Sustained local anesthetic composition containing SAIB

The present invention relates generally to the field of controlled delivery systems, and more specifically controlled delivery systems containing an active substance that is able to provide local anesthetic effects, which systems are suitable for use in connection with surgical and medical procedures and as postoperative drugs. convalescence procedures.

BACKGROUND ART [0002] Biodegradable controlled delivery systems for active agents are well known in the art. Biodegradable drug delivery vehicles are useful because they avoid the need to dispose of the device with the used drug.

[0003] The most common carrier materials used in controlled delivery systems are polymers. The field of biodegradable polymers has developed rapidly since the description and synthesis and biodegradability of lactic acid by Kulkarni et al. (1966) Arch. Surg. 93: 839. Examples of other polymers that are reported to be useful as matrix material in controlled delivery systems include polyanhydrides, polyesters such as polyglycolide and lactic acid glycol acid copolymers, polyamino acids such as polylysine, polyethylene oxide polymers and copolymers, polyethylene oxide ) terminated with an acrylic group, polyamides, polyurethanes, polyorthoesters, polyacrylonitriles and polyphosphazenes, see, for example, U.S. Patent Nos. 4,891,225 and 4,906,474 (polyanhydrides); 4767628 (polylactide, copolymer of lactic acid with glycolic acid); 4530840 (polylactide, polyglycolide and copolymers); and 5234520 (biodegradable polymers for controlled delivery in the treatment of periodontal disease).

[0004] Biologically degradable materials are well known, including, for example, cross-linked gelatin. Hyaluronic acid was cross-linked and used as a degradable swellable polymer in biomedical applications (see, for example, US Patent No. 4,957744 and Della Valle et al. (1991) Polym. Mater. Sci. Eng., 62: 731-735).

[0005] Biodegradable hydrogels have also been developed for use in controlled delivery systems serving as carriers for biologically active materials such as hormones, enzymes, antibiotics, anti-cancer agents and cell suspensions, see, for example , US Patent No. 5,149543.

[0006] Hydrogel compositions are also commonly used as cell and tissue culture media, prosthetics impression materials, tampon materials or as solid phase materials in exclusion or affinity chromatography applications. For example, non-porous, deformed and / or derivatized agarose-based hydrogel compositions have been used in high performance liquid and affinity chromatography (Li et al. (1990) Preparative Biochem. 20: 107-121), and super-porous agarose hydrogel beads were used as a carrier in hydrophobic interaction chromatography (Gustavsson et al. (1999) J. Chromatography 830. 275-284).

EP2415484B1 PZ / 2693 / AGR [0007] At present, many dispersion systems are also used as carriers of substances, especially biologically active compounds. Dispersion systems used for pharmaceutical and cosmetic preparations can be classified as either suspensions or emulsions. Suspensions consist of solid particles ranging from several nanometers to hundreds of microns dispersed in a liquid carrier using dispersing agents. Solid particles include microspheres, microcapsules and nanospheres. Emulsions are essentially dispersions of one liquid in another, stabilized by the interphase film of emulsifying agents such as surfactants and lipids. Emulsion preparations include water-in-oil and oil-in-water emulsions, multiple emulsions, microemulsions, microdroplets and liposomes. Microdroplets are single-layer phospholipid vesicles that consist of a spherical lipid layer with an oil phase inside, for example, those described in US Patent Nos. 4,622,219 and 4,725,442. Liposomes are phospholipid vesicles obtained by mixing water-insoluble polar lipids with an aqueous solution. Unfavorable entropy caused by mixing water-insoluble lipids leads to the formation of a highly ordered set of concentrically closed phospholipid membranes with an entrapped aqueous solution.

[0008] Several in situ implant production systems have been described. For example, US Patent No. 4,938,763 describes a method of making an implant by dissolving a non-reactive, water-insoluble thermoplastic polymer in a biocompatible water-soluble solvent to obtain a liquid, introducing liquid into the body, and allowing the dispersion of the solvent to form a solid implant. The polymer solution can be introduced into the body using a syringe. The implant may take the shape of a surrounding cavity. Alternatively, the implant can be made of reactive, liquid oligomeric polymers that do not contain solvent and which cure in situ to form a solid material, usually with the addition of a curing catalyst.

[0009] Many polymeric controlled delivery systems for local anesthetics have been described in the art. Although such polymeric delivery systems can provide adequate controlled release properties for the anesthetic and, moreover, overcome the difficulties associated with injecting pure anesthetics (such as scattering away from the destination, introduction into the bloodstream, and systemic toxicity), it is difficult to overcome some of the disadvantages associated with with polymer systems, such as the inability to avoid the systemic initial rapid release (burst) of anesthetic or the need to provide enhancers to improve the under-release of the anesthetic from the system.

[0010] US 2004/101557 relates to non-polymer compositions forming high viscosity liquid materials for administering biologically active substances in a controlled manner.

SUMMARY OF THE INVENTION [0011] Non-polymeric controlled release systems for administering the anesthetic agent of interest are provided. The object of the present invention is therefore to provide a controlled delivery system with prolonged action, releasing anesthetic for a prolonged period of time sufficient to provide local effect

EP2415484B1 PZ / 2693 / AGR anesthesia at the injection site for 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. It is also an object of the present invention to enable the release of an active anesthetic from a prolonged anesthetic composition without initial burst.

[0012] In particular, it is an object of the present invention to provide a composition comprising an anesthetic agent and a pharmaceutically acceptable non-polymeric carrier. The non-polymeric carrier controls the release of the anesthetic providing an anesthetic effect characterized by prolonged local anesthesia after administration to the patient without initial burst 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 administration.

[0013] In one aspect of the invention, the non-polymeric carrier is sufficient to provide a controlled release profile of a first order anesthetic or a release profile of a pseudo zero order anesthetic. In a preferred embodiment, the anesthetic is bupivacaine free base. In other embodiments, the composition is capable of providing a mean steady state plasma concentration (CSS) anesthetic concentration in a sustained release mode 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 250 ng / ml or at least about 300 ng / ml, or at least about 350 ng / ml.

[0014] The non-polymeric carrier is a liquid, more specifically a high viscosity liquid carrier material ("HVLCM") having a viscosity of at least about 5000 cP at 37 ° C and which does not crystallize as such under ambient or physiological conditions. Such liquid carrier materials may be combined with a solvent in which the carrier material is soluble. The solvent is sufficient to reduce HVLCM viscosity. The solvent is the second anesthetic, namely benzyl alcohol. The compositions are provided in liquid form. In some embodiments, the composition further comprises a material that is not miscible with the non-polymeric carrier, for example when the composition is an emulsion. In these compositions, the carrier may be in either dispersed or continuous emulsion form.

[0015] The present invention thus provides a composition comprising an anesthetic agent and a pharmaceutically acceptable non-polymeric carrier. The non-polymeric carrier controls the release of the anesthetic providing an anesthetic effect characterized by prolonged local anesthesia after administration to the patient, wherein the composition can provide a mean steady state plasma concentration of the anesthetic (CSS) in a sustained release mode of at least about 200 ng / ml over a period of at least about 24 hours when the composition is administered subcutaneously, preferably at least 250 ng / ml or at least about 300 ng / ml, or at least about 350 ng / ml.

[0016] In one aspect of the invention, the composition may provide a steady state plasma concentration of anesthetic (CSS) in a sustained release mode for a period of at least about 48 hours. In another aspect, the composition is further characterized by the absence of significant initial burst. In yet other aspects, the non-polymeric carrier is sufficient to provide a controlled release profile of the first order anesthetic or the profile

EP2415484B1 PZ / 2693 / AGR release pseudo-zero order anesthetic. In a preferred embodiment, the anesthetic is bupivacaine free base.

[0017] A method is therefore provided for providing a local anesthetic effect to a patient. The method includes administering the compositions of the invention to, next to, on or adjacent to a particular site. The non-polymeric carrier controls the release of the anesthetic to provide an anesthetic effect characterized by prolonged local anesthesia after administration to the patient, without initial burst and lasting at least about 24 hours after administration. [0018] In one aspect, the composition is used by topical, transdermal, injection or implant implantation at a particular site. In certain embodiments, the composition is administered to a surgical wound site, and the composition is administered to and / or adjacent to the wound.

[0019] In particular, the present invention provides a liquid composition providing prolonged local anesthesia when administered to a patient, wherein the composition comprises bupivacaine as an anesthetic, sucrose acetate isobutyrate as a pharmaceutically acceptable non-polymeric carrier and benzyl alcohol as the solvent for said carrier, wherein bupivacaine is present in an amount of 20 to 10% by weight based on the total weight of the composition.

[0020] Furthermore, the present invention provides the use of bupivacaine as an anesthetic, sucrose acetate isobutyrate as a pharmaceutically acceptable non-toxic polymeric carrier and benzyl alcohol as the solvent for said carrier for the preparation of a liquid composition providing prolonged local anesthesia after administration to the patient, wherein bupivacaine is present in an amount from 20 to 10% by weight based on the total weight of the composition.

BRIEF DESCRIPTION OF THE FIGURES [0021]

Figure 1 shows the average plasma level of bupivacaine during 0-144 hours (pharmacodynamic results) of the example for group 1.

Figure 2 shows the average plasma level of bupivacaine during 0-12 hours (pharmacodynamic results) of the example for group 1.

Figure 3 shows the average plasma level of bupivacaine during 0-300 hours (pharmacodynamic results) of the example for group 2, with data for subgroup 3 being represented by the lower curve (O), data for subgroup 2 being represented by the middle curve ( □), and the data for subgroup 1 is represented by the upper curve (Δ).

Figure 4 shows the mean plasma level of bupivacaine over 0-12 hours (pharmacodynamic results) of the example for group 2, with data for subgroup 3 represented by the lower curve (O), data for subgroup 2 represented by the middle curve ( □), and the data for subgroup 1 is represented by the upper curve (Δ).

Figure 5 shows the mean pain score at the incision site "at rest" recorded using the 0 to 100 mm visual analog scale (VAS) of the example for group 2, where the data for subgroup 3 is represented by the upper curve (Δ), data for subgroup 2 is represented by the middle curve (□), and data for subgroup 1 is represented by the lower curve (O).

EP2415484B1

VP / 2693 / AGR

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS [0022] Before proceeding with the detailed description of the present invention, it should be understood that the invention is not limited to exemplary specific process parameters, which may of course vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only and is not intended to be limiting.

[0023] All publications, patents and patent applications cited in the present specification, both above and below, are hereby incorporated by reference in their entirety.

[0024] It should be noted that the singular forms used in the present description and the appended claims include their plural counterparts, unless the content clearly indicates otherwise. Thus, for example, reference to "a non-polymeric carrier" includes a mixture of two or more such carriers, reference to "solvent" includes a mixture of two or more such carriers, and reference to "anesthetic agent" includes a mixture of two or more such agents e.t.c.

[0025] The term "without initial burst (rapid release)", as used herein, is intended to mean that the agent to which it refers is not released from the composition after normal administration and becomes pharmacologically available in a significant amount during a predetermined initial period. The presence and level of initial burst of an agent from a given composition can easily be determined by a person skilled in the art using standard pharmacological test methods well known in the art. Suitable methods for in vitro release characterization include paddle technique according to USP II, using standard buffer, mixing and thermal conditions. The rapid release (burst) characteristics of a given composition can easily be determined using standard in vivo tests, for example, by monitoring the concentration of the agent of interest in the animal's plasma over a given period of time. In the compositions of the present invention, preferably less than about 40 to 60% of the anesthetic is released within the first 24 hours, more preferably less than about 30 to 50%, and even more preferably less than about 20 to 40% is released during this initial period of time. In certain other preferred embodiments of the invention, less than about 5 to 10% of the anesthetic is released within the first hour, more preferably less than about 3 to 7% is released during this initial period of time.

[0026] Accordingly, the compositions of the present invention contain bupivacaine in a controlled release system that releases bupivacaine over an extended period of time. Bupivacaine is present in the compositions of the invention in an amount of 20 to 10% by weight, depending on their intended use.

[0027] The anesthetic is provided in the composition in neutral form, in free form or in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt", as used herein, is intended to mean those salts that retain the biological effectiveness and properties of inert anesthetics, and are not otherwise acceptable for pharmaceutical uses. Pharmaceutically acceptable salts include salts of acidic or basic groups that may be present in anesthetics. Means

Anesthetic anesthetics, which are basic in nature, can form a wide variety of salts with various inorganic and organic acids. EP2415484B1 PZ / 2693 / AGR Pharmaceutically acceptable acid addition salts of basic anesthetics suitable for use in the present invention are those that form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, hydrogen phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, fumensate gluconate, gluconate, sugar, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamonate (i.e. 1,1'-methylene-bis- (2-hydroxy-3-naphthoate)) salts. Amine-containing anesthetics may form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above. Suitable base salts can be formed with bases that form non-toxic salts, e.g., aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine, see, for example, Berge et al. (1977) J. Pharm. Sci. 66: 1-19.

[0028] The ability of an anesthetic to provide a state of prolonged local anesthesia refers to the ability of the agent of interest to determine the local (local) state of complete or partial inhibition of sensory perception and / or motor function. Numerous methods and devices for such assessment will be apparent to those skilled in the art. For non-human animals, these methods include measuring the level of spontaneous movement of test rats (using, for example, commercially available devices and software from Med Associates Inc., St Albans, VT) where data on total distance traveled can be collected , the number of counts for physical activity in the form of walking, stereotypes, climbing on hind legs, time spent in various types of movement and time spent resting of tested animals; visualization of rat prick reaction; and a rat paw withdrawal model from a hot plate, for example, according to the procedure described in detail in IACUC No. 9511-2199.

[0029] The sensory examination of human patients is also a useful way to assess local anesthetic effects. The test often focuses on three main areas, mechanical test (pin prick, von Frey's hair), thermal test (heat, hot, cold) and tactile test (touch). Such testing methods have been described in the 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. (1996) 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 effect of the test agent can be tested in relation to the onset of action, maximum intensity and duration of action by the following specific methods: 1) mechanical sensory test (threshold for mechanical pain using von Frey's hair), 2) reaction test for a lintel (mechanical) stimulus using a single von Frey hair; 3) thermal sensory test (threshold for feeling heat); 4) the threshold for feeling thermal pain; 5) test of supra-threshold (thermal) stimulus; 6) the threshold of feeling cold; and 7) tactile sensory test (threshold for feeling mechanical touch). These data are an indicator of the relief experienced by the patient in local pain, local numbness and / or local nerve blockade in response to administration of the test anesthetic. Reactions

EP2415484B1 PZ / 2693 / AGR can be characterized by a verbal rating scale of 0-10 (for example, where 0 = no pain and 10 = worst imaginable pain) or a visual analogue scale from 0 to 100 mm (for example, where 0 = no pain and 100 mm = worst conceivable pain).

[0030] Benzyl alcohol is an example of an anesthetic that can be used to provide the initial anesthetic effect of bupivacaine and is an example of an anesthetic that can be used to provide local prolonged anesthesia.

[0031] Benzyl alcohol as the solvent is an additional anesthetic.

[0032] The non-polymeric SAIB carrier serves to control the release of the anesthetic from the composition of the present invention in such a way as to provide prolonged local anesthesia beginning within about 2 hours after administration and lasting at least about 24 hours or longer. In some compositions of the invention, the non-polymeric carrier material is sufficient to provide a controlled release profile of at least one first order anesthetic 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 weight percent based on the total weight of the composition (wt%) or in an amount from about 95 to 10 weight %, or in an amount of from about 75 to 25% by weight

[0033] The compositions of the present invention may further comprise one or more additional ingredients, for example pharmaceutically acceptable excipient materials that can act as dispersing agents, bulking agents, binders, carriers, stabilizing agents, glidants, antioxidants, pH regulators, irritants and the like. It will be apparent to those skilled in the art that certain excipient materials may perform several of the above-mentioned functions in a particular formulation. Thus, any number of suitable excipient materials may be mixed with or included in the compositions of the present invention to provide bulking properties, change the rate of active agent release, increase or decrease water absorption, pH regulation, provide structural support, facilitate production process and for other applications known to those skilled in the art. The term "excipient" generally refers to a substantially inert material that is non-toxic and does not interact with other components of the composition in a harmful manner. The proportions in which the excipient may be present in the composition depend on the purpose for which the excipient is used and the type of excipient.

[0034] For example, suitable excipients that can also act as stabilizing agents for the active substances include pharmaceutical grade dextrose, sucrose, lactose, trehalose, mannitol, sorbitol, inositol, dextran and the like. Such stabilizers may therefore be sugars, such as monosaccharide, disaccharide or polysaccharide, or sugar alcohol. 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 can be added to slow down the hydration and dissolution kinetics include fatty acids and their pharmaceutically acceptable salts (e.g., magnesium stearate, stearic acid, zinc stearate, palimitic acid and sodium palitate).

[0035] In the compositions of the present invention, it may also be beneficial to use charged lipids and / or detergents as excipients. Suitable charged lipids include, without limitation, phosphatidylcholines (lecithin) and the like. Detergents will usually be nonionic, anionic, cationic or amphoteric surfactants. Examples

EP 2415484B1 PZ / 2693 / AGR suitable surfactants include, for example, Tergitol® and Triton® (Union Carbide Chemicals and Plastics) surfactants; polyoxyethylene sorbitans, for example, TWEEN® surfactants (Atlas Chemical Industries); polysorbates; poly (oxyethylene glycol) ethers, for example Brij; pharmaceutically acceptable fatty acid esters, for example lauryl sulfate and salts thereof; amphiphilic surfactants (glycerides, etc.); and similar materials.

[0036] Other excipient materials may be added to modify the porosity, for example, materials such as sucrose, dextrose, sodium chloride, sorbitol, lactose, polyethylene glycol, mannitol, fructose, polyvinylpyrrolidone or their appropriate combinations may be added. Additionally, the anesthetic agent or agents may be dispersed using oils (e.g., sesame oil, corn oil, vegetable oil) or a mixture thereof with a phospholipid (e.g. lecithin) or medium chain fatty acid triglycerides (e.g. Miglyol 812) to receiving a suspension in oil.

[0037] Still other excipient materials that can be included in the compositions of the present invention include diluents containing various buffers (e.g., Tris-HCl, acetate buffer); pH adjusting agents and ionic strength modifying agents; additives such as antioxidants (e.g. ascorbic acid, glutathione, sodium metabisulfite); preservatives (e.g. thimerosal, benzyl alcohol, methyl paraben, propyl paraben); and dispersing agents such as water-soluble polysaccharides (e.g. mannitol, lactose, glucose, starches), hyaluronic acid, glycine, fibrin, collagen and inorganic salts (e.g. sodium chloride).

[0038] The organic solvent will be present in the composition in an amount from about 99.5 to about 1 weight percent based on the total weight of the composition (wt%), in an amount from about 95 to 10 wt%, in an amount from about 75 to 25 wt. or in an amount of from about 60 to 40% by weight In some embodiments, the organic solvent diffuses or is washed out of the composition into an aqueous medium after being placed within the biological system, as a result of which the non-polymeric carrier material coagulates to form a solid matrix. Preferably, the non-polymeric carrier is cured in situ to form a solid matrix within about 1-5 days after administration (implantation), preferably within about 1-3 days, preferably within about 2 hours.

[0039] Many suitable additives can be included in the composition to give it selected properties. For example, a small amount of a biodegradable thermoplastic polymer such as polylactide, polycaprolactone, polyglycolide or a copolymer thereof may be added to provide a more consistent solid implant or composition with a higher viscosity to hold it in place during solidification. Such thermoplastic polymers are disclosed in US Patent Document No. 4,938,76 to Dunn et al.

[0040] Optionally, a blowing agent may be added to the composition. The blowing agent may be any organic or inorganic pharmaceutically acceptable substance that is substantially soluble in water or body fluid and will spread from the non-polymeric carrier material and / or solid implant matrix to the surrounding body fluid at the implantation site. The blowing agent preferably may be insoluble in the organic solvent to form a homogeneous mixture with the non-polymeric carrier material. The blowing agent can also be a water-immiscible substance that degrades quickly to the substance

EP2415484B1 PZ / 2693 / AGR water-soluble. In some compositions, the blowing agent is combined with a non-polymeric carrier and an organic solvent in the mixture. Suitable blowing 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 hydroxylpropyl cellulose, carboxymethyl cellulose, polyethylene glycol and polyvinylpyrrolidone and the like. Solid crystals that provide a specific pore size, such as salt or sugar, are preferred.

[0041] SAIB HVLCM viscosity decreases when mixed with a solvent to form a low viscosity liquid carrier material ("LVLCM") that can be administered using standard medical devices. The LVLCM composition is usually easier to introduce into the body than the HVLCM composition because it flows into and out of syringes and other implantation agents more easily. It can also be easily prepared as an emulsion. The LVLCM material may have any desired viscosity, but its viscosity is substantially lower than the viscosity of the corresponding HVLCM. For example, for in vivo applications, LVLCM viscosity less than about 6000 cP, less than about 4000 cP, less than about 1000 cP, or less than 200 cP is usually useful.

[0042] Sucrose acetate isobutyrate may be obtained according to the procedures described in US Patent Document No. 2931802.

[0043] The solvent is typically added to the composition in an amount ranging from about 99.7 percent to about 0.5 percent by weight based on the total weight of the composition (wt.%), From about 95 percent to about 1 wt.%, From about 75 to about 10 wt. or from about 50 to 15 wt. The solvent is typically present in the composition in an amount ranging from about 55 percent to 10% by weight.

[0044] In yet other embodiments of the invention, the composition comprises a material that is not miscible with HVLCM such that, in combination with HVLCM, alone or in combination with a solvent for HVLCM, the resulting composition forms an emulsion. Such emulsions may contain HVLCM in the dispersed phase, for example in the case of SAIB / MIGLYOL® mixtures that are emulsified in water and glycerin, or may contain HVLCM as a continuous phase component, such as in the case of an aqueous solution that is emulsified in HVLCM or an HVLCM solution in a water-miscible solvent.

[0045] The anesthetic agent is added in an amount sufficient to provide the patient being treated with an effective amount to achieve the desired effect. The amount of anesthetic included in the composition depends on the final desired duration and release profile and the concentration of anesthetic required to achieve the intended effect.

[0046] The concentration of the anesthetic in the composition will also depend on the rate of absorption, inactivation and excretion of that particular agent as well as other factors known to those skilled in the art. It should be understood that the size of the doses will also vary depending on the severity of the condition to be alleviated. It should further be understood that, for any particular patient, specific dosage regimens should be adjusted over time, in accordance with the individual needs and professional judgment of the person administering or supervising the administration of the composition, and that the concentration ranges given herein are exemplary only and are not intended to limit the range or the implementation of the claimed composition. The composition may be administered in one dose or may be divided into several smaller doses to be administered at different intervals, either sequentially or simultaneously.

EP2415484B1 PZ / 2693 / AGR [0047] As described above, various additives may optionally be included in the composition of the present invention to modify its properties, and in particular to modify the release properties of the composition with respect to the anesthetics contained therein. Additives may be present in any amount sufficient to impart the desired properties to the composition. The amount of additive used will generally be a function of the type of additive and effect to be achieved and can be easily determined by a person skilled in the art. Suitable additives are described in US Patent No. 5,747,058, the entire contents of which are hereby incorporated by reference. More specifically, 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 like sodium citrate. In general, the less water-soluble the additive, i.e., the more lipophilic it is, the more it reduces the rate of release of the anesthetic, compared to the same composition without the additive. In addition, it may be desirable to include additives that improve properties such as strength and porosity of the composition.

[0048] Additives can also be derived to increase the delivery time of the anesthetic, which makes the composition more suitable for medical applications that require or respond to administration over an extended period. Suitable additives in this context include those disclosed in US Patent Nos. 5,747,058 and 5736152. In particular, suitable additives for this purpose include polymer additives such as cellulose polymers and biodegradable polymers. Suitable cellulose polymers include cellulose acetates, cellulose ethers and butyrate cellulose acetate. Suitable biodegradable polymers include polylactones, polyanhydrides and polyorthoesters, in particular poly (lactic acid), poly (glycolic acid), polycaprolactone and copolymers thereof.

[0049] When present, the additive is usually present in the composition in an amount ranging from about 0.01 percent to about 20 weight percent, more particularly from about 0.1 percent to about 20 weight percent, based on the total weight of the composition, and more typically present in the composition in an amount ranging from 1, 2 or 5 percent to about 10 percent by weight. Some additives, such as buffers, are present in the composition only in small amounts.

[0050] The following categories are non-limiting examples of classes of additives that can be used in the compositions of the present invention.

[0051] One category of additives are biodegradable polymers and oligomers. Polymers can be used to modify the release profile of the delivered anesthetic to increase the integrity of the composition or otherwise modify its properties. Non-limiting examples of suitable biodegradable polymers and oligomers include: polylactide, copolymers of lactic acid with glycolic acid, polyglycolide, polycaprolactone, polyamides, polyanhydrides, polyamino acids, polyorthoesters, polycanoacrylates, polyphosphazines, polyphosphoesters (polyesteramides, polydioxanates, polyacetals, polyglycolate, polyglate ), poly (alkylene succinates), poly (malic acid), chitin, chitosan and copolymers, terpolymers, oxidized cellulose or combinations or mixtures of the aforesaid materials.

EP2415484B1 PZ / 2693 / AGR [0052] Examples of poly (? -Hydroxy acids) include poly (glycolic acid), poly (DL-lactic acid) and poly (L-lactic acid), and copolymers thereof. Examples include poly (caprolactone), poly (valalerolactone) and poly (butyrolactone).

[0053] Without resorting to any theoretical considerations, it is believed that when the composition comprises a biodegradable polymer, some of the polymer may precipitate or coagulate on the surface of the composition because any solvent diffuses from the material upon administration to the patient. The polymer can therefore be added as a release-modifying agent by affecting the release of the anesthetic or anesthetics, or can be added as part of a composition containing pre-formed microspheres, implants, or ground polymer particles. Precipitation or coagulation of the polymer produces a coating at least partially surrounding the liquid core of such a composition. This coating is porous and still allows the solvent to diffuse into surrounding tissues. The rate of solvent release and the extent of film formation, as well as its porosity, can be controlled by the amount and type of solvent and polymer in the composition.

[0054] Other additives for use in the compositions of the invention are non-biodegradable polymers. Non-limiting examples of other non-degradable polymers that can be used as additives include: polyacrylates, ethylene vinyl acetate copolymers, cellulose and cellulose derivatives, acyl substituted cellulose acetates and their derivatives, non-degradable polyurethanes, polystyrenes, poly (vinyl chloride), poly ( vinyl fluoride), polyvinylimidazole, chlorosulfonated polyolefins, polyethylene oxide and polyethylene.

[0055] Preferred non-biodegradable polymers include polyvinylpyrrolidone, ethylene vinyl acetate copolymers, polyethylene glycol, cellulose acetate butyrate ("CAB") and cellulose acetate propionate ("CAP").

[0056] Another class of additives that can be used in the compositions of the invention are natural and synthetic oils and fats. Animal oils or oils from vegetable seeds or nuts usually contain glycerides of fatty acids, mainly oleic, palmitic, stearic and linoleic acid. As a rule, the more hydrogen a molecule contains, the higher the oil density. [0057] 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, fennel oil, camellia oil, corn oil, castor oil, oil from cottonseed and soybean oil, either crude or refined and medium chain fatty acid triglycerides.

[0058] Fats are usually esters of glycerin and higher fatty acids such as stearic and palmitic acid. Such esters and mixtures thereof are solid at room temperature and have a crystal structure. Examples of lard and tallow. In general, oils and fats increase the hydrophobicity of a non-polymeric carrier system, slowing down the decomposition and absorption of water.

[0059] The above described compositions of the present invention are used to provide prolonged local anesthesia at the target site. In particular, the compositions are formulated as a liquid and then administered to the patient by topical, transdermal, parenteral (e.g., injections, implants, etc.) administration or similar methods of administration. Compositions containing an anesthetic and a pharmaceutically acceptable non-polymeric carrier are used to provide anesthetic effect characterized by

EP2415484B1 PZ / 2693 / AGR prolonged local anesthesia after administration to a patient without initial burst and duration of at least about 24 hours after administration, and preferably at least about 36 to 48 hours after administration, more preferably at least about 48 to 72 hours after administration. In some embodiments, the local anesthetic effect begins within about 2 hours after administration to the patient, preferably within about 1 hour after administration, and in some cases, within about 30 minutes after administration to the patient.

[0060] The term "patient", as used herein, refers to any vertebrate for which it is desirable to provide a state of local anesthesia. The term is broadly applicable to any animal to be treated using the compositions of the present invention, such as birds, fish and mammals including humans. In some embodiments, the compositions of the present invention are suitable for providing prolonged anesthesia in veterinary practice and animal husbandry, for example, in birds and mammals, when the state of the prolonged local anesthetic effect is convenient or desired. In some cases, the compositions are particularly suitable for use in pets, such as dogs and cats, and may additionally be used in horses. In preferred embodiments, the term "patient" is intended to mean a human patient. In addition, the term "patient" does not refer to a particular age, and therefore the compositions are suitable for use in patients of any age, such as infants, adolescents, adolescents and adults.

[0061] In preferred embodiments, the compositions of the present invention are particularly suitable for use in the treatment of wounds. Non-polymeric support systems allow easy application of anesthetic to the wound, directly within the wound and / or in a place adjacent to the wound, by very simple application methods such as dripping, spraying, painting, coating, molding or other manual application of the liquid composition on the wound. These compositions can therefore be applied to wounds of any size or shape and ensure uniform distribution of the anesthetic over the entire wound surface for better retention and effectiveness. Wounds that can be treated using such methods can range from the most superficial to deep, from surface to cut, and from surgical (or otherwise intentional) to accidental. If the composition is intended for injection, it can be applied to the subcutaneous space by continuous injection with withdrawal of the needle along the wound on all its sides or outside the border area. A combination of methods can be used, e.g. the composition is applied directly to the wound, e.g. prior to surgical wound closure, and further along the wound. In a particularly preferred embodiment, the compositions are for use as a local anesthetic in the treatment of postoperative post-cut wound pain. The use of the compositions of the invention in this way can eliminate or at least reduce the need for adjunctive therapies, such as systemic administration of narcotic analgesics to treat such postoperative pain. Accordingly, the compositions can be used to treat postoperative pain that accompanies all types of medical procedures, such as major surgery (e.g. thoracotomy, aortic surgery, bowel resection), less serious surgery (e.g. caesarean section, uterine resection) and appendectomy) and

EP2415484B1 PZ / 2693 / AGR minor surgery (laparoscopy, arthroscopy and biopsy procedures), which may otherwise be debilitating and may require pain treatment for 3 to 5 days after surgery.

[0062] The compositions described herein can therefore be administered in carrying out the methods of the present invention using various techniques. For example, the compositions may be administered topically, systemically (e.g., mucosa, orally, rectally, vaginally or intranasally), parenterally (intravenously, subcutaneously, intramuscularly or intraperitoneally) or similar methods. The compositions can be used by injection, pouring, spraying, immersion, as an aerosol or using a coating applicator. Aerosols or mists of the composition may be administered using an aerosol propellant, for example, for topical administration, or using a suitable nebulizer, for example, for nasal or oral mucosal administration.

[0063] Preferably, the compositions are administered in the form of a liquid by injection, or in the form of an aerosol, paste or emulsion. When used as an aerosol, any solvent present in the aerosol solution will usually evaporate after application, allowing the composition to obtain a coating structure. Alternatively, an aerosol or emulsion may be obtained without a solvent. In this situation, the aerosol propellant can also serve as a solvent. Aerosols and emulsions can be prepared by methods known to those skilled in the art, see, for example, Ansel, HC et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, ed. 6 (1995).

[0064] In addition to the uses described above, the compositions of the invention may be administered by means of an osmotic pump. In one embodiment, the device is designed for implantation in a patient's tissue and intended for sustained release over time.

[0065] It is also possible to administer the composition of the invention using a porous or non-porous tube, preferably made of extruded biodegradable polymer. A tube with varying degrees of porosity can be made, depending on the characteristics of the composition and the desired release characteristics. The composition of the invention is introduced into a tube, the ends of which can be left open, allowing the biologically active compound to diffuse out through the ends of the tube, or can be closed with an additional porous or non-porous polymer. Porous end caps and porous tubes allow the active compound to diffuse through the pores over time. Non-porous end caps as well as non-porous tubes allow the polymer-soluble anesthetic to diffuse through the polymer and into surrounding tissues. Non-porous materials that are not solvents for the anesthetic but that are biodegradable will release the active agent after sufficient degradation. The compositions of the invention may be prepared and stored as multi-component systems until administration. The number of different ingredients will depend in part on the characteristics of the composition. Before administration, the ingredients are combined and mixed, for example, to obtain a homogeneous mixture that can be administered to a patient. Solvents or additives may be added to one or all ingredients, or they may be a separate ingredient that is also mixed with others before administration. Separation of the composition into a multi-component mixture allows optimization of storage conditions for each component and minimizes any adverse interactions between the components over time. The result is increased storage stability.

EP2415484B1 PZ / 2693 / AGR

EXAMPLE [0066] The following is an example of a particular embodiment of the method of the present invention.

General methods [0067] The in vivo efficacy of the compositions of the invention can be evaluated in rats using a hot plate model, for example according to the procedure described in detail in IACUC No. 9511-2199. The performance criteria defined for the compositions of the invention are average reaction latency greater than about 2 seconds, with a 12-second limit (this limit is set to prevent any possible damage to the animal). A reaction delay of 2 seconds demonstrates a statistically significant effect of the local anesthetic. Preferably, the average reaction latency in a rat hot plate model is greater than 7 seconds. Preferably, the percentage of corresponding animals is 50% or more. Preferably, the composition of the invention achieves an average reaction latency in a rat hot plate model greater than about 7 seconds to about 12 seconds, with a percentage of corresponding rats representing at least 50% of the animals tested.

[0068] A description of the rat hot plate model is provided below. The study involved male Sprague Dawley rats (Harlan Laboratories, Indianapolis, Ind.) With an average body weight of 275 g. The hot plate test consists of gently holding the animal's body with the plantar surface of the hind paw placed on a hot plate heated to 56 ° C. Baseline reaction latency is determined prior to unilateral injection of the anesthetic composition around the rat sciatic nerve.

[0069] Sensory tests in human models are also useful for testing the compositions of the present invention. The activity of the local anesthetic can be tested in relation to the onset of action, maximum intensity and duration of action using seven different procedures: a) mechanical sensory test (threshold for mechanical pain using von Frey's hair), b) supra-threshold reaction test ( mechanical) using a single von Frey hair; c) thermal sensory test (threshold for feeling heat); d) thermal pain threshold; e) supra-threshold (thermal) response test; f) the threshold of feeling cold; ig) tactile sensory test (threshold for the feeling of mechanical touch). Different grade values ​​or different levels of results will be an indicator of the relief experienced by the patient in local pain, local numbness and / or local nerve blockade. The anesthetic effect of the compositions of the invention can further be characterized in terms of safety by using various measures of activity, such as systemic blood plasma levels achieved after administration at a localized site.

[0070] The threshold for the feeling of mechanical pain is defined as the smallest strength or number of von Frey hairs that produce a specific sensation of pain or discomfort, and the threshold for the feeling of mechanical touch is defined as the smallest strength or number of von Frey hairs that cause a feel or pressure. The threshold for mechanical touch and the threshold for mechanical pain can be determined simultaneously by using von Frey's hair with gradually changing stiffness (VFH) (available from Somedic A / B, Stockholm, Sweden). It was previously established that each VFH hair pressed against the weight until light bending means a force that increases logarithmically with each hair, covering a total range of 3 to 402 millinewtons (mN) (VFH No. 7 = 3 mN; VFH No. 8 = 13 mN ; VFH No.

EP2415484B1 PZ / 2693 / AGR

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).

[0071] Accordingly, in a human patient, the area injected with the composition obtained according to the present invention can be stimulated 8 times with each VFH hair at a rate of about 2 stimuli per second, starting from VFH No. 7 hair and going to VFH No. 17 hair. The smallest VFH hair number is recorded, which is felt as touch or pressure (mechanical touch threshold) and the smallest hair number, where half of the eight stimuli are painful or unpleasant (mechanical pain threshold). This procedure is repeated twice more and the median of three measurements is given. If the VFH No. 17 hair does not cause touch or pressure, the threshold of mechanical touch is set to 18. If the VFH No. 17 hair does not cause any pain or discomfort, the value of the mechanical pain threshold is assigned a value of 18. The pain response to the mechanical threshold stimulus caused by a single von Frey hair is determined by stimulating VFH No. 17 hair 5 times (402 mN) area injected. The patient estimates pain on a VRS scale of 0-10, in which zero (0) = no pain and ten = (10) pain as intense as you can imagine.

[0072] As discussed above, this test is performed using a single stiff von Frey hair that produces a pain response in patients. The pain reaction is determined by stimulating the injected or treated area with VFH No. 17 hair 5 times. Patients rate pain on a verbal score (VRS) scale from 0 to 10 as described above.

[0073] The thermal test (pain reaction to the threshold thermal stimulus) in the treated area is performed with a 45 ° C stimulus, lasting 5 seconds using a computerized thermode (available from Thermostest, Somedic A / B, Stockholm, Sweden) in the treated areas . The patient assesses pain according to the verbal assessment scale (VRS) from 0 to 10.

[0074] The heat sensing threshold is defined as the smallest perceived temperature rise from 32 ° C, the thermal pain perception threshold is defined as the lowest temperature felt as painful, and the cold feeling threshold is defined as the smallest perceptible temperature drop from 32 ° C. The threshold for feeling heat, the threshold for feeling thermal pain, the threshold for feeling cold is determined using a computerized Thermostest device (available from Somedic AB, Stockholm, Sweden) in the treated areas. Patients are instructed to press the button immediately after a specific sensation. Thermal thresholds are determined from an initial level of 32 ° C and increase (threshold of heat perception and threshold of thermal pain) or decrease (threshold of cold perception) at a rate of change of 1 ° C per second. For the threshold of heat sensation and the threshold of thermal pain detection the upper limit is 52 ° C. For the threshold of feeling cold the lower limit is 25 ° C.

[0075] Heat sensing threshold, thermal pain sensing threshold, cold sensing threshold is calculated as the median of three measurements, with 10-second intervals between each stimulus. If the patient feels no heat or pain at 52 ° C, the 53 ° C value is recorded for the threshold for feeling heat; if the patient does not feel pain at 52 ° C, the value of 53 ° C is recorded for the threshold of thermal pain sensation; and if the patient does not feel cold or pain at 25 ° C, the value of 24 ° C is recorded for the threshold of feeling cold.

Example

EP2415484B1 PZ / 2693 / AGR [0076] The following dose escalation, pharmacokinetic, pharmacodynamic (efficacy) assessment procedures are performed in human patients undergoing inguinal hernia surgery to assess the efficacy and pharmaceutical action of a controlled release bupivacaine composition containing acetate isobutyrate sucrose as a non-polymeric carrier and obtained by the method of the present invention. In the study, the efficacy of the SAIB / bupivacaine composition of the present invention, administered subcutaneously in combination with physiological saline (placebo) or bupivacaine hydrochloride (Marcain®) for wound infiltration, is compared with commercially available bupivacaine solution (Marcain®, bupivacaine hydrochloride BP, 5 , 28 mg / ml, equivalent to anhydrous bupivacaine hydrochloride 5 mg / ml) administered subcutaneously and as an infiltration agent in patients undergoing open inguinal hernia surgery.

[0077] The test composition is prepared / prepared using bupivacaine free base prepared in sucrose acetate isobutyrate (SAIB) as a non-polymeric carrier, in addition with benzyl alcohol (BA) serving as a solvent for bupivacaine and the SAIB carrier. Benzyl alcohol is also an anesthetic. The composition is made / prepared by combining about 66 wt. SAIB carrier, 22 wt. benzyl alcohol as a solvent / anesthetic and 12 wt. bupivacaine, to provide single doses containing 159.5 mg bupivacaine in 1.25 ml injection volume (319 mg in 2.5 ml total volume). The composition is provided / provided as a clear liquid for injection.

[0078] The study was designed to include 3 groups of up to 91 patients (6 patients in group 1; 15 patients in group 2; and up to 70 patients in group 3). In particular, group 1 consisted of 6 healthy men, aged 23 to 52 years. In group 1, all patients received 2.5 ml of the total injected volume of the SAIB / BA / bupivacaine composition (containing 319 mg bupivacaine), administered as two subcutaneous continuous injections with needle withdrawal along each side of the surgical wound (0.5 ml / cm along 5 cm total cut length suggested), with infiltration of the cut wound (including sub-fascial space) with 10 ml saline solution before wound closure. Continuous needle withdrawal injections were used 0.5 to 1.0 cm from and parallel to the cut wound edge and were performed by inserting the needle subcutaneously, parallel and along the length of the incision, continuously injecting as the needle was withdrawn. The anesthetic / analgesic effect was evaluated in the time-to-first analgesic test and in the total analgesic intake test (within 4 days). Plasma bupivacaine concentration was measured periodically throughout the study, especially for the first 24 hours to assess the extent of early release of bupivacaine from the SAIB controlled release composition.

[0079] The results of the time test until the first administration of the additional analgesic are presented in Table 1 below.

EP2415484B1 PZ / 2693 / AGR

Table 1. Time to first administration of additional analgesic

<td>Patient No.</td><td>Time to first administration of the medicine analgesic</td>

<td> 1</td><td>8 hours</td>

<td> 2</td><td>1 hour</td>

<td> 3</td><td>1 hour</td>

<td> 4</td><td>1 hour</td>

<td> 5</td><td>2 hours</td>

<td> 6</td><td>3 hours</td>

<td>(Average)</td><td>2.6 hours</td>

[0080] The results of the test for total intake of additional painkiller (within 4 days) are shown in Table 2 below.

Table 2. Total intake of additional painkiller

<td>Patient No.</td><td>Day 1</td><td>Day 2</td><td>Day 3</td><td>Day 4</td>

<td> 1</td><td> 2</td><td> 5</td><td> 1</td><td> 1</td>

<td> 2</td><td> 4</td><td> 4</td><td> 3</td><td> 4</td>

<td> 3</td><td> 3</td><td> 1</td><td> 1</td><td> 1</td>

<td> 4</td><td> 10</td><td> 5</td><td> 3</td><td> 1</td>

<td> 5</td><td> 2</td><td> 1</td><td> 1</td><td> 1</td>

<td> 6</td><td> 4</td><td> 1</td><td> 2</td><td> 3</td>

<td>(Average)</td><td> 4,16</td><td> 2,8</td><td> 1,8</td><td> 1,8</td>

[0081] The SAIB / BA / bupivacaine composition was found to be well tolerated, with the injections not causing any visible redness, swelling, itching, discoloration or any other adverse effects at the injection site, or any unacceptable tissue reaction throughout the study. In addition, bupivacaine pharmacokinetic studies indicate sustained release of bupivacaine as an active substance from the SAIB carrier, with bupivacaine being released for 4 days. The results of pharmacokinetic studies are shown in Figures 1 and 2. As can be seen, the SAIB / BA / bupivacaine composition released bupivacaine as the active substance rapidly (within about 1 hour of administration) without initial burst and showed essentially steady, steady state release for at least the first 3 days of treatment. Observed mean Cmax was 277 ng / ml ± 109; Tmax was 23 hours ± 21; and Css was 191 ng / ml ± 13.

[0082] Group 2 consisted of 15 healthy men, 26 to 54 years old. Group 2 was divided into three subgroups, the first subgroup (n = 5) was given 5.0 ml total injected volume of the SAIB / BA / bupivacaine composition (containing 638 mg bupivacaine) as two subcutaneous continuous injections with needle withdrawal along each side of the surgical wound ( 0.5 ml / cm along the suggested 5 cm total length of the cut wound), with infiltration of the cut wound (including sub-fascial space) before closing the wound with 10 ml of saline solution. Second subgroup

EP2415484B1 PZ / 2693 / AGR (n = 5) was administered 5 ml total injected volume of the composition SAIB / BA / bupivacaine (containing 638 mg bupivacaine) as two subcutaneous continuous injections with withdrawal of the needle along each side of the surgical wound (0.5 ml / cm along the suggested 5 cm total length of the cut wound), with infiltration of the cut wound (including the sub-fascial space) before closing the wound with 10 ml of Marcain® (0.5% bupivacaine-HCl), resulting in a total of 688 mg of bupivacaine administered per patient. The third subgroup (n = 5) was administered 5 ml of the total injected volume of the Marcain® composition (0.5% bupivacaine-HCl) as two subcutaneous continuous injections with needle withdrawal along each side of the surgical wound (0.5 ml / cm along a suggested 5 cm total length of the cut wound) with infiltration of the cut wound (including the sub-fascial space) before closing the wound with 10 ml of Marcain®, giving a total of 75 mg of bupivacaine administered per patient.

[0083] The anesthetic / analgesic effect was evaluated in the time to first administration of additional analgesic test, incision site pain assessment test "at rest" and the total intake of additional analgesic test (within 4 days). Plasma bupivacaine concentration was measured periodically throughout the study, especially for the first 24 hours to determine the amount of early release of bupivacaine from the SAIB controlled release composition.

[0084] The results of the time-to-first analgesic and total analgesic intake test (within 4 days) test results for all three subgroups of group 2 are shown in Table 3 below.

Table 3. Average time to first additional analgesic administration and average total intake of additional analgesic (over 4 days)

<td>Subgroup</td><td>number patients</td><td>Treatment</td><td>Average time to first pass additional medicine analgesic (in h.)</td><td>Average number dose additional medicine analgesic within 4 days</td>

<td> 1</td><td>n = 5</td><td>SAIB / BA / bupivacaine and saline solution physiological (total dose 638 mg)</td><td> 60,4*</td><td> 2,6</td>

<td> 2</td><td>n = 5</td><td>SAIB / BA / bupivacaine and Marcain® (total 688 mg dose)</td><td> 44,9*</td><td> 2,4</td>

<td> 3</td><td>n = 5</td><td>Marcain® (total 75 mg dose)</td><td> 23</td><td> 11,0</td>

<td colspan="5">(* Three patients in subgroup 1 and two patients in subgroup 2 did not receive doses an additional painkiller for the entire 4-day period).</td>

EP2415484B1 PZ / 2693 / AGR [0085] Again, the SAIB / BA / bupivacaine composition was well tolerated (subgroups of patients 1 and 2), the injections not causing any visible redness, swelling, pruritus, discoloration or any other adverse effects at the injection site , or any unacceptable tissue reaction throughout the duration of the study. In addition, bupivacaine pharmacokinetic studies indicate sustained release of bupivacaine as an active substance from the SAIB carrier, with bupivacaine being released for 4 days. The results of pharmacokinetic studies are shown in Figures 3 and 4. As can be seen, the SAIB / BA / bupivacaine composition released bupivacaine as the active substance rapidly (within about 1 hour of administration) without initial burst and showed essentially steady, steady state release for at least the first 3 days of treatment.

[0086] The results of pharmacodynamic studies for all three subgroups of group 2 are shown in Table 4 below.

Table 4. Pharmacodynamic results for group 2

<td>Subgroup</td><td>number patients</td><td>Treatment</td><td>Cmax (ng / ml)</td><td>Tmax (hours)</td><td>Css (ng / ml)</td>

<td> 1</td><td>n = 5</td><td>SAI B / BA / bup ivacaine and saline physiological (total dose 638 mg)</td><td> 470 ± 155</td><td> 21 ± 25</td><td> 311 ± 58</td>

<td> 2</td><td>n = 5</td><td>SA IB / BA / bup ivacaine and Marcain® (total 688 mg dose)</td><td> 310 ± 60</td><td> 21 ± 25</td><td> 291 ± 40</td>

<td> 3</td><td>n = 5</td><td>Marcain® (total 75 mg dose)</td><td> 180 ± 88</td><td> 0,6 ± 0,2</td><td>No data</td>

[0087] Based on the results of the Group 2 study, it can be concluded that the controlled release compositions of the present invention provide an effective local anesthetic effect for at least 4 days after surgery, significantly reducing the need for additional analgesics. In fact, 50% of patients receiving the SAIB / BA / bupivacaine compositions of the present invention (5 out of 10 patients in subgroups 1 and 2) did not require the use of additional painkillers for the entire 4-day period. Patients in subgroups 1 and 2 who were not required to use additional painkillers were able to wait for their first additional painkillers for about 2-3 days, feeling effective local anesthesia for at least 2 days after surgery. In addition, the number of doses of additional painkillers in subgroups 1 and 2 was drastically reduced compared to control patients (subgroup 3) who required an average of 11 doses over a 4-day study period, compared to doses of 2.4 to 2.6 in such same time period.

EP2415484B1 PZ / 2693 / AGR [0088] In addition, evaluation of the pharmacokinetic data for group 2 indicates that an effective subcutaneous bupivacaine dose of 638-688 mg may be administered repeatedly using the controlled release composition of the present invention to provide an effective concentration of bupivacaine at steady state plasma of about

300 ng / ml.

[0089] The results of the "resting state" incision pain test for all three subgroups of group 2 are shown in Figure 5. Data for subgroup 3 are represented by the upper curve (Δ), data for subgroup 2 are represented by the middle curve (□ ) and the data for subgroup 1 is represented by the lower curve (O). For convenience, the average time to administration of the first additional analgesic is shown on each curve. The intensity of the incision pain was recorded using a visual analogue scale (VAS) 0 to 100 mm, with a score range from 0 (no pain) to 100 (worst imaginable pain). Each VAS result was recorded as a single vertical line on the scale. The test was carried out as follows. On the day of surgery (day 0), the score of incision pain was initially recorded 60 minutes after administration of the test composition (as discussed above, subgroup 1 received the SAIB / BA / bupivacaine and saline solution composition, subgroup 2 received the SAIB / BA / bupivacaine and Marcain composition ®, and subgroup 3 received Marcain®). Then, incision pain scores were recorded every 30 minutes in the 4-hour evaluation period, then every hour in the 8-hour evaluation period and finally at 12-hour evaluation. On the following days from 1 to 3, recording of the score of incision pain in the morning was continued based on the time the test composition was given on day 0. The measurements were continued at 4-hour intervals over a 12-hour evaluation period (4 measurements). The duration of use of any accompanying (additional) medication during this 4-day evaluation period was also noted.

[0090] Reviewing the results of the incision pain assessment test shown in Figure 5, it can be seen that for both subgroups that received the SAIB / BA / bupivacaine compositions tested (subgroups 1 and 2), lower average VAS scores were obtained for all times throughout the entire test. compared to the group that received the composition of Marcain® (subgroup 3). These results show that the compositions of the present invention provide prolonged local anesthesia at the site of the cut wound, lasting at least about 36 to 48 hours after administration to the patient.

[0091] Patients in group 3 will be divided into 2 treatment subgroups. The first subgroup will receive 7.5 ml of the total injected volume of the SAIB / BA / bupivacaine composition (containing 958 mg bupivacaine), administered as two subcutaneous continuous injections with needle withdrawal along each side of the surgical wound (0.75 ml / cm along a suggested total 5 cm total cut wound length) with cut wound infiltration (including sub-fascial space) before closing the wound with 10 ml of Marcain® (0.5% bupivacaine-HCl), resulting in a total of 1.008 mg of bupivacaine administered per patient. The second subgroup will receive 7.5 ml of the total injected volume of the Marcain® composition (0.5% bupivacaine-HCl) administered as two subcutaneous continuous injections with needle withdrawal along each side of the surgical wound (0.75 ml / cm along a suggested total length of 5 cm) cut wound) with infiltration of the cut wound (including the sub-fascial space) before closing the wound with 10 ml of Marcain®, obtaining a total of 87.5 mg of administered bupivacaine per patient.

EP2415484B1 PZ / 2693 / AGR [0092] The anesthetic / analgesic effect will be assessed in the time to first administration of the additional analgesic test and in the total intake of the additional analgesic test (within 4 days). The plasma concentration of bupivacaine will be measured periodically throughout the duration of the study, especially for the first 24 hours to determine the amount of early release of bupivacaine from the SAIB controlled release composition. Higher doses of the controlled release SAIB / BA / bupivacaine composition obtained according to the present invention are expected to show similar or even better results in terms of efficacy compared to those obtained by the patients in Group 2 tested.

[0093] It should be understood that the present invention described above, variants and modifications thereof are obvious to those skilled in the art within the scope of the appended claims.

EP2415484B1 PZ / 2693 / AGR