Sustained local anesthetic composition containing saib

Description

TECHNICAL FIELD

The present invention generally relates to the field of controlled delivery systems, and more particularly to controlled delivery systems, containing an active agent capable of providing a local anesthetic effect, which systems are suitable for use in conjunction with surgical and therapeutic treatment and as medicaments for use in post-operative recovery procedures.

BACKGROUND OF THE INVENTION

[0002] Biodegradable controlled delivery systems for active ingredients are well known in the art. Biodegradable drug delivery vehicles are useful because their use prevents the exhausted device from having to be removed.

[0003] The most common carrier materials used in controlled delivery systems are polymers. The field of biodegradable polymers is developing rapidly since the synthesis and biodegradability of polylactic acid were described in the publication: Kulkami et al. (1966) Arch. Surg. 93: 839. Examples of other polymers that have been described as useful as matrix material for controlled delivery systems include polyanhydrides, polyesters such as polyglycolides and lactide-glycolide copolymers, polyamino acids such as polylysine, polymers and copolymers of polyethylene oxide terminated with an acrylic group. poly (ethylene oxide), polyamides, polyurethanes, poly (orthoesters), polyacrylonitriles, and polyphosphazenes. See, e.g., U.S. Pat. US US 4,891,225 and US 4,906,474 (polyanhydrides); US 4,767,628 (polylactide, lactide-glycolide acid copolymer); US 4,530,840 (polylactide, polyglycolide, and copolymers); and US 5,234,520 (biodegradable polymers for controlled delivery in the treatment of periodontal disease).

[0004] Degradable materials of biological origin are well known and include, for example, cross-linked gelatin. Hyaluronic acid was cross-linked and used as a degradable swellable polymer for biomedical applications (see, e.g., U.S. Patent No. 4,957,744 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 and as carriers of biologically active materials,

PZ / 1489 / AG EP 1 809 329 1 such as hormones, enzymes, antibiotics, anti-cancer agents, and cell suspensions. See, e.g., U.S. Patent No. US US 5,149,543.

[0006] Hydrogel compositions are also commonly used as supports for cell and tissue culture, matrix materials for prosthetics, materials for tampons, or as solid phase materials for gel permeation or affinity chromatography applications. For example, non-porous, deformed, and / or agarose-derivatized hydrogel compositions are used in high performance liquid chromatography and affinity chromatography methods (Li et al. (1990) Preparative Biochem. 20: 107-121), and beads of super porous agarose hydrogel are used as a carrier in hydrophobic interaction chromatography (Gustavsson et al. (1999) J. Chromatography 830: 275-284).

[0007] Many dispersion systems are also currently used as carriers for substances, especially biologically active compounds. Dispersion systems used in pharmaceutical and cosmetic formulations can be categorized either as suspensions or emulsions. Suspensions consist of solid particles ranging in size from a few nanometers to hundreds of microns, dispersed in a liquid medium by the use of suspending agents. Solid particles include microspheres, microcapsules, and nanospheres. Emulsions are generally dispersions of one liquid within another, stabilized by an interfacial film of emulsifying agents such as surfactants and lipids. Emulsion formulations include water-in-oil and oil-in-water emulsions, multiple emulsions, microemulsions, microdroplets, and liposomes. Microdroplets are unilayered phospholipid vesicles that consist of a spherical lipid layer with an oil phase inside, for example, such as those described in US Pat. US US 4,622,219 and US 4,725,442. Liposomes are phospholipid vesicles obtained by mixing water-insoluble polar lipids with an aqueous solution. The unfavorable entropy caused by the mixing of the insoluble lipid in water leads to the formation of a highly ordered set of concentrically closed phospholipid membranes with trapped aqueous solution.

[0008] Many systems have been described for the creation of an implant in situ. For example, in US Patent No. US 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 form a liquid, placing the liquid inside the body, and allowing the solvent to dissipate to form a solid implant. The polymer solution can be placed into the body using a syringe. The implant may take the shape of the body cavity surrounding it. Alternatively, the implant may be formed from reactive, liquid polymers

PZ / 1489 / AG ΕΡ 1 809 329 Β1 oligomeric, solvent-free and curing in place to form solids, usually with the addition of a curing catalyst.

[0009] A number of polymeric controlled delivery systems for the local delivery of anesthetics have been described in the art. Although such polymeric delivery systems can provide adequate controlled-release properties for the anesthetic and further overcome the drawbacks of injecting anesthetic agents without admixture (e.g., dispersion from the target site, entry into the bloodstream, and systemic toxicity), some drawbacks associated with polymer systems, such as failure to avoid systemic initial burst of anesthetic, or the need to provide enhancement agents to overcome under-release of the anesthetic from the systems. U.S. Patent Specification US US 2004/101 557 relates to non-polymeric compositions that form highly viscous liquid materials to deliver biologically active substances in a controlled manner.

SUMMARY OF THE INVENTION

[0010] Controlled delivery non-polymeric delivery systems are provided for administering the anesthetic of interest. Thus, it is an object of the present invention to provide a sustained action and controlled delivery system that releases the anesthetic for a prolonged period of time sufficient to provide a local anesthetic effect at the site of administration for at least about 24 hours after administration, preferably at least about 36 to 48 hours. hours after administration, and more preferably at least about 48 to 72 hours after administration. It is also an object of the present invention that the release of the active anesthetic from the sustained anesthetic composition occurs without an initial burst.

[0011] More specifically, it is an object of the present invention to provide a composition comprising an anesthetic and a pharmaceutically acceptable non-polymeric carrier. The non-polymeric carrier controls the release of the anesthetic to provide an anesthetic effect characterized by sustained local anesthesia after administration to the patient with no initial burst and a duration of at least about 24 hours after administration, preferably at least about 36 to 48 hours after administration, and more preferably at least about 24 hours after administration. at least about 48 to 72 hours after administration.

[0012] Accordingly, the present invention provides a liquid composition for providing prolonged local anesthesia after administration to a patient, the composition comprising

PZ / 1489 / AG ΕΡ 1 809 329 Β1 is made of 12% by weight of bupivacaine as an anesthetic, 66% by weight of sucrose acetate isobutyrate as a pharmaceutically acceptable non-polymeric carrier and 22% by weight of benzyl alcohol as a solvent for said carrier.

[0013] The present invention further relates to the use of bupivacaine as an anesthetic, sucrose acetate isobutyrate as a pharmaceutically acceptable non-polymeric carrier, and benzyl alcohol as a solvent for said carrier for the preparation of a liquid composition for providing prolonged local anesthesia after administration to a patient, said composition comprising 66% by weight of sucrose acetate isobutyrate, 22 wt% benzyl alcohol and 12 wt% bupivacaine.

[0014] The carrier is a non-polymeric carrier. The carrier is substantially insoluble in water or in an aqueous biological system. The composition then comprises a solvent which is soluble in water or in an aqueous system. The solvent is thus capable of dispersing, diffusing, or eluting from the composition when placed within a biological system, thus the carrier may then form a solid implant in situ.

[0015] The carrier is a liquid. It is a highly viscous liquid carrier material ("HVLCM"), which has a viscosity of at least about 5,000 cP at 37 ° C and which does not crystallize unadulterated 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 lower the viscosity of the HVLCM material.

[0016] The present invention thus provides a composition comprising an anesthetic and a pharmaceutically acceptable non-polymeric carrier. The non-polymeric carrier controls the release of the anesthetic to provide an anesthetic effect characterized by prolonged local anesthesia after administration to the patient, the composition then allowing for a sustained mean steady state plasma concentration (C_pp) anesthetic, which is 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.

[0017] In one aspect of the invention, the composition allows for a sustained mean steady state blood plasma concentration (C_pp) for a period of at least about 48 hours. In another aspect, the composition is then characterized as having no significant initial burst. In still other aspects, the non-polymeric carrier is sufficient to provide either a first order anesthetic controlled release profile or a release profile.

PZ / 1489 / AG EP 1 809 329 Β1 of a pseudo-zero order anesthetic. In a preferred embodiment, the anesthetic is bupivacaine free base.

[0018] In this way, a method is obtained that provides a local effect on the patient. The method comprises administering a composition of the invention at, near, at, or adjacent to the 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, with no initial burst, and a duration of at least about 24 hours after administration.

[0019] In one aspect, the composition is administered by topical administration, transdermal administration, injection, or as an implant at a given site. In some embodiments, a composition is administered to the site of a surgical wound, and the composition is administered to and / or proximal to the wound.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

[0020]

Figure 1 shows the mean plasma levels of bupivacaine over a period of 0 to 144 hours (pharmacodynamic results) of Example, Test Group 1.

Figure 2 shows the mean plasma levels of bupivacaine over 0 to 12 hours (pharmacodynamic results) of Example, Test Group 1.

Figure 3 shows the mean plasma levels of bupivacaine over a period of 0 to 300 hours (pharmacodynamic results) of Example, Test Group 2 where subgroup 3 data is represented by the lower curve (0), subgroup 2 data is represented by the middle curve (□) and subgroup 1 data is represented by the upper curve (Δ).

Figure 4 shows the mean plasma levels of bupivacaine over a period of 0 to 12 hours (pharmacodynamic results) of Example, Test Group 2 where subgroup 3 data is represented by the lower curve (0), subgroup 2 data is represented by the middle curve (□) and subgroup 1 data is represented by the upper curve (Δ).

Figure 5 is the mean "resting" incision site pain scores recorded using the 0 to 100mm Visual Analogue Scale (VAS) of Example, Study Group 2, where subgroup 3 data is represented by the upper curve (Δ), data subgroup 2 is represented by the middle curve (□) and the data of subgroup 1 is represented by the lower curve (O).

PZ / 1489 / AG ΕΡ 1 809 329 Β1

DETAILED DESCRIPTION OF SPECIFIC IMPLEMENTATIONS

[0021] Before describing the present invention in detail, it should be understood that the present invention is not limited to the specific process parameters exemplified, which may, of course, vary. It should also be understood that the terminology used herein is for the purposes of describing particular embodiments of the invention only, and is not intended to be limiting.

[0022] All publications, patents and patent applications cited herein, whether previously described or supra or infra, are hereby incorporated by reference in their entirety.

[0023] It should be noted that, as used herein and in the appended claims, the singular forms also include their plural equivalents, unless the content clearly indicates otherwise. Thus, for example, reference to "non-polymeric carrier" includes a mixture of two or more such carriers, reference to "solvent" includes a mixture of two or more such solvents, and reference to "anesthetic" includes mixtures of two or more such agents, and the like.

[0024] The term "without an initial burst," as used herein, is intended to mean that the particular agent to which the term refers is not released from the composition upon normal administration and does not become pharmacologically available in appreciable amount during a predetermined initial period. time. The presence and level of initial burst of agent in a given composition can be readily determined by one skilled in the art using standard pharmacological testing techniques well known in the art. Suitable in vitro flare-release characterization methods include the USP II "Paddle Method" using standard buffer, agitation and heating conditions. The burst release characteristics of a given composition can also be readily determined using standard in vivo testing, such as monitoring blood plasma concentrations of an agent of interest in an animal patient 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 in 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 time. initial period of time. In certain other preferred embodiments, 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.

PZ / 1489 / AG EP 1 809 329 Β1

[0025] Accordingly, the composition of the present invention comprises one anesthetic, bupivacaine, in a controlled release system that releases the anesthetic over an extended period of time.

[0026] The ability of an anesthetic to provide a state of prolonged local anesthesia refers to the ability of the administered agent to establish an quantifiable local (regional) state of complete or partial inhibition of the sense of sensation and / or motor function. The numerous methods and tools for making such an assessment will readily come to the mind of one of ordinary skill in the art. For non-human animal patients, these methods involve measuring spontaneous movement in a rat assay (using, for example, commercially available equipment and software from Med Associates Inc., St. Albans, VT), which can collect data on total distance traveled, walking count, stereotype, hind leg standing, time spent in various movements, and time spent at rest by test subjects; visualizing the pinprick reaction in rats; and a rat model of hotplate foot removal, e.g., following the procedure detailed in IACUC No. 9511-2199.

[0027] Sensory testing in human patients is also a useful method of assessing the local anesthetic effect. The examination is often focused on three broad areas, mechanical examination (pin prick, von Frey hair), thermal examination (warm, hot, cold) and tactile examination (touch). Such testing techniques are described in the literature. See, for example, Dahl, et al. (1993) Pain 53: 43-51; Moiniche, et al. (1993) Brit. J. of Anesthesia 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 Anesthesia 76 (6): 806-810; and Pedersen, et al. (1998) Pain 74: 139-151. For example, the local anesthetic activity of a test agent can be tested in terms of onset, peak intensity, and duration of effect using specific procedures such as: 1) mechanical sensory testing (mechanical pain detection threshold using von Frey hair; 2 ) supra-threshold (mechanical) single von Frey hair testing; 3) thermal sensory testing (heat detection threshold); 4) heating pain pain threshold; 5) over-threshold testing (heating); 6) cold detection threshold; and 7) tactile sensory testing (mechanical touch detection threshold). These data indicate whether the patient experiences local pain relief, local numbness, and / or local nerve blockage in response to administration of the anesthetic to be tested. The pain response can be characterized using a verbal rating scale from 0 to

PZ / 1489 / AG EP 1 809 329 Β1 (e.g. where 0 = no pain and 10 = worst imaginable pain) or a visual analog scale from 0 to 100 mm (e.g. where 0 = no pain and 100 mm = worst pain imaginable).

[0028] A non-polymeric carrier material, SAIB, is used for the controlled release of the anesthetic from the compositions of the present invention so as to provide sustained local anesthesia starting within about 2 hours after administration and for a duration of at least about 24 hours or longer.

[0029] SAIB HVLCM reduces its viscosity 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 typically easier to place in the body than the HVLCM composition because it flows in and out of syringes or other implant means more easily. It can also be easily formulated into an emulsion.

[0030] Sucrose acetate isobutyrate can be prepared following the procedures described in US Pat. US U.S. Patent No. 2,931,802.

[0031] The solvent is at least water-soluble and will therefore rapidly diffuse into body fluids or other aqueous medium after administration, causing the composition to coagulate and / or increase its viscosity.

[0032] The compositions of the present invention are used to provide prolonged local anesthesia at a target site. In particular, the compositions are formulated into a liquid and then administered to the patient by topical, transdermal, parenteral (e.g., injection, implant, etc.) or similar delivery techniques. Compositions, comprising an anesthetic and a pharmaceutically acceptable non-polymeric carrier, are used to provide an anesthetic effect characterized by prolonged local anesthesia after administration to the patient without initial burst and a duration of at least about 24 hours post-administration, preferably at least about 36 to 48 hours post-dose. administration, and more preferably at least about 48 to 72 hours after administration. In some embodiments, initiation of local anesthesia occurs within about 2 hours of administration to the patient, preferably within about 1 hour of administration, and in some cases within about 30 minutes of administration to the patient.

[0033] The term "patient" as used herein refers to any vertebrate in which it is desired to provide a state of local anesthesia. Thus, this term generally refers to any animal that can 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 sustained delivery

PZ / 1489 / AG ΕΡ 1 809 329 Β1 anesthesia in veterinary practice and zootechnics, e.g., birds and mammals, whenever a long-term state of local anesthesia is convenient or desirable. In some cases, the compositions are particularly suitable for use with companion animals such as dogs or cats, and may additionally be used with horses. In preferred embodiments, the term "patient" is intended to refer to a human patient. Moreover, the term "patient" does not indicate any particular age, and thus the compositions are suitable for use with patients of any age, such as infant, adolescent, adult and elderly patients.

[0034] In preferred embodiments, the compositions of the present invention are particularly suitable for use in the treatment of wounds. The non-polymeric carrier systems allow easy application of the anesthetic to the wound, either directly inside the wound and / or adjacent to the wound, using very simple application techniques such as dripping, spraying, painting, coating, molding or otherwise manually manipulating the liquid composition into the wound. hurts. The compositions can therefore be applied to wounds of any size and shape, and will provide an even distribution of the anesthetic throughout the wound area for improved containment and efficiency. Wounds that can be treated using such methods can range from the most superficial to deep, from superficial wounds to fragmentary wounds, and from surgical (or other deliberate) wounds to accidental wounds. If the composition is to be injected, it can be applied to the subcutaneous space by means of drainage injection along the wound at all sides or outside the border area. Combined approaches may also be used, such as in which the composition is both applied directly to the wound, e.g., prior to surgical closure of the wound, and additionally along the length of the wound. In a particularly preferred embodiment, the "stand-by" compositions are for use as a local anesthetic for the treatment of post-operative incision pain. Thus, the use of the compositions of the present invention avoids or at least reduces the need to provide additional therapies such as systemic administration of narcotic analgesics to treat such post-operative pain. Accordingly, the compositions can be used to treat post-operative pain that accompanies all types of medical procedures, such as major surgery (e.g. thoracic dissection, aortic repair, bowel resection), indirect surgical operations (e.g., caesarean section, hysteroctomy, and appendectomy), and minor surgical operations (laparoscopy, arthroscopy, and biopsy procedures) that may otherwise be debilitating and debilitating may require pain management for 3 to 5 days after surgery.

PZ / 1489 / AG EP 1 809 329 Β1

[0035] In addition to the uses described above, the compositions of the present invention may be administered using osmotic pumps. In one embodiment, the device is designed to be implanted into the tissue of a patient, and intended to provide a sustained release effect over time.

[0036] It is also possible to administer the composition of the invention using a porous or non-porous tube, preferably made of an extruded biodegradable polymer. The tube can be manufactured with varying degrees of porosity depending on the characteristics of the composition and the desired release characteristics. The composition of the invention is inserted into a tube and the ends of the tube may be left open allowing the biologically active compound to diffuse outwardly from the tube ends, or may be plugged with additional porous or non-porous polymer. Porous plugs and porous tubes allow the active ingredient to diffuse through the pores over time. The non-porous plugs as well as the non-porous tubes allow the diffusion of anesthetic agents that are soluble in the polymer through the polymer and into the surrounding tissues. Non-porous materials that are not solvents for the anesthetic but that are biodegradable will release the anesthetic when sufficiently degraded. The compositions of the invention may be manufactured and stored in multi-component systems until ready for administration. Prior to administration, the ingredients are combined and mixed, e.g., to obtain a homogeneous composition which can then be administered to a patient. The solvent may be added to one or all of the ingredients, or it may form a separate ingredient that is also mixed with the other ingredients prior to administration. Separating the composition into a multi-component mixture allows the storage conditions to be optimized for each component and minimizes any detrimental interactions between the components over time. The result is increased storage stability.

EXAMPLE

[0037] The following is an example of a specific embodiment for carrying out the present invention.

General meotdy

[0038] The in vivo efficacy of the compositions of the invention can be assessed in a rat hotplate model, e.g., according to the procedure detailed in IACUC No. 9511-2199. The performance criteria established for the compositions of the invention include the following: mean latency greater than about 2 seconds, with a 12 second limit (this limit was imposed to prevent any possible damage to

PZ / 1489 / AG EP 1 809 329 Β1 animal). The latency times of 2 seconds demonstrate the statistically significant effect of the local anesthetic. Preferably, the mean latency in the rat hotplate model is greater than 7 seconds. Preferably, the percentage of responders is 50% or more. Preferably, the compositions of the invention provide a mean latency in the rat hotplate model of greater than about 7 seconds to about 12 seconds, with a percentage of rats exhibiting an effect of at least about 50% of those tested.

[0039] The methodology of the rat hotplate model is summarized below. Male Sprague Dawley rats (Harlan Laboratories, Indianapolis, Ind.) With an average body weight of 275 g are used in the study. The hot-plate test involves gently holding the animal's body while the plantar surface of the hindpaw is placed on a hot plate heated to a temperature 56O. Basal lag is determined prior to unilateral injection of the anesthetic composition around the rat sciatic nerve.

[0040] Sensory testing in human models is also useful in testing the compositions of the present invention. Local anesthetic activity can be tested in terms of onset, peak intensity and duration of effect using seven specific procedures, such as: (a) mechanical sensory testing (mechanical pain detection threshold using von Frey hair; (b) supra-threshold (mechanical) single von Frey hair testing (c) thermal sensory testing (heat detection threshold); (d) heat pain pain sensing threshold; (e) over-threshold (heating) testing; (f) cold detection threshold; and (g) tactile sensory testing (mechanical touch detection threshold). Varying grades or levels of scores will indicate whether the patient is experiencing local pain relief, local numbness, and / or local nerve blockage. The anesthetic activity of the compositions of the invention can then be characterized for safety using various measures of activity, such as systemic blood plasma levels obtained when administered at a given site.

[0041] Mechanical Pain Detection Threshold is defined as the least force or number of von Frey hairs that produce a particular sensation of pain or discomfort, and Mechanical Touch Detection Threshold is defined as the least force or number of von Frey hairs that produce the sensation of pain or discomfort. touch or pressure. Mechanical Tactile Detection Threshold and Mechanical Pain Detection Thresholds can be determined concurrently using von Frey Gradual Varying Stiffness (VFH) hair (available from Somedic A / B, Stockholm, Sweden). It has previously been determined that each VFH hair pressed against the weight until it is gently bent represents a force that increases logarithmically with each hair, covering a total range of 3 to 402 millinewtons.

PZ / 1489 / AG ΕΡ 1 809 329 Β1 (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 # 12 = 98mN; VFH # 13 = 128mN; VFH # 14 = 133mN; VFH # 15 = 314mN; VFH # 16 = 350mN; VFH # 17 = 402mN).

[0042] Accordingly, in a human patient, the area into which the composition of the present invention is injected can be stimulated 8 times using each VFH hair at a rate of about 2 stimuli per second, starting with VFH hair No. 7 and moving to the VFH hair No. 17. The smallest VFH hair number that is felt as a touch or pressure (mechanical touch detection threshold) and the smallest hair number at which half of the eight stimulations are painful or unpleasant (mechanical pain threshold) are recorded. The procedure is repeated two more times and the median of the three measurements is recorded. In the event that VFH hair No. 17 does not feel like touch or pressure, then a Mechanical Touch Detection Threshold value of 18 will be assigned. If VFH hair No. 17 does not cause any pain or discomfort, then a Mechanical Pain Detection Threshold value of 18. The supra-threshold pain response to a mechanical stimulus induced by a single von Frey hair is determined by stimulating the injected areas with VFH # 17 hair (402 mN) five times. The patient estimates pain using a VRS scale from 0 to 10, where zero (0) = no pain and ten = (10) pain as intense as imaginable.

[0043] As discussed above, this test is performed using a single stiff von Frey hair that has been determined to cause a painful response in patients. Pain response is determined by stimulating the injected or otherwise treated area 5 times with VFH hair No. 17. Patients rate pain using a 0 to 10 verbal rating scale (VRS) as above.

[0044] Thermal testing (supra-threshold pain-heat response) in the treated area is determined by a 45 ° thermal stimulus lasting 5 seconds using a computerized thermode (available from Thermostest, Somedic A / B, Stockholm, Sweden). ) applied to the treated areas. The patient assesses pain using a 0 to 10 Verbal Rating Scale (VRS).

[0045] Heat Detection Threshold is defined as the smallest perceived temperature rise from 32 ° C, and Heat Pain Detection Threshold is defined as the lowest temperature felt as painful, while Cold Detection Threshold is defined as the lowest perceived temperature drop from 32 ° C. Heat Detection Threshold, Heat Pain Detection Threshold and

PZ / 1489 / AG EP 1 809 329 Β1 Cold Detection Threshold is determined using a Thermostest computerized device (available from Somedic A / B, Stockholm, Sweden) in the treated areas. Patients are instructed to press a button as soon as the specified impression is achieved. Thermal thresholds are determined from a tolerance level of 32X3 as the temperature increases (Heat Detection Threshold and Heat Pain Detection Threshold) or lowers (Cold Detection Threshold) at a rate of change in temperature of 1X3 per second. The upper limit is 52C for the Heat Detection Threshold and the Heat Pain Detection Threshold. The lower limit is 25C for the cold detection threshold.

[0046] Heat Detection Threshold; The Heat Pain Detection Threshold and the Cold Detection Threshold are calculated as the median of the three measurements, with time intervals of 10 seconds between each stimulus. If the patient feels no heat or pain at 52C, the 53C value is recorded for the heat detectability threshold; if the patient is pain-free up to 52X3, a value of 53X3 is recorded for the Heat Pain Detection Threshold; and if the patient does not feel any cold or pain at 25X3, the value of 24X3 is recorded for the cold sensing threshold. Example

[0047] The following dose escalation, pharmacokinetic, pharmacodynamic (efficacy) assessment was performed in human patients who had undergone surgical inguinal hernia repair procedures to evaluate the efficacy and pharmaceutical performance of controlled release bupivacaine compositions containing sucrose acetate isobutyrate as a non-polymeric carrier and prepared according to the present invention. The study compared the efficacy of the present SAIB / bupivacaine compositions administered subcutaneously in combination with saline (placebo) or as a wound infiltration with 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) by subcutaneous injection and as an infiltrate in patients undergoing inguinal hernia repair surgery.

[0048] The test composition was / is formulated using bupivacaine free base, formulated in sucrose acetate isobutyrate (SAIB) non-polymeric carrier, then containing benzyl alcohol (BA), which serves as a solvent for the bupivacaine and the SAIB carrier. Benzyl alcohol is also an anesthetic. The composition was / is prepared by combining about 66% by weight of SAIB carrier, 22% by weight of benzyl alcohol solvent / anesthetic, and 12% by weight

1 by weight of bupivacaine to provide discrete doses containing 159.5 mg of bupivacaine in 1.25 ml injection volume (319 mg in 2.5 ml total volume). The composition was / is provided in the form of a clear liquid for injection.

[0049] The study is intended to cover 3 test groups with up to 91 patients (6 patients for test group 1; 15 patients for test group 2; and up to 70 patients for test group 3). In particular, test group 1 consisted of 6 healthy men ranging in age from 23 to 52 years. In study group 1, all patients received 2.5 ml of a total injection volume of SAIB / BA / bupivacaine (containing 319 mg bupivacaine), administered as two subcutaneous drip injections along each side of the surgical wound (0.5 ml / cm along the suggested 5 cm of the total length of the incision wound), using 10 ml of saline infused into the incision wound (including the subfascial incision) before closing the wound. Drain injections were administered as follows: 0.5 to 1.0 cm from and parallel to the wound edge of the incision, and were performed by subcutaneous insertion of the needle parallel and along the length of the incision, injecting continuously as the needle was withdrawn. Anesthetic / analgesic effect was assessed using the Time to First Supplemental Analgesic Medication test and the Total Supplemental Analgesic Medication Consumption Test (over the next 4 days). Plasma bupivacaine concentrations were measured periodically throughout the study period, particularly the first 24 hours to estimate the amount of early bupivacaine release from the SAIB controlled release composition.

[0050] The test results for the time to first administration of additional analgesic drug are shown in Table 1 below.

Table 1. Time to first administration of additional analgesic treatment

<td>Patient #</td><td>Time until your first painkiller is taken</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>Three hours</td>

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

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[0051] The results of the total consumption test of additional analgesic drug (over the next 4 days) are shown in Table 2 below.

Table 2. Total Consumption of Additional Analgesic Drug

<td>Patient #</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>

[0052] It was found that the SAIB / BA / bupivacaine composition was well tolerated, with injections not causing any visible redness, swelling, itching, discoloration or any other adverse symptoms at the injection site, or any unacceptable tissue reaction throughout the duration of the injection. research. In addition, pharmacokinetic evaluations of bupivacaine showed sustained release of the active ingredient bupivacaine from the SAIB carrier, with release of active bupivacaine over a period of 4 days. The results of the pharmacokinetic studies are shown in Figures 1 and 2. As can be seen, the SAIB / BA / bupivacaine composition released active bupivacaine rapidly (within about 1 hour of administration) without an initial burst, and showed substantially steady state release for at least the first 3 days after treatment. Observed means C_hasx was 277 ng / ml ± 109; T._max was 23 hours ± 21; and C._pp was 191 ng / ml ± 13.

[0053] Study group 2 consisted of 15 healthy men, aged 26 to 54 years. Study group 2 was divided into three subgroups, the first subgroup (n = 5) received 5.0 ml of the total injection volume of the SAIB / BA / bupivacaine formulation (containing 638 mg bupivacaine) administered as two subcutaneous drainage injections along each side of the surgical wound (0.5 ml / cm along the suggested 5 cm total length of the incision wound) using 10 ml of saline infused into the incision wound (including the subfascial incision) prior to wound closure. The second subgroup (n = 5) received 5 mL of the total injection volume of SAIB / BA / bupivacaine (containing 638 mg bupivacaine) administered as two subcutaneous drip injections along each side of the surgical wound (0.5 mL / cm along the suggested 5 cm the total length of the wound

PZ / 1489 / AG ΕΡ 1 809 329 Β1 incisions), using 10 ml of Marcain® (0.5% Bupivacaine-HCl) infiltrated into the wound of the incision (including the subfascial incision) before wound closure, for a total of 688 mg of administered bupivacaine per patient . The third subgroup (n = 5) received 5 ml of total injection volume of Marcain® (0.5% Bupivacaine-HCl) administered as two subcutaneous drip injections along each side of the surgical wound (0.5 ml / cm along the suggested 5 cm total incision wound length) together with 10 ml of Marcain® infused into the incision wound (including the subfascial incision) prior to wound closure for a total of 75 mg of administered bupivacaine per patient.

[0054] Anesthetic / analgesic effect was assessed using the Time to First Supplemental Analgesic Medication test, incision site pain "at rest", and Total Supplemental Analgesic Medication. Consumption test) (within the next 4 days). Plasma bupivacaine concentrations were measured periodically throughout the study period, particularly the first 24 hours to estimate the amount of early bupivacaine release from the SAIB controlled release composition.

[0055] The results of the test of time to first administration of additional analgesic drug and test of total consumption of additional analgesic drug (within 4 consecutive days) for all three subgroups of study group 2 are shown below in Table 3.

Table 3. Mean time to first administration of additional analgesic drug and mean total use of additional analgesic drug (over 4 consecutive days)

<td>Subgroup</td><td>Number of patients</td><td>Treatment</td><td>Average time to first administration of additional pain medication</td><td>Average number of doses of additional pain reliever medication in 4 days</td>

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

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

<td> 3</td><td>n = 5</td><td>Marcain® (75 mg total dose)</td><td> 2,3</td><td> 11,0</td>

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

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[0056] Again, the SAIB / BA / bupivacaine composition was well tolerated (patient subgroup 1 and 2) and the injections did not cause any visible redness, swelling, itching, discoloration or any other adverse symptoms at the injection site, or any unacceptable symptoms. tissue response throughout the test. In addition, pharmacokinetic evaluations of bupivacaine showed sustained release of the active ingredient bupivacaine from the SAIB carrier, with active bupivacaine being released over a period of 4 days. The results of the pharmacokinetic studies are shown in Figures 3 and 4. As can be seen, the SAIB / BA / bupivacaine composition released active bupivacaine rapidly (within about 1 hour of administration) without an initial burst, and showed substantially steady state release for at least the first 3 days after treatment.

[0057] The results of the pharmacodynamic studies for all three subgroups of test group 2 are shown in Table 4 below.

Table 4. The results of pharmacodynamic studies for the study group 2

<td>Subgroup</td><td>Number of 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>SAIB / BA / Bupivacaine and saline (638 mg total dose)</td><td> 470±155</td><td> 21 ±25</td><td> 311 ±58</td>

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

<td> 3</td><td>n = 5</td><td>Marcain® (75 mg total dose)</td><td> 180 ±88</td><td> 0,6 ±0,2</td><td>ON</td>

[0058] As can be seen from the results of the group 2 study, the on-the-spot controlled release compositions provide an effective local anesthetic effect for at least 4 consecutive days after surgery, greatly reducing the need for additional painkillers. In fact, 50% of the patients receiving the SAIB / BA / bupivacaine compositions of the present invention (5 out of 10 patients in subgroups 1 and 2) required no additional analgesics for the entire 4 day period. Patients in subgroups 1 and 2 who did not require additional analgesics could still wait for their first additional analgesics for approximately 2-3 days, demonstrating effective local anesthetic effect for at least 2 consecutive days after surgery. In addition, the number of doses of additional analgesic drugs in subgroups 1 and 2 decreased dramatically compared to the control group (subgroup 3) of patients who

They required an average of 11 doses over the 4 day testing period, as opposed to 2.4 to 2.6 doses for the same time period.

[0059] Moreover, a review of the pharmacokinetic data from test group 2 suggests that an effective subcutaneous dose of 638 to 688 mg of bupivacaine can be repeatedly administered using the controlled release composition of the present invention to provide an effective steady state blood plasma concentration of bupivacaine of about 300 ng / ml.

[0060] The results of the incision site pain test "at rest" for all three subgroups of study group 2 are illustrated in Figure 5. Subgroup 3 data is represented by the upper curve (Δ), subgroup 2 data is represented by the middle curve ( □) and subgroup 1 data is represented by the lower curve (O). For convenience, the mean elapsed time to administration of the first additional analgesic is shown on each curve. Incision pain intensity was recorded using a 0 to 100 mm visual analog scale (VAS) using a scoring system from 0 (no pain) to 100 (worst pain imaginable). Each VAS result was recorded as a single vertical line on the scale. The test was conducted as follows. On the day of surgery (day 0), incision pain scores were initially recorded within 60 minutes after administration of the test composition (as discussed above, subgroup 1 received SAIB / BA / bupivacaine and saline; subgroup 2 received SAIB / BA / bupivacaine and Marcain) ®; and subgroup 3 received Marcain® and Marcain®). Thereafter, incision pain scores were recorded every 30 minutes for the 4 hour evaluation time, then hourly for the 8 hour evaluation time, and finally at the 12 hour evaluation time. On the following days 1 to 3, incision pain scores were recorded in the morning based on the time the test composition was administered on day 0. These continued measurements were performed at 4 hour intervals over a 12 hour evaluation period (4 measurements). The duration of use of any concomitant (additional) drugs was also recorded during this 4-day evaluation.

[0061] As can be seen by reviewing the incision site pain evaluation test results illustrated in Figure 5, both subgroups that received the tested SAIB / BA / bupivacaine compositions (subgroups 1 and 2) showed lower mean VAS scores at all times throughout the test compared to to the group that received the test Marcain® composition (subgroup 3). These results show that the compositions of the present invention provide prolonged local anesthesia at the incision wound site for a duration of at least about 36 to 48 hours after administration to the patient.

[0062] Patients for test group 3 will be divided into 2 treatment subgroup. The first subgroup will receive 7.5 ml of the total injection volume of the composition

PZ / 1489 / AG ΕΡ 1 809 329 Β1

SAIB / BA / bupivacaine (containing 958 mg bupivacaine), administered as two subcutaneous drip injections along each side of the surgical wound (0.75 ml / cm along the suggested 5 cm total incision wound length) with 10 ml Marcain® (0.5% Bupivacaine -HCI) of the infiltrated incision (including the subfascial incision) prior to wound closure, for a total of 1.008 mg of administered bupivacaine per patient. The second subgroup would receive 7.5 ml of the total injection volume of Marcain® (0.5% Bupivacaine-HCl) administered as two subcutaneous drip injections along each side of the surgical wound (0.75 ml / cm along the suggested 5 cm total incision wound length) together with 10 ml of Marcain® infused into the wound of the incision (including the subfascial incision) prior to wound closure, for a total of 87.5 mg of administered bupivacaine per patient.

[0063] Anesthetic / analgesic effect will be assessed using the Time to First Supplemental Analgesic Medication test and the Total Supplemental Analgesic Medication Consumption Test (within the next 4 days) . Plasma bupivacaine concentration will be measured periodically throughout the study period, particularly the first 24 hours to estimate the amount of early release of bupivacaine from the SAIB controlled release composition. It is expected that a higher dose of the controlled release SAIB / BA / bupivacaine compositions prepared according to the present invention will provide similar or even better efficacy results as compared to those obtained by the test subjects in test group 2.

[0064] It will be understood that the present invention so described, variations and modifications thereof as would be apparent to those skilled in the art, fall within the scope of the appended claims.

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