Pharmacological composition of a solution for topical oral application for the treatment of oral conditions

Abstract

The present application is directed to a pharmacological composition of a solution for topical oral application, in the form of a gel, spray, mouthwash and / or paste or ointment, suitable for the treatment of oral conditions such as xerostomia or hyposalivation, the various periodontal diseases and / or oral pain, as well as all of the secondary conditions caused by radiotherapy of the neck and head, chemotherapy, use of drugs, mainly psychotropic, and / or systemic autoimmune diseases such as Sjoegren's Syndrome, or any other pathology, treatment or trauma that causes some damage in acute or chronic form as a secondary effect, such as the aforementioned conditions. This pharmacological composition comprises four (4) active components: Lidocaine, for the treatment of oral pain; Pilocarpine Hydrochloride and Malic Acid, for the treatment of xerostomia; and Chlorhexidine, an antiseptic widely used in dentistry for the treatment of oral infections.

Description

[0001] PHARMACOLOGICAL COMPOSITION OF A TOPICALLY APPLIED ORAL SOLUTION FOR THE TREATMENT OF ORAL CONDITIONS

[0002] DESCRIPTIVE MEMORY

[0003] This application is directed to a pharmacological composition of a solution for oral topical application, whether in the form of a gel, spray, mouthwash and / or paste or ointment, indicated for the treatment of oral conditions such as xerostomia or hyposalivation, different periodontal diseases and / or oral pain together with all those conditions caused secondarily by radiotherapy of the neck and head, chemotherapy, use of mainly psychotropic drugs and / or systemic autoimmune diseases such as Sjoegren's Syndrome, or any other pathology, treatment or trauma that has as a side effect some damage in an acute or chronic form such as the conditions indicated above.This pharmacological composition presents four (4) active components: Lidocaine, for the treatment of oral pain; Pilocarpine Hydrochloride and Malic Acid, for the treatment of xerostomia; and Chlorhexidine, an antiseptic widely used in dentistry for the treatment of oral infections.

[0004] Xerostomia has been defined primarily as a subjective sensation of dryness of the oral mucosa. Patients with xerostomia present with a variety of symptoms such as oral pain or discomfort, halitosis, oropharyngeal pain, taste disturbances along with impaired mastication and swallowing, malnutrition, angular cheilitis, difficulty speaking, and an increased risk of dental caries and oral infections. Pathophysiologically, it is caused by two factors: alteration of the glandular parenchyma or glandular functional alteration. Structural alteration is seen in diseases that involve destruction of the glandular parenchyma and therefore decreased saliva production, for example, infections, autoimmunity, post-radiotherapy. Indeed, it is the most common complication during and after radiotherapy for head and neck cancer.Salivary gland damage occurs in 95% of patients who received radiotherapy, leading to glandular dysfunction and subsequent hyposalivation, with significant alterations in salivary volume, consistency, and pH. On the other hand, glandular functional impairment corresponds to a decrease in salivary production within normal parenchyma or an alteration in salivary consistency due to biochemical changes, for example, due to medications, dehydration, lack of mechanical stimulation, or habits (smoking). Therefore, the impact of xerostomia on the patient's health and quality of life must be taken into consideration when designing better therapeutic products to treat this condition.

[0005] One of the most common manifestations of Sjogren's Syndrome (SS) is persistent salivary gland hypofunction. Treatment of glandular hypofunction is an extremely complex issue. A long list of i

[0006] SUBSTITUTE SHEET (RULE 26) Topical treatments and systemic interventions have been used in individuals with SS with the intention of restoring and / or stimulating in some way the function of the salivary glands or replacing saliva, thereby reducing the stressful symptoms of xerostomia and thus preventing complications from lack of saliva, in turn improving the quality of life of patients.

[0007] Abnormalities affecting the quality and quantity of saliva diminish patients' quality of life. Oral dryness, inflammation, and ulcers begin to appear in the early stages of xerostomia, resulting in difficulties speaking and swallowing. Speech difficulties affect patients' ability to communicate and work. Furthermore, any change in saliva quality leads to a reduction in the number of taste buds, so patients with xerostomia experience reduced nutritional intake, leading to significant weight loss in many patients. Microbial infections and dental caries develop due to the loss of saliva's antimicrobial and antifungal properties. The reduction in saliva production causes a feeling of thirst that affects the patient's sleep patterns, as they need to constantly hydrate their mouths.To relieve symptoms, the patient takes regular sips of fluid, which results in significant urine production that further disrupts sleep patterns.

[0008] Commercially available treatments for xerostomia aim to reduce the symptoms of dry mouth, either by using salivary substitutes when the salivary glands are completely damaged or by using salivary stimulants when there is residual salivary gland function. A large number of treatments have been proposed to enhance salivary function. Symptomatic treatments such as the use of artificial saliva, hydration of the mucous membranes with small sips of water, and stimulation through mastication are palliative treatments and often offer only limited short-term benefits.

[0009] Pilocarpine is a parasympathomimetic agent that stimulates muscarinic cholinergic receptors on the surface of exocrine glands. This drug can relieve the symptoms of xerostomia by stimulating salivary secretion from the glands. There is evidence that pilocarpine may even stimulate the production of mucins and other salivary constituents. Mucins are important for preventing infections and chemical or mechanical trauma to oral structures. Since mucin is only produced in minor salivary glands, any increase in the amount of mucin will significantly reduce xerostomia. However, since pilocarpine is a systemically administered (oral) drug, adverse effects such as sweating, rhinitis, excessive or frequent urination, nausea, fatigue, and headaches are common.

[0010] SUBSTITUTE SHEET (RULE 26) In a systematic review and meta-analysis, Mercadante et al. concluded that physicians can rely on the beneficial effects of pilocarpine use on dry mouth symptoms in patients with SS. However, adverse events associated with systemic pilocarpine use are common and contribute to 30% of treatment discontinuation.

[0011] The topical use of pilocarpine, whether as a spray, gel, or oral solution, has been little investigated. Recently, an experimental study in rats tested the application of a topical spray formulation of pilocarpine, which demonstrated a significant sialogogue effect compared to systemic use, while also having fewer adverse effects.

[0012] A patent search revealed a publication dated August 24, 2010, Brazilian office, application number PI0805520-3, which describes a gel for oral topical application with a concentration of 5% pilocarpine, 1-5% carboxymethylcellulose, about 10% pectin, 4% mineral oil and mint CSP 100 ml. The composition reportedly achieves the expected result. Another patent published on January 21, 2013, application number ES20080368017T 20080912 describes a sialagogue composition that includes, in a pharmaceutically acceptable vehicle suitable for peripheral administration, an M3 muscarinic agonist chosen from pilocarpine or pilocarpine hydrochloride, characterized by also including an alpha2 adrenergic antagonist chosen from yohimbine or yohimbine hydrochloride. Also, the composition reportedly achieves the expected result.There are other patents that seek (and achieve) expected results for improving the condition of xerostomia. However, all of the aforementioned patents focus on solving only one of the problems caused by xerostomia. The pharmacological composition sought to be patented in this document can solve all the problems affecting patients with or suffering from xerostomia by increasing salivary flow, providing antibacterial protection, and reducing oropharyngeal pain.

[0013] The present pharmacological composition contains pilocarpine hydrochloride, as described above, a parasympathomimetic agent that stimulates the salivary glands and improves salivary flow, in turn contains melic acid, a component that produces an increase in unstimulated salivary flow, chlorhexidine, an antimicrobial agent commonly used in the oral cavity, lidocaine, an anesthetic agent for local use, xylitol as a natural sweetener, methylcellulose used as a saliva substitute and potassium sorbate as a preservative. The presence of chlorhexidine helps enhance the beneficial effects necessary for patients suffering from xerostomia, since having less saliva production makes them more prone to infections in the oral cavity, from cavities to periodontal diseases. The presence of lidocaine helps with another beneficial effect for these patients.Along with the sensation of dry mouth, due to less saliva production, the symptoms of oropharyngeal pain increase and.

[0014] 3

[0015] SUBSTITUTE SHEET (RULE 26) Lidocaine contained in this pharmacological composition helps to mitigate these pains and considerably increase the quality of life.

[0016] This pharmacological composition can be presented in different percentages of each component:

[0017] - Pilocarpine hydrochloride between 4% and 10%

[0018] - Malic Acid between 0.2% and 1%

[0019] - Chlorhexidine between 0.05% and 2%

[0020] - Lidocaine HCI between 1% and 3%

[0021] - Xylitol between 2% and 7%

[0022] - Methylcellulose between 0.5% and 2%

[0023] - Potassium Sorbate between 0.5% and 2%

[0024] - Aqueous gel qsp 100 ml if formulated as a gel, demineralized water qsp 100 ml if formulated as a spray or mouthwash.

[0025] This pharmacological composition, used 3 times a day for 1 minute in the mouth, has 3 immediate effects on patients:

[0026] 1. Decreases xerostomia (there is an increase in salivary production)

[0027] 2. Reduces the risk of oral infections

[0028] 3. Reduces pain caused by dry mouth

[0029] This type of pharmacological composition can help not only patients treated with head and neck radiotherapy, but also patients suffering from systemic autoimmune diseases such as Sjoegren's syndrome or patients taking medications that cause xerostomia, especially patients taking antidepressant or anxiolytic medications without the adverse effects produced by medications used systemically.

[0030] APPLICATION EXAMPLES

[0031] This pharmacological composition has had positive effects when applied to patients undergoing head and neck radiotherapy and patients with Sjoegren's Syndrome, who present xerostomia as one of their main symptoms. The positive effect of this application is reflected in the results obtained in 32 patients undergoing head and neck radiotherapy who have been irradiated, affecting the salivary glands and decreasing their salivary flow. When starting treatment with this pharmacological composition, using it three times a day, 100% of the patients achieved an increase in salivary concentration to almost double, achieving normal parameters (stimulated saliva quantity between 1 and 2 ml / min). Similar results were obtained when applying this pharmacological composition to patients with Sjoegren's Syndrome.

[0032] SUBSTITUTE SHEET (RULE 26)

Claims

CLAIMS 1. Pharmacological composition of an oral topical application solution for the treatment of oral conditions CHARACTERIZED by comprising an oral topical composition of pilocarpine hydrochloride, malic acid, chlorhexidine, lidocaine, xylitol, methylcellulose, potassium sorbate and demineralized water.

2. Pharmacological composition according to claim 1, CHARACTERIZED by comprising between 4% and 10% of pilocarpine hydrochloride, between 0.2% and 1% of malic acid, between 0.05% and 2% of chlorhexidine, between 1% and 3% of lidocaine, between 2% and 7% of xylitol, between 0.5% and 2% of methylcellulose, between 0.5% and 2% of potassium sorbate and demineralized water or aqueous gel in an amount sufficient for one hundred (100) milliliters.

3. Pharmacological composition according to claim 1, CHARACTERIZED by being a pharmacological composition for oral use, whether in the form of a gel, spray, mouthwash and / or paste or ointment.

4. Pharmacological composition according to claim 1, CHARACTERIZED in that it also comprises a natural or synthetic flavoring in suitable concentrations that do not affect the therapeutic effects of the main components.

5. Pharmacological composition according to claim 1, CHARACTERIZED by being able to eliminate and / or add any other active component that replaces, enhances or complements the pharmacological effect of the active components of said composition.

6. Pharmacological composition according to claim 1, CHARACTERIZED in that it is indicated for the treatment of oral conditions, mainly xerostomia, hyposalivation, periodontal diseases, oral and pharyngeal pain, conditions caused secondarily by radiotherapy of the neck and head, chemotherapy, use of drugs and / or autoimmune diseases.