyrate of 2:6, is included in the scope of the invention for use in aerosol compounds. This material can be obtained according to the methods described in US patent Mo2931802.

As a rule, suitable esters of NM SM can be obtained by the reaction of one or more alcohols, in particular, one or more polyols, which will form the alcohol group of the resulting complex esters, with one or more carboxylic acids, lactones, lactams, carbonates or anhydrides of carboxylic acids, which will form acidic groups of obtained esters. The esterification reaction can be carried out simply by heating, although in some cases it is possible to use the addition of an esterification catalyst - a strong acid or a strong base. Alternatively, you can use such an esterification catalyst as tin 2-ethylhexanoate. The heated reaction mixture, with or without a catalyst, is heated with stirring, then dried, for example, under vacuum, to remove any unreacted starting materials and obtain a liquid product. Sucrose isobutyrate acetate can be prepared following the methods described in US Pat. No. 2,931,802.

In this regard, the polyol can be considered as an initiator of oligomerization in the sense that it provides a substrate for the esterification of carboxylic acids, in particular, oligomers of lactide, glycolide or other esterified hydroxy-substituted carboxylic acids.

In specific embodiments, the NMI SM can be mixed with a viscosity-reducing diluent to produce a viscosity-reduced liquid carrier material (I MI SM), which can then be mixed with one or more anesthetic agents to be delivered prior to administration. . These solvents may be water-soluble, water-insoluble, or miscible with water and may include acetone, benzyl alcohol, benzyl benzoate, M-(betahydroxyethyl)lactamidebutylene glycol, caprolactam, caprolactone, corn oil, decylmethyl sulfoxide, dimethyl ether, dimethyl sulfoxide, 1-dodecyl azacycloheptane- 2-one, ethanol, ethyl acetate, ethyl lactate, ethyl oleate, glycerol, glucofurol (tetraglycol), isopropyl myristate, methyl acetate, methyl ethyl ketone, M-methyl-2-pyrrolidone, MISI MOI E (esters of caprylic and/or capric acids with glycerol or alkylene glycols, for example, MYS MOI F 810 or 812 (caprylic/capric triglycerides), MYS MOI 818 (caprylic/capric/linoleic triglyceride), MYS MOI 829 (caprylic/capric/succinic triglyceride), MYS MOIF 840 (propylene glycol dicaprylate/caprate) , oleic acid, peanut oil, polyethylene glycol, propylene carbonate, 2-pyrrolidone, sesame oil, solketal (F-2-2,2-dimethyl-1,3-dioxolane-4-methanol), tetrahydrofuran, TAAM5SITOY F (monoethyl ether of diethylene glycol, carbitol), triacetin, triethyl citrate, diphenyl phthalate and their combination. In addition, if the composition is used as an aerosol, for example for topical application, the solvent may be or contain one or more propellants, such as SES propellants such as trichlorofluoromethane and dichlorofluoromethane, non-SES propellants such as tetrafluoroethane (B-134a) , 1,1,1,2,3,3,3-heptafluoropropane (d-227), dimethyl ether, propane and butane.

In particular, suitable solvents and/or propellants include benzyl benzoate, benzyl alcohol, triacetin, triethyl citrate, dimethyl sulfoxide, ethanol, ethyl lactate, glycerin, glucofurol (tetraglycol), M-methyl-2-pyrrolidone, MIS MY F 810, polyethylene glycol, propylene carbonate, 2-pyrrolidone and tetrafluoroethane.

Other possible solvents include perfluorodecalin, perfluorotributylamine, methoxyflurane, glycerol formal, tetrahydrofurfuryl alcohol, diglyme, and dimethylisosorbide.

When the composition is used as an MI SM for the administration of an anesthetic agent, it must contain a solvent in which the NMI SM is soluble. In specific cases, the anesthetic agent is also soluble in a solvent. In additional cases, the solvent is a second anesthetic agent in which the first anesthetic agent is soluble. The solvent is preferably non-toxic and otherwise biocompatible.

In specific embodiments, the solvent is at least water-soluble, so that after administration it will rapidly diffuse into the body fluid or other aqueous medium, causing the composition to coagulate and/or become more viscous. In other embodiments, the solvent is not completely miscible with water or body fluids, so that the diffusion of the solvent from the composition and the corresponding increase in viscosity of the composition are slowed. Suitable solvents that have this property, at least to some extent, include benzyl benzoate, MISSIONS MY F 810, benzyl alcohol and triethyl citrate. Benzyl alcohol may be particularly suitable as it is also an anesthetic agent.

When esters of 1,6-hexanediol or glycerol are used as NMI SM, some of the possible solvents are ethanol, M-methylpyrrolidone, propylene carbonate, and RES 400.

The solvent is typically added to the composition in an amount ranging from about 99.7 percent to about 0.5 percent by weight of the total weight of the composition (95 weight percent), from about 95 percent to about 1925 weight percent, from about 75 to about 1095 weight percent mass, or from about 50 to 1595 mass. The solvent is typically present in the composition in an amount ranging from about 55 percent to 1095 wt.

In other embodiments of the invention, the composition contains a material that is not miscible with the NMI SM, such that when it is combined with the NMI SM, alone or in combination with a solvent for the NMI SM, the resulting composition forms an emulsion. Such emulsions can contain NMI SM in the dispersed phase, as in the case of mixtures

ZAIV/MISI MOI F, emulsified in water or glycerol, or may contain NMI CM as a component of the dispersion phase, as in the case of an aqueous solution emulsified in NMI CM, or a solution of NM CM in a water-immiscible solvent.

Any of the non-polymeric controlled delivery systems described above may be formulated as a liquid, spray, cream, lotion, ointment, gel, suspension, oil, emulsion, microemulsion, solid, patch, film, particle, microparticle, powder, or other suitable form. a pharmaceutical composition suitable for use in the methods of this invention. In such compositions, an anesthetic agent (for example, a first anesthetic agent) is included in an amount sufficient to deliver to the subject to be treated an effective amount to achieve the desired effect. The amount of anesthetic agent included in the composition depends on the final desired duration and release profile and concentration of anesthetic required for the intended effect.

The concentration of anesthetic in the composition also depends on the rates of absorption, inactivation, and excretion of that particular agent, as well as other factors known to those skilled in the art. It should be noted that the dose values will vary depending on the severity of the condition to be alleviated. Furthermore, it should be understood that for any particular subject, specific dosage regimens should be adjusted over time according to individual need and the professional judgment of the person administering or monitoring the administration of the composition, and that the concentration ranges described herein are only are approximate and are not intended to limit the scope or implementation of the claimed composition. The composition may be administered in a single dose or may be divided into a number of smaller doses to be administered at different time intervals, either sequentially or simultaneously.

The anesthetic agent or agents will generally be present in the composition in the range of from about 0.1 to about 99.5 weight percent of the total weight of the composition (95 weight), from about 0.5 to about 7095 weight, or from about 1 percent to approximately 5095 wt. However, ranges with upper limits as low as about 4095, 3095, 2095, or 1095 and ranges with lower limits as high as about 595, 395, or 295 can be used. For very active anesthetic agents, ranges may be less than 195 wt. and possibly less than 0.000195.

Both soluble and insoluble anesthetic agents can be dispensed using non-polymeric carrier materials for controlled delivery. Moreover, it is additionally possible to compose compositions with polymer fillers to obtain a binder for delivery with modified properties, for example, a higher or lower rate of degradation. The resulting composition can be formed into microspheres or a macroscopic implant or other shapes and sizes according to methods known in the art.

Alternatively, a preformed microsphere, implant, or polymeric particle with an anesthetic agent incorporated therein can be combined with a non-polymeric carrier.

The microspheres can be prepared by a number of methods known in the art, as well as the methods described in US Patents MeMeb 291013 and 6440493. The polymeric particle can be prepared using melt extrusion, granulation, solvent mixing, adsorption, or the like, or the anesthetic agent can be adsorbed onto a polymer matrix such as an ion exchange resin. The resulting material, when combined with a suitable non-polymeric carrier, can be administered parenterally. In other embodiments, the anesthetic agent can be combined with a non-polymeric material such as calcium phosphate or sucrose to provide coating/barrier properties that prolong degradation. The non-polymeric carrier will then form a secondary barrier to provide improved delivery characteristics. The non-polymeric carrier phase may or may not contain other biologically active substances according to the specific requirements of the selected application. These other biologically active agents can be any suitable therapeutic and/or prophylactic drug, provided that the added substance is suitable for administration to the microspheres or implants according to methods known in the art.

As discussed above, a variety of additives may optionally be added to the compositions of the present invention to modify its properties and, in particular, to modify the release properties of the composition relative to the anesthetic agents contained therein. Additives may be present in any amount sufficient to provide the composition with the desired properties. The amount of additive used will generally depend on the nature of the additive and the effect to be achieved, and can easily be determined by the performer. Suitable additives are described in US Pat. No. 5,747,058, the entire contents of which are incorporated herein by reference. More specifically, suitable additives include water, biodegradable polymers, non-biodegradable polymers, natural oils, synthetic oils, hydrocarbons or hydrocarbon derivatives, inorganic salts, BBA (bovine serum albumin), surfactants, organic compounds such as sugars, and organic salts such as sodium citrate. As a general rule, the less water soluble, ie more lipophilic, an additive is, the more it will reduce the release rate of the anesthetic compared to the same composition without the additive. In addition, it may be desirable to include additives that increase properties such as efficiency or porosity of the composition.

The addition of additives can also be used to extend the delivery time of the anesthetic agent, making the composition suitable for medical applications that require or are sensitive to prolonged administration. Suitable additives in this regard include those described in US Pat. Nos. 5,747,058 and 5,736,152. In particular, suitable additives for this purpose include polymeric additives such as cellulosic polymers and biodegradable polymers. Suitable cellulose polymers include cellulose acetates, cellulose ethers, and cellulose acetate butyrates.

Suitable biodegradable polymers include polylactones, polyanhydrides and polyorthoesters, including polylactic acid, polyglycolic acid, polycaprolactone and their copolymers.

The additive, when present in the composition, is generally present in an amount ranging from about 0.01 percent to about 20 percent by weight, more specifically from about 0.1 percent to about 20 percent by weight, based on the total weight of the composition. and, more specifically, is present in the composition in an amount ranging from about 1, 2, or 5 percent to about 10 percent by weight. Specific additives such as buffers are present in the composition only in small amounts.

The following categories are non-limiting examples of the classes of additives that can be used in the compositions of the present invention.

One category of additives is biodegradable polymers and oligomers. Polymers can be used to change the release profile of the anesthetic agent to be delivered, to provide strength to the composition, or to modify the properties of the composition in another way. Suitable biodegradable polymers and oligomers include, but are not limited to, poly(lactide), poly(lactide-co-glycolide), poly(glycolide), poly(caprolactone), polyamides, polyanhydrides, polyamino acids, polyorthoesters, polycyanoacrylates , poly(phosphazines), poly(phosphoesters), polyetheramides, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, degradable polyurethanes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylenesuccinates, poly(malic acid), chitin, chitosan and copolymers, terpolymers, oxidized cellulose or a combination or mixture of the above materials.

Examples of poly(c-hydroxy acids) include poly(glycolic acid), poly(OH lactic acid) and poly(|!/-lactic acid) and their copolymers. Examples of polylactones include poly(ε-caprolactone), poly(β-valerolactone) and poly(γ-butyrolactone).

Without intending to be bound by any theory, it is believed that when the composition contains a polymer that is biodegradable, a portion of the polymer may precipitate or coagulate on the surface of the composition as any solvent included in the composition diffuses out of the material after administration to a subject. . The polymer may thus be added as a release modifier to influence the release of the anesthetic agent or agents, or may be added as part of a composition containing preformed microspheres, implants or ground polymer particles. Precipitation or coagulation of the polymer forms a shell that at least partially surrounds the liquid core of such a composition. This shell is porous and allows the solvent to continue to diffuse through it into the surrounding tissue. The rate of solvent release and the volume of shell formation, as well as its porosity, can be controlled by the amount and type of solvent and polymer used in the composition.

Other additives for use in these compositions are non-biodegradable polymers. Non-eroding polymers that can be used as additives include, but are not limited to, polyacrylates, ethylene-vinyl acetate polymers, cellulose and cellulose derivatives, acyl-substituted cellulose acetates and their derivatives, polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl fluorides , polyvinyl (imidazole), chlorosulfonated polyolefins, polyethylene oxide and polyethylene, which are not subject to erosion.

The best non-biodegradable polymers include polyvinylpyrrolidone, ethylene vinyl acetate, polyethylene glycol, cellulose acetobutyrate ("SAV") and cellulose acetopropionate ("SAP").

An additional class of additives that can be used in these compositions are natural and synthetic oils and fats. Oils of animal origin and those obtained from the seeds or nuts of plants usually contain glycerides of fatty acids, mainly oleic, palmitic, stearic and linoleic. As a rule, the more hydrogen a molecule contains, the more viscous the oil becomes.

Suitable natural and synthetic oils include, but are not limited to, vegetable oil, peanut oil, medium chain triglycerides, soybean oil, almond oil, olive oil, sesame oil, fennel oil, camellia oil, corn oil, castor oil, cottonseed oil and soybean oil, crude or refined, and medium-chain fatty acid triglycerides.

Fats, as a rule, are esters of glycerol and higher fatty acids, such as stearic and palmitic. Such esters and their mixtures are solid at room temperature and have a crystalline structure. Examples are lard and animal fat. As a rule, oils and fats increase the hydrophobicity of the non-polymer carrier system, slow down the degradation and absorption of water.

All of the compositions described above can be used in the methods of the present invention to provide long-lasting local anesthesia at a target site. In particular, the compositions can be formulated as a liquid, spray, cream, lotion, ointment, gel, suspension, oil, emulsion, microemulsion, solid, patch, film, particle, microparticle, powder or any other suitable form of pharmaceutical composition and then administered to the subject by means of local, transdermal, parenteral (for example, injection, implant, etc.) delivery or similar methods. Compositions comprising an anesthetic agent and a pharmaceutically acceptable non-polymeric carrier are used to provide an anesthetic effect characterized by prolonged local anesthesia after administration to a subject without an initial release and lasting at least about 24 hours after administration, preferably at least about 36-48 hours after administration, and , preferably at least about 48-72 hours after administration. In specific embodiments, the onset of local anesthesia occurs within approximately 2 hours of administration to the subject, preferably within approximately 1 hour of administration, and in some cases within approximately 30 minutes of administration to the subject.

The term "subject" as used herein refers to any vertebrate in which it is desirable to provide a state of local anesthesia. The term thus broadly refers to any animal to be treated with the compositions of the present invention, such as birds, fish and mammals, including humans. In specific embodiments, the methods of the present invention are suitable for providing long-term anesthesia in veterinary practice and animal husbandry, for example, for birds and mammals, where a long-term state of local anesthesia is convenient or desirable. In particular cases, the compositions are particularly suitable for use on domestic animals such as dogs or cats, and can additionally be used on horses. In preferred embodiments, the term "subject" refers to a human subject. In addition, the term "subject" does not imply a specific age, and the compositions are thus suitable for use with subjects of any age, such as pediatric, adolescent, adult, and elderly subjects.

In preferred embodiments, the compositions of this invention are suitable, in particular, for the treatment of wounds.

Non-polymeric carrier systems allow for easy application of the anesthetic agent or agents to the wound, either directly into the wound and/or adjacent to the wound, using very simple methods of application such as instillation, spraying, dabbing, smearing, dousing, or other manual treatment of the wound with a composition in the form of spray, cream, lotion, ointment, gel, suspension, oil, emulsion, microemulsion, flexible solid or patch, film, particle, microparticle or powder. Thus, the compositions can be applied to a wound of any size or shape and provide uniform distribution of the anesthetic agent or agents throughout the wound area for better retention and effectiveness. Wounds that can be treated using such methods can vary from very shallow to deep, from superficial to incisional, and from surgical (or otherwise intentional) to accidental. If the composition is intended for injection, it can be applied to the subcutaneous space using displaceable injections near the wound on all sides or external borders. You can also use combined methods, such where the composition is placed directly in the wound, for example, before surgical closure of the lumen, and, in addition, along the wound. In a particularly preferred embodiment, the methods according to the invention include the use of these compositions as a local anesthetic for the treatment of postoperative incisional pain. The use of these compositions in this manner may eliminate or at least reduce the need for additional treatment such as the administration of systemic narcotic analgesics to treat such post-operative pain. Accordingly, the compositions can be used to treat postoperative pain associated with all types of medical procedures, such as major surgery (eg, thoracotomy, aortic repair, bowel resection), intermediate surgery (eg, caesarean section, hysterectomy and appendectomy) and minor surgery (laparoscopy , arthroscopy and biopsy procedures, which can otherwise be exhausting and may require pain management for 3-5 days after surgery.

Thus, the compositions described herein can be administered in the practice of these methods using a wide variety of methods. For example, the compositions may be administered topically, systemically (e.g., mucosal (oral, rectal, vaginal, or nasal), parenteral (intravenous, subcutaneous, intramuscular, or intraperitoneal), etc. The compositions may be administered by injection, infusion, spraying, by Aerosol or Coated Applicator Aerosols or mists of the composition may be administered using an aerosol propellant, such as for topical administration, or using a suitable nebulizer, such as for nasal or oral mucosal administration.

Preferably, the compositions are administered as liquids by injection or as an aerosol, paste or emulsion. When applied in an aerosol, any solvent present in the aerosol solution will generally evaporate after application, allowing the composition to form a film. Alternatively, the aerosol or emulsion can be prepared without a solvent. In this situation, the aerosol propellant can also function as a solvent.

Aerosols and emulsions can be prepared using methods known to those skilled in the art. See, for example, Apvei, N.S. Yei ai., Rpappaseshisa! bozade Bogpt5 apa Ogpid Oeyeiimegu buzietv, 51ХХІ

Eyop (1995).

In addition to the applications described above, these compositions can be administered by osmotic pumps. In one embodiment, a device is developed for implantation into the subject's tissue and for sustained release over time.

It is also possible to introduce the compositions according to the invention using a porous or non-porous tube, preferably made of an extruded biodegradable polymer. It is possible to obtain a tube with different degrees of porosity depending on the composition and the desired release characteristics. The composition of the invention is inserted into a tube, and the ends of the tube can be left open, allowing the biologically active compound to diffuse from the ends of the tube, or can be closed with an additional porous or non-porous polymer. Porous caps and porous tubes allow the compound to diffuse through the pores over time. Nonporous caps, like nonporous tubes, allow anesthetic agents that are soluble in the polymer to diffuse through it into the surrounding tissue. Non-porous materials that are not solvents for the anesthetic but are biodegradable will release the anesthetic when sufficiently degraded. The compositions of the invention can be prepared and stored as multicomponent systems until they are ready for administration. The number of different components will partly depend on the characteristics of the composition. Before administration, the components are combined and mixed, for example, to obtain a homogeneous composition, which can then be administered to the subject.

Solvents or additives may be added to one or all of the components, or they may constitute a separate component that is also mixed with the others prior to administration. Dividing the composition into a multi-component mixture allows you to optimize the storage conditions for each component and minimize any harmful interactions between the components over time. As a result, stability during storage increases.

Below are examples of specific implementation options for the implementation of the present invention. The examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention in any way.

The effectiveness of IP mimo compositions and methods according to the invention can be evaluated in rats using the hot plate model, for example, by the method described in detail in IASIS Me9511-2199. The performance criteria adopted for the compositions of the invention are an average delay of greater than about 2 seconds, with an interruption at 12 seconds (this interruption is set to prevent any possible damage to the animal). Delays of 2 seconds are indicative of a statistically significant effect of the local anesthetic. Better, the average latency for rats in the hot plate model is greater than 7 seconds. Better yet, the percentage of responders is 5,095 or more. Preferably, the compositions of the invention provide an average latency for rats in the hot plate model of greater than about 7 seconds to about 12 seconds, with a percentage of rats showing an effect of at least about 5095 of those tested.

The essence of the hot plate method for rats is as follows. Male rats of Zrgadie YuRameu (Napap and Arogayutiez, Ipaiaparoiyiv, Ipa.) with an average weight of 275 g are used. The study on a hot plate consists in carefully supporting the animal's body, while the plantar surface of the hind paw is placed on a hot plate at 56"C. The exit delay is determined before a unilateral injection of an anesthetic composition near the rat's sciatic nerve.

Sensory testing on human models is also applicable for testing compositions of the present invention. Local anesthetic activity can be assessed with respect to onset, peak value, and duration of effect using seven specific methods: (a) mechanical sensory testing (mechanical pain recognition threshold using Frey fibers); (p) suprathreshold (mechanical) test using a separate Frey fiber; (c) thermal sensory test (warm recognition threshold); (a) threshold for recognition of pain from heat; (is) over-the-limit (hot) test; and (d) tactile sensory testing (mechanical touch recognition threshold). Different degrees or levels of results may be indicative of local analgesia, local numbness and/or local nerve block experienced by the subject. The anesthetic activity of the compositions and methods according to the invention can be further characterized relative to safety by various indicators of activity, such as systemic levels in blood plasma obtained after administration to a localized area.

The mechanical pain recognition threshold is defined as the smallest force or number of Frey fibers that give a certain sensation of pain or discomfort, and the mechanical touch recognition threshold is defined as the smallest force or number of Frey fibers that give a certain sensation of touch or pressure. Mechanical touch recognition thresholds and mechanical pain recognition thresholds can be determined simultaneously using Frey fibers of increasing stiffness (MEN) (available from Zhotedis A/V, Stockholm, Sweden). It was previously determined that each MEN pressed against equilibrium to a slight flexion provides a force that increases for each fiber, covering the full range from 3 to 402 millinewtons (mN) (MEN Me7-3mN; MEN Me 8-13mMN; MEN Me9-20mN ;

MEN Me10-39mMN; MEN Me11-59MN; MEN Me12-98mMn; MEN Me13-128mMN; MEN Me14-133mMN; MEN Me15-314mMN;

MEN Me16-350mMN; MEN Me17-402mN).

Accordingly, in a human subject, the site after injection of the composition obtained according to the present invention can be stimulated 8 times with each MEN at a rate of approximately 2 stimuli per second, starting with MEN Me7 and moving to MEN Me17. The smallest MEN number that is perceived as touch or pressure (mechanical touch recognition threshold) and the smallest fiber number, half of the eight stimulations that are painful or unpleasant (mechanical pain recognition threshold), are recorded. The procedure is repeated two more times and the median of the three measurements is reported. If no sensation of touch or pressure is received for MEN Me17, the value of the recognition threshold for mechanical touch is estimated as 18. If no pain or discomfort is received for MEN Me17, the value of the recognition threshold for mechanical pain is estimated as 18. Suprathreshold pain response - mechanical for Frey fiber - determined by stimulating the injection site five times the MEN

Me17 (402nM). The subject rates the pain using a UA5 scale of 0-10, where zero (0) is no pain and ten (10) is pain as intense as imaginable.

As discussed above, this test is performed on a single tough Frey fiber, which is defined as causing a pain response in subjects. The pain reaction is determined by stimulation of the area after injection or other treatment 5 times MEN Me17. Subjects rated pain on a verbal rating scale (UA5) from 0 to 10 as above.

Thermal testing (excess pain response to heat) for the treated area is determined by stimulation of 45°C for 5 seconds using a computerized thermosensor (available from Tpeptozieevi, Zotedis A/B, Stockholm, Sweden) on the treated areas. Sub' the subject evaluates the pain according to the verbal rating scale (MA5) 0-10.

The threshold for recognition of warm is defined as the smallest perceived increase in temperature from 32"C, the threshold for recognizing pain from hot is defined as the smallest temperature that is perceived as painful, and the threshold for recognizing cold is defined as the smallest perceived decrease in temperature from 3270. The threshold for recognizing warm, the threshold for recognizing pain from hot and cold recognition thresholds are determined with a computerized thermosensor (available from Zotedis A/V, Stockholm, Sweden) on treated areas.

Subjects are instructed to press a button as soon as they achieve a particular sensation. Thermal thresholds are determined from the initial 32"C and increase (threshold for recognition of warm and threshold for recognition of pain from hot) or decrease (threshold for recognition of cold) at a rate of change of 1"C per second. The upper limit of termination is 52"С for the threshold of recognition of warm and the threshold of recognition of pain from hot.

The lower limit of termination is 25"7C for the cold detection threshold.

Warm recognition threshold, hot pain recognition threshold, and cold recognition threshold are calculated as the median of three measurements with 10 second intervals between each stimulus. If the subject did not perceive heat or pain at 52"C, the value of 53"C was recorded as the threshold for recognition of heat; if the subject did not perceive pain at 52"C, the value of 53"C was recorded as the threshold for recognizing pain from hot; and if the subject did not perceive cold or pain at 25"C, the value of 247C was recorded as the cold recognition threshold.

Example 1

The system of a non-polymeric liquid carrier containing an anesthetic agent was prepared as follows. Sucrose isobutyrate acetate (5AIV) was combined with the 5AIV carrier solvent M-methylpyrrolidone (MMP) to obtain a 70:30 mixture. To this mixture was added either 2.595 (w/v) or 595 bupivacaine (free base) to produce the two test compositions.

Male Zrgadie YuOameu rats (275-300 g) were divided into two tested groups of 8 animals each.

Test compounds were administered to quadrupeds using a needle and syringe to deliver either 25 or

BOmg doses of bupivacaine. A skin startle reaction test was then used to determine the presence of a local anesthetic effect, where an involuntary startle was used under skin stimulation using a pin for 10 random sites within the ISM relative to the injection site. Percent inhibition of pin recognition was then calculated by taking the baseline response minus the test response, divided by the baseline response, and multiplied by 100.

The results obtained indicate that both test compositions provide a local anesthetic effect lasting up to approximately 60-72 hours, with onset of activity within 1 hour of administration.

Example 2

Subjects. Male Fischer 344 rats (Snapev Vimeg Iarogayuguev) (M-96) were used for the study. Animals were kept under a reversed light:dark cycle (dark 5:00-17:00) in a vivarium with temperature and humidity control. During the experimental periods, rats were given ad libitum access to food and water. All experiments were performed during the dark phase of the light-dark cycle. All procedures were approved

By the Industrial Committee on Animal Care and Use of the Center for Medical and Sanitary Disciplines of UUaKke Eoghesi University.

Surgical procedure. After anesthesia with 595 pairs of isoflurane in oxygen, the left lower quadrant of the abdomen was shaved. During the surgical procedure, anesthesia was maintained using 2.0-2.595 pairs of isoflurane in oxygen. 0.5 cm below the lowest rib on the left side and parallel to it, a 3-cm incision penetrating the peritoneal cavity was placed. Internal organs and musculature were vigorously manipulated by inserting a 5/cm index finger into the peritoneal cavity and stretching the musculature. Approximately 10 cm of the small intestine was brought to the surface and carefully manipulated.

The intestine was placed inside the peritoneal cavity and the wound was sutured in 3 layers, which consisted of the peritoneal lining, the muscles of the abdominal press, and the skin using chrome catgut 4.0.

The outer surface of the wounds was covered with antibiotic powder (RoiuzrogipF, Siaho-Meisote, Nezeagsp Tpapdie

Raik, MIS), and animals, etc. introduced 75,000 units. procaine, penicillin C. Falsely treated animals were anesthetized, shaved, kept under isoflurane anesthesia for 20 minutes. and administered to them, etc. procaine penicillin (5.

Administration of bupivacaine composition with controlled release. Test animals were injected with either vehicle (70:30, 5AIV:MMP), 1.2595 (w/v), 2.590, or 595 bupivacaine according to Table 1. The formulation was administered after suturing the skin using the offset injection method of 1.0 and 1.5 ml syringe with a 22 gauge needle, so that 0.25 ml of the composition was evenly distributed along the section of the incision approximately 0.5 cm above the wound area. The second injection was carried out in the same way 0.5 cm below the wound site. For groups K and GG, an additional injection of 0.1 ml or 1.2595 (w/v) or 595 bupivacaine was performed on top of the peritoneal lining using the displacement injection method before suturing the outer muscle layer.

Compositions with bupivacaine allow you to stay on the peritoneal lining for 1-2 minutes. before suturing the extrinsic muscle to achieve sufficient viscosity and thus prevent washout of the composition through the extrinsic muscle during the suturing process.

Table 1

Groups were treated as described below. All groups, with the exception of group B, underwent surgical laparotomy as described above.

Measurement of spontaneous locomotion. Research behavior was assessed starting at 24 hours. after laparotomy using commercially available equipment and software (May

Avzosiaies Ips., 5. AIrapv, MT). Activity chambers consisted of 17" x 17" acrylic enclosures 15" high with an open top. Dual arrays of 16 infrared emitters, spaced 1" apart, were placed in the X and Y directions, 1" above the floor surface, with one aligned lines by infrared detectors on opposite sides of the chamber. A third set of infrared emitters and detectors was placed in the X direction, 7 cm above the floor surface, so that the rats used in these studies had to stand on their hind legs to intercept these beams. Each chamber for activity, they were placed in a dimly lit and sound-attenuated room. Sessions were conducted 16, 24, 40, 48, and 72 hours after surgery and lasted for 10 min. Measurements collected included total distance traveled, total number of beam interruptions as in X, as well as M direction (walking indicators), repeated interruptions of rays within the limits

Ccm from the animal in the absence of locomotion (stereotypy), total number of interruptions in the upper X direction (hind-paws), time spent in locomotion, time spent in stereotypy, time spent in hind-paws, and time spent in recreation All measurements were collected in segments along the BHV. within a session and also summed for the entire session.

Measuring the return of anesthesia using the pin prick test. 96 hours after surgery, the animals were quickly placed in a clear acrylic receiving chamber that provided access to the peritoneal cavity. A slightly blunted 20 gauge needle was pressed in the area within 0.5 cm from the area of the peritoneal wound with sufficient force to a noticeable dent in the peritoneal tissue. The needle was left in place for 10 seconds or until the animal responded by flinching or moving away from the needle. Each animal was tested 2-3 times in the wound area.

An area at least 10 cm away from the wound area was tested in the same manner as the positive control measurement.

Data analysis. Data were analyzed using a 2-factor ANOVA for repeated measures with individual behavioral indices as independent measures and treatment group and time after surgery as dependent variables. After that, analyzes were carried out using the I-test

Bonferroni-Danna test for multiple comparisons with the sham-operated control group and using Fisher's protected 50's for all pairwise comparisons.

Results (Distance Traveled) The effects of surgery and perioperative treatment with either vehicle or bupivacaine are shown for each time point in Figures 1-5. There was a significant mean effect of treatment group and time after surgery on distance walked with no significant interaction between these variables (Table 1).

Table 2

Results of the 2-factor AMOMA for distance traveled (cm) and Average

Source og Sum of squares quadratic Value E Value P (| Remainder | 435 | 728855Е8 | 16755366

Dependent: distance

Further analysis using the Bonferroni-Dunn i-test for multiple comparisons with the control group revealed that all bupivacaine-injected groups were not significantly different from sham, while untreated or vehicle-treated incision animals remained statistically different from sham. controls during the study (table 2). Further analysis of all pairwise comparisons using Fisher's protected 50 revealed that only the 595 bupivacaine or 1.2595 bupivacaine groups in both the peritoneal lining and the extrinsic muscle were not significantly different from the sham treatment (Table 3).

Table C

Fisher protected I 50 for all pairwise comparisons, distance traveled (cm)

M8. Difference Critical difference Value of R

Carrier

WITH

Section 5

Run 1.2595 5

Covered Race 2.590 10.55867 464.48674 9644

Because 5

Run 2.595 8 outside 1.2590

Wabeg 596

Q - Definitely different at this level

Walking indicators. The statistical results for these walking measures are qualitatively similar to the results described for distance traveled above. Gait performance data were assessed for each individual time point after surgery. As for in-session distance walked, there was a significant main effect of both treatment group and time after surgery on walking performance, with no significant interaction between these variables (Table 4).

Table 4

Results of the 2-Factor AMOMA for walking measures and Mean

Source o Sum of squares quadratic Value EE Value Р 5.70066Е6 8.1438Е5 1.9317 «0631 8.44878Е6 2.1122Е6 5.0101 0006 1.42666Е7 5.09522Е5 1.2086 21681 1.83392Е81 4295 | (77/11

Dependent: showy 1 walk

A follow-up Bonferroni-Dunn n-test using walking performance as the independent measure yielded results similar to those for distance walked (Table 5).

Table 5 Bonferroni-Dunn i-test for multiple comparisons, walking measures

M8. Difference Critical difference Value of R

Incorrect processing -354.50000 325.73352 .0029 Z -346.51061 333.05428 0045 Z

Run 1.2595 -281.00000 325.73352 0182

Coated inside/outside 590 -213.43333 325.73352 0725

Run 2.590 -207.28333 325.73352 0811

Inside and outside 1.2595 -174.08333 325.73352 51427

Race 595 -128.61667 325.73352 2785

Q - Definitely different at this level

Fisher's protected 50 analysis of all pairwise comparisons revealed that the sham group was significantly different only from the incision control group, the vehicle-treated group, and the lowest-dose bupivacaine group (1.259) (Table 6).

Table 6

Fisher's AND 50 protected for all pairwise comparisons, walk rates

M8. Difference Critical difference Value of R

Section 7.98939 238.22966 59475

Run 1.259 73.50000 232.99321 5356

Coated inside/outside 595 141.06667 232.99321 2347

Run 2.595 147.21667 232.99321 2150

Inside and outside 1.2595 180.41667 232.99321 1288 zareg 5905 225.88333 232.99321 0574

Incorrect processing 354.50000 232.99321 .0029 Z

Carrier Zabeg 1.259 65.51061 238.22966 5891

Coated inside/outside 59 133.07727 238.22966 2129

Run 2.595 139.22727 238.22966 2513

Inside and outside 1.2595 172.42727 238.22966 1556

Run 595 217.89394 238.22966 0729

False finish 346.51061 238.22966 0045 Z zZabreg 1.2595 Coated inside/outside 590 67.56667 232.99321 .5690

Run 2.595 73.71667 232.99321 5344

Inside and outside 1.2595 106.91667 232.99321 3676

Run 595 152.38333 232.99321 1993

Incorrect processing 281.00000 232.99321 0182 5

Covered Run 2.595 6b.15000 232.99321 .9586 in/out

For

Inside and outside 1.2595 39.35000 232.99321 7401 zareg 595 84.81667 232.99321 4747

False processing 213.43333 232.99321 0725 zZabreg 2.595 Inside and outside 1.2595 33.20000 232.99321 7796 zareg 5905 78.66667 232.99321 5073

Incorrect processing 207.28333 232.99321 0811

Inside and Race 595

Incorrect processing 174.08333 232.99321 51427

Run 595 Wrong finish 128.61667 232.99321 2785

Q - Definitely different at this level

Indicators of stereotypy. There were no significant differences between groups for close movements (stereotypy), but there was a significant main effect of time after surgery and a significant interaction between treatment group and time after surgery (Table 7, Figs. 11-15). Further analysis using the I-test

Bonferroni-Danna found that the time point of 40 h. significantly differed from other time points by this measurement (Table 8). With the exception of the 40-hour time point. and reanalysis of the remaining data by 2-factor AMOMA revealed a more or less significant effect of treatment group on stereotypic behavior, a significant main effect of time after surgery, and a significant interaction between treatment group and time after surgery (Table 9). Follow-up Bonferroni-Dunn i-tests revealed no significant differences between treatment groups, but Fisher's protected 50 i-tests revealed that all groups were significantly different from sham-treated controls except for the highest dose of bupivacaine (595), as was of the group treated with 1.2595 bupivacaine, both at the level of the peritoneal lining and at the layer of the abdominal muscles (table 10).

Table 7 2-factor AMOMA, indicators of stereotypes and Average

Source o Sum of squares quadratic Value of EE Value of P 8.17653Е6 1.16808Е6 1.2165 2921 2.00711Е7 5.01778Е6 5.2258 0004 4.64266Е7 1.65809Е6 1.7268 0131 4.17686Е98 961 | /!/

Dependent: showing 1 stereotypy

Table 8

Bonferroni-Dunn for multiple comparisons with control, time after surgery

Mv8. Difference Critical difference Value Р 16 -95.29474 367.84078 »5ОЗ1 -44.54737 367.84078 7542 300.09474 367.84078 .0354 415.45263 367.84078 0037 5

Q - Definitely different at this level

Table 9 2-factor AMOMA, excluding the 40-hour time point, indicators of stereotypy and Average

Source ag Sum of squares quadratic Value E Value Р 1.2537Е7 1.791Е6 1.8741 00729 9.26855Е6 3.08952Е6 32329 0225 3.24302Е7 1.54429Е6 1.816 0435 3.32568Е8 яBBб56Е5 | 7. І 77777777

Dependent: indicators of stereotypy

Table 10

Fisher's protected I 50 for all pairwise comparisons, with the exception of the 40-hour time point, indicators of stereotypy

Mv8. Difference Critical Value P difference

Section 8 8

Wabeg 1,257 8

Zareg 2.59 8 inside/outside

For

Carrier 5 outside 1.2590

Zareg 59

Q - Definitely different at this level

Vertical indicators (rising on the hind legs). There was a significant main effect for hindpaw lifting for both treatment group and time after surgery, as well as a significant interaction between these variables (Table 11). Further analysis using the Bonferroni-Dunn I-test revealed significant differences between the sham-treated control and all treatment groups (Table 12). According to the results of Fisher's test for protected I 50, consistent data were obtained with no significant differences, except for the difference of the group with a false treatment from all other treatments (Table 13).

Table 11 2-factor AMOMA, vertical indicators

Source og Sum of squares quadratic Value of EE Value of P (Residual | 435 | 259082 and 15909 | 59559417. | /

Dependent: vertical indicators

Table 12

Bonferroni-Dunn for multiple comparisons with control, vertical indicators

Mv8. Difference Critical difference Value of R

False processing | Zaregi, 2596 | 2520000 | 1224308 | 0001 |5

WITH

5 5 5

C - Much different at this level

Table 13

Fisher's 50% protected for all pairwise comparisons, vertical indicators

Mv8. The difference is anise, the value of R

Race 122535

WITH

Media 5 inside/outside

Because 8

Race from 8

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Race 2.595 in

Q - Definitely different at this level

Pin prick stimulus. The animals were stimulated with a pin prick in the area within 0.5 cm of the incision after 9 hours. after surgery. All animals responded to this stimulus, with the exception of one animal in the NN group (1.2595 bupivacaine injected into both the abdominal muscle layer and the peritoneal lining). This animal responded normally to the pinprick stimulus when it was given at a site approximately 3 cm from the incision site.

The results. Postoperative treatment with the vehicle used for the sustained release formulation (control) had no significant effect on activity measurements compared to laparotomy without other treatment. There was a clear effect of carrier on stereotyped behavior at some of the late time points. These data consistently support a reliable analgesic effect of 595 bupivacaine in the sustained-release formulation, which was likely present at the late time points studied. Bupivacaine controlled-release formulation 595 consistently provided significant analgesia and reversed the effect of laparotomy on all behavioral measures except vertical activity. Some analgesic effects were found after the introduction of 1.259o bupivacaine both at the level of the peritoneal lining and on the outer layer of the abdominal muscles, but the effects were not as persistent as those found after the introduction of 595 bupivacaine only on the outer layer of the abdominal muscles. The effect of 595 bupivacaine is stronger at the 48 and 72 hour time points. The reason(s) why these animals showed less activity at the earlier time points is not entirely clear, as these animals showed normal feeding and body surface grooming behavior in their home cages and probably lack of stress. These data prove that the local anesthetic effect using the compositions of the invention with controlled release, which contain the anesthetic bupivacaine, is sufficient to control pain after surgery.

Example C

A subsequent dose-escalation, safety, and pharmacokinetic evaluation was conducted in healthy human volunteers to evaluate the safety/tolerability and preliminary pharmacokinetics of a controlled-release formulation of bupivacaine containing a non-polymeric carrier of sucrose acetate isobutyrate.

The compositions were made using the free base of bupivacaine, formulated in a non-polymeric carrier of sucrose acetate isobutyrate (ZAIV), which additionally contains M-methyl-2-pyrrolidone (MMP), which acts as a solvent for bupivacaine and the 5AIV carrier. The composition was obtained by mixing the 5AIIV carrier and MMP solvent (70:30 carrier) with

Boss mass. of bupivacaine to obtain separate doses, which contain 137.5 mg of bupivacaine in an injection volume of 2.5 ml.

The composition was provided in the form of a liquid for injections.

The study included two cohorts. Cohort 1 consisted of 6 healthy male subjects aged 22 to

From 8 years old. For cohort 1, all subjects received injections with a total volume of 2.bml of the composition

ZAIV/MMP/bupivacaine (containing 137.5 mg of bupivacaine) in the first injection site, injected into the abdominal subcutaneous area in the form of a 5 cm displaceable injection; and a 2.5 ml injection of vehicle-only placebo (5BAIV/MMP) into the second injection site, also administered subcutaneously in the abdominal area as a 5 cm displaceable injection.

After the injections, the subjects were observed for up to eight hours to monitor the local condition of the tissues in the injection area, and plasma samples were collected. Additional plasma samples were collected on days 1, 2, 3, 4, and 28. In all plasma samples, the concentration of bupivacaine in the blood was tested using generally accepted methods.

Cohort 2 also consisted of 6 healthy male subjects aged 22 to 38 years. Cohort 2 was divided into two subgroups, where the first subgroup (n-3) was injected with a total volume of bBml of the composition

ZAIV/MMP/bupivacaine (containing 275 mg of bupivacaine), injected into the abdominal subcutaneous area in the form of two

B5cm displaceable injections of 2.5 ml each. The other subgroup (n - 3) received placebo injections with a total volume of 2.5 ml containing only the vehicle (5AIV/MMP), also injected into the abdominal subcutaneous area in the form of two B5cm offset injections of 1.25 ml each. Here again, after the injection, the subjects were observed for up to eight hours to monitor the local condition of the tissues in the injection area and plasma samples were collected. Additional plasma samples were collected on days 1, 2, 3, 4 and 28.

As a result, the study found that the 5AIV vehicle and the 5AIV/MMP/bupivacaine formulations were well tolerated, where the injections did not result in any noticeable redness, swelling, itching, discoloration, or any other adverse symptom at the injection site. or any adverse tissue reaction during the duration of the study. In addition, the evaluation of the pharmacokinetics of bupivacaine showed a sufficiently slow (prolonged) release of active bupivacaine from the 5AIIV carrier, with the release of active bupivacaine over a period of 3-4 days. These pharmacokinetic results are presented in Figure 1. As can be seen, post-injection Tmax plasma bupivacaine concentrations in Cohort 1 (v4ng/ml) and Cohort 2 (174ng/ml) were below the published established plasma toxic concentration ranges (approximately 1-4μg/ml). In addition, a comparison between cohort 1 and cohort 2 curves showed that bupivacaine plasma levels increased in an essentially linear fashion with increasing dose. Moreover, AOS evaluation showed 10095 bioavailability of bupivacaine.

Example 4

The following dose-escalation, safety, pharmacokinetic, and pharmacodynamic (efficacy) evaluations were performed in human patients undergoing hernia repair procedures to evaluate the efficacy and pharmacokinetics of a controlled-release formulation of bupivacaine containing a non-polymeric carrier of sucrose acetate isobutyrate and prepared according to an invention The study compared the effectiveness of these ZAIIV/bupivacaine compositions, administered subcutaneously in combination with a saline wound infiltrate (placebo) or bupivacaine hydrochloride (MagsaipF)), with the effectiveness of a commercially available bupivacaine solution (MagsaipF), bupivacaine hydrochloride BP, 5.28mg/ml , equivalent to 5 mg/ml of anhydrous bupivacaine hydrochloride), injected subcutaneously and as an infiltrate in the open groin area of patients with hernia repair.

The tested composition was/are formulated using the free base of bupivacaine formulated in a non-polymeric carrier of sucrose acetate isobutyrate (5AIV), which additionally contains benzyl alcohol (BA), which acts as a solvent for bupivacaine and the 5AIV carrier. Benzyl alcohol is also an anesthetic agent. The composition was/is obtained by combining approximately 6bbo" wt. carrier 5AIV, 2295 wt. solvent/anesthetic of benzyl alcohol and 1295 wt. of bupivacaine to obtain separate doses, which contain 159.5 mg of bupivacaine in an injection volume of 1.25 ml (31U9 mg in 2.5 ml of total volume). The composition was/are provided as an injectable clear liquid.

The study design includes a cohort of up to 91 patients (6 patients for cohort 1; 15 patients for cohort 2; and up to 70 patients for cohort 3). In particular, cohort 1 consisted of b healthy subjects - men aged 23 to 52 years. In cohort 1, all patients were injected with a total volume of 2.5 ml of the ZAIV/BA/bupivacaine composition (containing 31–9 mg of bupivacaine), administered as two offset subcutaneous injections along each side of the surgical wound (0.5 ml/cm along estimated 5 cm of the total length of the incised wound) with 1 Oml of saline infiltrated into the incised wound (including the subfascial one) before wound closure. Displaced injections were administered 0.5-1.06 m from and parallel to the edges of the wound incision, and were performed by advancing the needle subcutaneously, parallel and along the length of the incision, infusing continuously with needle withdrawal. Anesthetic/analgesic effect was evaluated using tests of time to the first additional analgesic drug and total use of additional analgesic drug (within 4 days). The concentration of bupivacaine in the plasma was measured periodically during the entire course of the study, in particular during the first 24 hours to assess the amplitude of the early release of bupivacaine from the composition of ZAIV with controlled release.

The results of the time to first additional analgesic test are shown in Table 14 below.

Table 14

Time to the first additional analgesic analgesic 776 | ...yyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyy

The results of the general use of an additional analgesic drug (within 4 days) are shown below in Table 15.

Table 15

General use of additional analgesic medication 6 |4 1 1121 z

As in the study of Example 3, it was again found that the ZAIV/VA/bupivacaine formulation was well tolerated, where the injections did not result in any noticeable redness, swelling, itching, discoloration, or any other adverse symptom at the site. ection or any adverse tissue reaction during the duration of the study. In addition, evaluation of the pharmacokinetics of bupivacaine showed sustained release of active bupivacaine from the 5AIV carrier with release of active bupivacaine over a period of 4 days.

Pharmacokinetic results are presented in Figures 2 and 3. As can be seen, the 5AIV/BA/bupivacaine formulation rapidly released active bupivacaine (within approximately 1 hour of administration) without an initial release and showed essentially sustained release with a steady state during at least the first From the days of treatment. The average Stach that was observed was 277ng/ml109; Ttah was 23 hours 221; and St. was 19 Eng/mlai13.

Cohort 2 consisted of 15 healthy male subjects aged 26 to 54 years. Cohort 2 was divided into three subgroups, where the first subgroup (n-5) was injected with the composition ZAIV/BA/bupivacaine (containing 638 mg of bupivacaine) in a total volume of 5.0 ml, administered as two offset subcutaneous injections along each side of the surgical wound (O0.bml/cm along the predicted Bbsm of the total length of the incised wound) with 1Oml of saline infiltrated into the incised wound (including the subfascial one) before closing the wound. The other subgroup (n-5) was injected with the composition ZAIV/BA/bupivacaine (containing 638 mg of bupivacaine) in a total volume of 5 ml, administered as two offset subcutaneous injections along each side of the surgical wound (0.5 ml/cm along the intended 5 cm total length of the incised wound) with 1 Oml of MagsayipF (0.595 bupivacaine-HCI) infiltrated into the incised wound (including the subfascial one) prior to wound closure for a total of 688 mg of bupivacaine administered to each patient. The third subgroup (n-5) was injected with the composition MagsaipF (0.595 bupivacaine-NSI) in a total volume of

BbBml administered as two offset subcutaneous injections along each side of the surgical wound (0.5 ml/cm along the intended 5 cm total length of the incised wound) together with 10 ml MagsaipF) infiltrated into the incised wound (including subfascial) prior to wound closure for receiving only 75 mg of bupivacaine administered to each patient.

Anesthetic/analgesic effect was evaluated using tests of time to the first additional analgesic drug, pain scores in the incision site "at rest" and total use of additional analgesic drug (within 4 days). The concentration of bupivacaine in the plasma was measured periodically during the course of the study, in particular, during the first 24 hours to assess the amplitude of the early release of bupivacaine from the composition of ZAIV with controlled release.

The results of the test of time to the first additional analgesic drug and the test of total use of additional analgesic drug (within 4 days) for all three subgroups of cohort 2 are shown below in Table 16.

Table 16

Average time to first additional analgesic medication and total use of additional analgesic medication (within 4 days)

Average number of doses

Average time to overtime

Subgroup Number Treatment of the first additional analgesic patients with an analgesic drug, a drug administered within 4 days

ZAIV/BA/bupivacaine and 1 p-5 saline solution (total in A 2.6 dose 638mg

ZAIV/VA/bupivacaine and 2 p.o. MagsaipF (total dose 44.9" 2.4 ba8mg 75MG ("Three patients in subgroup 1 and two patients in subgroup 2 did not receive additional doses of analgesic during the entire period of 4 days)

The ZAIV/VA/bupivacaine formulation was again well tolerated (patient subgroups 1 and 2), where the injections did not result in any noticeable redness, swelling, itching, discoloration, or any other adverse symptom at the injection site or any adverse tissue reaction during the duration of the study. In addition, the evaluation of the pharmacokinetics of bupivacaine showed a prolonged release of active bupivacaine from the carrier 5AIIV carriers with the release of active bupivacaine over a period of 4 days. Pharmacokinetic results are shown in Figures 4 and 5. As can be seen, the 5AIV/BA/bupivacaine formulation rapidly released active bupivacaine (within approximately 1 hour of administration) without an initial release and showed essentially constant steady-state release during at least the first From the days of treatment.

Pharmacodynamics for all three cohort 2 subgroups are shown in Table 17 below.

Table 17

Pharmacodynamics for cohort 2. The number Stakh Ttakh St

ZAIV/VA/bupivacaine and saline total dose 688 mg

As can be seen from the results of the Cohort 2 study, these controlled-release formulations provide an effective local anesthetic effect for a period of at least 4 days after surgery, significantly reducing the need for additional analgesic drugs. In fact, 5,095 patients receiving the ZAIV/VA/bupivacaine compositions of the present invention (5 of 10 patients in subgroups 1 and 2) did not require additional analgesic medication during the entire 4-day period. Those patients in subgroups 1 and 2 who required additional analgesic drugs were still able to wait for the first additional analgesic drugs for approximately 2 to 3 days, indicating an effective local anesthetic effect for a period of at least 2 days after surgery. In addition, the number of doses of additional analgesic drugs in subgroups 1 and 2 was significantly reduced compared to control patients (subgroup 3), who required an average of 11 doses during the 4-day test period compared with 2.4-2.6 doses during the same period

Moreover, a review of the pharmacokinetic data for cohort 2 suggests that an effective subcutaneous dose of 638-688 mg of bupivacaine can be reproducibly administered using the controlled release compositions of the present invention to provide an effective steady-state bupivacaine plasma concentration of approximately 100 ng/ml.

The results of the test of pain indicators in the incision area "at rest" for all three subgroups of cohort 2 are presented in Fig. b. The data of subgroup C are shown on the upper curve (A), the data of subgroup 2 are shown on the middle curve (o), and the data of subgroup 1 are shown on the lower curve (92). For convenience, the mean time to the first additional analgesic is shown on each curve. Pain intensity in the incision site was recorded using a 0-100mm visual analog scale (MA5) with indicators ranging from 0 (no pain) to 100 (worst imaginable pain). Each MA5 indicator was recorded as a separate vertical line on the scale.

The tests were carried out as follows. On the day of surgery (day 0), pain scores in the incision site were first recorded 60 minutes after the administration of the tested composition (as discussed above, subgroup 1 was administered 5AIV/BA/bupivacaine and saline; subgroup 2 was administered 5AIV/BA/bupivacaine and MagsaipF); and subgroup C was administered MagsaipF and MagsaipF). Thereafter, pain scores at the incision site were recorded every 30 minutes until the 4 hour evaluation time point, and then every time until the 8 hour evaluation time point, and finally at the 12 hour evaluation time point. On subsequent days 1 through 3, pain scores at the incision site were recorded in the morning, based on the time when the test composition was administered on day 0. These follow-up measurements were made at 4-hour intervals during the 12-hour evaluation period (4 measurements). The timing of any concomitant (adjunctive) medications was also noted during this 4-day assessment.

As can be seen from the review of the results of the test of pain indicators in the section of the incision shown in Fig

Fig.b, for both subgroups that were injected with the test compositions of ZAIV/BA/bupivacaine (subgroups 1 and 2) showed lower mean values of MA5 at any time during the test compared to the group that was injected with the test composition MagsaipF (subgroup 3). These results show that the compositions of the present invention provide long-lasting local anesthesia in the area of the cut wound for at least about 36-48 hours after administration to the subject.

Cohort C patients will be divided into 2 treatment subgroups. The first subgroup will be injected with the composition

ZAIV/VA/bupivacaine (containing 958 mg of bupivacaine) in a total volume of 7.5 ml, administered as two staggered subcutaneous injections along each side of the surgical wound (0.75 ml/cm along the intended B5 cm of the total length of the cut wound) along with 1 Oml of MagsaipF (0.595 bupivacaine-NSI) infiltrated into the incised wound (including subfascial) prior to wound closure for a total of 1.008 mg of bupivacaine administered to each patient.

The other subgroup will receive injections of the composition MagsaipF (0.595 Bupivacaine-HCI) in a total volume of 7.5 ml, administered as two offset subcutaneous injections along each side of the surgical wound (0.75 ml/cm along the intended 5 total length of the cut wound) together with 1Oml of MagsaipF) infiltrated into the cut wound (including subfascial) prior to wound closure to yield a total of 87.5mg of bupivacaine administered to each patient.

Anesthetic/analgesic effect was evaluated using tests of time to the first additional analgesic drug and total use of additional analgesic drug (within 4 days). The concentration of bupivacaine in the plasma was measured periodically during the course of the study, in particular during the first 24 hours to assess the amplitude of the early release of bupivacaine from the composition

ZAIV with controlled release. It is expected that a higher dose of the ZAIV/VA/bupivacaine controlled-release composition obtained according to the present invention will provide the same or even higher efficacy results compared to the results of cohort 2 of the test subjects.

It is understood that this invention, thus described, variants and modifications thereof, as will be apparent to those skilled in the art, will be included within the scope of the appended claims.

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