RO127727B1 - Pharmaceutical bioadhesive disk-type preparations based on chlorhexidine metal complexes and process for preparing the same - Google Patents

Abstract

The invention relates to a pharmaceutical preparation of the bioadhesive disk type, having antimicrobial, antifungal, anti-inflammatory and wound healing effects and to a process for preparing the same. According to the invention, the preparation comprises 0.01...0.1% metal complexes of cyclohexidine with Cu(II), Zn(II), Ag(I), a solution (1:3) of propyl p-hydroxybenzoate : methyl p-hydroxybenzoate, gelatin, sorbitol, glycerol and water, presented as smooth translucent yellowish disks having a surface pH in the range of 4.5...6.25. The process claimed by the invention consists in hot dissolving the weighed starting materials in water, pouring the mixture into moulds, gellifying the same at the ambient temperature, followed by the control and conditioning of the final product.

Description

The invention relates to pharmaceutical preparations such as bioadhesive disks based on metal complexes of chlorhexidine and to a process for obtaining them. The pharmaceutical preparations with action on the oropharyngeal mucosa, of bioadhesive disks type, are intended for the field of human and veterinary health as the case may be, regarding the disinfectant and antimycotic action, and can be used for the treatment of mucous membranes, for the disinfectant, antimicrobial action.

In recent years there has been an increasing concern and demand for the production of commonly marketed antimicrobial agents, as the main active ingredients in addition to alcohols, iodine, iodoform, hexachlorophen and chlorhexidine (CHX). CHX is active against Gram positive bacteria and less active against Gram negative bacteria, fungi, and Proteus species; it is active only against certain types of viruses (hepatitis, herpes simplex, HIV, cytomegalovirus and respiratory virus). CHX - reduced activity against mycobacteria and null for endospores and protozoan cysts. CHX acts on: the cell membrane causing its destruction and loss of intracellular material, respiratory inhibition and cytoplasmic coagulation.

Chlorhexidine (DCI) is a strong base with low water solubility. To increase water solubility, CHX forms salts with acids: gluconic acid (CHX-digluconate 20 g / 100 mL, CHX-acetate 1.9 g / 100 mL) [US 2006/0051385 A1].

Regarding the nature of the metal ions used as coordination centers, a large number of studies target complexes of metals with significant biological relevance, such as zinc, copper and silver. Of the biological actions specific to these metal ions, their greatest interest has been aroused by their antimicrobial and healing activity [Bryan Greener, Antimicrobial biguanide metal complexes, J. Pharmaceutical Sciences, 69 (2), 215-217, 2006], [Farrigton, K.L. , Morrow, LE, Antimicrobial Metals: A Nonantibiotic Approach to Nosocomial Infections - Silver and copper may prove key in preventing a problem that kills nearly 88,000 per year, 2005, www.rxrned.com/monographs]. The complex combination of Ag (1) with sulfodiazine, a coordination polymer in which the Ag ⁺ ion is pentacoordinated, is a much more effective antibacterial agent compared to the free ligand against bacterial strains, such as Pseudomonas aeruginosa and Staphylococcus aureus [US 20030035848 A1 / 2003], [US 2002/0072480 A1],

Pharmaceutical preparations such as bioadhesive disks with antimicrobial activity, proposed within the patent, intended for the exercise of the disinfectant action of the metal complexes through a synergistic effect due to the combination of the antibacterial and antifungal action of chlorhexidine and its derivatives with that of Z, metal and Ag ions. concomitant with the increase in therapeutic efficacy, they can be used for the treatment of mucous membranes and for oral hygiene.

The antibacterial capacity of the silver ions is correlated with the oxidation state and it is proven that the silver ions in oxidation states II and III have a better / more efficient and stronger antibacterial action than Ag (l). However, AgNO ₃ and other complexes, such as Ag (l) -su | fadiazine, are effective antibacterial agents with Ag (l). A nanocrystalline Ag (III) -CHX complex - synthesized by reverse microemulsion technique - exhibited strong antibacterial activity on Gram-positive bacteria (Enterococcus faecalis (ATCC 29212), Staphylococcus aureus (ATCC 25923), Staphylococcus epidermidis (ATCC 12) Propionibacterium acnes (ATCC 6919)) and Gram-negative (Acinetobacter calcoaceticus (ATCC 23055), Citrobacterfreundii (ATCC 6750), Klebsiella pneumonia (ATCC 10031), and Pseudomonas aeruginosa (ATCC 27853)) and on methicillin-resistant strains.

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Staphylococcus aureus. The minimum inhibitory (MIC) concentrations of the Ag (III) -CHX 1 complex were much lower than those of the free ligand, (chlorhexidine base), AgNO ₃ and Ag (1) sulfadiazine [Synthesis of Highly Antibacterial Nanocrystalline Trivalent Silver 3

Polydiguanide, Sukdeb Pal, Eun Jeong Yoon, Yu Kyung Tak, Eiing Chil Choi, and Joon

Myong Song, J. AM. CHEM. SHOCK. 2009,131,16147-16155], 5

Chlorhexidine complexes with Ag (III) were obtained in the form of stable compositions at ambient temperature, compatible with the materials used as substrate in medical devices 7, and were used in the treatment or prophylaxis of microbial (bacterial) infections [US WO 2007/000590 Al], [US 2006/0051385 A1]. 9

The antimicrobial action of such CHX-Ag (I II) complexes is superior to that of the free ligand or Ag (I) ion in the compounds AgNO ₃ or Ag (I) -sulfadazine, already used 11 in the clinical treatment of bacterial infections. Articles for medical use (antiseptic film instrumentation, eg inhibition probes - avoidance of nosocomial infections, 13 bioadhesive antimicrobial dressings) produced by impregnation with CHX-Ag (III) (by immersion in the complex solution) or by coating with CHX-Ag ( lll) powders can be kept for 15 (several years) at ambient pressure and temperature in traditional sterile packaging. CHX-Ag (I II) dispersed by mechanical mixing in IntraSiteGel (Smîth & Nephew Medical Ltd.) leads to 17 obtaining a chemically stable hydrogel with antimicrobial action against Staphylococcus aureus (zone of inhibition = 6.4 mm), Pseudomonas aeruginosa (zone of Pseudomonas aeruginosa). inhibition = 5.4 mm) 19 [US 2002/0072480 A1], [US WO 2007/000590 A1].

CHX complexes with Ag (l) and Ag (ll): [Ag (CHX)] ⁺ and [Ag (CHX)] ²⁺ exhibited 21 higher antibacterial activity and higher lethal velocities compared to chlorhexidine and AgNO3 and may represent a new generation / class of antibacterial agents in the treatment of wounds. These 23 complexes [Ag (CHX)] (NO3) and [Ag (CHX)] (NO3) 2 were synthesized by precipitation from neutral or weakly acidic (H2SO4, 2N) aqueous solutions of chlorhexidine (CHX) and AgNO3. Complex 25 [Ag (CHX)] (NO3) 2 with Ag (II) was obtained in 2 steps: oxidation of Ag (1) from CHX: AgNO3 solution with persulfate sodium (Na2S2O8), formation of CHX complex: Ag (II) [ Metallopharmaceuticals 27 based onsilver (l) andsilver (ll) polydiguanide complexes: activityagainstburnwound pathogens, Pal S, Yoon EJ, Park SH, Choi EC, Song JM, J Antimicrob Chemother. 2010; 65 (10): 2134-40], The antibacterial activity of these complexes was determined by determining the MIC and MBC concentrations on 4 Gram-positive and 4 Gram-negative bacteria: Acinetobacter calcoaceticus, Pseudomonas aeruginosa, Citrobacter freundii , Staphylococcus epidermidis, Enterococcus faecalis, Staphylococcus aureus, Klebsiella 33 pneumoniae. MIC concentrations for [Ag (CHX)] ⁺ and [Ag (CHX)] ²⁺ complexes were much lower than those of chlorhexidine, AgNO3 and the Ag-sulfadiazine complex. The 35 lethal / biocidal velocities of [Ag (CHX)] ⁺ and [Ag (CHX)] ²⁺ complexes on the tested bacteria were 2-8 times higher than those corresponding to chlorhexidine or AgNO ₃ at concentrations equal to 37 MIC or 4 times larger than this.

In clinical trials, oral care products (toothpaste, mouthwash) containing 39 chlorhexidine mixtures: Zn (ll) have been shown to be more effective in controlling the formation of dental plaque, gingivitis and volatile sulfur compounds in the oral cavity. (ie breath 41 odor, whale) than the products containing only chlorhexidine.

CHX mouthwash is extensively used as an adjuvant in the treatment of periodontitis 43 and there are preliminary studies showing that CHX inhibits numerous glycosidic and proteolytic activities of oral bacteria, e.g. P. gingivalis [Inhibition of Porphyromonas gingivalis 45 proteininases (gingipains) by chlorhexidine: synergistic effect of Zn (ll), C. A. Cronan, J.

Potempa, J. Travis, J. A. Mayo, Oral Microbiology Immunology 2006: 21: 212-217]. 47

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The activities of the enzymes responsible for the gingival pain lys (Kgp) and arg (2 forms, RgpB and HrgpA) were measured in the presence of varying concentrations of CHX and in the presence of the CHX mixture: Zn. Inhibition constants (K) were determined in both cases. RgpB, HrgpA and Kgp were inhibited by chlorhexidine with K, with micromolar domain values. For RgpB and HrgpA, the inhibitory effects of CHX were potentiated 30-fold upon the addition of Zn (II). The CHX-Zn (II) interaction causes a synergistic effect in inhibiting HrgpA and RgpB. For Kgp, the effects of Zn (I) and CHX on inhibitory activity were antagonistic.

Zinc and chlorhexidine ions exhibit a synergistic inhibitory effect on in vitro growth of S. sobrinus and S. sanguis. The effects on the bacterial plaque were determined for 8.0 mM, 0.44 mM CHX and the combination of the two, the more effective the combination [E. Gierstein, A. A. Scheie, G. Rolla, Scandinavian Journal of Dental Research, 1988, 96 (6), 541-550],

Zinc ions, chlorhexidine (CHX) and cetylpyridinium chloride are known compounds for inhibition of volatile S-based compounds (VCS). Zinc ions at 1% concentration have an unpleasant taste, it is desirable to be efficient at lower concentrations.

CHX has an unpleasant taste of 0.2%. Zn has the best anti-VCS effect in the concentration of 1%, 1 h, CHX has the same effect at 0.2%, in 3 h [A. Young, G. Jonski, G. Rolla, European Journal of Oral Sciences, 2003,111 (5), 400],

Copper is a metal of clinical interest, an essential metal in human nutrition and has low toxicity.

Chlorhexidine and Cu ²⁺ , 1.1 mM solutions were used in experiments aimed at reducing bacterial plaque. Chlorhexidine, at 1.1 mM, is more effective than Cu ²⁺ [MS Waler, G. Rolla, Scandinavian Journal of Dental Research, 1982,90 (2), 131133],

Complexes based on CHX-i are found in the following formulations: [GB 1128833/1966] and [PEP 1340490 B1 / 2003], chlorhexidine-based mouthwash, as a solution for oral hygiene based on chlorhexidine and ascorbic acid, which has no side effect pigmentation of the teeth. To the solution of chlorhexidine and ascorbic acid (with the role of reducing Fe ³⁺ to Fe ²⁺ , preventing the Maillard reactions), sodium metabisulphite is added to stabilize ascorbic acid (to prevent its oxidation) in aqueous solution. With sodium encryption the pH of the mouthwash is maintained at values: 5.7-6.3, range in which the activity of chlorhexidine is maximum.

Other patents containing chlorhexidine compounds [WO 03/096999 A1], Formulations for masking unpleasant taste (composition 1.4% wt. NaF, 4.3% wt. Chlorhexidine acetate, 14.3% aspartame, 74.0 - 74.3% microcrystalline cellulose, 5.7% polyoxyethylene glycol 4000, 0.0-0.3% peppermint oil; [WO 03/084461 A2], Oral formulations containing chlorhexidine or salts (digluconate, diacetate, hydrochloride), zinc salt, zinc gluconate and masking / flavoring agent - saccharin or saccharin salt; [US 2005/0191247 A1], chlorhexidine complexes with Cu ²⁺ and Zn ²⁺ salts, are present in concentrations of 1%, 0 , 5%, 0.1%, at least 0.01%.

At present, a significant number of antiseptic medicines containing as active substance chlorhexidine, administered as solutions, mouthwashes or gels, for external use, as OTC [1], Medical Agenda, Medical Publishing House, Bucharest, are produced and marketed. 2009, Memomed, 15th Edition, Minesan Publishing House and University Publishing House, 2009, in:

1. Oral-dental, prosthetic-orthodontic conditions (Corsodyl Mint Mouthwash solution SmithKline Beecham / England; Corsodyl gel - SmithKline Beecham / England; Chlorhexidin Dental solution - ACO; Plack out solution - Santa / Greece; Plack out gel - Santa / Greece; Peridex Procter & Gambie Comp .; Dentosmin-P - Arzneimittelwerk / Germany; TrachisanEngelhard / Germany);

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2. Skin, gynecological disorders and surface amphysepsis (Betagin - Biopharm 1

S.A./Romania; Chlorhexidine-Gifrer Barbezat / France; Chlorhexidine gluconate - Ferrosan;

Chlorhexidin - Biofarm S.A./Romania; Clohexin-A, -B, -C- Pharma Labor / Romania; Desmanol - 3

Schulke Mayr / Germany; Hibiscrub - Zeneca LtdVAnglia; Hibitane - ICI-Zeneca / England;

Septofort - Pharmavit). 5

Disadvantages or limits of chlorhexidine present as active principle in the current pharmaceutical preparations marketed: 7

Transformation of the ligand into a water-soluble form. CHX (free base) is insoluble in water and exists only at pH> 12. CHX is used as the salt of some organic acids: CHX diacetate, 9

CHX dihydrochloride, CHX digluconate. However, the possibility of unwanted interactions of the metal ion with other organic or inorganic species or co-precipitation makes these species -11 sources not very suitable for CHX ligand. Since pKa values for CHX (2.2 and 10.3) show that CHX is diprotonated over the entire range of physiological pH values, its solubilization can be easily achieved by treatment with dilute H ₂ SO ₄ and conversion to CHX ^{2 +} -2 (HSO ₄ ). 15

Limitations of chlorhexidine present as active principle in the present commercialized pharmaceutical forms consist of obtaining liquid pharmaceutical forms (mouthwashes) that allow 17 a decrease of the chlorhexidine concentration in the oral cavity by rapid dilution with saliva, adverse reactions, limitation of antimicrobial activity as well. duration of therapeutic effect. 19

The technical problem solved by the invention consists in the presentation of pharmaceutical preparations such as bioadhesive disks based on metal complexes of chlorhexidine for the treatment of mucous membranes, for disinfectant, antimicrobial action and a process for obtaining them. 2. 3

Pharmaceutical preparations such as bioadhesive disks based on metal complexes of chlorhexidine according to the invention, consist of 0.01 ... 0.1% metal complexes of 25 chlorhexidine, 35 ... 70% solution of propyl p-hydroxybenzoate: p- methyl hydroxybenzoate, in a ratio of 1: 3, 20 ... 35% gelatin, 4 ... 10% 70% sorbitol, 5 ... 20% glycerin, the percentages being by weight.

The process of obtaining pharmaceutical preparations such as bioadhesive disks based on 29 metal complexes according to the invention removes the above disadvantages by allowing the gelatin to soak for about 30 minutes with the preservative solution, after which 31 is brought to the water bath, glycerol and sorbitol are added 70% and further heated until the gelatine is completely dissolved), and in a portion of the preservative solution initially retained the active substance, metal complexes of chlorhexidine are dissolved and the solution obtained is added over the semi-fluidized mixture, carefully to avoid the incorporation of air into the mass, 35 fixed volumes are taken using a graduated syringe, from the hot solution and placed in polyethylene patterns, and after gelation, at room temperature, the discs are removed from 37 patterns and kept at 37 room temperature for 24 hours and conditioned in amino boxes plastic, in a cool place, away from light. 39

By applying the invention, the following advantages are obtained:

- The formulation of bioadhesive discs using as a ligand the 41-chlorhexidine diacetate complex with Cu (II) and Zn (II) salts allows the prolongation of the therapeutic action and the preservation of the cohesion against the phenomena of salivary and mechanical erosion; 43

- the pharmaceutical form falls within the official quality parameters;

- the pharmaceutical preparation is maintained for an extended time at the buccal level to achieve an increased concentration of the drug substance released;

- the pharmaceutical preparation maintains its cohesion with the salivary and mechanical erosion phenomena 47;

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- The antimicrobial activity evaluated in vitro showed the potentiation of the activity towards the chlorhexidine diacetate and the metal salts themselves.

By combining chlorhexidine and its salts, with metal ions with their own pharmacological activity (antibacterial, antifungal, healing, anti-inflammatory) in compounds with disinfectant and antifungal properties, problems caused by the use of free CHX can be eliminated. Chlorhexidine metal complexes as antimicrobial agents have the structure corresponding to the general formula:

and the chemical formula [M ^a M ^b (CHX) (R ¹ ) 2 (R ² ) 2] -X, wherein

M ^a and M ^b are the same or different, and are chosen from a group consisting of Cu, Zn and Ag; R ¹ are each CI or together CH _g COO

R ² is selected from a group consisting of CH ₃ COO and CI or absent;

X = is selected from a group consisting of 2NO ₃ -2C ₂ H ₅ OH, 2Cl, 2NO ₃ and 2C ₂ H ₅ OH;

In a first aspect of the invention, pharmaceutical preparations such as bioadhesive disks based on chlorhexidine metal complexes increase the contact of the preparation with the buccal mucosa, respectively topical route, respectively, the prolongation of the therapeutic action, as well as the possibility of using new compounds not used in therapeutics, active in vitro at lower concentrations compared to the chlorhexidine salts used;

In another aspect of the invention, pharmaceutical preparations such as bioadhesive discs based on metal complexes of chlorhexidine eliminate the adverse reactions (irritating contact dermatitis - free CHX) and minimize the side effects (decongestant gingivitis, discoloration of the teeth and tongue, alteration of taste, allergies that can lead to anaphylactic shock);

In another aspect of the invention, pharmaceutical formulations / compositions having a solubility in aqueous media above the minimum inhibitory concentration (MIC) of the treated organism are described;

In another aspect of the invention, the choice of excipients is described so as to avoid the formation of insoluble CHX-anionic excipient complexes;

In another aspect of the invention, the pharmaceutical preparations are chemically stable in the pH range = 5.5-7, the maximum efficacy range of CHX;

In another aspect of the invention, it is described to avoid contamination of the product in the synthesis process - to keep the biological activity unaltered.

For obtaining pharmaceutical preparations such as bioadhesive discs that immobilize a system that contains an active substance, on the site of action and which allows its easier resorption, metal complexes of chlorhexidine. In the case of the present invention, the use of an active substance is intended for the exercise of a local action, and due to the bioadhesive system used this action will be extended which allows to improve the therapeutic efficacy. The adhesion on biological surfaces is based on particular mechanisms that depend on the structure of the bioadhesive layer, as well as on the nature and structure of the pharmaceutical form used.

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The gelatin is allowed to soak for about 30 minutes with the preservative solution, after which it is added to the water bath, 70% glycerol and sorbitol are added and further heated until the gelatin is completely dissolved. In a portion of the solution of propyl p-hydroxybenzoate: methyl p-hydroxybenzoate (1: 3) initially retained dissolve the active substance, metal complexes of chlorhexidine, and the solution obtained is added over the semi-fluidized mixture, stirring gently to avoid incorporation. air mass. Using a graduated syringe, remove fixed volumes from the hot solution and place them in polyethylene patterns. After gelation, at room temperature, the discs are removed from the pattern and kept at room temperature for 24 hours. After preparation, the obtained bioadhesive discs are subjected to quality control, in which the organoleptic properties, thickness, mass uniformity, pH are determined. surface, imbibing capacity and relative density, according to FRX, are conditioned in aminoplast boxes, in a cool place, away from light.

The following are two non-limiting examples of the invention, in connection with table 1 and the figure which represents the technological scheme of the process for obtaining pharmaceutical preparations of bioadhesive disks based on chlorhexidine metal complexes.

Example 1.20 g gelatin is allowed to soak for about 30 minutes with 50 g preservative solution, then placed on the water bath, add 5 g glycerol and 4 g 70% sorbitol and continue to warm until the gelatin is completely dissolved, and in a portion of the preservative solution initially retained, 0.05 g of chlorhexidine metal complexes are dissolved and the obtained solution is added over the semi-fluidized mixture, stirring gently to avoid the incorporation of air into the mass, and then a fixed volume of 1 mL is taken with the help. of a graduated syringe, from the hot solution and placed in polyethylene patterns, and after gelation, at room temperature, the disks are removed from the pattern and kept at room temperature for 24 hours and conditioned in aminoplast boxes, kept in a cool place , protected from light.

Example 2. 35 g of gelatin is allowed to soak for about 30 minutes with 60 g of preservative solution, after which it is placed on the bale of water, 20 g of glycerol and 9 g of 70% sorbitol are added and further heated until the solution is completely dissolved. of the gelatin, and in a portion of the preservative solution initially retained, 0.1 g of metal chlorhexidine complexes are dissolved and the solution obtained is added over the semi-fluidized mixture, stirring gently to avoid the incorporation of air into the mass, then a fixed volume of 2 is taken. mL with a graduated syringe, from the hot solution and placed in polyethylene patterns, and after gelation, at room temperature, the disks are removed from the pattern and kept at room temperature for 24 hours and stored in aminoplast boxes, preservation in a cool place, away from light.

Table 1

Non-limiting examples of embodiment of the invention

Nr. crt. Name of the substance Quantity (g)% Example 1 Example 2 1 1,1'-hexamethylene-bis- [5- (4-chlorophenyl) biguanidescupper and zinc diacetate 0.05-0.1 0.01 - 0.1 2 Gelatine 20-30 25 - 35 3 glycerol 5-10 10-20 4 Sorbitol 70% 4-10 5-9 5 Propyl p-hydroxybenzoate solution: methyl p-hydroxybenzoate (1: 3) 50 - 70 35 - 60

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Pharmaceutical preparations of bioadhesive disks according to the invention are obtained, with the physico-chemical characteristics of table 2.

Table 2

Physical and chemical characteristics of pharmaceutical preparations such as bioadhesive disks based on metal complexes of chlorhexidine

Characteristic Results appearance Surface smooth, translucent, yellowish discs with no air bubbles thickness 1.55 - 2.15 mm The pH of the surface 4.5 to 6.25 Uniformity of mass of unidose preparations 0.090 - 0.120 g Soaking index 0.920 to 2.450

The process for obtaining pharmaceutical preparations of bioadhesive discs according to the invention consists of the following technological scheme shown in the figure.

Following the study on antimicrobial activity, it was observed that pharmaceutical preparations such as bioadhesive disks containing metal complexes of chlorhexidine exhibit increased antimicrobial activity against microbial strains Staphylococcus aureus (inhibition diameter 1-17 mm), Escherichia coli diameter (diameter 1) - 9 mm) and Candida albicans (inhibition diameter 1 - 8 mm) compared to the ligands and the complex combinations from which they were obtained.

Topical pharmaceutical preparations for external use based on chlorhexidine metal complexes, conditioned in the form of bioadhesive disks, were tested in vitro in fibroblast cultures. In order to test the effect of the studied compounds on the cells, the cell viability (using the MTT method) and the cell morphology were analyzed. Cytotoxicity was tested by the extract method (in the case of products conditioned in solid form), taking into account several concentrations of the extracts and several degrees of dilution of the products in solution form. The obtained results demonstrated a pronounced cytotoxic effect of the products in the form in which they were obtained, compared to the control cell sample. At concentrations less than 1 mg / mL of conditioned product in the form of bioadhesive discs, no effects of fibroblast morphology were observed, as they have a viability of over 95% after 24 h of cultivation in the presence of the respective extracts.

Testing the antioxidant activity of pharmaceutical preparations such as bioadhesive disks and based on metal complexes of chlorhexidine according to the invention, by the chemiluminescence method, showed that they have antioxidant activity values in the field of 5095%, indicating them as efficient antioxidant agents.

Claims (3)

1. Pharmaceutical preparations of bioadhesive disks based on metal complexes of 3 chlorhexidine, characterized in that they consist of 0.01 ... 0.1% metal complexes of chlorhexidine, 35 ... 70% p-hydroxybenzoate solution. propyl: methyl ρ-hydroxybenzoate, in 5 ratio of 1: 3, 20 ... 35% gelatin, 4 ... 10% sorbitol 70%, 5 ... 20% glycerin, the percentages by weight. 7 Pharmaceutical preparations of bioadhesive disks, according to claim 1, characterized in that they are in the form of smooth, translucent, 9-surface discs, yellowish, without air bubbles, with a surface pH between 4.5 and 6.25, topical for external use, which present antimicrobial and antioxidant activity, having disinfectant and antifungal action, are biocompatible, have low or negligible toxicity and are not polluting environmental factors. 13 3. Process for obtaining pharmaceutical preparations such as bioadhesive disks based on chlorhexidine metal complexes, as defined in claim 1, characterized in that the gelatin is allowed to soak for about 30 minutes with the preservative solution, and then placed on the bath. water, add glycerol and sorbitol 70% and further heat 17 until the gelatin is completely dissolved, and in a portion of the preservative solution initially retained, the metal complexes of chlorhexidine are dissolved and the obtained solution is added over 19 semifluidified mixture, stirred, stirred. carefully to avoid the incorporation of air into the mass, fixed volumes are taken using a graduated syringe, from the hot solution and placed in 21 polyethylene patterns, and after gelation, at room temperature, the discs are removed from the pattern and kept at room temperature. the room for 24 hours and is packaged in boxes of 23 aminoplast, preservative it has a cool place, away from light.