Sustained local anesthetic composition containing saib

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DESCRIPTION

Prolonged local anesthetic composition containing SAIB

5 TECHNICAL FIELD

The present invention relates generally to the field of controlled delivery systems, and more particularly controlled delivery systems containing an active agent that is capable of providing a localized anesthetic effect, in which the systems are suitable for use in relation to with surgical treatments and

10 doctors, and as medications for use in postoperative recovery procedures.

BACKGROUND OF THE INVENTION

Biodegradable controlled delivery systems of active agents are well known in the art. The

fifteen Biodegradable vehicles for drug delivery are useful because they eliminate the need to remove the device with the drug used up.

The most common vehicle materials used for controlled delivery systems are polymers. The field of biodegradable polymers has developed rapidly since the synthesis and biodegradability of lactic polyacid was referred by Kulkarni et al. (1966) Arch. Surg. 93: 839. Examples of other polymers that have been reported as useful as matrix material for controlled delivery systems include polyanhydrides, polyesters such as polyglycolide and polylactide-co-glycolide, polyamino acids such as polylysine, polymers and copolymers of ethylene polyoxide, polyoxide of ethylene with acrylic termination, polyamides, polyurethanes, polyorthoesters, polyacrylonitriles and polyphosphazenes. See, for example, US Pat. No. 4

25 891 225 and 4 906 474 (polyanhydrides); 4,767,628 (polylactide, lactic-co-glycolic polyacid); 4,530,840 (polylactide, polyglycolide and copolymers); and 5,234,520 (biodegradable polymers for controlled delivery in the treatment of periodontal disease).

Degradable materials of biological origin are well known and include, for example, cross-linked gelatin. He

30 Hyaluronic acid has been crosslinked and used as a degradable polymer with swelling capacity for biomedical applications (see, for example, US Patent 4,957,744 and Della Valle et al. (1991) Polym. Mater. Sci. Eng ., 62: 731-735).

Biodegradable hydrogels have also been developed for use in controlled delivery systems and serve

35 as vehicles of biologically active materials such as hormones, enzymes, antibiotics, antineoplastic agents and cell suspensions. See, for example, US Pat. No. 5 149 543.

Hydrogel compositions are also commonly used as substrates for cell and tissue cultures, impression materials for prostheses, wound dressing materials, or as solid phase materials in

40 size exclusion applications or affinity chromatography. For example, non-porous derived and / or deformed agarose hydrogel compositions have been used in high performance liquid chromatography and affinity chromatography procedures (Li et al. (1990) Preparative Biochem. 20: 107-121), and they have used superporous agarose hydrogel beads as support in hydrophobic interaction chromatography (Gustavsson et al. (1999) J. Chromatography 830: 275-284).

Four. Five Many dispersion systems are also currently in use as vehicles of substances, in particular biologically active compounds. The dispersion systems used for pharmaceutical and cosmetic formulations can be classified as suspensions or emulsions. The suspensions are formed by solid particles whose size is between a few nanometers and hundreds of micrometers, dispersed in a

fifty liquid medium using suspending agents. Solid particles include microspheres, microcapsules and nanospheres. Emulsions are generally dispersions of one liquid in another stabilized by an interfacial film of emulsifiers such as surfactants and lipids. Emulsion formulations include water-in-oil and oil-in-water emulsions, multiple emulsions, microemulsions, microgoticles and liposomes. Microgoticles are unilaminar phospholipid vesicles that consist of a spherical layer of lipids

55 with an oil phase inside, such as those described in US Pat. No. 4 622 219 and 4 725

442 Liposomes are phospholipid vesicles prepared by mixing water-insoluble polar lipids with an aqueous solution. The unfavorable entropy caused by the mixing of the water-insoluble lipid produces a highly ordered structure of concentric closed phospholipid membranes with trapped aqueous solution.

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A series of systems for forming an implant in situ has been described. For example, US Pat. No. 4,938,763 describes a process for forming an implant by dissolving a water-insoluble non-reactive thermoplastic polymer in a water-soluble biocompatible solvent to form a liquid, placing the liquid inside the

5 organism, and allowing the solvent to dissipate to produce a solid implant. The polymer solution can be placed in the body by means of a syringe. The implant can take the form of the surrounding cavity. Alternatively, an implant can be formed from reactive liquid oligomeric polymers that do not contain solvent and that are cured in place to form solids, usually with the addition of a curing catalyst.

10 A series of controlled delivery polymeric systems for the supply of local anesthetics has been described in the art. Although such polymeric delivery systems may provide adequate controlled release properties for the anesthetic and further overcome the disadvantages associated with the injection of anesthetics (eg, dispersion away from the target point, entry into the bloodstream and toxicities

fifteen systemic), it is difficult to overcome certain disadvantages associated with polymeric systems, such as the inability to avoid the initial systemic rapid release of the anesthetic or the need to provide potentiating agents in order to overcome a too low release of the anesthetic from the systems.

US-2004/101 557 refers to non-polymeric compositions that form high viscosity liquid materials for the supply of biologically active substances in a controlled manner.

SUMMARY OF THE INVENTION

Non-polymeric controlled delivery systems are provided for the administration of an anesthetic agent of

25 interest. Thus, an object of the present invention is to provide a long-acting controlled delivery system that releases an anesthetic for a prolonged period of time, sufficient to provide a local anesthetic effect at an administration site for at least approximately 24 hours after administration. , preferably at least about 36 to 48 hours after administration, and more preferably at least about 48 to 72 hours after administration. It is also an object of the present

30 invention that the release of the active anesthetic agent from the long-acting anesthetic composition takes place without an initial rapid release.

A more particular object of the present invention is to provide a composition containing a pharmaceutically acceptable anesthetic and non-polymeric carrier. The non-polymeric vehicle controls the release of the

35 anesthetic to provide an anesthetic effect characterized by prolonged local anesthesia after administration to a subject without an initial rapid release and lasting at least about 24 hours after administration, preferably at least about 36 to 48 hours after administration, and more preferably at least about 48 to 72 hours after administration.

40 In one aspect of the invention, the non-polymeric vehicle is sufficient to provide a first order controlled release profile of the anesthetic or a pseudo-order release profile of the anesthetic. In a preferred embodiment, the anesthetic is bupivacaine in the form of free base. In other embodiments, the composition is capable of providing a prolonged steady-state (Css) average plasma concentration of the anesthetic of at least about 200 ng / ml for a period of at least about 24 hours when the

Four. Five The composition is administered subcutaneously, preferably at least about 250 µg / ml, or at least about 300 ng / ml, or at least about 350 ng / ml.

The non-polymeric vehicle is a liquid, more specifically a high viscosity liquid carrier material ("MVLAV") that has a viscosity of at least about 5,000 cP at 37 ° C and that does not crystallize cleanly under ambient or physiological conditions . Said liquid carrier materials may be combined with a solvent in which the carrier material is soluble. The solvent is sufficient to reduce the viscosity of the MVLAV. The solvent is a second anesthetic agent, specifically benzyl alcohol. The compositions are provided in liquid form. In some embodiments, the composition further includes a material that is immiscible with the non-polymeric vehicle, for example in which the composition is an emulsion. In these compositions, the vehicle

55 It may be present in the dispersed phase or in the continuous phase of the emulsion.

The present invention thus provides a composition containing a pharmaceutically acceptable non-polymeric anesthetic and vehicle. The non-polymeric vehicle controls the release of the anesthetic to provide an anesthetic effect characterized by prolonged local anesthesia after administration to a subject, in which

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The composition is also capable of providing a prolonged steady state plasma concentration (Css) of the anesthetic 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 250 ng / ml, or at least about 300 ng / ml, or at least about 350 ng / ml.

5 In one aspect of the invention, the composition is capable of providing a prolonged steady state plasma concentration (Css) for a period of at least about 48 hours. In another aspect, the composition is further characterized by having no substantial initial rapid release. In other additional aspects, the non-polymeric vehicle is sufficient to provide a controlled first release profile.

10 order of the anesthetic or a release profile of the pseudo-order of the anesthetic. In a preferred embodiment, the anesthetic is bupivacaine in the form of free base.

A procedure is thus provided to provide an anesthetic effect at a site in a subject. The method comprises the administration of a composition according to the invention in, near, within

fifteen or adjacent to the site. The non-polymeric vehicle controls the release of the anesthetic to provide an anesthetic effect characterized by prolonged local anesthesia after administration to the subject without an initial rapid release and which lasts for at least approximately 24 hours after administration.

In one aspect, the composition is administered by topical administration, transdermal administration, injection or

twenty as an implant on site. In some embodiments, the composition is administered at a site that is a surgical wound, and the composition is administered in and / or adjacent to the wound.

Specifically, the present invention provides a liquid composition to provide prolonged local anesthesia after administration to a subject, the bupivacaine composition comprising an anesthetic,

25 Sucrose acetate isobutyrate as a pharmaceutically acceptable non-polymeric vehicle and benzyl alcohol as a solvent for said vehicle, wherein bupivacaine is present in an amount of 20 to 10% by weight with respect to the total weight of the composition.

In addition, the present invention provides the use of bupivacaine as an anesthetic, sucrose acetate isobutyrate.

30 as a pharmaceutically acceptable non-polymeric vehicle and benzyl alcohol as a solvent for said vehicle for the preparation of a liquid composition to provide prolonged local anesthesia after administration to a subject, in which bupivacaine is present in an amount of 20 to 10% in weight with respect to the total weight of the composition.

35 BRIEF DESCRIPTION OF THE FIGURES

Figure 1 illustrates the average plasma bupivacaine levels for 0-144 hours (the pharmacodynamic results) according to the Example, Cohort 1.

40 Figure 2 illustrates the mean plasma bupivacaine levels for 0-12 hours (pharmacodynamic results) according to Example, Cohort 1.

Figure 3 illustrates the mean plasma bupivacaine levels for 0-300 hours (the pharmacodynamic results) according to Example, Cohort 2, in which the subgroup 3 data are represented by the

Four. Five lower curve (◊), the subgroup 2 data is represented by the central curve () and the subgroup 1 data is represented by the upper curve ().

Figure 4 illustrates the mean plasma bupivacaine levels for 0-12 hours (the pharmacodynamic results) according to Example, Cohort 2, in which the subgroup 3 data are represented by the

fifty lower curve (◊), the subgroup 2 data is represented by the central curve () and the subgroup 1 data is represented by the upper curve ().

Figure 5 illustrates the average pain scores at the “resting” incision site recorded by using a visual analog scale (VAS) from 0 to 100 mm according to the Example, Cohort 2, in which the subgroup 3 data

55 they are represented by the upper curve (), the subgroup 2 data is represented by the central curve () and the subgroup 1 data is represented by the lower curve (◊).

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

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Before describing the present invention in detail, it will be understood that the present invention is not limited to the process parameters illustrated in particular which, of course, may vary. It should also be understood that the terminology used herein is only intended to describe particular embodiments of the invention, and is not intended to be limiting.

5 All publications, patents and patent applications cited herein, either previously or below in the text, are incorporated herein in their entirety by reference.

It should be noted that, as used herein and the appended claims, the forms

10 singular "un", "una" and "el / la" include plural referents unless the content specifies otherwise, so, for example, the reference to "a non-polymeric vehicle" includes a mixture of two or more than said vehicles, the reference to "a solvent" includes a mixture of two or more of said vehicles, the reference to "an anesthetic" includes mixtures of two or more of said agents, and the like.

fifteen The phrase "without an initial rapid release", as used herein, means that the particular agent referred to is not released from the composition after normal administration and remains pharmacologically available in an appreciable amount during a predetermined initial period. The presence and level of an initial rapid release of an agent from a given composition can easily be determined by the person skilled in the art by employing pharmacological assay techniques.

twenty standard well known in the art. Suitable in vitro rapid release characterization procedures include the USP II Paddle Method, which uses standard buffer, mixing and heat conditions. The rapid release characteristics of a given composition can also be readily determined using standard in vivo tests, such as monitoring of plasma concentrations of the agent of interest in an animal subject, for a given period of time. In the compositions of the present invention, it is released

25 preferably less than about 40 to 60% of the anesthetic agent within the first 24 hours, more preferably less than about 30 to 50%, and more preferably still less than about 20 to 40% is released within this period of time. initial. In some other preferred embodiments, less than about 5 to 10% of the anesthetic agent is released within the first hour, more preferably less than about 3 to 7% is released within this initial period of time.

30 Accordingly, the compositions of the present invention contain bupivacaine in a controlled release system that releases bupivacaine for a prolonged period of time. Bupivacaine is present in the compositions in an amount of 20 to 10% by weight, depending on the intended use thereof.

35 The anesthetic agent is provided in the composition in a neutral form, as a free base form, or in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt", as used herein, applies to those salts that retain the biological efficacy and properties of neutral anesthetics and are otherwise unacceptable for pharmaceutical use. Pharmaceutically acceptable salts include salts of acidic or basic groups, groups that may be present in the agents

40 anesthetics Those anesthetic agents that are of a basic nature are capable of forming a wide variety of salts with various inorganic and organic acids. Pharmaceutically acceptable acid addition salts of basic anesthetics suitable for use herein are those that form non-toxic acid addition salts, that is, salts comprising pharmacologically acceptable anions, such as hydrochloride, hydrobromide, iodhydrate salts, nitrate, sulfate, bisulfate, phosphate, acid phosphate,

Four. Five isonicotinate, acetate, lactate, salicylate, citrate; tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, sucrate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e. 1,1'-methylene- bis- (2-hydroxy-3-naphthoate)). Anesthetic agents that include an amino fraction can form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Suitable basic salts can

fifty formed from bases that form non-toxic salts, for example, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts. See, for example, Berge et al. (1977) J. Pharm. Sci. 66: 1-19.

The ability of an anesthetic agent to provide a condition of prolonged local anesthesia refers to the ability of the subject's agent to establish a assessable state of total or partial localized (regional) inhibition of sensory perception and / or motor function. The expert in the field will come up with numerous procedures and tools to easily perform said assessment. With respect to non-human animal subjects, these procedures include the measurement of spontaneous locomotion in laboratory rats (using, for example, equipment and software commercially available from Med Associates Inc., St. Albans, VT), in which they can be collected data on total distance traveled, outpatient counts, stereotyping, aging, time invested in the various

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movements and time spent at rest for test subjects; visualization of reaction to the puncture test in rats; and the model of removal of the rat's leg from a hot plate, for example, in accordance with the procedure described in detail in IACUC No. 9511-2199.

5 Sensory tests in human subjects also represent a useful way of assessing the local anesthetic effect. The tests are often concentrated in three general areas, mechanical tests (puncture test, von Frey filaments), thermal tests (warm, hot, cold) and tactile (touch). These test techniques are described in the specialized literature. See, for example, Dahl, et al. (1993) Pain 53: 43-51; Moiniche, et al. (1993) Brit. J. of Anaesthesia 71: 201-205; Moiniche, et al. (1993) Regional Anesthesia 18: 300-303; Pedersen, et al. (nineteen ninety six)

10 Anesthesiology 84 (5): 1020-1026; Pedersen, et al. (1996) Brit J. of Anaesthesia 76 (6): 806-8810; and Pedersen, et al. (1998) Pain 74: 139-151. For example, the local anesthetic activity of a test agent can be examined with reference to the onset, maximum density and duration of effect through the use of specific modalities: 1) mechanical sensory tests (mechanical pain detection threshold using filaments of von Frey; 2) supraumbral (mechanical) tests using a single von Frey filament; 3) thermal sensory tests (threshold of

fifteen heat detection); 4) heat pain detection threshold; 5) supraumbral (heat) tests; 6) cold detection threshold; and 7) tactile sensory tests (mechanical touch detection threshold). These data are indicative of local pain relief experienced by the subject, local numbness and a local nerve block in response to the administration of a test anesthetic agent. The response to pain can be characterized using a Verbal Classification Scale from 0 to 10 (for example, in which 0 = absence of pain and 10 = the worst

twenty imaginable pain) or a Visual Analog Scale of 0 to 100 mm (for example, in which 0 = absence of pain and 100 mm = the worst pain imaginable).

Benzyl alcohol is an example of an anesthetic that can be used to provide an initial anesthetic effect. Bupivacaine is an example of an anesthetic that can be used to provide local anesthesia.

25 prolonged

The benzyl alcohol used as a solvent is an additional anesthetic.

The non-polymeric carrier material, SAIB, is used to control the release of the anesthetic agent with respect to

30 the compositions of the present invention, so that a prolonged local anesthesia is provided that has an onset within about 2 hours of administration and a duration of at least about 24 hours or more. In some compositions of the present invention, the non-polymeric carrier material is sufficient to provide a first order controlled release profile of the at least one anesthetic, or a pseudo-order release profile. Consequently, the non-polymeric vehicle will be present in the composition in

35 an amount of about 99.5 to about 1% by weight with respect to the total weight of the composition (% by weight), or in an amount of about 95 to 10% by weight, or in an amount of about 75 to 25% by weight.

The compositions of the present invention may further include one or more additional components, by

40 example pharmaceutically acceptable excipient materials that can act as dispersing agents, fillers, binders, vehicles, stabilizers, glidants, antioxidants, pH regulating agents, anti-irritants, and the like. The person skilled in the art will appreciate that some excipient materials can serve several of the functions referred to above in any particular formulation. Thus, any number of suitable excipient materials can be mixed or incorporated into the compositions herein.

Four. Five invention to provide loading properties, alter the release rates of the active agent, increase or prevent water collection, control the pH, provide structural support, facilitate manufacturing processes and other uses known to those skilled in the art. The term "excipient" generally refers to a substantially inert material that is not toxic and does not interact with other components of the composition in a harmful manner. The proportions in which a particular excipient may be present in the composition

fifty they depend on the purpose for which the excipient is provided and the identity of the excipient.

For example, suitable excipients that can also act as stabilizers for active agents include pharmaceutical grades of dextrose, sucrose, lactose, trehalose, mannitol, sorbitol, inositol, dextran and the like. Such stabilizers can thus be a saccharide such as a monosaccharide, a disaccharide, a

55 polysaccharide or an alcoholic sugar. Other suitable 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 for hydration and slow dissolution kinetics include fatty acids and pharmaceutically acceptable salts thereof (eg, magnesium stearate, stearic acid, zinc stearate, palmitic acid and sodium palmitate) .

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It may also be useful to employ a detergent and / or lipid excipient loaded in the compositions of the present invention. Suitable charged lipids include, without limitation, phosphatidylcholines (lecithin), and the like. The detergents will normally be a nonionic, anionic, cationic or amphoteric surfactant. Among the examples of

5 suitable surfactants include, for example, Tergitol® and Triton® surfactants (Union Carbide Chemicals and Plastics); polyoxyethylene sorbitan, for example, TWEEN® surfactants (Atlas Chemical Industries); polysorbates; polyoxyethylene ethers such as, for example, Brij; esters of pharmaceutically acceptable acid grades, for example, lauryl sulfate and salts thereof; amphiphilic surfactants (glycerides, etc.); and similar materials.

10 Other excipient materials may be added to alter the porosity, for example, materials such as sucrose, dextrose, sodium chloride, sorbitol, lactose, polyethylene glycol, mannitol, fructose, polyvinylpyrrolidone or appropriate combinations thereof. In addition, the anesthetic agent or agents can be dispersed with oils (for example, sesame oil, corn oil, vegetable) or a mixture thereof with a phospholipid (for example, lecithin), or medium chain fatty acid triglycerides ( for example, Miglyol 812) to provide an oily suspension.

fifteen Additional excipient materials that may be incorporated into the compositions of the present invention include diluents of various buffer content (eg, Tris-HCl, acetate); pH and ionic strength modifying agents; additives such as antioxidants (for example, ascorbic acid, glutathione, sodium metabisulfite); preservatives (for example, Thimersol, benzyl alcohol, methylparaben, propylparaben); and agents

twenty dispersants such as water soluble polysaccharides (for example, mannitol, lactose, glucose, starches), hyaluronic acid, glycine, fibrin, collagen and inorganic salts (for example, sodium chloride).

The organic solvent will be provided in the composition in an amount of about 99.5 to about 1% by weight with respect to the total weight of the composition (% by weight), in an amount of about 25 to 95 to 10% in weight, in an amount of about 75 to 25% by weight, or in an amount of about 60 to 40% by weight. In some embodiments, the organic solvent is diffused or leached from the composition in an aqueous medium after placement within a biological system, whereby the non-polymeric carrier material coagulates to form a solid matrix. Preferably, the non-polymeric vehicle solidifies in situ to form a solid matrix approximately within 1-5 days after the

30 administration (implantation), preferably within a period of approximately 1-3 days, preferably within a period of approximately 2 hours.

A series of suitable additives may be included with the composition in order to impart selected characteristics to the composition. For example, the composition may include a smaller amount of a polymer.

35 biodegradable thermoplastic such as polylactide, polycaprolactone, polyglycolide or a copolymer thereof, in order to provide a more coherent solid implant or a composition with higher viscosity so that it remains in place while solidifying. Such thermoplastic polymers are disclosed in US Pat. No. 4,938,763 to Dunn et al.

40 Optionally, a pore forming agent may be included in the composition. The pore forming agent may be any pharmaceutically acceptable organic or inorganic substance that is substantially soluble in water or body fluids, and will dissipate from the non-polymeric carrier material and / or the solid matrix of an implant in the surrounding body fluids. at the implant site. The pore forming agent may preferably be insoluble in the organic solvent to form a uniform mixture with the carrier material.

Four. Five not polymeric. The pore forming agent can also be a water immiscible substance that rapidly degrades into a water soluble substance. In some compositions, the pore forming agent is combined with the non-polymeric carrier and the organic solvent in a mixture. Suitable pore-forming agents that can be used in the composition include, for example, sugars such as sucrose and dextrose, salts such as sodium chloride and sodium carbonate, polymers such as

fifty hydroxypropyl cellulose, carboxymethyl cellulose, polyethylene glycol and polyvinyl pyrrolidone, and the like. Solid crystals that will provide a defined pore size, such as salt or sugar, are preferred.

The MVLAV SAIB reduces its viscosity, when mixed with a solvent to form a low viscosity liquid carrier material ("MVLBV") that can be administered using standard medical devices. The composition of the MVLBV is normally easier to place in the body than an MVLAV composition, since it flows more easily when entering and leaving the syringes or other means of implantation. It can also be easily formulated as an emulsion. The MVLBV can have any desired viscosity, but its viscosity is generally lower than the corresponding MVLAV. As an example, the viscosity ranges for the MVLBV of less than about 6,000 cP, less than about 4,000 cP, less than

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approximately 1,000 cP or less than 200 cP, are normally useful for in vivo applications.

Sucrose acetate isobutyrates can be prepared following the procedures described in US Pat. No. 2 931 802.

5 The solvent is usually added to the compositions in an amount in the range of about 99.7% to about 0.5% by weight with respect to the total weight of the composition (% by weight), from about 95% to about 1% by weight, about 75 to about 10% by weight, or about 50 to 15% by weight. The solvent is normally present in the

10 composition in an amount in the range of about 55% to 10% by weight.

In other further embodiments of the invention, the composition includes a material that is not miscible with the MVLAV, so that when combined with the MVLAV alone or in combination with a solvent for the MVLAV, the resulting composition forms an emulsion. Such emulsions may contain the MVLAV in the phase.

fifteen dispersed, as in the case of mixtures of SAIB / MIGLYOL® that are emulsified in water or glycerol, or may contain the MVLAV as a component of the continuous phase, as in the case of an aqueous solution that is emulsified in the MVLAV or a MVLAV solution in a solvent immiscible with water.

The anesthetic agent is included in an amount sufficient to deliver the subject to be subjected to

twenty Treatment an effective amount to achieve a desired effect. The amount of anesthetic agent incorporated into the composition depends on the final desired duration and release profile, and on the concentration of anesthetic required for the intended effect.

The concentration of the anesthetic in the composition will also depend on the rates of absorption, inactivation and

25 excretion of that particular agent, as well as other factors known to the person skilled in the art. It should be noted that the dosage values ​​will also vary with the severity of the condition that will be relieved. It should also be understood that for any particular subject, specific dosage regimens must be adjusted over time according to the individual need and professional judgment of the person administering

or supervises the administration of the compositions, and that the concentration ranges set forth herein

30 Descriptive reports are illustrative only and are not intended to limit the scope or practice of the claimed composition. The composition can be administered in a dosage, or it can be divided into a series of smaller doses that will be administered in varying time intervals, either sequentially or concurrently.

As discussed above, a variety of additives may optionally be added to the compositions.

35 of the present invention to modify the properties thereof, and in particular to modify the release properties of the composition with respect to the anesthetic agents contained therein. The additives may be present in any amount sufficient to impart the desired properties to the composition. The amount of additive used will in general be a function of the nature of the additive and the effect that will be achieved, and can easily be determined by the professional. Suitable additives are described in the

40 U.S. Patent No. 5,747,058, the content of which is incorporated in its entirety as a reference herein. More particularly, suitable additives include water, biodegradable polymers, non-biodegradable polymers, natural oils, synthetic oils, carbohydrates or carbohydrate derivatives, inorganic salts, BSA (bovine serum albumin), surfactants, organic compounds, such as sugars, and organic salts, such as sodium citrate. In general, the less soluble in water, that is, the more lipophilic,

Four. Five The additive will further reduce the release rate of the anesthetic agent, compared to the same composition without the additive. In addition, it may be desirable to include additives that increase properties such as strength or porosity of the composition.

The addition of additives can also be used to prolong the delivery time for the anesthetic agent,

fifty making the appropriate composition for medical applications that require or respond to long-term administration. Suitable additives in this regard include those disclosed in US Pat. No. 5,747,058 and 5,736,152. In particular, polymeric additives, such as cellulosic polymers and biodegradable polymers, are included among the additives suitable for this purpose. Suitable cellulosic polymers include cellulose acetates, cellulose ethers and cellulose acetate butyrates. Among the polymers

55 Suitable biodegradable include polylactones, polyanhydrides and polyorthoesters, in particular, lactic polyacid, glycolic polyacid, polycaprolactone and copolymers thereof.

When present, the additive is normally present in the compositions in an amount in the range of about 0.01% to about 20% by weight, more particularly from about 0.1

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% to about 20% by weight, based on the total weight of the composition, and more normally, is present in the composition in an amount in the range from about 1, 2 or 5% to about 10% in weight. Some additives, such as buffers, are present only in small amounts in the composition.

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

A category of additives is that of oligomers and biodegradable polymers. The polymers can be used to

10 alter the release profile of the anesthetic agent to be supplied, to add integrity to the composition, or to otherwise modify the properties of the composition. Non-limiting examples of suitable biodegradable oligomers and polymers include: poly (lactide), poly (lactide-co-glycolide), poly (glycolide), poly (caprolactone), polyamides, polyanhydrides, polyamino acids, polyorthoesters, polycyanoacrylates, poly ( phosphakines), poly (phosphoesters), polyesteramides, polydioxanones, polyacetals, polykettals, polycarbonates, polycarbonates

fifteen degradable polyurethanes, polyhydroxybutyrates, polyhydroxivalerates, alkylene polyoxalates, alkylene polysuccinates, poly (malic acid), chitin, chitosan and copolymers, tert-polymers, oxidized cellulose or combinations or mixtures of the above materials.

Examples of poly (-hydroxy acids) include poly (glycolic acid), poly (DL-lactic acid) and poly (L-acid

twenty lactic acid), and its copolymers. Examples of polylactones include poly (-caprolactone), poly (-valerolactone) and poly (-butyrolactone).

While it is not desired to be limited by any theory, it is believed that when the composition contains a biodegradable polymer, a part of the polymer may precipitate or coagulate on the surface of the composition when any included solvent diffuses from the material after administration. to the subject The polymer can thus be added as a release modifying agent to influence the release of the anesthetic agent or agents, or it can be added as part of a composition containing preformed ground microspheres, implants or polymer particles. Precipitation or coagulation of the polymer forms a coating that at least partially surrounds the liquid core of said composition. This coating is porous, and allows the

30 solvent continues to diffuse through it into the surrounding tissue. The rate of solvent release and the magnitude of the coating 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 with the present compositions are non-biodegradable polymers. Among the examples no

35 Limitations of non-degradable polymers that can be used as additives include: polyacrylates, ethylene vinyl acetate polymers, cellulose and cellulose derivatives, cellulose acetates substituted with acyl and derivatives thereof, non-degradable polyurethanes, polystyrenes, vinyl polychloride, polyfluoride of vinyl, polyvinyl (imidazole), chlorosulfonated polyolefins, ethylene polyoxide and polyethylene.

40 Preferred non-biodegradable polymers include polyvinylpyrrolidone, ethylene vinyl acetate, polyethylene glycol, cellulose acetate butyrate ("CAB") and cellulose acetate propionate ("CAP").

An additional class of additives that can be used in the present compositions are natural and synthetic oils. Oils from animals or vegetable seeds normally include glycerides from

Four. Five fatty acids, mainly oleic, palmitic, stearic and linoleic acids. As a rule, the more hydrogen the denser molecule contains, the oil becomes.

Non-limiting examples of suitable natural and synthetic oils include vegetable oil, peanut oil, medium chain triglycerides, soybean oil, almond oil, olive oil, sesame oil,

fifty Fennel oil, camellia oil, corn oil, castor oil, cottonseed oil and soybean oil, either raw or refined, and medium chain fatty acid triglycerides.

Fats are typically glyceryl esters of higher fatty acids such as stearic and palmitic. Said esters and mixtures thereof are solid at room temperatures and show crystalline structure. The butter of

55 Pork and tallow are examples. In general, oils and greases increase the hydrophobia of a non-polymeric vehicle system, slowing down degradation and water collection.

The compositions of the present invention described above are used to provide prolonged local anesthesia at an object site. In particular, the compositions are formulated as a liquid and then

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administer to a subject topically, transdermally, parenterally (eg, injection, implant, etc.) or similar delivery techniques. The compositions, which contain the pharmaceutically acceptable anesthetic and non-polymeric carrier, are used to provide an anesthetic effect characterized by prolonged local anesthesia after administration to the subject without an initial rapid release and a duration of at least about 24 hours.

5 after administration, preferably at least about 36 to 48 hours after administration, and more preferably at least about 48 to 72 hours after administration. In some embodiments, the onset of local anesthesia takes place approximately in the first 2 hours of administration to the subject, preferably approximately in the 1 hour of administration, and in some cases approximately in the 30 minutes from administration to the subject.

10 The term "subject", as used herein, refers to any vertebrate in which it is desired to provide a state of local anesthesia. The term thus refers broadly to any animal that will be treated with the compositions of the present invention, such as birds, fish and mammals including the human being In some embodiments, the compositions of the present invention are suitable

fifteen to provide prolonged anesthesia in veterinary practice and animal exploitation, for example, birds and mammals, as long as a state of long-term local anesthesia is convenient or desirable. In some cases, the compositions are especially suitable for use with pets such as dogs or cats, and can also be used with horses. In preferred embodiments, the term "subject" refers to a human subject. In addition, the term "subject" denotes no particular age, and the compositions are thus

twenty suitable for use with subjects of any age, such as lactating subjects, adolescents, adults and the elderly.

In preferred embodiments, the compositions of the present invention are particularly suitable for use in the treatment of wounds. Non-polymeric vehicle systems allow the anesthetic agent to be easily applied to the wound, either directly inside the wound and / or adjacent to the wound, using very simple application techniques such as dripping, spraying, painting, extension, molding or others to manually manipulate a liquid composition in the wound. The compositions can thus be used with any sized and modeled wound, and will provide a uniform distribution of the anesthetic agent over the entire area of ​​the wound for better retention and efficacy. Wounds that can be treated using such procedures in a range from the most superficial to the deep, from the superficial to the incised and from the surgical (or deliberate for other reasons) to the accidental ones. If the composition is to be injected, it can be applied to the subcutaneous space using a drag injection along the wound on all external sides or boundaries. Combination approaches can also be employed, such as those in which the composition extends directly over the wound, for example, before the surgical closure of the wound, and also along the wound In a particularly preferred embodiment, the compositions of The present invention are for use as a local anesthetic for the treatment of postoperative incision pain. The use of the compositions of the present invention in this manner can eliminate or at least mitigate the need to provide auxiliary therapies, such as the administration of systemic narcotic analgesics in order to treat said postoperative pain. Accordingly, the compositions can be used to treat postoperative pain that accompanies all types of medical intervention, such as major surgery interventions (eg, thoracotomy, aortic repair,

40 bowel resection), immediate surgical interventions (for example, cesarean section, section, hysterectomy and appendectomy), and minor surgeries (laparoscopy, arthroscopy and biopsy procedures), which may be debilitating and may require pain treatment for 3 to 5 days after of surgery

The compositions described herein can thus be administered in the practice of

Four. Five Procedures of the present invention using a wide variety of procedures. For example, the compositions may be administered topically, systemically (eg, mucosa (oral, rectal, vaginal or nasal), parenteral (intravenous, subcutaneous, intramuscular or intraperitoneal), or the like. The compositions may be applied by injection, pouring, spray, spray or coating applicator. Aerosols or mists of the composition can be administered using an aerosol propellant, for example, to

fifty topical administration, or using a suitable nebulizer, for example, for nasal or oral mucosal administration.

Preferably, the compositions are administered as liquids by injection, or in an aerosol, paste or emulsion. When used in an aerosol, any solvent present in the aerosol solution will usually evaporate after application, allowing the composition to settle as a film. Alternatively, the

55 aerosol or emulsion can be prepared without solvent. In this situation, the aerosol propellant can also act as a solvent. The formation of aerosols and emulsions can be achieved using techniques known to those skilled in the art. See, for example, Ansel, HC et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, sixth edition (1995).

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In addition to the uses described above, the compositions of the present invention can be administered through osmotic pumps. In one embodiment, a device is designed for implantation in the subject's tissue, and designed to produce prolonged release over time.

5 It is also possible to administer the compositions of the invention using a porous or non-porous tube, desirably made of extruded biodegradable polymer. The tube can be prepared with varying degrees of porosity depending on the characteristics of the composition and the desired release characteristics. The composition of the invention is introduced into the tube, and the ends of the tube can be left open, which allows the biologically active compound to diffuse from the ends of the tube, or it can be closed with porous polymer or

10 No additional porous. Porous plugs and porous tubes allow the active compound to diffuse through the pores over time. Non-porous plugs, as well as non-porous tubes, allow anesthetic agents that are soluble in the polymer to diffuse through it and into surrounding tissues. Non-porous materials that are not solvents for the anesthetic, but that are biodegradable, will release the anesthetic when they degrade sufficiently. The compositions of the invention can be prepared and stored as systems

fifteen multicomponent until ready for administration. The number of different components will depend, in part, on the characteristics of the composition. Before administration, the components are combined and mixed, for example, to achieve 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 form a separate component, which is also mixed with the others before administration. The separation of the

twenty Composition in a multi-component mixture allows you to optimize the storage conditions for each component, and minimizes any harmful interaction between components over time. The result is an improvement in storage stability.

EXAMPLE

25 An example of a specific embodiment for carrying out the present invention is given below.

General procedures

30 The in vivo efficacy of the compositions of the invention can be assessed in the rat using a hot plate model, for example, according to the procedure described in detail in IACUC No. 9511-2199. The efficacy criteria established for compositions of the invention are average latency greater than about 2 seconds, with a cut of 12 seconds (this cut is imposed to avoid any possible damage to the animal). The latencies at 2 seconds are demonstrative of a statistically significant effect of the local anesthetic.

35 Preferably, the average latency according to the hot plate model in rats is greater than 7 seconds. Preferably, the percentage of respondents is 50% or greater. Preferably, the compositions of the invention provide a medium latency according to the hot plate model in rats greater than between about 7 seconds and about 12 seconds, in which the percentage of rats showing the effect is at least about 50% of those tested.

40 The hot plate methodology in rats is summarized as follows. Male Sprague Dawley rats (Harlan Laboratories, Indianapolis, Ind.) With an average weight of 275 gm are used. The hot plate study is to gently hold the animal's body while placing the plantar surface of the hind leg on a hot plate heated to 56 ° C. Reference latency is determined before unilateral injection of the composition of

Four. Five anesthetic around the sciatic nerve of the rat.

Sensory tests in human models are also useful in testing the compositions of the present invention. The activity of the local anesthetic can be examined with reference to the beginning, the maximum density and the duration of the effect using seven specific modalities: (a) mechanical sensory test (threshold of detection of mechanical pain using von Frey filaments; (b) test ( mechanical) supraumbral using a single von Frey filament; (c) thermal sensory tests (heat detection threshold); (d) heat pain detection threshold; (e) supraumbral (thermal) test; (f) cold detection threshold; and (g) touch detection tests (mechanical touch detection threshold). The varying degrees or levels of the results will be indicative of the local pain relief experienced by the subject, local numbness and / or local nerve block. The anesthetic activity of

55 Compositions of the invention can be further characterized with respect to safety by various activity measures such as systemic blood plasma levels achieved after administration at the localized site.

The mechanical pain detection threshold is defined as the minimum force or number of a von Frey filament

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It produces a definite sensation of pain or discomfort, and the threshold of detection of mechanical touch is defined as the minimum force or number of a von Frey filament that produces a sensation of touch or pressure. The mechanical touch detection threshold and the mechanical pain detection thresholds can be determined simultaneously using progressively rigid von Frey filaments (VFH) (available from Somedic A / B, Stockholm, Sweden).

5 It has previously been determined that each VFH pressed against a balance until it flexes slightly represents a force that logarithmically increases with each filament, to cover a total range of 3 to 402 millinewtons (mN) (VFH No. 7 = 3 mN; VFH No. 8 = 13 mN; VFH No. 9 = 20 mN; VFH No. 10 = 39 mN; VFH No. 11 = 59 mN; VFH No. 12 = 98 mN; VFH No. 13 = 128 mN; VFH No. 14 = 133 mN; VFH No. 15 = 314 mN; VFH No. 16 = 350 mN; VFH No. 17 = 402 mN).

10 Consequently, in a human subject, an area injected with a composition produced in accordance with the present invention can be stimulated 8 times with each VFH at a rate of approximately 2 stimuli per second, starting with VFH # 7 and advancing to VFH n . 17. The lowest VFH number that is detected by touch or pressure (mechanical touch detection threshold) and the lowest number of the filament in which half is recorded

fifteen of the eight stimulations are painful or unpleasant (threshold of detection of mechanical pain). The procedure is repeated two more times and the average of the three measures is communicated. If VFH No. 17 does not produce the sensation of touch or pressure, a mechanical touch detection threshold value of 18 will be assigned. If VFH No. 17 does not produce any pain or discomfort, a pain detection threshold value will be assigned 18 mechanic The mechanical supraumbral pain response for a single von Frey filament is determined by stimulating the injected areas

twenty five times with VFH No. 17 (402 mN). The subject values ​​pain using an ECV scale of 0-10, in which zero (0) = absence of pain, and ten = (10) the most intense pain imaginable.

As discussed above, this test is performed with a single rigid von Frey filament that is determined to produce a painful response in subjects. The response to pain is determined by stimulating an area

25 injected or treated by other means 5 times with VFH No. 17. Subjects rate pain on the Verbal Classification Scale (CVD) from 0 to 10, as before.

Thermal tests (response to supraumbral-heat pain) in a treated area is determined by a 45 ° C stimulus, which lasts 5 seconds using a computerized thermode (available from Thermostest, Somedic A / B, 30 Stockholm, Sweden) in areas treated. Subject assesses pain on a Verbal Classification Scale (CVD) of 0 to

10.

The heat detection threshold is defined as the lowest temperature increase from 32 ° C perceived, the heat pain detection threshold is defined as the lowest temperature perceived as painful, and the cold detection threshold is defined as the smallest decrease in temperature from 32 ° C perceived. The heat detection threshold, the heat pain detection threshold and the cold detection threshold are determined with a computerized Thermostest (available from Somedic AB, Stockholm, Sweden) in treated areas. Subjects are instructed to press a button as soon as the specified sensation is reached. The thermal thresholds are determined from a reference line of 32 ° C and increased (heat detection threshold and threshold of

40 heat pain detection) or reduced (cold detection threshold) at a rate of change of 1 ° C per second. The upper cutoff limit is 52 ° C for the heat detection threshold and the heat pain detection threshold. The lower cutoff limit is 25 ° C for the cold detection threshold.

The heat detection threshold, the heat pain detection threshold and the cold detection threshold are

Four. Five calculated as the average of the three measurements, with intervals of 10 seconds between each stimulus. If the subject has not perceived warmth or pain at 52 ° C, the value 53 ° C is recorded as a heat detection threshold; if the subject has not perceived pain at 52 ° C, the value of 53 ° C is recorded as a threshold for heat pain detection; and if the subject has not perceived coldness or pain at 25 ° C, the value 24 ° C is recorded as a cold detection threshold.

fifty Example

The following evaluation of the dose scale, pharmacokinetics and pharmacodynamics (efficacy) is carried out in human patients who have undergone surgical repair interventions of an inguinal hernia in order to assess the efficacy and pharmaceutical performance of compositions. of controlled release bupivacaine 55 comprising a non-polymeric sucrose acetate isobutyrate vehicle and prepared in accordance with the present invention. The study compares the efficacy of the present SAIB / bupivacaine compositions administered subcutaneously in combination with a saline serum (placebo) or a wound infiltrate of bupivacaine hydrochloride (Marcain®), against a commercially available bupivacaine solution (Marcain ®, BP bupivacaine hydrochloride, 5.28 mg / ml, equivalent to anhydrous bupivacaine hydrochloride 5 mg / ml) administered

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subcutaneously and as an infiltrate in repair patients of open inguinal hernia.

The test composition was / is formulated using bupivacaine free base formulated in a non-polymeric sucrose acetate isobutyrate (SAIB) vehicle which further includes benzyl alcohol (BA) which acts as a solvent for bupivacaine and the SAIB vehicle. Benzyl alcohol is also an anesthetic agent. The composition was prepared / prepared by combining approximately 66% by weight of the SAIB vehicle, 22% by weight of the benzyl alcohol solvent / anesthetic and 12% by weight of bupivacaine, to provide individual dosages containing 159.5 mg. of bupivacaine in an injection volume of 1.25 ml (319 mg in a total volume of 2.5 ml). The composition was provided / provided as a clear liquid.

10 injectable

The study is designed to include 3 Cohorts with 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 6 healthy male subjects, between 23 and 52 years of age. For Cohort 1, all patients received injections of 2.5-15 ml of total volume of the composition of SAIB / BA / bupivacaine (containing 319 mg of bupivacaine), administered as two subcutaneous injections of drag on each side of the wound Surgical (0.5 ml / cm along a wound incision of 5 cm in total length) with 10 ml saline serum infiltrated in the incision wound (including subfascial) before wound closure. Drag injections were administered between 0.5 and 1.0 cm from and in parallel to the margins of the incision wound, and were made by advancing the needle subcutaneously, 20 in parallel and along the length of the the incision, injecting continuously while the needle was removed. The anesthetic / analgesic effect was assessed using time tests until the first supplementary analgesic medication and consumption of total supplementary analgesic medication (within 4 days). Plasma bupivacaine concentration was measured periodically throughout the course of the study, particularly in the first 24 hours to assess the extent of early release of bupivacaine from the composition of

25 controlled release of SAIB.

Table 1 below shows the results of the Time test until the first supplementary analgesic.

30 Table 1. Time until the first supplementary analgesic.

<dl><dt>Patient # </dt><dd>Time until the first analgesic taken </dd></dl>

<dl><dt>1 </dt><dd>8 hours </dd></dl>

<dl><dt>2 </dt><dd>1 hour </dd></dl>

<dl><dt>3 </dt><dd>1 hour </dd></dl>

<dl><dt>4 </dt><dd>1 hour </dd></dl>

<dl><dt>5 </dt><dd>2 hours </dd></dl>

<dl><dt>6 </dt><dd>3 hours </dd></dl>

<dl><dt>(Half) </dt><dd>2.6 hours </dd></dl>

Table 2 below shows the results of the consumption of total supplementary analgesic medication (in the course of 4 days). 35 Table 2. Total supplementary analgesic medication consumption.

<dl><dt>Patient # </dt><dd>Day 1 Day 2 Day 3 Day 4 </dd></dl>

<dl><dt>1 </dt><dd> 2 5 </dd><dt>1 </dt><dd /><dt>1 </dt><dd /></dl>

<dl><dt>2 </dt><dd> 4 4 3 4 </dd></dl>

<dl><dt>3 </dt><dd /><dt>3 </dt><dd> 1 1 1 </dd></dl>

<dl><dt>4 </dt><dd> 10 5 3 1 </dd></dl>

<dl><dt>5 </dt><dd> 2 1 1 1 </dd></dl>

<dl><dt>6 </dt><dd> 4 1 2 3 </dd></dl>

<dl><dt>(Half) </dt><dd> 4,16 2,8 1,8 1,8 </dd></dl>

It was found that the composition of SAIB / BA / bupivacaine was well tolerated, when the injections did not produce

40 no observable results of flushing, swelling, itching, discoloration, or any other adverse symptoms at the injection site, or any unacceptable tissue reaction over the course of the study. In addition, pharmacokinetic evaluations of bupivacaine showed an extended release of active bupivacaine from

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SAIB's vehicle, releasing active bupivacaine for a period of 4 days. The pharmacokinetic results are presented in Figures 1 and 2. As can be seen, the composition of SAIB / BA / bupivacaine released active bupivacaine rapidly (in about 1 hour after administration) without an initial rapid release and showed a substantially constant release. steady state for at least the first 3

5 days of treatment The mean Cmax observed was 277 ng / ml ± 109; the Tmax was 23 hours ± 21; and the Css was 191 ng / ml ± 13.

Cohort 2 consisted of 15 healthy male subjects, between 26 and 54 years of age. Cohort 2 was divided into three subgroups, the first subgroup (n = 5) received injections of 5.0 ml of the total volume of the composition of 10 SAIB / BA / bupivacaine (containing 638 mg of bupivacaine), administered as two injections trailing subcutaneous on each side of the surgical wound (0.5 ml / cm along a suggested incision wound of 5 cm in total length) with 10 ml saline serum infiltrated in the incision wound (including subfascial) before of the wound closure. The second subgroup (n = 5) received injections of 5 ml of total volume of the composition of SAIB / BA / bupivacaine (containing 638 mg of bupivacaine), administered as two subcutaneous injections of 15 drag on each side of the surgical wound (0.5 ml / cm along a suggested incision wound of 5 cm in total length) with 10 ml of Marcain® (Bupivacaine-HCl 0 , 5%) infiltrated the incision wound (including subfascial) before wound closure to produce a total of 688 mg of bupivacaine administered per patient. The third subgroup (n = 5) received injections of 5 ml of total volume of the Marcain® composition (0.5% Bupivacaine-HCl) administered as two subcutaneous entrainment injections on each side of the surgical wound (0.5

twenty ml / cm along a suggested incision wound of 5 cm in total length) together with 10 ml of Marcain® infiltrated the incision wound (including subfascial) before wound closure to produce a total of 75 mg of Bupivacaine administered by patient

The anesthetic / analgesic effect was assessed using Time tests until the first analgesic medication

25 Supplementary, Pain scores at the site of incision "at rest" and consumption of total supplementary analgesic medication (within 4 days). Plasma bupivacaine concentration was measured periodically throughout the course of the study, particularly during the first 24 hours to assess the extent of early release of bupivacaine from the controlled release composition of SAIB.

30 Table 3 below shows the results of the Time test until the first supplementary analgesic and the consumption test of total supplementary analgesic medication (in the course of 4 days) for the three subgroups for Cohort 2.

Table 3. Average time to the first supplementary analgesic and Average consumption of total supplementary analgesic medication 35 (over the course of 4 days).

<dl><dt>Subgroup </dt><dd>Number of patients Treatment Average time to first supplementary analgesic (hours) Average number of doses of supplemental analgesics taken for 4 days </dd></dl>

<dl><dt>1 </dt><dd>n = 5 SAIB / BA / Bupivacaine and Saline Serum (638 mg total dose) 60.4 * 26 </dd></dl>

<dl><dt>2 </dt><dd>n = 5 SAIB / BA / Bupivacaine and Marcain® (688 mg total dose) 44.9 * 2.4 </dd></dl>

<dl><dt>3 </dt><dd>n = 5 Marcain® (75 mg total dose) 2. 3 11.0 </dd></dl>

<dl><dt>(* Three patients from Subgroup 1 and two patients from Subgroup 2 did not take supplementary analgesic doses for the entire 4-day period). </dt><dd /></dl>

Again, the composition of SAIB / BA / bupivacaine was well tolerated (subgroup 1 and 2 patients), in which the

injections did not produce any observable results of flushing, swelling, itching, discoloration, or any other adverse symptoms at the injection site, or any unacceptable tissue reaction throughout the duration

of the study. In addition, pharmacokinetic evaluations of bupivacaine showed an extended release of the

Bupiva active caine from the SAIB vehicle, releasing active bupivacaine for a period of 4 days. The

Pharmacokinetic results are presented in Figures 3 and 4. As can be seen, the composition of

SAIB / BA / bupivacaine released active bupivacaine rapidly (approximately 1 hour after administration) without an initial rapid increase and showed a substantially steady state release

stationary for at least the first 3 days of treatment.

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Table 4 below shows the pharmacodynamics for the three subgroups of Cohort 2. Table 4. Pharmacodynamics for Cohort 2.

<dl><dt>Subgroup </dt><dd>Number of patients Treatment Cmax (ng / ml) Tmax (hours) Css (ng / ml) </dd></dl>

<dl><dt>1 </dt><dd>n = 5 SAIB / BA / Bupivacaine and Saline Serum (638 mg total dose) 470 ± 155 21 ± 25 311 ± 58 </dd></dl>

<dl><dt>2 </dt><dd>n = 5 SAIB / BA / Bupivacaine and Marcain® (688 mg total dose) 310 ± 60 21 ± 25 291 ± 40 </dd></dl>

<dl><dt>3 </dt><dd>n = 5 Marcain® (75 mg total dose) 180 ± 88 0.6 ± 0.2 NA </dd></dl>

As can be seen from the results of the Cohort 2 study, the controlled release compositions of the present invention provide an effective local anesthetic effect in the course of at least 4 days 10 after surgery, which greatly reduces the need for supplementary analgesic medications. In fact, 50% of the patients who received the SAIB / BA / Bupivacaine compositions of the present invention (5 of the 10 patients in subgroups 1 and 2) did not require additional pain medications for the entire 4-day period . Patients in subgroups 1 and 2 who required supplementary analgesic medications remained able to wait for their first additional pain medications.

fifteen for about 2-3 days, showing an effective local anesthetic effect in the course of at least 2 days after surgery. In addition, the dose amount of supplementary analgesic medications in subgroups 1 and 2 was dramatically reduced with respect to control patients (subgroup 3) who required an average of 11 doses during the 4-day trial period compared to 2, 4 to 2.6 doses during the same period.

twenty In addition, a review of the Cohort 2 pharmacokinetic data 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 plasma concentration. of bupivacaine of approximately 300 ng / ml.

25 The results of the scoring test of the "resting" incision site for the three subgroups of Cohort 2 are represented in Figure 5. The data in subgroup 3 are represented by the upper curve (), the data in subgroup 2 they are represented by the central curve () and the data of subgroup 1 are represented by the lower curve (0). For convenience, the average time to the first supplementary analgesic is shown on each curve. The intensity of the incision pain was recorded using a visual analog scale (VAS) from 0 to 100 mm with

30 scores between 0 (absence of pain) and 100 (the worst pain imaginable). Each EAV score was recorded as a single vertical line on the scale. The test was administered as follows. On the day of surgery (Day 0), the incision pain scores were recorded initially at 60 minutes after administration of the test composition (as discussed above, subgroup 1 received SAIB / BA / bupivacaine and serum saline; subgroup 2 received SAIB / BA / bupivacaine and Marcain®; and subgroup 3 received

35 Marcain® and Marcain®). Subsequently, incision pain scores were recorded every 30 minutes during the entire 4-hour evaluation time point, and then every hour during the 8-hour evaluation time point, and finally at the 12-hour evaluation time point. hours. On Days 1 to 3 of follow-up, the incision pain scores were recorded in the morning based on the time the test composition was administered on Day 0. These follow-up measures were taken at 4-hour intervals during a

40 12-hour evaluation period (4 measures). The time of use of any concomitant (supplementary) medication during this 4-day evaluation was also noted.

As can be seen by reviewing the results of the Pain Score test of the incision site depicted in Figure 5, the two subgroups that received the SAIB / BA / bupivacaine test compositions

Four. Five (subgroups 1 and 2) showed lower mean EAV scores at all times during the test than the group that received the Marcain® test composition (subgroup 3). These results demonstrate that the compositions of the present invention provide prolonged local anesthesia at the site of the incision wound lasting at least about 36 to 48 hours after administration to the subject.

fifty Patients for Cohort 3 will be divided into 2 treatment subgroups. The first subgroup will receive injections of 7.5 ml of total volume of the composition of SAIB / BA / bupivacaine (containing 958 mg of bupivacaine),

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administered as two subcutaneous entrainment injections on each side of the surgical wound (0.75 ml / cm along a suggested incision wound of 5 cm in total length) with 10 ml of Marcain® (Bupivacaine-HCl at 0, 5%) infiltrated the incision wound (including subfascial) before wound closure to produce a total of 1.008 mg of bupivacaine administered per patient. The second subgroup will receive injections of 7.5 ml of total volume

5 of the composition of Marcain® (0.5% Bupivacaine-HCl) administered as two subcutaneous injections of drag on each side of the surgical wound (0.75 ml / cm along a suggested 5 cm incision wound total length) together with 10 ml of Marcain® infiltrated in the incision wound (including subfascial) before wound closure to produce a total of 87.5 mg of bupivacaine administered per patient.

10 The anesthetic / analgesic effect will be assessed using the Time tests until the first supplementary analgesic medication and Total supplementary analgesic medication consumption (in the course of 4 days). The concentration of bupivacaine in plasma will be measured periodically throughout the course of the study, particularly during the first 24 hours to assess the magnitude of the early release of bupivacaine from the controlled release composition of SAIB. SAIB / BA / Bupivacaine controlled release compositions are expected

fifteen Higher doses prepared in accordance with the present invention will provide similar or even higher efficacy results than those of Cohort 2 test subjects.

Once the present invention is thus described, it will be understood that variations and modifications thereof as would be apparent to the person skilled in the art will be within the scope of the appended claims.

20