pharmaceutical composition in the form of emulsion or microemulsion

专利摘要:
EMULSIONS OR MICROEMULSIONS FOR USE IN ENDOSCOPIC MUCOSA RESECTION AND / OR ENDOSCOPIC DISSECTION OF THE SUBMUCOSA The invention provides a pharmaceutical composition in the form of an emulsion or microemulsion for use in an endoscopic procedure, where the endoscopic procedure preferably comprises the administration of the pharmaceutical composition to a human being. The invention described herein provides a method for performing an endoscopic procedure, the method preferably comprising administering a pharmaceutical composition in the form of an emulsion or microemulsion to a human.
公开号:BR112016011345B1
申请号:R112016011345-4
申请日:2014-11-18
公开日:2021-01-05
发明作者:Luigi Maria Longo；Luigi Moro；Enrico FRIMONTI；Alessandro REPICI
申请人:Cosmo Technologies Ltd.；
IPC主号:

专利说明:

[0001] The present invention relates to a pharmaceutical composition in the form of an emulsion or microemulsion and its use as an aid during endoscopic procedures in which it is injected into a target tissue in order to form a pillow. In more detail, the invention relates to a method for performing an endoscopic procedure, which comprises injecting the pharmaceutical composition in the form of an emulsion or microemulsion into a target tissue of a patient, in order to form a pillow, in which pillow is then optionally subjected to an endoscopic surgical procedure, such as resection. BACKGROUND OF THE INVENTION
[0002] Endoscopy is a medical diagnostic procedure that allows you to examine the inside of a hollow organ or body cavity using an instrument called an endoscope, without using invasive surgery. Endoscopy is used for diagnostic purposes, although minor non-invasive surgical and non-surgical interventions can be performed during an endoscopic procedure. Typically, minor interventions include cauterizing a bleeding vessel, enlarging a narrow esophagus, removing polyps, adenomas and small tumors, conducting biopsies, or removing a foreign object. Endoscopy is used by specialists to examine, for example, the gastrointestinal tract, the respiratory tract, the ear, the urinary tract, the female reproductive system and, through small incisions, normally closed body cavities, such as the abdominal cavity or pelvic (laparoscopy), the interior of a joint (arthroscopy) and the organs of the chest (thoracoscopy and mediastinoscopy). The endoscope is a flexible or rigid tubular instrument illuminated by fiber, usually optics, for visualizing the interior of a hollow organ or part thereof (such as the bladder, stomach, intestine or esophagus) for diagnostic or therapeutic purposes, which typically has , one or more working channels to allow the passage of instruments (such as tweezers, electrosurgical knife, endoscopic injection needles or scissors) or to facilitate the removal of biotic samples. It includes a suitable lamp and imaging device in its distal part, which can be inserted through naturally occurring openings in the body, such as the mouth, anus, ear, nose or through small surgical incisions. Given the wide variety of organs or body cavities that can be examined by endoscopic procedures, various types of endoscopes are found, such as, for example, laryngoscope, thoracoscope, angioscope, colonoscope, enteroscope, sigmoidoscope, rectoscope, proctoscope, anoscope, arthroscope, rhinoscope, laparoscope, hysteroscope, encephaloscope, nephroscope, esophagoscope, bronchoscope, gastroscope, amnioscope, cystoscope.
[0003] In particular, endoscopic procedures are widely applied in the gastrointestinal tract, either for diagnostic purposes or for minor surgical interventions. With the advancement and progress of imaging technology, endoscopic procedures can be used to accurately analyze the mucosa covering the gastrointestinal cavities and to detect small and large pathological lesions, such as inflamed tissue, polyps, pseudo-polyps, serrated lesions , adenomas, ulcerations, dysplasias, pre-neoplastic and neoplastic formations, tumors and the like. In addition, endoscopic procedures in the gastrointestinal tract allow the physician to perform minor interventions, surgical or non-surgical, which include, for example, biopsies and removal of pathological lesions (polyps, adenomas, dysplasias, Barrett's dysplasia, pre-neoplastic formations and neoplasms, tumors). Surgical interventions include two endoscopic resection procedures commonly used in digestive endoscopy to remove pathological lesions, which are endoscopic mucosal resection (EMR) and endoscopic submucosal (ESD) dissection. These two techniques have provided new alternatives for the minimally invasive treatment of gastrointestinal polyps, adenomas, dysphalias (such as Barrett's dysplasia) and early-stage cancer, which involve a minimal risk of lymph node metastasis. EMR is an endoscopic surgery for the removal of sessile or flat neoplasms confined to the superficial layers (mucosa and submucosa) of the GI tract. EMR is usually used for the removal of lesions smaller than 2 cm or the gradual removal of larger lesions. EMR also plays an important role in the evaluation of resected specimens for accurate pathological staging. In contrast to polypectomy, EMR involves elevating an injury to the muscle layer by injecting a fluid agent, usually common saline (NS), into the submucosal layer. EMR is also useful for obtaining samples for accurate histopathological staging, to determine the risk of lymph node metastasis. EMR facilitates the complete removal of the affected mucosa by excision through the middle or deep portion of the submucosa of the intestinal wall. Several EMR techniques have been described and four methods involving loop resection are commonly used: (1) the cut and inject method; (2) injection, lifting and a cutting method; (3) cap-assisted EMR (EMRC); and (4) EMR with ligation (EMRL). The injection and cutting technique, also known as submucosal injection polypectomy, has become widely used in recent years due to its simplicity. The diseased mucosa is lifted from the muscle layer, creating a submucosal fluid cushion, captured, strangled using an electrosurgical loop and then resected. However, an injection into the thin submucosal layer is a delicate process, the injected solution tends to dissipate quickly, flat and depressed lesions are difficult to capture with the loop compared to protruding lesions, and large lesions or lesions located in places of difficult access can be difficult to remove (Uraoka et al., Drug Design, Development and Therapy 2008: 2 131-138). Injection-assisted EMR is often used for large colon polyps that are flat. Endoscopic submucosal dissection (ESD), a relatively new procedure for endoscopic resection, was developed specifically for the removal of larger lesions. Lesions are dissected directly along the submucosal layer using an electrosurgical knife, resulting in a block resection of lesions, even large ones. ESD has been predicted to be able to replace conventional surgery to treat certain cancerous stages, but since it has a higher rate of perforation and bleeding complications than conventional EMR, a greater degree of skill and endoscopic experience is required than with the EMR procedure. Several solutions for submucosal injection have been previously developed and have proved satisfactory for use during EMR, but the introduction of the long ESD procedure requires a more lasting solution to help identify the cut line during dissection of the submucosal layer (Uraoka et al., Drug Design, Development and Therapy 2008: 2 131-138).
[0004] The use of submucosa injection is essential for a successful EMR, considering that the injection of fluid into the submucosa pads facilitates the isolation of the tissue to be removed from it before the capture of the target lesion with a trap, reducing thus the thermal injury and the risk of perforation and hemorrhage and, at the same time, facilitates en bloc resection. Submucosal injection is considered to play an important role in the EMR process, and the "ideal" submucosal injection solution must be both long-lasting and capable of producing a hemispherical shape to facilitate capture. In addition, providing a sufficiently high submucosa altitude is important for safe submucosa cutting during the ESD procedure (Uraoka et al, Drug Design, Development and Therapy 2008: 2. 131-138).
[0005] The ideal solution for injection-assisted EMR should be safe, inexpensive, non-toxic, easily available, easy to inject and should be able to provide a high, long-lasting level of submucosal pad. The characteristics of wound healing should also be considered to facilitate the closure of the wound created by the removal of the dried mucosa, as well as the presence of a coloring agent (such as a dye) that will allow the depth of the submucosal layer to be more easily distinguished, avoiding improper drilling during ESD.
[0006] Common saline solution (NS) has been commonly used for this purpose, but with it it is difficult to produce an adequate submucosal fluid cushion and maintain the desired height, particularly for high flat lesions, because of the rapid dispersion of the solution through the mucosal layers and absorption of the saline solution by the surrounding tissue (Uraoka et al, Drug Design, Development and Therapy 2008: 2 131-138). For this reason, in long-term procedures and in the removal of large lesions, such as large flat polyps, a repeated injection of the solution into the submucosal layer is necessary, with a consequent operational complication for the personnel of the endoscopic unit.
[0007] In order to overcome this rapid disappearance of the cushion, which represents a typical problem encountered with the use of NS, during the last decade several types of solutions have been described and tested for use in solution-assisted EMR. Each type of solution has its advantages and disadvantages. For example, hyaluronic acid (HA) solutions have been reported to be the best agents for submucosal injections. HA solutions provide long-lasting fluid pads and enable great success in block resections and low drilling complication rates. In addition, HA is safe and non-toxic, as it is a physiological component of the extracellular matrix. The main disadvantage of HA is its high cost, which makes it quite inaccessible for many endoscopic units. Other solutions have been tested and described, such as hypertonic dextrose and hydroxypropyl methylcellulose (HPMC, English, hypertonic dextrose and hydroxypropyl methylcellulose), which however have been reported to cause tissue damage and inflammation. Another injection solution recently investigated was a fibrinogen (FM) mixing solution, which has a high viscosity and produces a long-lasting submucosal elevation, thus reducing the number of injections per injury and shortening process times. In addition, the FM mix is inexpensive. The main disadvantage of FM is the possible risk of virus transmission; since FM is obtained through the fragmentation of coagulation proteins in human serum, contamination with hepatitis or other viruses is possible. As noted above, an ideal solution for EMR and ESD has not yet been developed and much research in this area is still ongoing.
[0008] Ideally, viscous solutions, such as HA solutions or HPMC solutions could meet the requirements of endoscopic resection processes, as these can provide a high, long-lasting cushion due to the low tendency for water coordinated by these polymers diffuse and spread to the tissues surrounding the lesion. However, the use of viscous solutions, such as HA solutions or HPMC solutions, brings some problems to the process, due to the difficulty of obtaining a viscous solution that flows through the injection devices. As a matter of fact, in gastrointestinal EMR and ESD procedures, injections of cushion-forming solutions are performed using endoscopic injection needles. As is well known in the art, endoscopic injection needles are devices that can be up to about 230 cm long and include a relatively long catheter inside which an inner injection tube having a sliding injection needle distal is arranged. A proximal acting manipulator is coupled to the catheter and the injection tube to move in relation to each other when necessary. Fluid access to the injection tube is usually provided through a luer connector on your wrist. Endoscopic injection needle devices are usually presented at the injection site, through the working channel of the endoscope. In order to protect the lumen of the endoscope's working channel from damage, the infusion needle device's grip is manipulated to withdraw the injection needle into the distal lumen of the catheter before inserting the device into the endoscope. This is important to avoid exposing the sharp tip of the injection needle as the device is moved through the endoscope lumen. When the distal end of the endoscopic injection needle device is located at the injection site, its identifier is again manipulated to move the injection needle distally out of the catheter lumen. When advanced to the most distal position, the exposed portion of the injection needle is approximately 4 to 6 mm in length. After the injection site has been punctured, the solution, usually contained in a 5 ml to 10 ml syringe provided with a luer-lock fitting attached to the injection needle handle, is presented through the injection tube and needle at the injection site. injection.
[0009] The injection needle and other accessories commonly used during endoscopic procedures, such as polypectomy traps, stapling devices, biopsy forceps and the like, are passed through one or more specific channels of the endoscope, usually called work channels or operating channels. Depending on the type of endoscope used in endoscopy of the gastrointestinal tract (for example gastroscope, enteroscope, colonoscope, duodenoscope, sigmoidoscope and the like), the internal diameter of the working channels can vary considerably. However, the most common endoscopes used in gastrointestinal endoscopy have working channels with an internal diameter in the range of about 2 mm to about 5 mm. Generally, manufacturers of endoscopic accessories produce accessories with external diameters that allow them to adjust all working channels. In particular, with regard to endoscopic injection needles, the outside diameter of the catheter ranges from 1.9 mm to 2.3 mm. Thus, considering that the inner injection tube is contained outside the catheter, its internal diameter is usually 1 mm or less. Such a small injection tube diameter causes a high dynamic resistance in terms of the flow of the solution, an aspect that is most observed and important when a viscous solution is used. For this reason, the viscous solutions used for EMRs and ESDs often need to be diluted before use, to make the solutions capable of flowing through the injection needle, with a loss of their characteristics of providing a high and long-lasting level. the cushion. To overcome this problem, WO2011 / 103245 A1 describes a kit and a method for delivering an injectable solution to a tissue treatment site for use in ESD. The kit includes a housing having a chamber, a proximal portion and a distal portion. A solution for injection with a viscosity greater than about 10,000 cP is provided in the chamber. The kit also includes a movable plunger positioned inside the proximal portion of the chamber, the plunger provides a seal on the proximal end portion. A pressure gauge is also provided with the kit. The strap is connected to the housing and a plunger advancing element having a plunger manipulator that is connected to it. The piston advance element is provided separately from the housing and includes a distal portion configured to operatively connect with the proximal portion of the housing. The kit also includes an internal shaft supplied separately from the housing and which has a proximal end portion configured to operatively connect with the distal portion of the housing, to receive the solution for injection through it, and a distal end configured for insertion into the site of fabric treatment. As a person skilled in the art will recognize, such a device allows the physician to apply a much higher pressure than when using a normal syringe, thus allowing the high viscosity solution, with a viscosity of 10,000 cP or greater, to flow into the injection tube. In addition, WO2011 / 103245 A1 discloses that materials suitable for inclusion in the solution for injection include methylcelluloses, such as carboxymethyl cellulose (CMC) and hydroxypropylmethylcellulose (HPMC), extracellular matrix proteins, elastin, collagen, gelatin, fibrin, agarose and alginate or mixtures thereof. However, the use of such a "high pressure" generation device during endoscopic examination is known to not be favorably accepted by experts in this technique, since it is complicated, that additional work is needed to put it in place , which is difficult to be operated on and which, therefore, represents a complication in EMR and ESD procedures.
[0010] Another attempt to overcome these problems is described in WO2009 / 070793 A1, which describes the use of inverse thermosensitive polymers purified in EMR. As is well known in the art, inverse thermosensitive polymers are polymers that, after dissolving in solvents (such as water) and in a concentration above the critical micellar concentration (CMC), provide solutions that show inverse viscosity characteristics, which means that the solutions show an increase in their viscosity with temperature. In particular, the polymer solutions form gels above the CGC (critical gelation concentration), when the temperature is raised above the CGT (critical gelation temperature). Gelling is due to physical entanglement and packaging of micellar structures and is reversible, so the gel changes back to a liquid form when the temperature is reduced below the critical gelling temperature. Polymers of this type are well known in the art and comprise, for example, poloxamers (marketed by BASF under the brand name Kolliphor®) and poloxamines (marketed by BASF under the brand name Tetronic®). Aqueous solutions of polymers in concentrations higher than CGC can be liquid at room temperature and can form a gel when heated to body temperature (ie, about 37 ° C). WO2009 / 070793 A1 discloses the use of a composition comprising a reverse thermosensitive polymer purified in an endoscopic procedure for resection of the gastrointestinal mucosa. The composition, called LeGoo-endo®, is an aqueous solution of purified poloxamer 237, in which the liquid is described as having a rapid reversible transition to gel as a result of its purified nature and allows the LeGoo-endo® to be liquid in room temperature and become a single gel as it emerges from the catheter at the EMR site, as the solution is warmed to body temperature. WO2009 / 070793 A1 teaches that, in order to obtain the rapid transition from liquid to gel, it was necessary to use a purified poloxamer and that the purified poloxamer was obtained by a purification process aimed at obtaining a purified polymer characterized by less polydispersity of its molecular weight. In addition, WO 2009/070793 A1 discloses that it was necessary to develop an injection method through a catheter into the intestine or stomach of a purified solution of inverse thermosensitive polymer that makes the transition to a gel at body temperature. Among the challenges overcome, one was the fact that, due to the fact that the catheter rapidly reaches body temperature while still residing inside the body, the purified inverse thermosensitive polymer could gel inside the catheter before reaching the desired location in terms of EMR. The document WO2009 / 070793 A1 teaches that the problems in the gel were solved with a system comprising a high pressure needle catheter connected to a syringe filled with purified inverse thermosensitive polymer solution, in which said high pressure needle catheter was inside an administration device (for example, a syringe pump) that generated pressure on the syringe plunger, through a manual (for example, screws), electric or gas pressurized mechanism. As a matter of fact, in the example, in vivo, WO2009 / 070793 A1 reveals that five EMRs were performed on the colon of 2 pigs with LeGoo-endo® using a 23 gauge sclerotherapy needle with a 5 ml syringe and a balloon dilator gun; LeGoo-endo® was kept on ice during the intervention. Syringes containing saline solution were also kept on ice to cool the catheter just before poloxamer injections. As one skilled in the art will recognize, the operating procedure described in WO2009 / 070793 A1 is quite complex, for the following reasons: it requires the use of a special, high-pressure needle catheter and it requires an administration device (for example, a syringe pump) that generates pressure on the syringe plunger to deliver the purified reverse thermosensitive polymer solution.
[0011] US7909809 teaches a method to perform an interventional endoscopic procedure in the gastrointestinal tract, such as polypectomy, mucosetomy (EMR) and endoscopic submucosal dissection (EDS), the method comprising administration to a human or a thickening material damping that has phase transition characteristics from a low viscosity state (e.g., liquid phase) to a high viscosity state (e.g., gel phase) in response to a predetermined temperature (e.g., body temperature).
[0012] As outlined above, an ideal composition for mucosetomy (EMR) and for endoscopic submucosa (ESD) dissection has not yet been developed. As reported above, compositions in the form of a solution containing, for example, HA (hyaluronic acid) are known in the art. HA (hyaluronic acid) solutions are viscous and capable of providing long-lasting submucosal pads. In addition, they are safe and non-toxic. However, they are known to be very expensive.
[0013] Cellulose derivatives, such as HPMC and CMC, are inexpensive and their solutions are capable of providing long-lasting submucosal pads. However, due to their viscosity, a particular syringe pump-like device is needed to flow these derivatives into the injection needle, so they are known to be difficult and uncomfortable in terms of injection.
[0014] Inverse thermosensitive polymers, such as poloxamers and poloxamines, are inexpensive and their solutions, thanks to their gelation capacity at body temperature, are capable of providing long-lasting submucosal pads, however, being known in the state of the art that, to obtain the desired effect, such polymers must be present in the solution at a concentration equal to or greater than the critical gelation concentration (CGC), that is, above the concentration at which the phase transition from solution to gel occurs. In this way, these polymers are generally contained in the known solutions in an amount equal to or greater than 15% by weight relative to the weight of the composition (i.e., above the CGC); thus, the viscosity of the solutions is too high to allow them to be injected manually, requiring the use of a syringe pump, with an obvious disadvantage for the endoscopist.
[0015] Therefore, there is a need to provide a composition for use in an endoscopic procedure (particularly in EMR and ESD) capable of being safe, inexpensive and non-toxic, easily available, easy to inject and at the same time capable of providing an submucosa cushion with high level and long lasting. BRIEF DESCRIPTION OF THE FIGURES
[0016] Figure 1 shows the first pad generated by injecting the composition according to example 1 into the sub-mucous layer of an ex-vivo porcine stomach.
[0017] Figure 2 shows the second pad generated by the second injection of the composition according to example 1 in the sub-mucous layer of an ex-vivo porcine stomach.
[0018] Figure 3 shows the first pad of Figure 1 after cutting immediately after injection, in which a viscous product with a good consistency is visible in the sub-mucous layer.
[0019] Figure 4 shows a sample of the mucosa of the first pad of Figure 1 after resection, in which the product formed by the remains of injected composition connected to the excised part is visible.
[0020] Figure 5 shows the second pad of Figure 2, 15 minutes after the injection.
[0021] Figure 6 shows the second pad of Figure 2, after cutting, in which a viscous product with a good consistency similar to that of Figure 3 is visible in the sub-mucous layer.
[0022] Figure 7 shows a sample of the mucosa of the second pad of Figure 2, after resection, in which the product formed by the remains of injected composition connected to the excised part is visible.
[0023] Figure 8 shows the graph showing the distribution of the droplet size by intensity of the microemulsion, measured on the composition of example 15 after step a) of the manufacturing process (see also example 9 and table A of the example 17).
[0024] Figure 9 shows the graph showing the distribution by droplet size by microemulsion intensity, measured on the composition of example 15 after step d) of the manufacturing process (see also example 9 and table B of example 17 ).
[0025] Figure 10 shows the overlay graph that shows the comparison between the distribution of the size of the droplets by intensity of the microemulsion after step a) and after step d) of the manufacturing process, measured on the composition of example 15 ( see also example 9 and table C of example 17).
[0026] Figure 11 shows the graph showing the drop size distribution by microemulsion intensity (three replicates for each sample), measured on the composition of example 15 after step e) of the manufacturing process (see also example 9 and table D of example 17).
[0027] Figure 12 shows the height of the sub-mucosa pad formed by injecting a suitable volume of the composition of example 11, at time 0 and after 60 minutes.
[0028] Figure 13 shows an image showing an endoscopy in a piglet stomach (in vivo test in guinea pig example 21) and, in particular, the endoscopic injection needle contained in the working channel of the endoscope, which injects the composition of example 5 in the submucosal layer.
[0029] Figure 14 shows an image showing an endoscopy in a piglet stomach (in vivo guinea pig test of example 21) and, in particular, the submucosal pad at the end of administration. The intervention area has a contrasting blue color compared to the surrounding area.
[0030] Figure 15 shows an image showing an endoscopy in a piglet stomach (in vivo test in guinea pig of example 21), after 24 hours from the administration of the composition of example 5. In the area where the composition was injected at submucosal pad is no longer visible. The gastric mucosa does not show gross macroscopic changes due to the administration of the composition.
[0031] Figure 16 shows a graph that shows viscosity as a function of temperature, a reogram. SUMMARY OF THE INVENTION
[0032] The invention described herein provides a pharmaceutical composition in the form of an emulsion or microemulsion and its use in endoscopic procedures, preferably gastrointestinal endoscopic procedures.
[0033] The invention provides a pharmaceutical composition in the form of an emulsion or microemulsion for use in an endoscopic procedure, wherein the pharmaceutical composition comprises at least one inverse thermosensitive polymer and optionally at least one physiologically acceptable excipient. Preferably, the endoscopic procedure comprises administering the pharmaceutical composition to a human.
[0034] The invention described herein provides a method for performing an endoscopic procedure, wherein the pharmaceutical composition comprises at least one inverse thermosensitive polymer and optionally at least one physiologically acceptable excipient. Preferably, the method comprises administering a pharmaceutical composition in the form of an emulsion or microemulsion to a human. DESCRIPTION OF THE INVENTION
[0035] The invention described herein provides a pharmaceutical composition in the form of an emulsion or microemulsion in which the pharmaceutical composition comprises at least one thermosensitive polymer in an amount below the critical gelation concentration (CGC), in which the pharmaceutical composition remains in the liquid phase up to a temperature of about 40 ° C under laboratory test conditions, and its use in endoscopic procedures. Preferably, endoscopic procedures are gastrointestinal endoscopic procedures. Most preferably, gastrointestinal endoscopic procedures are performed in the esophageal region, in the stomach and / or in the small intestine (duodenum, jejunum, ileum), in the cecum, colon, sigmoid colon and / or rectum.
[0036] The invention described herein provides a pharmaceutical composition in the form of an emulsion or microemulsion for use in endoscopic procedures, wherein the pharmaceutical composition comprises at least one thermosensitive polymer in an amount below the critical gelling concentration (CGC), and wherein the pharmaceutical composition remains in the liquid phase to a temperature of about 40 ° C under laboratory test conditions.
[0037] The invention described herein provides a method for performing an endoscopic procedure, the method comprising administering a pharmaceutical composition in the form of an emulsion or microemulsion to a human, wherein the pharmaceutical composition comprises at least one thermosensitive polymer in reverse an amount below the critical gelling concentration (CGC), and in which the pharmaceutical composition remains in the liquid phase up to a temperature of about 40 ° C under laboratory test conditions.
[0038] According to the present invention, the endoscopic procedure is preferably an endoscopic resection that can be performed during a gastrointestinal endoscopy, more preferably a polypectomy, an endoscopic mucosal resection (EMR) and / or an endoscopic dissection of the submucosa (ESD).
[0039] According to the present invention, gastrointestinal endoscopy is preferably performed in the esophageal region, in the stomach and / or in the small intestine (duodenum, jejunum, ileum), in the cecum, colon, sigmoid colon and / or rectum .
[0040] In addition, the invention described herein provides a kit for use in an endoscopic procedure, the kit comprising a pharmaceutical composition in the form of an emulsion or microemulsion, an endoscopic injection needle, a syringe and instructions for using it, where the pharmaceutical composition in the form of an emulsion or microemulsion comprises at least one inverse thermosensitive polymer and wherein the endoscopic procedure is preferably an endoscopic resection of the mucosa performed during a gastrointestinal endoscopy, more preferably a polypectomy, an endoscopic resection of the mucosa (EMR) and / or an endoscopic submucosa (ESD) dissection.
[0041] In more detail, the pharmaceutical composition in the form of an emulsion or microemulsion is injected into the target tissue to form a pad which can then optionally be subjected to an endoscopic surgical procedure, such as a resection procedure.
[0042] All publications, patents and patent applications cited herein, either above or below, are hereby incorporated by reference in their entirety. DESCRIPTION DETAILS OF THE INVENTION
[0043] The inventors have been working to discover innovative pharmaceutical compositions for use in endoscopic procedures, preferably endoscopic mucosal resection (EMR) and / or endoscopic submucosal dissection (ESD), incorporating the characteristics requested by endoscopists, the characteristics being preferably safety, low cost, absence of toxic effects, easy to be injected and ability to provide a high-level, long-lasting submucosal pad.
[0044] It has been surprisingly determined that pharmaceutical compositions in the form of emulsions or microemulsions that comprise at least one thermosensitive polymer in an amount below the critical gelation concentration (CGC), and that remain in the liquid phase up to a temperature of about 40 ° C in laboratory test conditions, demonstrate the ability to form a high cushion in the sub-mucosa, of long duration, being, however, safe, cheap, non-toxic and easy to be injected. It is, therefore, clear the consequent improvement brought by these compositions in endoscopic procedures, particularly in an endoscopic resection during a gastrointestinal endoscopy.
[0045] The elevated, long-lasting submucosal pad was surprisingly observed by the inventors as soon as the composition in the form of emulsion or microemulsion described herein was injected into the submucosal layer of the porcine stomach ex vivo, which constitutes a well-known model of the human gastrointestinal mucosa (Soo Hoon Eun et al. "Effectiveness of Sodium Alginate as a Submucosal Injection Material for Endoscopic Mucosal Resection in Animal", Gut and Liver ", Vol. 1, No. 1, June 2007, pp. 27-32).
[0046] As is well known in the art, inverse thermosensitive polymers are polymers that, after dissolving in water in a concentration above the critical gelation concentration (CGC), provide solutions that show reverse viscosity characteristics, which means that solutions exhibit an increase in their viscosity with temperature. In particular, aqueous solutions of the polymers form gels above the critical gelation concentration (CGC), when the temperature is raised above the critical gelation temperature (CGT). Gelling is due to physical entanglement and packaging of micellar structures and is reversible, so the gel changes back to a liquid form when the temperature is reduced below the critical gelling temperature. Polymers of this type are well known in the art, and comprise, for example, poloxamers (marketed by BASF under the brand name Kolliphor®) and poloxamines (marketed by BASF under the brand name Tetronic®). As is well known in the art, each type of poloxamer has a characteristic critical gel concentration (CGC). Among poloxamers, poloxamer 407 has the lowest CGC. As reported in Evren Algin Yapar et al, Tropical Journal of Pharmaceutical Research, October 2012 .; 11 (5): 855-866, in order to achieve relatively stable gels, these applications generally require polymer concentrations equal to or greater than 15% by weight, based on the weight of the solution. In addition, JJ-Escobar Chavez et al, Journal of Pharmacy & Pharmaceutical Sciences, 9 (3) :. 339-358, (2006) report that poloxamer 407 is of particular interest, since the concentrated solutions (> 20% w / w) of the copolymer are transformed from transparent low viscosity solutions to solid gels when heated to temperature of the body. As already mentioned, the aqueous solutions of the polymers form gels above the critical gelation concentration (CGC), when the temperature is raised above the critical gelation temperature (CGT). The critical gelation temperature (CGT) can be modulated by varying the concentration of the inverse thermosensitive polymer, which means that the higher the concentration of the polymer, the lower the critical gelation temperature (CGT). As is well known in the prior art, the inverse gel-forming ability of thermosensitive polymer solutions requires that the concentration of the polymers in the solutions be equal to or greater than the critical gelation concentration (CGC); if such polymers are contained in an amount less than CGC, the solutions do not transition from a liquid phase to a gel phase in response to the increase in temperature. At the time the present invention was developed, it was thought, in the state of the art, that the ability to form a gel after heating at body temperature (ie, about 37 ° C) under laboratory test conditions was a characteristic of aqueous solutions containing some types of inverse thermosensitive polymers in an amount equal to or above the critical gelling concentration (CGC), this was an essential feature to ensure the formation of a long-lasting submucosal pad, since the solutions were injected into the submucosa layer of the gastrointestinal tract. As a matter of fact, it was thought that the solutions would be able to form a long-lasting submucosal pad after injection into the submucosal layer of the gastrointestinal tract, due to the transition to a gel phase in response to rising temperatures (ie, body temperature). Thus, it was thought, in the state of the art, that the ability of aqueous solutions containing an inverse thermosensitive polymer in an amount equal to or greater than the critical gelation concentration (CGC) to form a long-lasting submucosa pad after inward injection the submucosal layer of the gastrointestinal tract was linked to its ability to gel by heating at body temperature (ie, about 37 ° C) under laboratory test conditions. In other words, it was thought that, in order to ensure the formation of a long-lasting cushion for the submucosa layer of the gastrointestinal tract, the solutions should contain an inverse thermosensitive polymer with a concentration equal to or greater than the critical gelation concentration ( CGC), since only in this case the solutions could have transitioned from a liquid phase to a gel phase in response to the increase in temperature (for example, body temperature).
[0047] It has now been determined that pharmaceutical compositions in the form of emulsions or microemulsions according to the present invention described herein, which do not have the ability to form a gel (i.e., remain in liquid phase) up to a temperature of about 40 ° C ° C under laboratory test conditions, preferably by heating to body temperature (ie around 37 ° C), are surprisingly capable of forming a long, long submucosal pad as it is injected into the layer submucosa of the porcine stomach (ex vivo). In particular, in a comparison test, the injection of different compositions into the submucosal layer of the porcine stomach maintained at a temperature of about 37 ° C, it was surprisingly determined that pharmaceutical compositions in the form of emulsions or microemulsions according to the present invention disclosed here, although unable to gel on heating to body temperature (ie about 37 ° C) under laboratory test conditions, were surprisingly able to form a high, long-lasting cushion in the above submucosal layer ( porcine stomach, ex vivo) similar in terms of height, shape and duration to that formed by conventional solutions, meaning that they comprise a thermosensitive polymer inverse to a concentration above the concentration of critical gelling that were able to gel by heating at temperature of the body (ie about 37 ° C) under laboratory conditions.
It was therefore surprisingly determined that the lack of gelling properties, observed under test conditions for pharmaceutical compositions in the form of emulsions or microemulsions according to the present invention disclosed herein, was not related to the ability to form a cushion submucosa of pharmaceutical compositions observed in the porcine stomach (ex vivo). As a technician in the state of the art will recognize, these results were unexpected and not obvious, inasmuch as they bring a significant advantage in endoscopic procedures. In the known state of the art it was, in fact, taught that the gel-forming ability of inverse thermosensitive polymer solutions by heating at body temperature (ie, about 37 ° C), under laboratory conditions, was related to gel-forming ability of solutions in models of resection procedures of the gastrointestinal mucosa ex vivo or in vivo.
[0049] The inventors surprisingly determined that pharmaceutical compositions in the form of emulsions or microemulsions according to the present invention disclosed herein have the ability to form a submucosal pad in models of gastrointestinal mucosal resection procedures ex vivo and / or in vivo, although the concentration of inverse thermosensitive polymer is contained in the pharmaceutical composition in an amount less than its critical gelation concentration (CGC) and, consequently, the pharmaceutical compositions will be able to gel at a temperature of about 40 ° C , especially after heating to body temperature (ie about 37 ° C), under laboratory test conditions.
[0050] The invention described herein provides a pharmaceutical composition in the form of an emulsion or microemulsion, in which the pharmaceutical composition comprises at least one thermosensitive polymer in an amount below the critical gelation concentration (CGC) and in which the pharmaceutical composition maintains in the liquid phase to a temperature of about 40 ° C under laboratory test conditions, in addition to its use in endoscopic procedures.
[0051] The invention described herein provides a pharmaceutical composition in the form of an emulsion or microemulsion for use in an endoscopic procedure, wherein the composition comprises at least one thermosensitive polymer in an amount below the critical gelling concentration (CGC) , and wherein the composition remains in the liquid phase to a temperature of about 40 ° C under laboratory test conditions.
[0052] In accordance with the present invention, the endoscopic procedure comprises administering the pharmaceutical composition to a human.
[0053] According to the present invention, the endoscopic procedure is preferably a gastrointestinal endoscopic procedure, more preferably performed in the esophageal region, stomach, small intestine (duodenum, jejunum, ileum), in the cecum, colon, sigmoid colon and / or in the rectum.
[0054] In more detail, the pharmaceutical composition is injected into a target human tissue in order to form a pillow that is then optionally subjected to an endoscopic surgical procedure, such as a resection procedure,
The invention disclosed herein thus also provides a method for carrying out an endoscopic procedure, the method comprising administering a pharmaceutical composition in the form of an emulsion or microemulsion to a human, wherein the composition comprises at least at least, a thermosensitive polymer in an amount less than the critical gelation concentration (CGC) value, and in which the composition remains in the liquid phase up to a temperature of about 40 ° C under laboratory test conditions. In more detail, the pharmaceutical composition is injected into a target human tissue in order to form a pad which is then optionally subjected to an endoscopic surgical procedure, such as a resection procedure.
[0056] According to the present invention, the pharmaceutical composition in the form of emulsion or microemulsion preferably remains in the liquid phase at a temperature between about 5 ° C and 40 ° C, more preferably at about 5 ° C, about 20 ° C, about 25 ° C, about 30 ° C and / or about 37 ° C, under laboratory test conditions.
[0057] According to a preferred embodiment of the invention, the pharmaceutical composition in the form of emulsion or microemulsion remains in the liquid phase, both at room temperature (i.e., about 20 to 25 ° C) and at body temperature ( (ie, about 37 ° C) under laboratory test conditions.
[0058] According to another preferred embodiment, the pharmaceutical composition in the form of emulsion or microemulsion of the present invention has a viscosity of less than about 150 cP (centipoise), more preferably below about 100 cP (centipoise), more preferably below about 50 cP (centipoises). According to another preferred embodiment, the pharmaceutical composition in the form of emulsion or microemulsion of the present invention has a viscosity of less than about 20 cP (centipoise), more preferably below about 10 cP. According to the present invention, viscosity is preferably measured at about 25 ° C, about 30 ° C and / or about 37 ° C, more preferably using a Brookfield LVDV-III Ultra Programmable Rheometer® viscometer equipped with a Brookfield Small Sample Adapter® device for small samples and using a Brookfield® spindle No. 31 shaft.
[0059] Alternatively, viscosity is measured using a Brookfield LVDV-III Ultra Programmable Rheometer® viscometer equipped with a Brookfield Enhanced UL Adapter® device and using a Brookfield® spindle N. 00 axis.
[0060] According to another embodiment of the invention, the endoscopic procedure is an endoscopic resection procedure performed during a gastrointestinal endoscopy, preferably a polypectomy, an endoscopic mucosal resection (EMR) and / or an endoscopic dissection submucosa (ESD).
[0061] According to the present invention, the endoscopic procedure is preferably a gastrointestinal endoscopic procedure, most preferably performed in the esophageal region, in the stomach, in the small intestine (duodenum, jejunum, ileum), in the cecum, in the colon, in the sigmoid colon and / or the rectum.
[0062] According to the present invention, polypectomy, endoscopic mucosal resection (EMR) and / or endoscopic submucosal (ESD) dissection are used for the removal of lesions of mucous membranes, polyps, pseudo-polyps, flat polyps, adenomas, serrated lesions, dysplasias, Barrett's dysplasia, pre-neoplastic formation, neoplastic formations and / or tumors during gastrointestinal endoscopy.
[0063] According to the present invention, polypectomy, endoscopic mucosal resection (EMR) and / or endoscopic submucosal dissection (ESD) are also used for the removal of pathological mucosal tissue and / or dysplasia in the case of esophagitis , erosive esophagitis, Barrett esophageal (such as in ablation procedures) and / or gastrointestinal hypersecretion pathological conditions, such as Zollinger-Ellison syndrome.
[0064] According to one embodiment, the pharmaceutical composition in the form of an emulsion or microemulsion is administered to a human by injection through an endoscopic injection needle provided with a retractable needle and a syringe.
[0065] According to the present invention, the pharmaceutical composition in the form of an emulsion or microemulsion can preferably be a water-in-oil emulsion or microemulsion, or an oil-in-water emulsion or microemulsion. According to a preferred embodiment, the pharmaceutical composition in the form of an emulsion or microemulsion is an oil-in-water emulsion or microemulsion.
[0066] According to an embodiment, the pharmaceutical composition in the form of an emulsion or microemulsion for use in an endoscopic procedure comprises: an aqueous phase; an oily phase; at least one surfactant; at least one reverse thermosensitive polymer; optionally, at least one physiologically acceptable excipient; wherein at least one inverse thermosensitive polymer is comprised in an amount below the critical gelation concentration (CGC), and where the composition is in the liquid phase up to a temperature of about 40 ° C under laboratory test conditions.
[0067] According to another embodiment, the pharmaceutical composition in the form of an emulsion or microemulsion for use in an endoscopic procedure comprises: an aqueous phase; an oily phase; at least one surfactant; at least one reverse thermosensitive polymer; optionally at least one co-surfactant; optionally, at least one physiologically acceptable excipient; wherein at least one inverse thermosensitive polymer is comprised in an amount below the critical gelation concentration (CGC), and where the composition is in the liquid phase up to a temperature of about 40 ° C under laboratory test conditions.
[0068] According to another embodiment, the pharmaceutical composition in the form of an emulsion or microemulsion for use in an endoscopic procedure comprises: an aqueous phase; an oily phase; at least one surfactant; at least one reverse thermosensitive polymer; optionally at least one co-surfactant; at least one dye; optionally, at least one physiologically acceptable excipient; wherein at least one inverse thermosensitive polymer is comprised in an amount below the critical gelation concentration (CGC), and where the composition is in the liquid phase up to a temperature of about 40 ° C under laboratory test conditions.
[0069] According to another embodiment, the pharmaceutical composition in the form of an emulsion or microemulsion for use in an endoscopic procedure comprises: an aqueous phase; an oily phase; at least one surfactant; at least one reverse thermosensitive polymer; optionally at least one co-surfactant; at least one dye; optionally at least one agent characterized by having a trophic activity in the epithelial cells of the gastrointestinal mucosa; optionally, at least one physiologically acceptable excipient; wherein at least one inverse thermosensitive polymer is comprised in an amount below the critical gelation concentration (CGC), and where the composition is in the liquid phase up to a temperature of about 40 ° C under laboratory test conditions.
[0070] According to another embodiment, the pharmaceutical composition in the form of an emulsion or microemulsion for use in an endoscopic procedure comprises: an aqueous phase; an oily phase; at least one surfactant; at least one reverse thermosensitive polymer; optionally at least one co-surfactant; at least one dye; optionally at least one agent characterized by having a trophic activity in the epithelial cells of the gastrointestinal mucosa; optionally at least one therapeutic agent; optionally, at least one physiologically acceptable excipient; wherein at least one inverse thermosensitive polymer is comprised in an amount below the critical gelation concentration (CGC), and where the composition is in the liquid phase up to a temperature of about 40 ° C under laboratory test conditions.
[0071] According to another embodiment, the present invention relates to a pharmaceutical composition in the form of an emulsion or microemulsion which comprises, essentially consists of or consists of: an aqueous phase; an oily phase; at least one surfactant; at least one reverse thermosensitive polymer; optionally at least one co-surfactant; optionally at least one dye; optionally at least one agent characterized by having a trophic activity in the epithelial cells of the gastrointestinal mucosa; optionally at least one therapeutic agent; optionally, at least one physiologically acceptable excipient; wherein at least one inverse thermosensitive polymer is comprised in an amount below the critical gelation concentration (CGC), and where the composition is in the liquid phase up to a temperature of about 40 ° C under laboratory test conditions.
[0072] According to the present invention, the pharmaceutical composition in the form of an emulsion or microemulsion preferably remains in liquid phase at a temperature between about 5 ° C and about 40 ° C, more preferably at about 5 ° C and / or about 20 ° C and / or about 25 ° C and / or about 30 ° C and / or about 37 ° C, under laboratory test conditions.
[0073] According to the present invention disclosed herein, the main component of the aqueous phase of the pharmaceutical composition is water for injection. As is well known in the art, water for injection represents a highly purified component, distilled water, free of salts and carbon contaminants, and free of microorganisms and bacterial endotoxins. Water for injection is water purified by distillation or by a purification process that is equivalent or superior to distillation in removing chemicals and microorganisms. In some embodiments of the invention disclosed herein, the aqueous phase may comprise, in its form, one or more dissolved inorganic salts selected from the group comprising, but not limited to: chlorides, bromides, iodides, phosphates, carbonates, bicarbonates, sulfates, nitrates and the like. In some embodiments, the aqueous phase may comprise, in dissolved form, one or more organic salts selected from the group it comprises, but is not limited to: citrates, maleates, fumarates, acetates, lactates and the like. Any mixture of the above inorganic and organic salts can be used to form the appropriate pharmaceutical composition, generally to buffer the pH of the composition at suitable biocompatible intervals or to achieve the required osmotic pressure by the biological environment where the pharmaceutical composition has to be injected. In some embodiments, the aqueous phase of the pharmaceutical composition described herein can comprise an amount of one or more inorganic and / or organic salts or mixtures thereof, in order to have a final pharmaceutical composition that is hypotonic. In some embodiments, the aqueous phase of the pharmaceutical composition described herein can comprise an amount of one or more inorganic and / or organic salts or mixtures thereof, in order to have a final pharmaceutical composition that is isotonic. In some embodiments, the aqueous phase of the pharmaceutical composition described herein can comprise an amount of one or more inorganic and / or organic salts or mixtures thereof, in order to have a final pharmaceutical composition that is hypertonic. In accordance with the present invention disclosed herein, inorganic salts and / or organic salts or mixtures thereof can be present in an amount ranging from 0% to 5% by weight with respect to the weight of the composition, more preferably from 0.1 % to 4% by weight in relation to the weight of the composition, much more preferably between 0.5% and 3% by weight in relation to the weight of the composition. According to a preferred embodiment, the inorganic and / or organic salts or mixtures thereof can be present in an amount ranging from 0.3% to 0.7% by weight relative to the weight of the composition.
[0074] In a preferred embodiment, the aqueous phase of the pharmaceutical composition contains dissolved sodium chloride. According to the latter embodiment, sodium chloride is present in an amount ranging from about 0% to about 5% by weight relative to the weight of the composition, more preferably from about 0.1% to about from 3% by weight relative to the weight of the composition, more preferably from about 0.5% to about 2% by weight in terms of the weight of the composition.
[0075] According to a preferred embodiment, sodium chloride can be present in an amount ranging from 0.3% to 0.7% by weight relative to the weight of the composition. Most preferably, sodium chloride is present in an amount of about 0.44% w / w.
[0076] In some embodiments, the aqueous phase of the pharmaceutical composition described herein comprises a buffer. In some embodiments, the buffer is a phosphate buffer. In some embodiments, the buffer is a citrate buffer. In some embodiments, the buffer is a bicarbonate buffer. In a preferred embodiment, the buffer is a phosphate buffer added with one or more inorganic salts unable to buffer the pH. According to the latter embodiment, the concentration of the phosphate buffer and inorganic salts unable to buffer the pH is such that there is an aqueous phase which is phosphate buffered saline (PBS). As is well known in the art, PBS is a water-based salt solution containing sodium chloride, sodium phosphate and, optionally, potassium chloride and potassium phosphate. PBS for medical applications is an isotonic solution, that is, its osmolarity and pH are compatible with those of the human body. Various compositions and methods of preparing PBS are well known in the art.
[0077] In accordance with the present invention disclosed herein, the pH value of the pharmaceutical composition in the form of emulsion or microemulsion ranges from about 4.0 to about 9.0, more preferably from about 5.0 to about from 8.0, much more preferably from about 5.5 to about 7.5. In accordance with the present invention, the pH value of the pharmaceutical composition in the form of an emulsion or microemulsion can be adjusted within the desired range by techniques common to and well known to experts, such as, for example, the addition of bases and / or physiologically acceptable acids.
[0078] According to the present invention disclosed herein, the oil phase of the pharmaceutical composition comprises at least one lipophilic compound. In some embodiments, at least one lipophilic compound can be selected from the group of natural oils, which comprises, but is not limited to: almond oil, canola oil, castor oil, corn oil, cottonseed oil, olive oil, safflower oil, sesame oil, soy oil and the like. In some embodiments, at least one lipophilic compound can be selected from the group of fatty acid esters, which comprises, but is not limited to: isopropyl palmitate, isopropyl myristate, ethyl oleate and the like. In some embodiments, at least one lipophilic compound can be selected from the group of fatty alcohols, which comprises, but is not limited to: myristic alcohol, oleyl alcohol and the like. In some embodiments, at least one lipophilic compound can be selected from the group of fatty acids, which comprises, but is not limited to: myristic acid, oleyl acid, palmitic acid and the like. In some embodiments, at least one lipophilic compound can be selected from the group of triglycerides, such as medium-length triglycerides and / or the like. In some embodiments, at least one lipophilic compound can be selected from the group of diglycerides. In some embodiments, at least one lipophilic compound can be selected from the group of monoglycerides. Any mixture of the above lipophilic compounds can be used to form the appropriate pharmaceutical composition. In one embodiment, the lipophilic compound of the oil phase is sesame oil. In another embodiment, the lipophilic compound of the oily phase is almond oil. In another embodiment, the lipophilic compounds of the oil phase are medium chain triglycerides. In a preferred embodiment, the lipophilic compound of the oil phase is soybean oil.
[0079] According to the present invention disclosed herein, the oily phase of the pharmaceutical composition ranges from about 0.001% to about 20% by weight relative to the weight of the composition, preferably from about 0.01% to about 2% by weight with respect to the weight of the composition, more preferably from about 0.02% to about 1% by weight with respect to the weight of the composition. According to a preferred embodiment, the oil phase is contained in the composition of the invention in an amount from about 0.01% by weight to about 0.5% by weight, based on the weight of the composition.
[0080] More preferably, the oil phase is contained in the composition of the invention in an amount of about 0.08% by weight or about 0.16% by weight, based on the weight of the composition. Much more preferably, the oil phase is contained in the composition of the invention in an amount of about 0.02% w / w or about 0.05% w / w or about 0.1% by weight, relative to weight composition. In accordance with the present invention disclosed herein, the pharmaceutical composition in the form of an emulsion or microemulsion contains at least one inverse thermosensitive polymer at a concentration lower than the critical gelation concentration (CGC). In this sense, the pharmaceutical composition in the form of an emulsion or microemulsion is not capable of transition from a liquid phase to a gel phase in response to an increase in temperature up to 40 ° C under laboratory test conditions, such as from from room temperature (ie, about 20 to 25 ° C) to body temperature (ie, about 37 ° C). Thus, the pharmaceutical composition in the form of an emulsion or microemulsion according to the present invention disclosed herein is in a liquid phase up to a temperature of about 40 ° C, preferably both at room temperature (i.e., about 20 to 25 ° C) and body temperature (ie about 37 ° C) under laboratory test conditions. Each type of inverse heat-sensitive polymer is characterized by a specific critical gelation concentration (CGC); such concentrations are well known in the art and can be easily found in the scientific literature. In accordance with the present invention disclosed herein, at least one inverse thermosensitive polymer can be selected from the group comprising, but not limited to, polyoxyethylene-polyoxypropylene block copolymers, such as poloxamers and the like. The poloxamer can be selected from the group comprising, but not limited to: poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407 and the like. Any mixture of the above inverse thermosensitive polymers can be used to form the appropriate pharmaceutical composition. In a preferred embodiment, at least one thermosensitive polymer reverse of the pharmaceutical composition is poloxamer 188. In a preferred embodiment, at least one thermosensitive polymer reverse of the pharmaceutical composition is poloxamer 407. Furthermore, in another preferred embodiment , at least one inverse thermosensitive polymer is a mixture of poloxamer 188 and poloxamer 407.
[0081] According to the present invention, useful inverse thermosensitive polymers are purchased on the market and used without any purification step.
[0082] According to the present invention disclosed herein, at least one inverse thermosensitive polymer is present in an amount below the concentration of critical gelation (CGC), preferably below about 15% by weight relative to the weight of the pharmaceutical composition , more preferably between about 2% and about 14.5% by weight relative to the weight of the pharmaceutical composition, more preferably between about 3% and about 12% by weight relative to the weight of the pharmaceutical composition, even more preferably between about 5% and about 11% by weight relative to the weight of the pharmaceutical composition. Preferably, at least one inverse thermosensitive polymer is present in an amount of about 7%, or about 8%, or about 9%, or about 10% by weight relative to the weight of the composition.
[0083] According to one embodiment, at least one inverse thermosensitive polymer is poloxamer 407 and is contained in an amount of about 9% by weight relative to the weight of the composition.
[0084] According to another embodiment, at least one inverse thermosensitive polymer is poloxamer 188 and is contained in an amount of about 10% by weight relative to the weight of the composition.
[0085] According to another preferred embodiment, at least one inverse thermosensitive polymer is a mixture of poloxamer 188 and poloxamer 407, and such a mixture is contained in an amount of about 10% by weight relative to the weight of the composition.
[0086] According to the present invention disclosed herein, at least one surfactant can be selected from the group of nonionic surfactants, which comprises, but is not limited to: PEG monoester surfactants - fatty acids, such as PEG- Hydroxystearate, PEG-30 stearate, PEG-40 laurate, PEG-40 oleate and the like; surfactants of PEG-fatty acid diesters, such as PEG-32 dioleate, PEG-400 dioleate and the like; polyoxyethylene sorbitan esters of fatty acids, such as polysorbate 20, polysorbate 60, polysorbate 80 and the like; alkyl polyoxyethylene ethers, such as PEG-20 keto stearyl ether, polyoxy 25 keto stearyl ether, ketomacrogol 1000 and the like; sorbitan fatty acid esters surfactants, such as sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, and the like; propylene glycol esters of fatty acids; polyglycerol esters of fatty acids; polyoxyethylene castor oil derivatives, such as polyoxyl 5 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, hydrogenated polyoxyl 40 castor oil and the like; polyoxyl 8-glyceride caprilocaproil; polyoxylglycerides such as caprylocaproyl polyoxylglycerides, lauroyl polyoxylglycerides, oleoyl polyoxylglycerides and the like Ceteareth 16, Ceteareth 20, Steareth 10, Steareth 20, Ceteth 20 and the like. Any mixture of the above nonionic surfactants can be used to form the appropriate pharmaceutical composition. In one embodiment, the nonionic surfactant is polysorbate 80. In a preferred embodiment, the nonionic surfactant is PEG-15 hydroxystearate (also known as polyoxyl-15-hydroxystearate).
[0087] In accordance with the present invention disclosed herein, at least one surfactant may be selected from the group of ionic surfactants that comprises, but is not limited to: egg lecithin, hydrogenated egg lecithin phosphatidyl choline, soy lecithin, hydrogenated soy lecithin, glycerophosphocholine, soy lysolecithin, phospholipids, hydrogenated phospholipids, sodium lauryl sulfate and the like. Any mixture of the above ionic surfactants can be used to form the appropriate pharmaceutical composition. The ionic surfactants above are marketed by Lipoid, under the brand name Lipoid®. In one embodiment, the ionic surfactant is egg lecithin. In another embodiment, the ionic surfactant is hydrogenated egg lecithin phosphatidyl choline. In another embodiment, the ionic surfactant is soy lecithin. In addition, in another embodiment, the ionic surfactant is hydrogenated soy lecithin.
[0088] According to the present invention disclosed herein, at least one surfactant is contained in an amount ranging from about 0.001% to about 10% by weight relative to the weight of the pharmaceutical composition, preferably from about 0.005% to about 5% by weight with respect to the weight of the pharmaceutical composition, more preferably between about 0.01% to about 2% by weight in terms of the weight of the pharmaceutical composition. According to a preferred embodiment, at least one surfactant is contained in an amount of about 0.08% or about 0.1% or about 0.5% or about 0.6% by weight the weight of the pharmaceutical composition.
[0089] The pharmaceutical composition of the invention described herein can comprise at least one co-surfactant. The addition of at least one co-surfactant to the mixture of phases of the oil phase - surfactant - aqueous phase is advantageous since the co-surfactant acts in synergy with the surfactant in reducing the interfacial tension of the droplets of the dispersed phase of the emulsion or microemulsion , with a stabilizing effect on the system. In the preparation of pharmaceutical compositions in the form of emulsions or microemulsions according to the present invention disclosed herein, at least one co-surfactant can be selected from groups that include, but are not limited to: lower and medium chain alcohols, such as ethanol , propanol, isopropanol and the like; glycols, such as propylene glycol and the like; polyethylene glycols, such as PEG 200, PEG 300, PEG 400 and the like; DMSO; long-chain alcohols, such as cetyl alcohol, myristyl alcohol, oleyl alcohol and the like; glycerol; low-chain esters, such as ethyl acetate, ethyl lactate and the like; fatty acid esters, such as ethyl oleate, isopropyl myristate, isopropyl palmitate and the like; fatty acids, such as oleic acid, myristic acid and the like; fatty acid salts, such as sodium oleate, sodium palmitate, sodium stearate and the like. Any mixture of the above surfactants can be used to form the appropriate pharmaceutical composition. In one embodiment, the co-surfactant is propylene glycol. In another embodiment, the co-surfactant is glycerol. In another embodiment, the co-surfactant is sodium oleate. In a preferred embodiment, the co-surfactant is a mixture of glycerol and sodium oleate.
[0090] In accordance with the present invention disclosed herein, at least one surfactant is contained in an amount ranging from about 0.00001% to about 1% by weight relative to the weight of the pharmaceutical composition, preferably between about 0.00005% to about 0.05% by weight relative to the weight of the pharmaceutical composition, more preferably between about 0.0001% to about 0.01% by weight relative to the weight of the pharmaceutical composition.
[0091] The pharmaceutical composition of the invention described herein can comprise at least one dye. Dyes are widely used in compositions for endoscopic procedures. In particular, in compositions for EMR and / or ESD procedures, the dyes are useful for application on the lesion margins to be resected and on the physiological structures underlying the mucosa. Thus, the endoscopist can easily see the lesion that needs to be removed and he can perform the procedure with less risk of damaging the submucosal layer or muscle tissue. The dye has the function of making the submucosal layer immediately available to the endoscopist, so that the surgical procedure is safer and that there is less risk of damaging the structures below the mucosa, such as the submucosa layer itself, and the external muscle wall.
[0092] In the preparation of the pharmaceutical composition according to the present invention disclosed herein, at least one dye can be selected from vital dyes (or absorbent dyes), non-vital dyes (or contrast dyes) and reactive dyes. Vital dyes (or absorption dyes), such as methylene blue solution, identify specific types of epithelial cells by preferential absorption or diffusion across the Lugol cell membrane; dyes of the non-vital type (or dye by contrast), such as indigo carmine, seep through the cracks in the mucous membranes and the topography of the surface highlighting the mucosal irregularities; Reactive dyes, such as Congo red and phenol red, undergo chemical reactions with specific cell constituents, resulting in a color change similar to a pH indicator. In accordance with the present invention disclosed herein, the vital dye (or absorption dye) can be selected from the group comprising, but not limited to: Lugol's solution, methylene blue, toluidine blue, crystal violet and the like. In accordance with the present invention disclosed herein, the non-vital dye (or the contrast dye) can be selected from the group it comprises, but is not limited to: indigo carmine and the like. According to the present invention disclosed herein, the reactive dye can be selected from the group it comprises, but is not limited to: Congo red, phenol red and the like. Any mixture of the above dyes can be used to form the appropriate pharmaceutical composition. According to a preferred embodiment, at least one dye is methylene blue. According to another preferred embodiment, at least one dye is indigo carmine.
[0093] In accordance with the present invention disclosed herein, at least one dye is contained in an amount ranging from about 0.0001% to about 0.2% by weight relative to the weight of the pharmaceutical composition, preferably from about 0.0002% to about 0.05% by weight with respect to the weight of the pharmaceutical composition, more preferably between about 0.0005% to about 0.01% by weight with respect to the weight of the pharmaceutical composition . Most preferably, the at least one dye is contained in the composition of the invention in an amount of about 0.001% by weight or about 0.002% by weight, based on the weight of the composition.
[0094] The pharmaceutical composition of the invention described herein can comprise at least one agent characterized by having a trophic activity in the epithelial cells of the gastrointestinal mucosa. Trophic agents are substances capable of promoting cell growth, differentiation and survival. In digestive endoscopy, resection procedures such as polypectomy, EMR and / or ESD are generally not followed by suturing. In other words, once the lesion has been removed through one of the processes, the mucosa is not sutured and the wound is left open; thus, wound healing should occur naturally. In this sense, the incorporation in the pharmaceutical compositions according to the present invention of at least one agent that notably has a trophic activity in the epithelial cells of the gastrointestinal mucosa can be advantageous, in that the pharmaceutical compositions can have a positive, beneficial effect, about the wound in terms of its healing, promoting cell growth and differentiation for rapid closure and healing of the surgical wound.
[0095] In the preparation of pharmaceutical compositions in the form of emulsions or microemulsions according to the present invention disclosed herein, at least one agent characterized by having a trophic activity in the epithelial cells of the gastrointestinal mucosa can be selected from the groups comprising, but not limited to, limited to: amino acids and their salts, such as arginine, glutamine, glutamic acid, citrulline, proline, cysteine and the like; short-chain fatty acids (SCFA) and their salts, such as acetic acid and its salts, propanoic acid and its salts, butyric acid and its salts, and the like; carbohydrates, such as glucose, fructose, galactose, sucrose, maltose, lactose and the like; polyamines and their salts, such as putrescein, spermidine, spermine and the like; fatty acids and their salts, such as oleic acid and its salts, linoleic acid and its salts, myristic acid and its salts, stearic acid and its salts and the like; vitamins, such as vitamin A, vitamin B2, vitamin C, vitamin D, and the like. Any mixture of the above agents, characterized by having a trophic activity in the epithelial cells of the gastrointestinal mucosa, can be used to form the appropriate pharmaceutical composition. In one embodiment, at least one agent characterized by having a trophic activity in the epithelial cells of the gastrointestinal mucosa is sodium butyrate. In another embodiment, at least one agent characterized by having trophic activity in the epithelial cells of the gastrointestinal mucosa is vitamin B2 sodium. In a preferred embodiment, at least one agent characterized by having a trophic activity in the epithelial cells of the gastrointestinal mucosa is glutamic acid.
[0096] According to the present invention disclosed herein, at least one agent characterized by having a trophic activity in the epithelial cells of the gastrointestinal mucosa is contained in an amount ranging from about 0.01% to about 5% by weight in with respect to the weight of the pharmaceutical composition, preferably between about 0.05% to about 3% by weight with respect to the weight of the pharmaceutical composition, more preferably between about 0.1% to about 2% by weight with respect to weight of the pharmaceutical composition.
[0097] The pharmaceutical composition of the invention described herein can comprise at least one therapeutic agent. In the preparation of pharmaceutical compositions in the form of emulsions or microemulsions according to the present invention disclosed herein, at least one therapeutic agent can be selected from groups that include, but are not limited to: antibiotics, such as penicillins, cephalosporins, aminoglycosides, macrolides , rifamycins, metronidazole and the like; non-steroidal anti-inflammatory drugs, such as ketorolac and its salts, indomethacin, piroxicam, ketoprofen and its salts, and metamizole and its salts, and the like; non-steroidal anti-inflammatory drugs, such as cortisol, prednisolone and its esters, methylprednisolone and esters thereof, triamcinolone acetonide, betamethasone and their esters, and the like; local anesthetics, such as lidocaine and its salts, mepivacaine and its salts, bupivacaine and its salts, and the like; vasoconstrictor drugs, such as epinephrine and its salts, norepinephrine and its salts, and the like. Any mixture of the above therapeutic agents can be used to form the appropriate pharmaceutical composition and to achieve specific therapeutic effects. In one embodiment, at least one therapeutic agent is a local anesthetic, such as lidocaine hydrochloride. In another embodiment, at least one therapeutic agent is a vasoconstrictor drug, such as epinephrine hydrochloride. In addition, in another embodiment, the pharmaceutical composition according to the present invention disclosed herein comprises a local anesthetic and a vasoconstrictor, such as lidocaine hydrochloride and epinephrine hydrochloride.
[0098] In addition, at least one physiologically acceptable excipient can be added to the pharmaceutical composition according to the present invention disclosed herein, to obtain a final composition for use in endoscopic procedures provided with appropriate characteristics and stability. For example, at least one physiologically acceptable excipient can be selected from antioxidants, preservatives, antimicrobial agents, polymers provided with bioadhesive properties, viscosity-increasing agents, solvents and chelators.
[0099] The pharmaceutical composition in the form of an emulsion or microemulsion of the invention disclosed herein can be packaged in primary packages of configurations well known in the art. Suitable primary packaging types can be selected from the group that comprises, but is not limited to: ampoules, vials, bottles, pre-filled syringes and the like. In one embodiment, the pharmaceutical composition in the form of an emulsion or microemulsion of the invention disclosed herein is packaged in 5 ml or 10 ml pre-filled syringes. In a preferred embodiment, the pharmaceutical composition in the form of an emulsion or microemulsion of the invention disclosed herein is packaged in 10 ml, 20 ml or 50 ml bottles. In another preferred embodiment, the pharmaceutical composition in the form of an emulsion or microemulsion of the invention disclosed herein is packaged in 10 ml, 20 ml or 50 ml ampoules. The pharmaceutical composition in the form of an emulsion or microemulsion of the invention disclosed herein is administered by means of endoscopic injection needles. Preferably, the composition is administered manually at room temperature.
[0100] Another aspect of the invention described herein provides a kit for use in an endoscopic procedure, the kit comprising: a pharmaceutical composition in the form of an emulsion or microemulsion according to the present invention disclosed herein; an endoscopic injection needle; instructions for use.
[0101] In preparing the kit, the pharmaceutical composition in the form of an emulsion or microemulsion according to the present invention disclosed herein can be packaged in primary packages of configurations well known in the art. The types of suitable primary packaging can be selected from the group that comprises, but is not limited to: ampoules, vials, bottles, pre-filled syringes and the like. In one embodiment, in preparing the kit, the pharmaceutical composition in the form of an emulsion or microemulsion of the invention disclosed herein is packaged in 5 ml or 10 ml pre-filled syringes. In a preferred embodiment, for the preparation of the kit, the pharmaceutical composition in the form of an emulsion or microemulsion of the invention disclosed herein is packaged in 10 ml, 20 ml or 50 ml bottles. In another preferred embodiment, for the preparation of the kit, the pharmaceutical composition in the form of an emulsion or microemulsion of the invention disclosed herein is packaged in 10 ml, 20 ml or 50 ml ampoules. In preparing the kit according to the present invention described herein, suitable endoscopic injection needles can have a needle diameter ranging from 12 gauge to 35 gauge, preferably from 15 gauge to 30 gauge, more preferably from 17 to 28 gauge . In preparing the kit according to the present invention described herein, suitable endoscopic injection needles can have a length ranging from 100 cm to 300 cm, preferably from 120 cm to 260 cm, more preferably from 140 cm to 250 cm. In preparing the kit according to the present invention described herein, suitable endoscopic injection needles can have an external diameter ranging from 1.0 mm to 4.0 mm, preferably between 1.5 mm and 3.0 mm, more preferably from 1.8 mm to 2.5 mm. In the preparation of the kit according to the present invention described here, the appropriate endoscopic injection needles may consist of materials selected from the group that includes, but is not limited to: polymers or copolymers, such as polyethylene (PE), polypropylene ( PP), polyvinyl chloride (PVC), polycarbonate (PC), polytetrafluoroethylene (PTFE), polyethylene terephthalate (PET), polystyrene (PS), polyamide (PA), epoxy resins, polyurethane, polyester, methyl polymethacrylate and the like; rubbers, such as silicone rubber, natural rubber and the like; metals and metal alloys such as aluminum, titanium, iron, chromium, nickel, molybdenum, stainless steel, and the like. Any combination of the above materials can be used to form the appropriate endoscopic injection needle. Endoscopic injection needles suitable for the preparation of the kit according to the present invention described here can be easily found on the market; for example, a suitable injection needle can be selected from commercially available injection needles that include, but are not limited to, Cook® AcuJect® variable injection needles, Cook® Injetaflow® variable injection needles, Boston catheter needles Scientific Interject® Injection Therapy, G- Flex® injection needles, Endo-Flex Sclerotherapy Needles injection needles, ConMed® Clique-Tip®, Medi-Globe® Injetra® injection needle, Olympus® InjectorForce MAX® injection needle, US Endoscopy® Articulator® injection, the US Endoscopy®Vari-Safe® injection needle, Kimberly-Clarck® catheter injection needle, and the like.
[0102] In a preferred application of the invention, the pharmaceutical composition in the form of emulsion or microemulsion according to the present invention described herein is used in an endoscopic resection procedure by suctioning a volume of emulsion from its primary container by syringe, with the injection of an adequate volume of the emulsion through an endoscopic injection needle inserted into the working channel of the endoscope immediately under the mucosal surface layer, to deposit a volume of liquid into the submucosal layer, which becomes a cushion when in position. The elevation of the mucosal surface allows the endoscopist to easily perform a resection of the mucosal lesion found during the execution of the endoscopic procedure, even if the lesion is flat and therefore does not protrude into the intestine or the esophageal or gastric lumen.
[0103] According to a preferred embodiment of the invention described here, the pharmaceutical composition in the form of emulsion or microemulsion is in liquid phase, both at room temperature (i.e., about 20 to 25 ° C) and at temperature of the body (that is, about 37 ° C). According to another preferred embodiment, the composition has a viscosity of less than about 150 cP (centipoises), more preferably below about 100 cP (centipoises), more preferably below about 50 cP (centipoises). According to another preferred embodiment, the composition has a viscosity of less than about 20 cP (centipoises), preferably below about 10 cP (centipoises).
[0104] According to the present invention, viscosity is measured at about 25 ° C, about 30 ° C and / or about 37 ° C, preferably using a Brookfield LVDV-III Ultra Programmable Rheometer viscometer ® equipped with a Brookfield Small Sample Adapter® device for small samples and using a Brookfield® spindle N 31 axis. Alternatively, viscosity is measured using a Brookfield VDVE-III Ultra Programmable Rheometer® viscometer equipped with an enhanced UL Adapter® device and using a Brookfield® spindle No. 00 shaft.
[0105] In a preferred embodiment, the viscosity of the pharmaceutical composition in the form of an emulsion or microemulsion, measured at 25 ° C, is less than 150 cP, preferably less than 100 cP, more preferably less than 50 cP. In a preferred embodiment, the viscosity of the pharmaceutical composition in the form of an emulsion or microemulsion, measured at 30 ° C, is less than 150 cP, preferably less than 100 cP, more preferably less than 50 cP. In a preferred embodiment, the viscosity of the pharmaceutical composition in the form of an emulsion or microemulsion, measured at 37 ° C, is less than 150 cP, preferably less than 100 cP, more preferably less than 50 cP. In a more preferred embodiment, the viscosity of the pharmaceutical composition in the form of an emulsion or microemulsion, measured at 25 ° C, 30 ° C and / or 37 ° C is less than 20 cP, preferably less than 10 cP .
[0106] The presence of at least one dye in the cushion helps the endoscopist to visualize the structures below the mucosa (for example, the submucosa layer and the external muscular wall), thus decreasing the risk that the endoscopist, performing the procedure resection, may cause damage to the structures. In fact, the dye will make the professional able to distinguish between the cavity of the cushion and the mucosa floor. The removal of the lesion from the mucosal surface generates a hole in this floor, which has to be healed, and the presence of an agent characterized by trophic activity in the epithelial cells of the gastrointestinal mucosa, in the pharmaceutical compositions according to the present invention disclosed here, has the goal of accelerating the healing of the mucosal wound. The persistence of the pad generated by the injected volume of the pharmaceutical composition in the form of emulsion or microemulsion according to the present invention described here, of long duration, is sufficient to allow the endoscopic resection procedure to be carried out without the need for inject the composition every few minutes, a procedure that usually happens when normal saline is used.
[0107] In view of the above comment, a first advantage provided by the composition in the form of emulsion or microemulsion of the invention is to ensure administration manually and at room temperature (20 to 25 ° C), without the need for cooling the composition and / or the endoscopic injection needle.
[0108] A second advantage of the composition of the invention is to avoid any risk of having an unwanted gelation inside the endoscopic injection needle while the composition is administered during the endoscopic procedure.
[0109] Another advantage of the composition of the invention is its ability to provide an elevated and / or long-lasting pillow, sufficient to allow a safe completion of endoscopic surgical resection, such as polypectomy, EMR and / or ESD.
[0110] Another advantage is the possibility of adding at least one dye, obtaining an improvement in the visibility of the submucosal layer on the part of the operator, with the consequent improvement of safety and the reduction of the risk of damaging the structures below the mucous.
[0111] Another advantage is the possibility of adding at least one trophic agent, obtaining an improvement in the healing of mucosal wounds, through the promotion of related cell growth and differentiation. DEFINITIONS
[0112] References in this specification to "an embodiment", "embodiment" and the like indicate that the described embodiment may include a particular aspect, feature, structure or feature. In addition, these phrases may, but need not necessarily, refer to an embodiment elsewhere in this specification. In addition, when a particular aspect, feature, structure or feature is described in connection with an embodiment, which is within the skill of a person skilled in the art, it affects or connects to the aspect, feature, structure or feature with other embodiments, whether or not explicitly described.
[0113] The terms "comprising", "having", "including" and "containing" are to be interpreted as open terms (ie, which means "including, but not limited to") and are to be considered as providing support also for terms such as "consist essentially of", "consist essentially of", "consist of" or "consisting of".
[0114] The terms "consist essentially of", "consists essentially of" should be interpreted as a semi-closed condition, meaning that there are no other ingredients that materially affect the basic and new characteristics (and optionally physiologically acceptable excipients and / or adjuvants) of the invention that are included.
[0115] The terms "consists of", "consisting of" are to be interpreted as a closed term.
[0116] The singular forms "one", "one", "a" and "o" include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to "a compound" includes a plurality of such compounds. Note also that claims can be drafted to exclude any optional elements. As such, this instruction is intended to serve as an antecedent basis for the use of exclusive terminology, such as "only", "only" and the like, in connection with the recitation of claim elements or the use of a "negative" limitation.
[0117] The term "and / or" means any of the items, any combination of the items, or all the items with which this term is associated.
[0118] Unless otherwise indicated in this document, the term "about" is intended to include, for example, approximate percentages by weight for the range recited that are equivalent in terms of the functionality of the individual ingredient, the composition, or the embodiment.
[0119] A person skilled in the art will recognize that, for any and all purposes, especially in terms of providing a written description, all of the ranges cited herein also cover any and all possible sub-ranges and combinations of these sub-ranges, as well as the individual values that make up the range, particularly integer values. A recited range includes each specific value, integer, decimal, or identity within the range.
[0120] A person skilled in the art will recognize that when members are grouped together in a common way, such as in a Markush group, the invention covers not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group. Furthermore, for all intents and purposes, the invention encompasses not only the main group, but also the main group in the absence of one or more of the group members. Therefore, the invention provides for the express exclusion of any one or more of the members of a recited group. Therefore, caveats can be applied to any of the described categories or embodiments in which any one or more of the elements, species, or embodiments cited can be excluded from such categories or embodiments, for example, as used in an explicit negative limitation.
[0121] The term "emulsion" refers to a heterogeneous compound preparation of two immiscible liquids (by convention described as oil and water), one of which is dispersed as fine drops uniformly over the other. The phase present as small droplets is called the dispersion, dispersed phase or internal phase and the support liquid is known as the continuous or external phase. Emulsions are conveniently classified as oil-in-water (O / W) or water-in-oil (W / O), depending on whether the continuous phase is aqueous or oily. Multiple emulsions, which are prepared from oil and water by reemulsifying an existing emulsion to provide two dispersed phases, are also of pharmaceutical interest. Various oil-in-water-in-oil (O / W / O) emulsions are a w / o type of emulsions in which water globules contain dispersed oil globules themselves. On the other hand, water-in-oil-in-water (W / O / W) emulsions are those in which the internal and external aqueous phases are separated by oil.
[0122] "Microemulsions" are thermodynamically stable, transparent (or translucent) dispersions of oil and water that are stabilized by an interfacial film of surfactant molecules. The surfactant can be pure, be a mixture, or be in combination with a co-surfactant, such as a medium chain alcohol. Microemulsions are easily distinguished from normal emulsions for their transparency, low viscosity and, more fundamentally, for their thermodynamic stability and their ability to form spontaneously. The dividing line, however, between the size of a swollen micelle (~ 10-140 nm) and a drop of fine emulsion (~ 100-600 nm) is not well defined, although microemulsions are very labile systems and a drop of microemulsion be able to disappear within a fraction of a second, while other forms of drops occur spontaneously in other parts of the system. The previous definitions of "emulsion" and "microemulsion" have been taken from "Encyclopedia of Pharmaceutical Technology", third edition, Informa Healtcare.
[0123] The term "mucosetomy" (EMR) refers to an endoscopic technique developed for the removal of sessile or flat neoplasms confined to the superficial layers (mucosa and submucosa) of the GI tract.
[0124] The term "endoscopic mucosal dissection" (ESD) refers to an endoscopic technique developed specifically for the removal of larger lesions.
[0125] "Endoscopic injection needles", also known under the names "injection needles" or "injection needle catheters" or "endoscopic injection needle catheters", are devices that can be up to 230 cm long, and which include a relatively long catheter into which an inner injection tube having a distal sliding injection needle is discarded. Generally, a proximal-acting manipulator is attached to the catheter and the injection tube to move relative to each other when necessary. The needle is generally retractable. Fluid access to the injection tube is usually provided via a luer connector on the cuff. Endoscopic injection needle devices are usually presented at the injection site, through the working channel of the endoscope. In order to protect the lumen of the endoscope's working channel from damage, the infusion needle device's grip is manipulated to withdraw the injection needle into the distal lumen of the catheter before inserting the device into the endoscope. This is important to avoid exposing the sharp tip of the injection needle as the device is moved through the endoscope lumen. When the distal end of the endoscopic injection needle device is located at the injection site, its identifier is again manipulated to move the injection needle distally out of the catheter lumen. When advanced to the most distal position, the exposed portion of the injection needle is approximately 4 to 6 mm in length. The terms "in (or less) laboratory test conditions" or "in laboratory conditions" or "in laboratory tests", as used herein, refer to in vitro conditions, such as methods, equipment and instruments routinely used in laboratory tests to perform a physical examination and chemical characterization of a composition. The term refers to methods, equipment and instruments used and performed in the laboratory. As an example, the viscosity test or the climatic chamber test, described in examples 6 and 7 presented below and used to verify whether a composition is in liquid or gel phase are tests carried out in the laboratory, therefore, they are performed under "laboratory test conditions".
[0126] The terms "up to 40 ° C" or "temperature up to 40 ° C" refer to any temperature between 5 ° C and 40 ° C, preferably about 5 ° C, about 20 ° C, about 25 ° C, about 30 ° C and / or 37 ° C.
[0127] A "body temperature" refers to the level of heat produced and sustained by body processes. Heat is generated within the body through the metabolism of lost nutrients and the body's surface through radiation, by convection and evaporation of perspiration. Heat production and loss are regulated and controlled in the hypothalamus and brain stem. The normal temperature of the adult body, as measured orally, is 37 ° C, although small variations are usually recorded throughout the day.
[0128] An "ambient temperature" (RT) is generally defined as the ambient air temperature in the environment, whatever it is, to be used for a given procedure. More specifically, it is defined as between 20 and 25 ° C, however some ambient temperatures, by nature, do not fall within this range. Generally, protocols that require measurements to be performed in RT require that temperatures do not fall below 18 ° C and do not exceed 27 ° C.
[0129] The term "critical gelling concentration" (CGC), for a reverse temperature sensitive polymer solution, is the concentration of the polymer above which the solution is capable of transition from a liquid phase to a gel phase, in response to a rise in temperature.
[0130] The term "critical gelation temperature" (CGT) represents the temperature above which a solution containing an inverse thermosensitive polymer with a concentration equal to or greater than critical gelation concentration transitions from a liquid phase to a gel phase.
[0131] The term "Lugol's solution" is a solution of elemental iodine and potassium iodide in water.
[0132] "Viscosity" defines the resistance of a liquid or semi-solid against a flow. The flow of liquids or semi-solids is described by viscosity or, more precisely, by shear viscosity n. The shear viscosity of a fluid manifests its resistance to the shear flow, in which the adjacent layers move parallel to each other at different speeds. The common units for measuring viscosity are pascal-seconds (Pa.s), poise (P) and centipoises (cP) (centipoises). 1 poise (P) corresponds to 0.1 Pascal second (Pa-s); 1 centipoise (cP) corresponds to 1 millipascal second (mPa • s).
[0133] The terms "percentage by weight relative to the weight of the composition (w / w)" and "percentage by weight relative to the volume of the composition (w / v)" define the percentage amount of a component or substance in the composition. Considering that the density of the composition in the form of emulsion or microemulsion is equivalent to the density of water (1.0 g / mL), the percentage by weight in relation to the weight of the composition (w / w) is considered equivalent to the percentage by weight relative to the volume of the composition (w / v). For the purpose of the present invention, the two definitions are interchangeable.
[0134] PEG: polyethylene glycol.
[0135] The following examples are included for purposes of illustrating certain aspects and embodiments of the invention, and are not intended to limit the invention. EXAMPLES Example 1 - Emulsion

[0136] The manufacture of the composition is described below (per 10.00 kg of final composition):
[0137] In a suitable container equipped with a stirrer, 8600 ml of water for injection are loaded; then 90.00 g of sodium chloride are added. The mixture is kept under stirring until complete dissolution is achieved. The solution obtained is cooled to a temperature between 5 ° C and 10 ° C; then 1000.00 g of poloxamer 188 is added with stirring. The mixture is kept under stirring until complete dissolution is achieved.
[0138] In a suitable container equipped with a stirrer, about 181 ml of water for injection is loaded; the temperature is raised to 80 ° C. 2.40 g of egg lecithin, 0.50 g of glycerol and 0.06 g of sodium oleate are added, with stirring. The agitator is operated until complete homogenization; then 16.00 g of soy oil are added. The mixture is kept at t = 80 ° C, under stirring, until a homogeneous emulsion is formed. The emulsion is then cooled to a temperature below 30 ° C.
[0139] The emulsion obtained in step b) is added to the mixture obtained in step a), with stirring. Then 0.10 g of methylene blue is added with stirring. The mixture is kept under stirring until homogeneity is achieved.
[0140] The pH of the mixture in step c) is measured and adjusted, if necessary, within the range of 5.0 to 7.0.
[0141] The mixture is brought to a final weight of 10.00 kg by adding water for injection.
[0142] The final composition is filtered through a 0.45 μm filter and is packed in 20 ml bottles closed with rubber lids and aluminum rings. The vials are sterilized at 121 ° C for 20 minutes. Example 2 - Emulsion

[0143] The composition was obtained by a process similar to that described in Example 1. Example 3 - Emulsion

[0144] The composition was obtained by a process similar to that described in Example 1. Example 4 - Emulsion

[0145] The composition was obtained by a process similar to that described in Example 1. Example 5 - Emulsion


[0146] The manufacture of the composition is described below (per 10.00 kg of final composition):
[0147] In a suitable container equipped with a stirrer, 8600 ml of water for injection are loaded; then 90.00 g of sodium chloride are added. The mixture is kept under stirring until complete dissolution is achieved. The solution obtained is cooled to a temperature between 5 ° C and 10 ° C; then 1000.00 g of poloxamer 188 is added with stirring. The mixture is kept under stirring until complete dissolution is achieved.
[0148] In a suitable container equipped with a stirrer, about 181 ml of water for injection is loaded; the temperature is raised to 80 ° C. 2.40 g of egg lecithin, 0.50 g of glycerol and 0.06 g of sodium oleate are added, with stirring. The stirrer is operated until complete homogenization is achieved; then 16.00 g of soy oil are added. The mixture is kept at t = 80 ° C, under stirring, until a homogeneous emulsion is formed. The emulsion is then cooled to a temperature below 30 ° C.
[0149] The emulsion obtained in step b) is added to the mixture obtained in step a), with stirring. Then, 0.10 g of methylene blue and 100.00 g of L-glutamic acid are added with stirring. The mixture is kept under stirring until homogeneity is achieved.
[0150] The pH of the mixture from step c) is measured and adjusted within the range of 5.0 to 7.0 by adding 10% NaOH in water for injection.
[0151] The mixture is brought to a final weight of 10.00 kg, by adding water for injection.
[0152] The final composition is filtered through a 0.45 μm filter and is packed in 20 ml bottles closed with rubber lids and aluminum rings. The vials are sterilized at 121 ° C for 20 minutes.
[0153] Example 6: Viscosity measurement in the laboratory test
[0154] The viscosities of pharmaceutical compositions according to examples 1 to 4 were measured under laboratory conditions at three different temperatures: t = 25 ° C, t = 30 ° C and t = 37 ° C. Measurements were performed using a Brookfield LVDV-III Ultra Programmable RheometerTM equipment equipped with a Brookfield Small Sample AdapterTM small sample device. The Brookfield Small Sample AdapterTM small sample device has a sample chamber that is provided in a water jacket so that precise temperature control has been achieved through a circulating thermostated water bath. For the measurements, two different mandrels were used, depending on the viscosity value: for low viscosity values (recorded at t = 25 ° C, 30 ° C and 37 ° C for the compositions according to examples 1 to 4 and at t = 25 ° C and 30 ° C for reference), the BrookfieldTM device with axis N. 31 was used; for high viscosity values (recorded at t = 37 ° C for reference), a BrookfieldTM device with axis N. 25 was used.
[0155] A 407 poloxamer solution in normal saline was used as a reference. The reference was prepared by dissolving poloxamer 407 in normal saline to obtain a final concentration of poloxamer 407 equal to its critical gelation concentration (about 15% by weight relative to the total weight of the solution). The composition of the reference solution is shown below:

[0156] The viscosities of the compositions according to examples 1 to 4 are shown in the following table in relation to the reference solution:

[0157] The reference solution showed a gel-forming ability after heating from 25 ° C to body temperature (ie 37 ° C), under laboratory conditions, in which it changes from a liquid state, with a viscosity of about 60 cP, to a gel state, with a viscosity of 1044 cP. The pharmaceutical compositions according to examples 1 to 4 do not show any capacity for gel formation, since their viscosities remained significantly constant by heating from 25 ° C to body temperature (i.e., 37 ° C ). Example 7: Phase characterization by means of a climate chamber test
[0158] In order to characterize whether a composition in the form of emulsion or microemulsion of the invention is in liquid or gel phase, a climatic chamber test was carried out in addition to the viscosity test described in example 6. The compositions Pharmaceutical products according to examples 1 to 4 and the reference solution described in example 6 (poloxamer 407, 15% in normal saline) were packaged in sealed bottles, which were then placed in a climate chamber with thermostatic control at 40 ° C. ° C. After two hours, the phase (liquid or gel) of the compositions was easily verified by turning the flasks upside down: in the case of the compositions according to examples 1 to 4 there was a liquid flow, while the flask was being turned upside down. On the contrary, in the case of the reference solution (poloxamer 407, 15% in normal saline), there was no liquid flow into the bottle, and the gel phase composition remained on top of the bottle. Example 8: Injection of the composition according to example 1 into the ex vivo porcine stomach submucosa layer
[0159] An ex vivo porcine stomach was placed in a water bath maintained at 37.0 ° C ± 0.5 ° C by means of a calibrated thermostat. Once the stomach reached the desired temperature (37 ° C ± 0.5 ° C), it was then placed on an examination surface. The composition according to example 1 was injected into the submucosal layer of the stomach via an endoscopic injection needle; the volume injected was 5.0 ml ± 0.5 ml, in order to create a visually adequate submucosal pad. Two injections were performed. In both cases, the submucosal pads generated (Figures 1 and 2) were able to raise the mucosal wall in an appropriate way to allow the typical resection of polyps through a loop or an electro scalp, in accordance with the procedures of typical endoscopic resections such as EMR and ESD. One of the pads was cut with a scalpel, immediately after the injection; after cutting, the composition appeared to have provided a viscous product into the submucosal layer that showed a good consistency (Figure 3). A sample of the mucosa was resected and visually examined: the product formed by the composition according to example 1 remained attached to the excised part (Figure 4). The other pillow was kept in place for 15 minutes after the injection, before cutting. During this time, the pillow did not show any change in shape and height (Figure 5). After 15 minutes, the second pillow was cut in a similar way to the first pillow (Figure 6). Visual examination of the samples after cutting revealed the presence of a viscous product within the submucosal layer that had a consistency similar to that obtained in the first pad (Figure 7). The test revealed that the composition according to example 1, which was not able to transition from a liquid phase to a gel phase when heating from 25 ° C to body temperature (ie, 37 ° C ) under laboratory test conditions (as reported in examples 6 and 7) was, on the contrary, capable of generating a high-level, long-lasting submucosal pad once injected into the submucosal layer of a porcine stomach. Cutting such a cushion revealed that the composition according to example 1 had surprisingly formed a viscous product when inside the submucosal layer; after removing a sample of mucosa from the pad, the product remained attached to the sample for 10 minutes. Example 9 - Microemulsion

[0160] The manufacture of the composition is described below.
[0161] In a suitable container equipped with a stirrer, the lipophilic compound and the nonionic surfactant are loaded and mixed; then an adequate amount of hot water for injection is poured over the oil phase under agitation. The mixture is kept stirred and heated until a microemulsion is obtained.
[0162] In a second container, the remaining amount of water for injection is heated; then, the microemulsion prepared in step a) is poured dropwise with stirring.
[0163] The polymer is added to the microemulsion of step b), and the mixture is kept under stirring until complete dissolution is achieved.
[0164] Sodium chloride is added with stirring until complete dissolution is achieved.
[0165] The dye is added under vigorous stirring until complete dissolution is achieved.
[0166] The pH of the mixture from step e) is measured (specification: 5.0 to 7.5).
[0167] The mixture is brought to the final volume by adding water for injection.
[0168] The final composition is sterilized by sterilizing filtration, due to the very small droplet size of the microemulsion (less than 100 nm). Thus, it is filtered through a 0.22 μm filter and is packed by aseptic processing in closed bottles with rubber lids and aluminum rings. Example 10 - Microemulsion

[0169] The composition was obtained by a process similar to that described in example 9. Example 11 - Microemulsion

[0170] The composition was obtained by a process similar to that described in example 9. Example 12 - Microemulsion


[0171] The composition was obtained by a process similar to that described in example 9. Example 13 - Microemulsion

[0172] The composition was obtained by a process similar to that described in example 9. Example 14 - Microemulsion

[0173] The composition was obtained by a process similar to that described in example 9. Example 15 - Microemulsion

[0174] The composition was obtained by a process similar to that described in example 9. Example 16 - Microemulsion

[0175] The composition was obtained by a process similar to that described in example 9, without step e). Example 17 - Microemulsion droplet size characterization by dynamic light scattering (DLS)
[0176] The oil-in-water microemulsions of the present invention are thermodynamically stable, can be prepared spontaneously, and are transparent.
[0177] The dynamic light scattering (DLS) technique was used to characterize the size of the microemulsion droplets.
[0178] EQUIPMENT: Zetatamanhor Nano® ZSP from Malvern Instruments
[0179] SAMPLE PREPARATION: None, undiluted sample
[0180] MEASUREMENT CONFIGURATION:
[0181] measurement type: size
[0182] Sample:
[0183] Material: No configuration (material optical properties are not required for intensity-based distribution)
[0184] Dispersant: water with mass viscosity at 25 ° C
[0185] General options: use dispersing viscosity as sample viscosity
[0186] Temperature: 25 ° C, with 60 seconds of equilibration time
[0187] Cell: disposable cells DTS0012 MEASUREMENT:
[0188] Measurement angle: 173 ° backscatter (standard NIBS)
[0189] Measurement period: Automatic
[0190] Measurement number: at least three
[0191] Instructions: none
[0192] Advanced:
[0193] Extend life of large particles: No
[0194] Positioning method: Search for ideal position
[0195] Automatic selection Attenuation: Yes
[0196] The following are the DLS analyzes of the microemulsion of example 15.
[0197] Two samples were taken at the end of steps a) and d), and then were analyzed using the device parameters reported above.
[0198] In table A, presented below, the results of the DLS analyzes in the sample from step a) are reported. The relevant graph is shown in Figure 8. Table A


[0199] The results show a distribution of monodisperse particles with a Z average of about 14 nm and an extremely low polydispersity index.
[0200] In table B, below, the results of the DLS analysis in the sample from step d) are reported. The relevant graph is shown in Figure 9. Table B

[0201] The graph shows a single particle distribution with an average Z of about 14 nm and a low polydispersity index. The measurements are reproducible with a good interception of the correlation function (0.960).
[0202] In table C, below, a comparison between the results obtained in step a) and in step d) is reported. The relevant graph is shown in Figure 10. Table C

[0203] From the overlap of the particle size distributions and the two dimensional data, the two samples are considered equal: the small differences between them are not significant and can be attributed to an experimental variability. Thus, the two samples are equal, both in terms of distribution and the average Z.
[0204] In table D, below, the results of the DLS analysis in the example of step e) are reported. The relevant graph is shown in Figure 11. Table D

[0205] The graph shows a single particle distribution with a mean Z of about 28 nm.
[0206] DLS analyzes of the microemulsion in the sample from step e), examples 11 to 13 and 14 are reported in table E below: Table E

[0207] DLS analyzes of the microemulsion in the sample from steps a), d) of example 12 are reported in table F below: Table F
Example 18 - Cytotoxicity
[0208] The composition according to example 15 was subjected to an in vitro cytotoxicity study on mammalian fibroblasts ATCC BalbC 3T3, according to the ISO 10993-5 standard.
[0209] After 24 hours of testing, the following results were obtained:
[0210] The reduction in cell vitality in the well of the composition of example 15 was 14.68%, and the composition was considered to be non-cytotoxic. Example 19 - Cytotoxicity
[0211] The composition according to example 10 was subjected to an in vitro cytotoxicity study on mammalian fibroblasts ATCC BalbC 3T3, according to ISO 10993-5.
[0212] After 24 hours of testing, the following results were obtained:
[0213] The reduction in cell vitality in the composition of example 10 was 6.22%, and the composition was considered to be non-cytotoxic. Example 20 - Ex vivo tests on pig stomachs
[0214] During product development, the cushioning capacity of the different prototype formulations was assessed using various ex vivo tests on pig stomachs. The porcine stomach was selected as a test system, as it is a widely accepted model of the human gastrointestinal mucosa. In addition, in the scientific literature many works published on submucosal injection agents describe the use of this model to assess the performance of different agents in terms of height and duration of the submucosal pad.
[0215] The effectiveness of the pharmaceutical compositions according to the present invention was evaluated in the ex vivo test, in terms of height and duration of the submucosal pad after the injection of a suitable volume.
[0216] A brief description of the method is reported here, below. Materials
[0217] frozen pork stomach
[0218] plexiglass support.
[0219] 10 ml Luer-Lock syringe
[0220] standard endoscopic injection needle Method
[0221] The frozen porcine stomach is defrosted and then kept at 37 ° C in a thermal blanket. The stomach is cut with a surgical scalpel, and the internal mucosa is cleaned using paper towels. A 10 cm x 10 cm square section is cut from the stomach and is positioned on the acrylic support. An appropriate volume of the pharmaceutical composition is injected through the endoscopic injection needle into the submucosal layer of the resected square sample of the porcine stomach. When the formation of the submucosal pad is complete, the needle is removed from the sample. The height and residence time of the obtained submucosal pad are assessed by visual inspection. The pad is monitored every 15 minutes for up to an hour. Results
[0222] As shown in Figure 12, the submucosa pad created after injecting an adequate amount of the composition in example 11 went from a height of 1.6 cm to 1.4 cm, thus losing only 0.2 cm over 1 hour from the injection.
[0223] The results for the compositions of examples 9, 11 and 13 are reported in the following table: Table G
Example 21 - Preliminary in vivo test on piglet
[0224] A harmful tolerance study on a piglet was carried out with the composition according to example 5. Purpose
[0225] The purpose of the study was to investigate the product's tolerance in a piglet after its gastric submucosal administration. Methods
[0226] A male Gottingen piglet, weighing approximately 20 kg and an age of about 10 months, was used for this study. The endoscopic procedure was performed using an Electronic Video Endocopes Fujinon EVE200 System and an Upper Gastrointestinal Electronic Video Endocopes EG-201FP. The submucosal injection agent was presented through the endoscope using an injection and an endoscopic needle. The animal was anesthetized before each endoscopic procedure. The test sample was administered (about 5 ml) by endoscopic submucosal injection, using an endoscopic injection needle (Medwork® injection needle, 230 cm x 2.3 mm, needle diameter 0.7 mm Ref. N. INJ1 -A1-07-5-23 -230). The animal was administered once with a submucosal injection in about 55 seconds, followed by observation for 24 hours. After administration, the injection site mucosa and the surrounding untreated mucosa were continuously examined for 25 minutes, during which time the test sample caused an adequate distension with a gap between the mucosa and submucosa layers. This distance was still persistent 25 minutes after the injection; other tests were performed at 60 minutes and 24 hours.
[0227] Subsequent general observation of the injection site about 60 minutes after the injection revealed the persistence of evident swelling.
[0228] During the 24-hour observation period, swelling of the gastric mucosa was no longer present and the gastric mucosa did not show any test article related to severe macroscopic changes.
[0229] Figures 13, 14 and 15 show the administration of the test substance, the submucosa pad and the appearance of the injection site within 24 hours after administration. Example 22 - Rheology
[0230] The variation in viscosity as a function of temperature was measured in the composition of example 16, using a rotary rheometer, Kinexus pro +.
[0231] The Kinexus Pro + equipment is a rotary rheometer that applies shear with controlled deformation to the sample, and is normally used to evaluate and study the rheological characterization (viscosity) of compositions, such as emulsions or microemulsions.
[0232] To proceed with the measurement, the composition of example 16 was equipped with a CP60 -2 ° cone plate with controlled shear and constant stress, 0.5 Pa; with an adjusted temperature range between 25 ° C and 50 ° C.
[0233] As reported in the graph in figure 16, the viscosity rogram against temperature demonstrates that the viscosity of the composition decreases with increasing temperature.

权利要求:
Claims (15)
[0001]
1. Pharmaceutical composition in the form of emulsion or microemulsion, which is in liquid phase up to a temperature of 40 ° C, in vitro, characterized by the fact that it comprises: a) an aqueous phase; b) an oily phase; c) at least one non-ionic surfactant; d) at least one poloxamer in an amount between 5% and 12% by weight, based on the weight of the composition; e) optionally, at least one physiologically acceptable excipient; f) at least one dye selected from Lugol's solution, methylene blue, toluidine blue, crystal violet, indigo carmine, Congo red and phenol red.
[0002]
2. Pharmaceutical composition in the form of an emulsion or microemulsion, according to claim 1, characterized by the fact that the composition is an oil-in-water emulsion or microemulsion.
[0003]
3. Pharmaceutical composition in the form of an emulsion or microemulsion, according to claim 1, characterized by the fact that the composition has a viscosity of less than 0.15 Pa.s (150 cP), preferably below 0.1 Pa (100 cP), more preferably below 0.05 Pa.s (50 cP), much more preferably less than 0.02 Pa.s (20 cP).
[0004]
4. Pharmaceutical composition in the form of emulsion or microemulsion, according to claim 3, characterized in that the viscosity is measured at 25 ° C, at 30 ° C and / or at 37 ° C.
[0005]
5. Pharmaceutical composition in the form of emulsion or microemulsion, according to claim 1, characterized by the fact that at least one poloxamer is in an amount between 5% and 11% by weight, based on the weight of the composition.
[0006]
6. Pharmaceutical composition in the form of emulsion or microemulsion, according to claim 1, characterized by the fact that at least one poloxamer is in an amount of 7%, 8%, 9% or 10% by weight, in relation to weight of the composition.
[0007]
Pharmaceutical composition in the form of an emulsion or microemulsion, according to claim 1, characterized by the fact that at least one poloxamer is selected from poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338 and poloxamer 407.
[0008]
Pharmaceutical composition in the form of an emulsion or microemulsion, according to claim 7, characterized by the fact that at least one poloxamer is poloxamer 188.
[0009]
Pharmaceutical composition in the form of an emulsion or microemulsion, according to claim 8, characterized in that the poloxamer 188 is in an amount of 10% by weight in relation to the weight of the composition.
[0010]
10. Pharmaceutical composition in the form of an emulsion or microemulsion, according to claim 1, characterized in that the oil phase comprises at least one lipophilic compound.
[0011]
11. Pharmaceutical composition in the form of an emulsion or microemulsion, according to claim 10, characterized by the fact that at least one lipophilic compound is selected from natural oils, such as almond oil, canola oil, castor oil , corn oil, cottonseed oil, olive oil, safflower oil, sesame oil, soybean oil; fatty acid esters, such as isopropyl palmitate, isopropyl myristate, ethyl oleate; fatty alcohols, such as myristic alcohol, oleyl alcohol; fatty acids, such as myristic acid, oleyl acid, palmitic acid, triglycerides, such as long-chain and / or medium-chain triglycerides; diglycerides and monoglycerides.
[0012]
12. Pharmaceutical composition in the form of an emulsion or microemulsion, according to claim 10, characterized by the fact that at least one lipophilic compound is a medium chain triglyceride.
[0013]
13. Pharmaceutical composition in the form of emulsion or microemulsion, according to claim 1, characterized by the fact that the non-ionic surfactant is selected from polysorbate 80 and PEG-15 hydroxystearate.
[0014]
14. Pharmaceutical composition in the form of an emulsion or microemulsion, according to any one of the preceding claims, characterized in that it additionally comprises at least one co-surfactant.
[0015]
15. Pharmaceutical composition in the form of an emulsion or microemulsion, according to claim 14, characterized by the fact that at least one co-surfactant is selected from propylene glycol, glycerol and sodium oleate.

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法律状态:
2018-03-06| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-05-15| B07B| Technical examination (opinion): publication cancelled [chapter 7.2 patent gazette]|

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2020-10-06| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-01-05| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 18/11/2014, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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ITMI2013A001924|2013-11-20|

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ITMI20131924|ITMI20131924A1|2013-11-20|2013-11-20|EMULSIONS OR MICROEMULSIONS FOR USE IN ENDOSCOPIC AND MUCOSAL RESECTIONING AND / OR|

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PCT/EP2014/074886|WO2015075024A1|2013-11-20|2014-11-18|Emulsions or microemulsions for use in endoscopic mucosal resectioning and/or endoscopic submucosal dissection.|

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