Advanced medication containing chitosan and azelaic acid microspheres

Abstract

The present invention relates to an advanced medication containing chitosan and azelaic acid microspheres. The present invention also relates to a process for producing the advanced medication and the use of the advanced medication in the treatment and / or prevention of skin and mucosal lesions.

Description

[0001] ADVANCED MEDICATION CONTAINING CHITOSAN AND AZELAIC ACID MICROSPHERES

[0002] DESCRIPTION

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to an advanced medication containing chitosan and azelaic acid microspheres , its use in the treatment and / or prevention of skin and mucosal lesions , and a method for its production .

[0005] BACKGROUND OF THE INVENTION

[0006] A product that promotes the tissue repair process , protecting the wound from infections , and maintaining optimal moisture and oxygen permeability conditions in the wound ' s microenvironment is considered an advanced medication .

[0007] Advanced medications can be classi fied into :

[0008] PASS IVE : used to absorb exudates and protect the lesion from external agents ;

[0009] INTERACTIVE or ACTIVE : play an active role in tissue repair by regulating the lesion ' s microenvironment and ensuring ideal conditions to facilitate the repair process ;

[0010] BIOACTIVE : interact with the repair processes by releasing or forming substances that act directly on the healing processes .

[0011] The application of advanced medications can be beneficial in the presence of certain skin lesions to promote healing . Lesions that can benefit from the application of advanced medications include wounds , ulcers , and skin sores , such as diabetic ulcers , pressure ulcers and sores (bedsores ) , general skin ulcers and sores, surgical wounds, cuts, puncture wounds, gunshot wounds, abrasions, excoriations, fissures and cracks in the skin, chapped skin, burns, and acne lesions.

[0012] In particular, pressure ulcers are areas of tissue damage of the skin and / or underlying tissues mainly caused by pressure, stretching, or friction. This type of damage (also known as pressure ulcer, sore, or decubitus ulcer) is largely preventable but remains a significant issue in hospital wards and in the community due to the number of patients involved and the time and resources required to treat the problem.

[0013] Vascular lesions of the lower limbs are defined as skin wounds with a vascular etiology (venous, arterial, and / or mixed) located below the knee down to the foot and lasting at least eight to ten weeks. Chronic leg ulcers are a very common condition in the Western world, primarily affecting the elderly, thus resulting in a high social cost.

[0014] Diabetic ulcers, particularly those responsible for diabetic foot, occur when diabetic neuropathy or arteriopathy of the lower limbs compromises the function or structure of the foot. These two conditions, also defined as neuropathic foot or ischemic foot, are fundamentally different. However, in most subjects, especially the elderly, both conditions coexist, leading to what is known as neuroischemic foot.

[0015] A surgical wound is a discontinuity in tissues caused by a mechanical agent. In clinical practice, two main types of surgical wounds can be encountered: - wounds that heal by primary intention, where the edges are brought together by the application of sutures. These wounds heal quickly, usually developing a linear scar that is often barely visible;

[0016] - wounds that heal by secondary intention, where the edges are not brought together, often due to infection. Healing is slow, and the resulting scar can vary in size.

[0017] Cuts are one of the most common household accidents, caused by sharp objects like knives or glass. They typically appear as linear wounds with clean edges.

[0018] Puncture wounds are caused by pointed objects (daggers, nails, etc.) , resulting in deeper lesions rather than surface ones. Besides the entry hole, these wounds have a tract that goes deep and can even be penetrating or through-and-through if there is also an exit hole.

[0019] Gunshot wounds are caused by bullets (pellets or shrapnel) of various shapes and sizes from firearms or explosive devices. When the bullet has a very high penetrating force, it can exit the body, creating an exit hole that is usually larger and more ragged than the entry hole, as the bullet drags tissue fragments along its path, increasing its size.

[0020] Abrasions are wounds caused by superficial damage to the skin, not deeper than the epidermis. They are less severe than lacerations, and bleeding, if present, is minimal. The most common abrasions occur when the skin is rubbed against a rough surface. They can be classified as : first-degree abrasion : it involves only epidermal damage ;

[0021] - second-degree abrasion : it involves the epidermis and dermis and may bleed slightly;

[0022] - third-degree abrasion : it involves damage to the subcutaneous layer of the skin and is often called an avulsion when the skin layers are completely removed .

[0023] Excoriations are superficial skin inj uries of traumatic origin that af fect the epidermis and superficial dermis . Excoriations mani fest with varying degrees of pain, swelling, redness , and skin irritation, and possible bleeding . Depending on the degree of epidermal removal , there are two types of excoriations :

[0024] - first-degree excoriation : the lesion involves the outermost epidermal layer . It is a mild wound, usually not accompanied by bleeding, and tends to heal within a few days ;

[0025] - second-degree excoriation : the wound is deeper, involving the dermis as well , and is often accompanied by bleeding . Healing occurs within 5-7 days .

[0026] Fissures or cracks are thin, elongated cuts that form in the stratum corneum or deeper and are caused by dry skin, inadequate skin nourishment , the use of aggressive detergents , the use of medications , and other factors .

[0027] Chapping are small cracks that can form in various parts of the body . The causes of their formation are mainly external agents , but in some cases , endogenous factors can also contribute to this condition . The appearance of chapping is primarily favored by the loss of normal elasticity and, especially, skin hydration. Skin dehydration typically occurs due to weather conditions, such as excessive exposure to the sun, wind, and cold. However, the onset of chapping can also be linked to other factors, such as trauma (excessive rubbing) , cosmetics (use of aggressive and unsuitable products) , bacterial (infections) , and nutritional (vitamin deficiencies, dehydration) .

[0028] A burn is an acute traumatic wound caused by contact with a flame, hot liquids or solids, chemicals, electricity, or radiant energy. Depending on the depth, they are classified as superficial first and second degree, deep second degree, and third degree; the optimal treatment for the first two is medication that generally allows healing within two weeks; in the case of deep burns, the optimal treatment is surgical.

[0029] Acne lesions are a common skin condition caused by the inflammation of hair follicles and sebaceous glands. Acne lesions primarily appear on the face but can also present on the neck, shoulders, chest, and back. The cause of acne is often linked to excessive sebum production, the presence of bacteria (such as Propionibacterium acnes) on the skin, and inflammation. Acne can manifest in different forms of skin lesions, including :

[0030] - comedones: clogged pores with a combination of sebum, dead skin cells, and keratin. Comedones can be open (blackheads) or closed (whiteheads) ;

[0031] - papules: small, raised lesions on the skin, pink or red in color; - pustules : similar to papules but also containing pus , appearing with a white or yellow head;

[0032] - nodules : larger, deeper lesions that develop under the skin . They can be painful and may cause scarring;

[0033] -cysts : pus- filled lesions that can be very large and painful . They can cause scarring and often require medical intervention for treatment .

[0034] Various substances or products exhibit properties beneficial for the regeneration of tissues af fected by lesions . Furthermore , from commercially available products or from scienti fic and patent literature , numerous attempts are known to combine various substances to create ef fective medications that promote the tissue repair process , protect against infections , and maintain the optimal microenvironment , such as by keeping the temperature and oxygen permeability of the af fected tissue constant .

[0035] Despite numerous attempts are known ( from commercially available products or from scienti fic and patent literature ) to combine various substances to create advanced medications capable of promoting the tissue repair process of the skin and mucosa, there remains a need to combine di f ferent substances with varying properties in proportions that exhibit synergistic ef fects in terms of promotion of the tissue repair process , protecting against infections , and maintaining constant temperature and oxygen permeability of the af fected tissue , while also being well-tolerated by the skin and mucosa . Indeed, there are various technical problems that an ideal advanced medication should solve . In particular, such advanced medications should :

[0036] - be ef fective on the skin and / or mucosa,

[0037] - exhibit very low toxicity / cytotoxicity towards the healing tissue , but activity against microorganisms to ensure microbial load control ,

[0038] - be well-tolerated, comfortable , and not painful ,

[0039] - have prolonged ef ficacy over time ,

[0040] - be suitable for prolonged and / or repeated use ,

[0041] - be easy to apply,

[0042] - not require frequent changes ,

[0043] - not adhere to the lesion tissue ,

[0044] - have a non-unpleasant odor,

[0045] - be easily removable / detachable or absorbable ,

[0046] - control unpleasant odors that may come from the lesion, allow the gaseous exchange of oxygen, carbon dioxide , and water vapor with the environment ,

[0047] - provide mechanical protection (protect the lesion from potential trauma ) ,

[0048] - maintain a constant moist environment in contact with the tissue lesion,

[0049] - be impermeable to external microorganisms , not show adverse interactions with other concurrent treatments the subj ect is undergoing .

[0050] Overall , advanced medications should have good compliance from the users , for example , by providing an ef fective dose of active ingredients that act synergistically and for a prolonged period, being suitable for use on both the skin and the oral and / or genital mucosa, and without requiring numerous daily applications .

[0051] SUMMARY OF THE INVENTION

[0052] The above aim has been achieved through an advanced medication comprising chitosan and azelaic acid .

[0053] The inventors of the present invention have surprisingly found that these ingredients ( chitosan and azelaic acid) exhibit a synergistic, prolonged antimicrobial ef ficacy against skin and mucosal pathogens , and low irritability on the skin and mucosa .

[0054] Thus , an obj ect of the present invention is an advanced medication containing chitosan and azelaic acid microspheres , as outlined in claims 1 to 6 .

[0055] Another obj ect of the invention is a process for producing the advanced medication, as outlined in claims 7 to 9 .

[0056] Another obj ect of the invention is the advanced medication for use in the treatment and / or prevention of skin and mucosal lesions in human and animal subj ects , wherein animals include pets , livestock, and wild animals , as outlined in claim 10 .

[0057] Non-limiting examples of skin and mucosal lesions that can particularly benefit from the application of the advanced medication of the present invention include , but are not limited to , diabetic ulcers , pressure ulcers and sores (bedsores) , general skin ulcers and sores, surgical wounds, cuts, puncture wounds, gunshot wounds, abrasions, excoriations, fissures and cracks in the skin, chapped skin, burns, acne lesions, and the like.

[0058] The advanced medication of the present invention can be applied to both humans and animals, including pets, livestock, and wild animals.

[0059] The text of the appended claims forms an integral part of this description.

[0060] Additional features and advantages of the advanced medication according to the invention will be apparent from the following description of exemplary embodiments, given by way of indication and not limitation.

[0061] BRIEF DESCRIPTION OF THE DRAWINGS

[0062] Figure 1 shows the particle size distribution of two different batches of chitosan and azelaic acid particles .

[0063] Figure 2 is a SEM image of chitosan and azelaic acid microspheres, which appear to have a spherical morphology .

[0064] Figure 3 shows the DTA profile of chitosan and azelaic acid microspheres.

[0065] Figure 4 shows the FT-IR spectrum of chitosan and azelaic acid microspheres.

[0066] Figure 5 shows the appearance of chitosan and azelaic acid microspheres under an optical microscope after 5 days in the degradation medium. Figure 6 is a graph showing the degradation over time of chitosan and azelaic acid microspheres , evaluated by the release of azelaic acid over time .

[0067] Figure 7 is a scanning electron microscope ( SEM) micrograph of the batch of microspheres produced on an industrial scale .

[0068] DETAILED DESCRIPTION OF THE INVENTION

[0069] According to a first embodiment , the present invention relates to an advanced medication containing chitosan and azelaic acid microspheres , in which the chitosan and azelaic acid are crosslinked by at least 20% w / w relative to the total weight of the composition containing chitosan and azelaic acid .

[0070] The crosslinking of chitosan is carried out by azelaic acid under the reaction conditions speci fied in Example 1 , wherein azelaic acid acts as the crosslinking agent .

[0071] The degree of crosslinking is determined qualitatively by infrared ( IR) spectroscopy by evaluating the formation of the band corresponding to the amide bond . The amount of crosslinked polymer is considered as the fraction of the mixture remaining undissolved after storage for 35 days in water, in acetate buf fer pH 4 , and in phosphate buf fer pH 7 . See Example 2 .

[0072] According to a preferred embodiment , the present invention relates to an advanced medication containing chitosan and azelaic acid microspheres , in which the chitosan and azelaic acid are present in a weight ratio of 80:20 to 90:10.

[0073] According to a further preferred embodiment, the present invention relates to an advanced medication containing chitosan and azelaic acid microspheres, in which the chitosan and azelaic acid are present in a weight ratio of 85:15.

[0074] According to another preferred embodiment, the present invention relates to an advanced medication containing chitosan and azelaic acid microspheres, in which the microspheres formed by chitosan and azelaic acid have a median particle size (D50) of 10 to 15 micrometers .

[0075] As used herein, the term "advanced medication" means an advanced medication suitable for the treatment of skin and mucosal lesions. There are primary and secondary medications: primary medications are placed directly on the wound bed and act directly, while secondary medications are used as an adjunct or to secure primary medications. Non-limiting examples of primary medications include alginates, hydrocolloids, hydrofibers, and polyurethane foams. Non-limiting examples of secondary medications include non-woven fabric gauze, cotton gauze, and fastening systems such as adhesive patches or self-adhesive bandages.

[0076] As used herein, the terms "% by weight" or "% w / w" mean the percentage by weight relative to the total weight of the composition. As used herein, the term "chitosan" means a linear polysaccharide composed of D-glucosamine and N-acetyl- D-glucosamine, linked by |3 ( 1 — 4 ) bonds. Chitosan is typically obtained by deacetylation of chitin, generally extracted from the exoskeleton of crustaceans (crabs, shrimp, etc.) with an aqueous solution of sodium hydroxide. Alternatively, chitosan can be of vegetable or fungal origin, meaning it is obtained by deacetylation of chitin present in fungi, where it constitutes the main component of the cell wall.

[0077] Characteristics that distinguish various types of chitosans and are responsible for their different properties include viscosity, degree of acetylation, and molecular weight.

[0078] Viscosity is measured in an aqueous solution of 1% acetic acid and expressed in centipoise (cP) . Viscosity is measured on a Brookfield rotational viscometer model NDJ-1, usable in a viscosity range from 10 to 100,000 cP. At room temperature, 3.0 g of the sample, previously dried to constant weight at 105±2°C, is placed in 300 ml of water with stirring. Then, 3.0 g of glacial acetic acid is added, and stirring is continued for 1 hour or until the sample is completely dissolved. The rotational viscometer is then used to determine the viscosity at 20±l°C.

[0079] The degree of acetylation is determined using NMR spectroscopy and ranges from 0% to 40%, while the molecular weight range varies from 3800 to 20,000 Daltons. For the purposes of the invention, vegetable or fungal chitosan has a viscosity of less than 100 cP and a degree of acetylation of less than 30%.

[0080] As used herein, the term "azelaic acid" means a dicarboxylic acid (nonanedioic acid, CAS number 123-99- 9) . It is a natural substance found in wheat, rye, and barley .

[0081] As used herein, the terms "chitosan and azelaic acid microspheres" or "crosslinked chitosan and azelaic acid microspheres" (also abbreviated as C-MS) mean microspheres formed by the crosslinking of chitosan by azelaic acid, which acts as the crosslinking agent.

[0082] As used herein, the term "subject" means a human or animal subject, where the animal can be a pet, livestock, or a wild animal.

[0083] The advanced medication of the invention may also include additional ingredients and excipients such as, but not limited to, other antimicrobial agents, plant extracts, essential oils, terpenes, rheology modifiers, pH regulators, preservatives, fragrances, viscosity modifiers, surfactants, and the like.

[0084] In certain embodiments, the advanced medication is in powder form.

[0085] In certain embodiments, the advanced medication is in cream form.

[0086] In certain embodiments, the advanced medication is in gel form. In certain embodiments , the advanced medication is in lotion form .

[0087] In certain embodiments , the advanced medication is in ointment form .

[0088] In certain embodiments , the advanced medication is in paste form .

[0089] In certain embodiments , the advanced medication is in the form of a filament coated or impregnated with said microspheres .

[0090] In certain embodiments , the advanced medication is in the form of a fabric gauze coated or impregnated with said microspheres .

[0091] In certain embodiments , the advanced medication is in the form of a non-woven fabric gauze coated or impregnated with said microspheres .

[0092] In certain embodiments , the advanced medication is in the form of a pad coated or impregnated with said microspheres .

[0093] In certain embodiments , the advanced medication is in the form of a patch comprising said microspheres .

[0094] In certain embodiments , the advanced medication is in the form of a sheet comprising said microspheres .

[0095] In certain embodiments , the advanced medication is in the form of a film comprising said microspheres .

[0096] In other embodiments , the advanced medication is in the form of 3D printed medications electrospun medications , spray or sponge , comprising said microspheres .

[0097] The advanced medication of the invention can be prepared according to conventional methods, such as those described in Remington, The Science and Practice of Pharmacy, edited by Allen, Loyd V., Jr, twenty-second edition, 2012. When the advanced medication takes the form of a filament, fabric gauze, non-woven fabric gauze, tampon, patch, sheet, or film, it can be prepared using techniques such as electrospinning and three-dimensional printing (3D printing) .

[0098] EXAMPLES

[0099] Example 1 - Synthesis of Chitosan and Azelaic Acid Microspheres (C-MS)

[0100] Chitosan and azelaic acid microspheres were prepared as follows: in a jacketed borosilicate glass reactor, an aqueous dispersion of 5 liters containing 1% by weight chitosan and 0.18% by weight azelaic acid was prepared. This suspension was thermostatted at 55°C for 30 minutes, then glacial acetic acid was added to obtain a 0.7% by weight solution relative to the water. The suspension was kept under vigorous stirring at 55°C for 15 hours, at the end of which a yellow colloidal suspension was obtained. This suspension was heated to 65°C and dried by atomization with the following operating parameters: inlet temperature: from 220°C to 300°C outlet temperature: from 105°C to 80°C feed rate: from 1.5 to 2.5 liters per hour. Example 2 - Characterization of Chitosan and Azelaic

[0101] Acid Microspheres (C-MS)

[0102] The microspheres obtained according to the procedure of Example 1 are an odorless powder with a light yellow color. They were characterized by the following properties .

[0103] Particle Size Distribution : the particle size distribution of the samples was obtained using a Malvern Mastersizer 2000 Laser Diffraction Particle Size Analyzer using dry samples (Scirocco) or aqueous dispersion (Hydro) after being suspended in deionized water with 1% Tween 80 for 10 minutes and then sonicated for an additional 10 minutes.

[0104] The particle size distribution is expressed as the D50 value, meaning the so-called "median". This divides the particle size distribution into equal amounts of smaller and larger particles than this value. The D50 was found to be 10-15 pm (see Figure 1) . Dio, which was Dio = 4-5 pm, and D90, which was D90 = 20-25 pm, were also calculated .

[0105] Morphology : the morphology and particle size of the samples were obtained using a scanning electron microscope (SEM) with a LEO 1525 FE-SEM with EDX probe Bruker Field Emission Scanning Electron Microscope, at magnifications from 250X to 10, 000X. The microspheres were found to have a spherical morphology (see Figure 2) . Differential Thermal Analysis (DTA) : the thermal properties of the samples were determined using a TG Perkin Elmer STA 8000 Simultaneous Thermal Analyzer. The analyses were carried out in nitrogen with a temperature program of 10°C / min. The following were observed (see Figure 3) :

[0106] - a first endothermic stage between 30°C and 110°C attributable to water evaporation

[0107] - a second exothermic stage between 180°C and 340°C due to the decomposition of chitosan, with a broad band because it depends on the molecular weight of the chitosan (the glass transition temperature increases with the molecular weight of the polymer)

[0108] - a third exothermic stage around 470°C and a fourth exothermic stage at 550°C, both typical of chitosan

[0109] - two endothermic transitions at 380°C and 500°C due to the melting and boiling of azelaic acid, respectively.

[0110] Infrared Spectroscopy (IR) : the IR spectrum was obtained using a FT-IR Jasco 4600 spectrophotometer. Each sample analyzed was previously mixed with FT-IR grade KBr and pressed to obtain pellets. The spectrum was recorded between 4000 and 450 cm-1 using 100 scans. A background spectrum of KBr alone was recorded before each analysis. The obtained FT-IR spectrum is shown in Figure 4.

[0111] Study of the Degradation of Microspheres and Release of Azelaic Acid from Them: 0.1 g of microspheres were dispersed in 100 ml of solution to obtain a 0.1% by weight dispersion of microspheres. Three dispersions were obtained using water, acetate buffer pH 4, and phosphate buffer pH 7 as solutions. The 100 ml dispersions were sealed in glass bottles and aged in a climate chamber at 40°C and 75% humidity for 35 days. Aliquots of the dispersions were taken at various times for analysis.

[0112] Results: after 1 day, a qualitative observation was made under an optical microscope. In all degradation media used, after 1 day, the microspheres appeared dissolved, but not completely. After 5 days, another observation was made using optical microscopy (see Figure 5) .

[0113] After 7 days, the appearance of the degradation media containing the microspheres was observed with the naked eye: the water and acetate buffer appeared clear, while the phosphate buffer was clear with a sediment at the bottom. Also at 7 days, a gas chromatographic (GC) analysis was performed by taking aliquots from the phosphate buffer degradation medium containing the microspheres and treating them according to the following analytical method:

[0114] - analysis of standards with known concentrations of azelaic acid

[0115] - esterification with diazomethane

[0116] - injection of the obtained dimethyl azelate in GC and detection of retention times - quanti fication of the concentration of dimethyl azelate from the peak area using 1-dodecanol as an internal standard .

[0117] In this way, the concentration of azelaic acid in the samples and the percentage of azelaic acid release in the dissolution medium were determined ( see Figure 6 ) . The results indicate that the degradation percentage of microspheres in phosphate buf fer at pH 7 increases over time . In particular, there is an initial burst release ( 30% after a few hours , 50% after 5 days ) followed by a slow release up to a maximum of 80% after 1 week, a value still stable after 1 month .

[0118] After 35 days of storage in the climate chamber, the weight loss was evaluated . By centri fuging the material present in the degradation medium, represented by the non-degraded microspheres , and analyzing the weight of the obtained pellet , it was observed that the dry weight was about 20% of the initial sample weight placed in the degradation medium . This result is consistent with the degradation data of the microspheres , which reaches a maximum of about 80% .

[0119] These data make the microspheres a suitable system for the prolonged release of chitosan, azelaic acid, and other potentially contained active ingredients for up to 30 days . It should be noted that the release of active ingredients from the microspheres occurs at pH values between 4 and 7 , corresponding to the physiological pH range of the skin and mucosa . Example 3 - Antimicrobial Activity Assay

[0120] Microorganisms and inocula: the assay was carried out using the following microorganisms:

[0121] Escherichia coii strain WDCM 00012, inoculum concentration 2300-11000 CFU total,

[0122] Pseudomonas aeruginosa strain WDCM 00025, inoculum concentration 2800-13000 CFU total,

[0123] Staphylococcus aureus strain WDCM 00032, inoculum concentration 200-830 CFU total,

[0124] Candida albicans strain WDCM 00054, inoculum concentration 2200-9100 CFU total, and

[0125] Aspergillus brasiliensis strain WDCM 00053, inoculum concentration 48-1900 CFU total.

[0126] Sample preparation: 1 g of product was dispersed in 10 ml of peptone solution, resulting in a suspension to which the pellet of the individual microbial strain was added. The obtained suspensions were stored at room temperature until plating. Plating was performed by taking 1 ml of suspension and spreading it on Petri dishes containing selective agar culture medium. The plates were incubated in a thermos tatted environment for the time necessary to allow sufficient microorganism growth for counting purposes. The incubation times for the different microorganisms were: 24 h for E. coli, 48 h for P. aeruginosa and S. aureus, 5 days for C. albicans and A. brasiliensis . By correcting the observed colony count for the dilution factor, the CFU (Colony Forming Units) per gram of product was obtained. The results are summarized in Tables 1 and 2 below.

[0127] Table 1. Results of the Antimicrobial Activity Assay

[0128] - Bacteria

[0129] Table 2. Results of the Antimicrobial Activity Assay

[0130] - Fungi

[0131] From the data summarized in the Tables above, it can be observed that the bacteria analyzed, particularly E. coll and S. aureus, are sensitive to the antimicrobial action of the advanced medication of the invention. Although less sensitive , P. aeruginosa also showed a signi ficant reduction .

[0132] Regarding fungi , the activity on C. albi cans was complete and very rapid . Although less sensitive , A. brasili ensi s also showed a signi ficant reduction .

[0133] Example 4 - Synthesis of Chitosan and Azelaic Acid Microspheres (C-MS) on an Industrial Scale

[0134] Industrial production was carried out without issues according to the procedure described in Example 1 , with excellent flowability of the obtained powder . The yield of the product was quantitative . The morphology and other chemical-physical characteristics were consistent with the sample prepared on a small laboratory scale ( see Example 1 and Figure 7 ) .

[0135] Example 5 - Preparation of an Advanced Medication in Sheet Form

[0136] An advanced medication was prepared using the following ingredients :

[0137] The production procedure for the aforementioned advanced medication is summari zed below :

[0138] - procurement of polycaprolactone with granulometry compatible with the additive manufacturing process via powder laser sintering technique from the international market , - CAD design of the parts to be made and export of the files in IGES-STEP format to allow subsequent processing with software that manages the "machine space , " preparation of the mixture containing polycaprolactone and other active agents , conventional ingredients and excipients ,

[0139] - the actual sintering process with the generation of parts immersed in a bed of unsintered powder, separation of the manufactured parts from the polycaprolactone powder,

[0140] - cleaning of the parts by blowing, using a vibrating table , and ultrasonic washing in a temperature- controlled alcohol solution, inspection of the parts , sterili zation, and packaging .

[0141] According to an alternative embodiment , the preparation of the advanced medication involves processing by electrospinning and includes the following steps :

[0142] - preparation of the polymer solution to be used for fiber production,

[0143] - loading of the solution into the delivery system, such as a syringe or pipette ,

[0144] - application of the electric field created between a needle connected to a high-voltage generator and a collection plate placed at a certain distance serving as the ground electrode , - dispensing of the solution through a needle, which acts as a nozzle, towards the collection plate; during the flow of the solution, solvent evaporation occurs, causing the polymer to solidify and form fibers, collection of the fibers deposited on the collection plate, forming a sheet or a mat of fibers,

[0145] - optional post-treatment of the collected fibers to improve their properties, through thermal or chemical solidification, heating, or crosslinking.

Claims

CLAIMS1. An advanced medication comprising chitosan and azelaic acid microspheres, wherein the chitosan and azelaic acid are cross-linked by at least 20% w / w based on the total weight of the chitosan and azelaic acid mixture .

2. Advanced medication according to claim 1, wherein the chitosan and azelaic acid are present in a weight ratio of 80:20 to 90:10, or 85:15.

3. Advanced medication according to any one of claims 1-2, wherein the microspheres formed by cross-linked chitosan and azelaic acid have a median particle size (D50) ranging from 10 to 15 micrometers.

4. Advanced medication according to any one of claims 1-3, wherein the chitosan is of fungal origin.

5. Advanced medication according to any one of claims 1-4, wherein the advanced medication can be in the form of a powder, cream, gel, lotion, ointment, paste, yarn, woven fabric, non-woven fabric, pad, patch, sheet, or film.

6. Advanced medication according to any one of claims 1-5, wherein the advanced medication can be in the form of a powder, cream, woven fabric, non-woven fabric,sheet, pad, 3D-printed dressings, electrospun dressings, spray, or sponge.

7. A process for the production of an advanced medication according to any one of claims 1-5, said process comprising the following steps: phase A: synthesis of chitosan and azelaic acid microspheres : i) dispersing chitosan and azelaic acid in water; ii) adding an aqueous solution of glacial acetic acid; iii) vigorously stirring the reaction mixture; iv) heating the reaction mixture; v) spray-drying the obtained solution; and phase B: recovering the powder for formulation in the desired form.

8. Process according to claim 7, wherein the phase B includes processing through three-dimensional printing and comprises the following steps: providing the polymeric support with a granulometry compatible with the additive manufacturing process using the Powder Laser Sintering technique; designing by Computer-Aided Design (CAD) the specific parts to be produced and exporting the files in IGES - STEP format to enable further processing with software that manages the 'machine space' ;preparing the mixture containing the polymeric support , active ingredients , and other optional ingredients and excipients ;- actual sintering process with the generation of parts immersed in a bed of unsintered powder ;- separing the produced parts from the polymeric support powder ; cleaning the pieces through blowing, using a vibrating platform, ultrasonically washing with controlled-temperature alcoholic solution;- checking the details , sterili zing, and packing .9 . Process according to claim 7 , wherein the phase B includes processing through electrospinning and comprises the following steps :- preparing the polymeric solution that will be used to produce the fibers ;- loading the solution into the dispensing system, such as a syringe or a pipette ;- applying an electric field created between a needle connected to a high-voltage generator and a collection plate placed at a certain distance , which acts as the ground electrode ;- dispensing the solution through a needle , which acts as a noz zle , towards the collection plate ; during the solution flow, solvent evaporation occurs , leading to polymer solidi fication and fiber formation;collecting the fibers that deposit on the collection plate, forming a sheet or a carpet of fibers;- optionally post-processing the collected fibers to enhance their properties, such as by thermal or chemical solidification, heating, or cross-linking.

10. Chitosan and azelaic acid microspheres as defined in any one of claims 1 to 5, wherein said microspheres are included in an advanced medication for use in the treatment and / or prevention of skin and mucosal conditions in a subject, wherein the skin and / or mucosal conditions are diabetic ulcers, pressure ulcers and sores (bedsores) , general skin ulcers and sores, surgical wounds, cuts, puncture wounds, gunshot wounds, abrasions, grazes, cracks and fissures of the skin, chapping, burns, and acne lesions.

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