Crystalline Complex Gelatin Biocapsules for Pharmaceutical Use

Description

1 / 11 Gelatinized biocapsules of crystalline complex for pharmaceutical use. Field of invention

[001] The present invention, “Gelatinous Biocapsules of Crystalline Complex for Pharmaceutical Use”, describes capsules composed of bovine gelatin and sodium alginate, incorporated with crystals of the crystalline complex made from 1,10phenanthroline and copper(II) in powder form with the potential to maximize biological activity. The objective of these capsules is to assist in clinical therapies through their use in controlled drug delivery systems. Fundamentals of the invention

[002] The search for efficient controlled drug delivery systems has driven research and development of new technologies in the field of bioengineering and materials science (Biondi et al., 2008). Among the various strategies explored, biocapsules have stood out for their unique properties and ability to protect and release bioactive compounds in a controlled manner (Rojas-Sánchez et al., 2022; Abbasiliasi et al., 2019).

[003] In this context, the proposed innovation is based on the development of biocapsules composed of a novel combination of copper(II) crystalline complex powder and 1,10-phenanthroline, bovine gelatin (BG), and sodium alginate (AL). Although bovine gelatin and sodium alginate are Petition 870240110047, dated 12 / 26 / 2024, page 7 / 25 2 / 11 widely used in the pharmaceutical industry due to their biocompatible and biodegradable properties, the differentiating factor of this proposal lies in the combination of these materials with the crystalline complex. This specific combination results in unexpected technical properties, such as the potentiation of therapeutic effects, the improvement in the controlled release of the active ingredient, or the increase in the stability of the formulation. The synergistic interaction between the components creates an enhanced functionality that would not be observed in the isolated use of each material, standing out as an innovative approach in the development of pharmaceutical systems (Rosellini et al., 2009).

[004] The technique of encapsulating crystalline complexes in powder form with organic polymeric materials involves the use of biocompatible and water-soluble polymers to encapsulate the crystals in order to protect them from adverse environments. This technique offers several advantages compared to traditional techniques, such as protection against degradation caused by external agents, controlled release of active compounds, and reduced toxicity of the complex. Furthermore, the organic polymeric materials used are more accessible, easier to handle, and less susceptible to purity problems compared to other materials used in encapsulation techniques. This technique has been widely studied and applied in various Petition 870240110047, dated 12 / 26 / 2024, page 8 / 25 3 / 11 areas, such as the pharmaceutical, cosmetics and food industries, demonstrating their promising potential for the development of new therapies and innovative products.

[005] Bovine gelatin is a natural polymer derived from collagen, known for its biocompatibility, gel-forming capacity, and adhesive properties, making it an excellent candidate for drug encapsulation (Foox & Zilberman, 2015). Alginate, a polysaccharide obtained from seaweed, is equally valuable due to its ability to form gels in the presence of divalent ions, such as calcium, providing a stable and porous matrix for the incorporation of bioactive substances (Abka-khajouei et al., 2022).

[006] The addition of the 1,10-phenanthroline and copper(II) complex to biocapsules aims to exploit the unique properties of this complex. The Cu(II) and 1,10-phenanthroline crystal powder is known for its antitumor, antimicrobial, and antioxidant properties (Ramos et al., 2023; Robertazzi et al., 2009), which can enhance the therapeutic efficacy of the drug delivery system. 1,10-phenanthroline is a ligand that forms stable complexes with metal ions (Sammes & Yahioglu, Chem, 1994), such as copper(II); these complexes can interact with biomolecules in a specific way, expanding the functionality of biocapsules.

[007] The combination of bovine gelatin and sodium alginate in the formation of biocapsules brings together the beneficial properties of Petition 870240110047, dated 12 / 26 / 2024, page 9 / 25 4 / 11 Both materials combine to create innovative drug delivery systems. This synergy promotes greater structural stability and protection of the encapsulated material against premature degradation, in addition to offering controlled release and specific targeting of the active ingredient. Gelatin contributes with its gelling and adhesive properties, while alginate forms robust three-dimensional networks, regulating the diffusion of the encapsulated contents. Together, these materials create biocompatible and biodegradable capsules, ideal for pharmaceutical applications, with technical benefits that would not be achieved with the isolated use of each component (Abbasiliasi et al., 2019).

[008] Prior art PI 102022008725-3 A2, entitled “Chitosan Microspheres with Copper(II) Ternary Crystal Complexed with 1,10-Phenanthroline and L-Tyrosine”, describes an invention intended to incorporate copper(II), 1,10-phenanthroline and L-tyrosine crystals into the chitosan polymer matrix. This integration modifies the contact surface of the microspheres, increasing their adhesion capacity and optimizing their use as a carrier for antitumor crystals. The invention ensures that the concentrations of the crystals remain within a desirable range, improving their bioavailability in chemotherapeutic treatments.

[009] In addition, prior art PI 102022008428-9 A2, entitled “Alginate Microspheres Incorporated with Petition 870240110047, dated 12 / 26 / 2024, page 10 / 25 5 / 11 "Phenanthroline-Iron Complexes: Production Process and Use" addresses a controlled drug delivery system using microspheres embedded with phenanthroline and iron complexes. This innovative process offers a cheap and easily obtainable synthesis method, which can bring significant benefits to the fields of medicine and pharmacology. The combination of alginate with phenanthroline and iron complexes demonstrates potential to improve the efficiency and precision of drug delivery in the body.

[0010] Based on the information presented above, it is possible to observe that none of them mentions obtaining Biocapsules made with bovine gelatin and sodium alginate as possible carrier agents for the copper(II) complex coordinated with 1,10-phenanthroline, intended for clinical therapies, i.e., for pharmaceutical use. It is important to emphasize that the previous references address the encapsulation of diverse crystalline complexes, with significant differences, such as molecules coordinated to metals, structure, particle size, and efficiency in biological activities.

[0011] However, bovine gelatin and sodium alginate biocapsules are able to retain the coordinated crystalline complex of copper(II) and 1,10-phenanthroline in a stable and controlled manner. Thus, this system has potential application in Petition 870240110047, dated 12 / 26 / 2024, page 11 / 25 6 / 11 clinical therapies that benefit from the therapeutic properties of copper(II) and 1,10-phenanthroline. Brief description of the drawings

[0012] The results obtained demonstrate that bovine gelatin and sodium alginate biocapsules with the incorporation of copper(II) crystal and 1,10-phenanthroline in the polymeric matrix were obtained with concentrations of the crystalline material in powder form of 1%, 3% and 5%.

[0013] Figure 1 shows the bovine gelatin and sodium alginate Biocapsules incorporated with the crystal in powder form of copper(II) and 1,10-phenanthroline at the following concentrations: (I) 1%, (II) 3% and (III) 5%. From the image it is possible to infer that the encapsulation was effective because the Biocapsules show the blue coloration corresponding to the complex.

[0014] Figure 2 shows the bovine gelatin and sodium alginate Biocapsule with the copper(II) and 1,10phenanthroline complex, having a diameter of approximately 3.0 mm.

[0015] Figure 3 shows the ray diffraction pattern The X-axis of the biocapsules is in the angular range of 5 to 50°, 2θ. The diffractogram reveals a nearly amorphous structure, and the presence of crystalline peaks (2θ=32° and 2θ=46°) indicates that the crystalline material was encapsulated by the polymeric matrix, since the polymeric matrix presents an amorphous profile according to the literature. In addition, there was an interaction between the matrix and the complex, resulting in changes in the pattern of... Petition 870240110047, dated 12 / 26 / 2024, page 12 / 25 7 / 11 in accordance with the modification of the concentrations of the crystalline material.

[0016] Figures 4, 5 and 6 show the graphs of TG / DTA where it is possible to monitor the thermal events of bovine gelatin and sodium alginate biocapsules. Description of the invention

[0017] The present invention relates to Biocapsules obtained from a solution of bovine gelatin and sodium alginate with the incorporation of Cu(II) crystal and 1,10-phenanthroline.

[0018] The invention could be better understood through the following description, in accordance with the steps of the synthesis process of the crystal and the biocapsules.

[0019] Crystal synthesis: The crystal with molecular formula C36H28CuN8O8 was obtained as described in the innovation under the Process Number: BR 10 2023 017946 0. The synthesis of Cu(II) and 1,10-phenanthroline crystals utilized the slow solvent evaporation technique through the following steps: a) Prepare aqueous solutions (37 ppm) of 1 mmol of copper(II) nitrate and (18 ppm) of 1 mmol of sarcosine and another methanolic solution (9010 ppm) of 1 mmol of 1,10-phenanthroline; b) Mix the copper(II) nitrate solution with the 1,10-phenanthroline solution; c) Add solution (b) drop by drop to the sarcosine solution; Petition 870240110047, dated 12 / 26 / 2024, page 13 / 25 8 / 11 d) Maintain the mixture from step (c) under constant magnetic stirring for 2 hours; e) Place in an oven at 35°C for slow evaporation of the solvent and crystal formation over 7 days; f) Pulverize the crystal obtained in step (e).

[0020] Biocapsule Production: Biocapsules are obtained by incorporating the crystal in powder form into the polymer matrix through the following steps: a) Prepare separately solutions of 20,000 ppm of deionized water with 95%, 97%, and 99% bovine gelatin and sodium alginate, keeping them under magnetic stirring for 24 hours at room temperature for complete solubilization; b) After dissolving both materials from the solutions in step (a), the crystalline complex in powder form is added at a concentration of 1% to the 99% bovine gelatin and sodium alginate (w / w) solution; 3% to the 97% bovine gelatin and sodium alginate (w / w) solution; and 5% to the 95% bovine gelatin and sodium alginate (w / w) solution. c) The mixtures from step b) remain under magnetic stirring for a period of 24 hours; d) Prepare an aqueous solution of 1-2% calcium chloride or zinc chloride; Petition 870240110047, dated 12 / 26 / 2024, page 14 / 25 9 / 11 (e) The solutions obtained in step (b) are slowly dripped into the solution from step (d), the drops form Biocapsules upon contact with the calcium chloride or zinc chloride solution; f) After obtaining the Biocapsules in step (d), they are filtered to then measure the diameter and be stored at a temperature of 50°C for 2-3h for dehydration.

[0021] Another aspect of the present invention, bovine gelatin and sodium alginate biocapsules incorporated with copper(II) and 1,10-phenanthroline complexes, is that they are characterized by the following formulations: - Formulation 1: 95% sodium alginate and bovine gelatin, 5% crystalline copper(II) powder and 1,10-phenanthroline, 1% to 2% calcium chloride (CaCl2) or zinc chloride (ZnCl2), preferably 2%; - Formulation 2: 97% sodium alginate and bovine gelatin, 3% crystalline copper(II) powder and 1,10-phenanthroline, 1% to 2% calcium chloride (CaCl2) or zinc chloride (ZnCl2), preferably 2%; Formulation 3: 99% sodium alginate and bovine gelatin, 1% crystalline copper(II) powder and 1,10-phenanthroline, 1% to 2% chloride Petition 870240110047, dated 12 / 26 / 2024, page 15 / 25 10 / 11 calcium (CaCl2) or zinc chloride (ZnCl2), preferably 2%. Examples of embodiments of the invention

[0022] Through Figure 1 it is possible to see that the Biocapsules were obtained, and through it we can speculate the incorporation of the crystalline complex of copper(II) and 1,10phenanthroline into the polymeric matrix only by the modification of the coloration.

[0023] To confirm this speculation, X-ray diffraction analyses were performed, which are shown in Figure 3, and from the diffraction patterns it was possible to confirm the formation of the new materials, with the emergence of crystalline peaks at 2θ=32° and 2θ=46°, resulting from the crystalline complex being incorporated into the amorphous polymeric matrix.

[0024] Through the TG / DTA curves observed in Figures 4, 5 and 6, it is possible to see that in the range of 66-172 °C the matrices have thermal stability, and above this range they lose water molecules. Further on, the decomposition process of organic materials (carbon chains) and possible partial oxidation of the metal are initiated.

[0025] Through the analyses mentioned above, the matrices have the potential to assist in clinical therapies. Thus, the present invention has the potential to maximize the biological activity (Table 1) of the ternary crystal of Petition 870240110047, dated 12 / 26 / 2024, page 16 / 25 11 / 11 copper(II) and 1,10-phenanthroline, combining with the biocompatibility of biopolymers. Table 1. Diameter of the inhibition circle zone exhibited by different concentrations of the 1,10phenanthroline and copper(II)-based crystal. Diameter of the zone (mm) Bacteria Control (AL+GB) 1% 3% 5% Gram-negative (-) Klebsiella pneumoniae 0 0 19 20 Gram-positive (+) Staphylococcus aureus 0 0 15 16 Petition 870240110047, dated 12 / 26 / 2024, page 17 / 25

Claims

1 / 3 CLAIMS 1. BIOCAPSULES, characterized by comprising a polymeric solution of bovine gelatin and sodium alginate together with the crystalline complex of copper(II) and 1,10-phenanthroline in powder form, are specifically defined by the following formulations: - Formulation 1: 95% sodium alginate and bovine gelatin, 5% crystalline powder of copper(II) and 1,10-phenanthroline, 1% to 2% calcium chloride (CaCl2) or zinc chloride (ZnCl2), preferably 2%; - Formulation 2: 97% sodium alginate and bovine gelatin, 3% crystalline powder of copper(II) and 1,10-phenanthroline, 1% to 2% calcium chloride (CaCl2) or zinc chloride (ZnCl2), preferably 2%; - Formulation 3: 99% sodium alginate and bovine gelatin, 1% crystalline copper(II) powder and 1,10phenanthroline, 1% to 2% calcium chloride (CaCl2) or zinc chloride (ZnCl2), preferably 2%.

2. Biocapsules, according to claim 1, characterized in that the solution of bovine gelatin and sodium alginate is in an aqueous medium (deionized water).

3. Biocapsules, according to claims 1 and 2, characterized by exhibiting thermal stability in the range of 66-172 °C. Petition 870240110047, dated 12 / 26 / 2024, page 18 / 25 2 / 3 4. Biocapsules, according to claims 1 to 3, characterized by having a diameter of approximately 3.0 mm.

5. PROCESS FOR OBTAINING THE BIOCAPSULES defined in claims 1 to 4, characterized by the following steps: a) Prepare, separately, solutions of 20000 ppm of deionized water with 95%, 97% and 99% bovine gelatin and sodium alginate, keeping them under magnetic stirring for 24h at room temperature for complete solubilization; b) After solubilization of both materials from the solutions in step (a), add the crystalline complex in powder form at a concentration of 1% to the 99% bovine gelatin and sodium alginate solution (w / w); 3% to the 97% bovine gelatin and sodium alginate solution (w / w) and 5% to the 95% bovine gelatin and sodium alginate solution (w / w); c) The mixtures from step b) remain under magnetic stirring for a period of 24h; d) Prepare an aqueous solution of 1-2% calcium chloride or zinc chloride;e) The solutions obtained in step (b) are slowly dripped into the solution from step (d), the drops form Biocapsules upon contact with the calcium chloride or zinc chloride solution; Petition 870240110047, dated 12 / 26 / 2024, page 19 / 25 3 / 3 f) After obtaining the Biocapsules in step (d), they are filtered to then measure the diameter and store them at a temperature of 50°C for 2-3 hours for dehydration. Petition 870240110047, dated 12 / 26 / 2024, page 20 / 25;

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