HK1059215B - Pharmaceutical compositions for the treatment of mucositis, stomatitis and behcet's syndrome - Google Patents

Description

Pharmaceutical composition for the treatment of mucositis, stomatitis and Behcet's syndrome

The present invention relates to pharmaceutical compositions comprising hyaluronic acid, glycyrrhetinic acid and polyvinylpyrrolidone for the treatment of painful ulcers and inflammations of moist surfaces, including the mouth, oropharynx, oesophagus, vagina and rectum, including but not limited to mucositis, stomatitis, Behcet's syndrome.

Background

The terms mucositis and stomatitis are often used interchangeably, but may include some general differences. Mucositis describes a toxic inflammatory reaction affecting the gastrointestinal tract, which may be caused by exposure to chemotherapeutic agents or ionizing radiation. Mucositis is typically manifested as erythema, burn-like lesions or random, focal to diffuse ulcerative lesions.

Stomatitis refers to an inflammatory reaction affecting the oral mucosa, with or without the appearance of ulcers, which may be caused or exacerbated by pharmacological treatments, in particular chemotherapy, or by radiotherapy. The degree of stomatitis can range from mild to severe; patients suffering from severe stomatitis cannot take anything in their mouth.

Many women develop aphthous ulcers of the mouth at specific times of the menstrual cycle and the same ulcers in the genital tract, particularly the vulva and vagina, at the same time. This condition is sometimes severe enough to cause urinary retention and requires potent analgesics and sedatives. The most severe form is known as behcet's syndrome.

In the following description, the more general term mucositis is also used to denote stomatitis. Studies on mucositis demonstrate this effect and support the claims.

Erythematous mucositis may appear as early as three days after chemotherapy or radiotherapy, but generally occurs within five to seven days. Ulcerative mucositis typically develops within seven days after chemotherapy is initiated, and can sometimes reach such a severe degree that the pharmacological treatment needs to be discontinued. Mucositis may involve the oral cavity and oropharynx as well as the gastrointestinal tract from the oral cavity to the anus. We here limit the experience to mucositis in easily accessible areas such as the mouth, oropharynx, oesophagus and rectum.

Because the percentage of mucositis occurring to various degrees in patients receiving chemotherapy is high (from 30 to 40%), there is a great need for a convenient and effective treatment. To date, no effective treatment has been achieved and attempts have been made to address this problem by using analgesics, antibacterial agents and oral care measures or alleviating symptoms.

Furthermore, the problem of mucositis is not limited to cancer patients, since mucositis often occurs in HIV patients, particularly in patients with kaposi's sarcoma, but also in patients with non-hodgkin's lymphoma, in frail elderly patients, and in patients receiving BRM therapy such as interleukin-2, TNF, interferon, lymphokine-activated lymphocytes, etc.

Disclosure of the invention

It has been surprisingly found that topical administration of a pharmaceutical formulation comprising hyaluronic acid, glycyrrhetinic acid and polyvinylpyrrolidone provides an effective therapeutic and prophylactic treatment of mucositis and stomatitis of various origins and severity and more generally of oro-pharyngeal and oesophageal lesions, especially those caused by dental instruments and radiotherapy or chemotherapy.

Accordingly, in a first aspect, the present invention provides a pharmaceutical composition comprising as active ingredients effective doses of hyaluronic acid, glycyrrhetinic acid and polyvinylpyrrolidone, the active ingredients being mixed with excipients and adjuvants to form a viscous and lubricious substance capable of sustained adhesion to surface epithelium suitable for topical administration to epithelial surfaces such as, but not limited to, the oropharynx and oesophagus.

Another aspect of the invention relates to the use of hyaluronic acid, glycyrrhetinic acid and polyvinylpyrrolidone for the preparation of a medicament for the topical treatment of inflammatory states of epithelial surfaces, such as, but not limited to, the oral mucosa, in particular mucositis and stomatitis.

Detailed disclosure of the invention

The compositions of the present invention are in the form of a slightly viscous aqueous solution (gel) capable of providing film-forming and coverage effects on epithelial surfaces such as, but not limited to, the oral mucosa.

Hyaluronic acid is present in a weight percentage of 0.01 to about 5%, preferably about 0.1%. Hyaluronic acid may also be present in the form of a sodium salt, preferably obtained biotechnologically, with a molecular weight ranging from 1.6 to 2.210⁶Da hyaluronic acid.

Polyvinylpyrrolidone or povidone (PVP) is a suspension and binder widely used in pharmaceutical technology. It is present in the formulations of the invention in a percentage by weight of from 1 to 20% by weight, preferably from 5 to 10%.

Glycyrrhetinic acid may be present in a weight percentage of 0.01 to 3% by weight.

Preferably, high molecular weight povidone is used, such as povidone K-30 to K-120, preferably povidone K-90 having an average molecular weight of about 1,000,000.

The compositions of the invention also contain excipients suitable for topical administration, such as:

-a tackifier;

-a surfactant;

-stabilizer-preservative;

-flavors, fragrances, sweeteners;

-a bioadhesive;

-a co-solvent.

Examples of such excipients include cellulose derivatives, acrylic or methacrylic acid polymers or copolymers, ethylene or propylene glycol, polyethoxylated hydrogenated castor oil, EDTA, sodium benzoate, sodium or potassium sorbate, dextrins, sodium saccharin, aspartame and other excipients commonly used in mouthwash or liquid oral form preparations.

The compositions of the present invention may further comprise other active ingredients having complementary effects or any useful activity, such as antibacterial/disinfectant agents, fungicides, analgesics, anti-inflammatory agents, emollients, local anesthetics, and the like. Suitable antimicrobial agents include quaternary ammonium salts such as benzalkonium chloride.

Finally, the compositions of the present invention may be presented in unit or multi-dose form, such as sachets, vials, ampoules, bottles and the like.

The dosage depends on a number of factors such as the severity, type and spread of the disease being treated: in principle, however, it is sufficient to wash or gargle for two or three minutes, three or more times per day, preferably before meals, with 1 to 50ml of solution, diluted or undiluted with water, in order to provide an optimal therapeutic or prophylactic effect. The treatment may be continued until the symptoms are alleviated, usually for 5-10 days. Longer-term treatment is not contraindicated, considering that the toxicity of the components in the formulations of the invention is very low, if at all.

The good therapeutic effect obtained by the use of the formulation of the invention is due to the synergistic effect between hyaluronic acid, glycyrrhetinic acid and polyvinylpyrrolidone, and the ability of the formulation to adhere to the oral mucosa also provides a protective coating for the exposed nerve endings, thus reducing pain and promoting healing and recovery of the injury. In addition, the wetting action of the composition is also beneficial as it protects the mucosa from further irritative damage.

The present invention will be explained in more detail with the following examples.

Example 1

Qualitative and quantitative composition percentage composition

Hyaluronic acid sodium salt 0.1

Glycyrrhetinic acid 0.06

PVP 9.0

Maltodextrin 6.00

Propylene glycol 2.94

Potassium sorbate 0.3

Sodium benzoate 0.3

Hydroxyethyl cellulose 1.5

Hydrogenated castor oil PEG-400.27

EDTA disodium 0.1

Benzalkonium chloride 0.5

Spice (Glycyrrhiza Comp.2717) 0.16

Saccharin sodium 0.1

Purified water 78.44

For its preparation, water is first placed in a turbo emulsifier, to which a mixture of potassium sorbate, sodium benzoate and disodium EDTA is then added, followed by hyaluronic acid and maltodextrin. After addition of the substances the mixture was stirred until complete dissolution of the components. After this, PVP was slowly added under stirring and vacuum (30mmHg) until it was completely dissolved. Sodium saccharin and hydroxyethyl cellulose are then added sequentially thereto, and all the components are placed under vacuum and stirred until they are completely dissolved. Then, hydrogenated castor oil 40/OE and fragrance, benzalkonium chloride, and propylene glycol and glycyrrhetinic acid were added thereto in this order, and after the addition of the components, they were stirred until the components were completely dissolved. After all the components were added, the mixture was stirred under vacuum for 30 minutes.

For the concentrated forms of the invention, 10ml or 15ml of the composition as described above are dispensed in sachets or monodose vials and diluted with 30-50ml of water before use; for the ready-to-use form of the invention, the above composition is diluted with purified water to a concentration of 50% and bottled in an amount of 200ml or 300 ml.

Example 2

Clinical trial

The evaluation was carried out with 30 patients between the ages of 30 and 60, of which 10 were AIDS patients between the ages of 30 and 40 receiving antiretroviral therapy. Patients suffer from oral inflammatory lesions of various pathologies:

12 oro-pharyngeal mucositis patients;

4 patients with aphthous lesions in the oral cavity;

4 patients with post-traumatic injury;

3 patients with oral lichen planus;

3 patients with radiotherapy-induced stomatitis;

3 patients with oral surgery side effects;

1 patient with leukoplakia.

The composition of example 1 in a 15ml sachet was diluted 1: 4 with water and the patient was treated with it. The slightly viscous solution was left in the mouth for 2-3 minutes, during which time it was rinsed and swirled in the mouth to distribute it evenly over the entire surface of the oral mucosa. The solution was then discarded.

The preparation is administered 60 min before meals, 3 times daily, and continuously for seven days.

The extent of inflammation and injury, the reduction or disappearance of dysphagia on solid and semi-solid foods and liquids, and the duration of action of the product were assessed at the end of the treatment.

After the first administration, more than 80% of patients already feel a pain reduction within a few hours, and can eat. The effect lasts three or four hours.

After 3-4 days of treatment, about 60% of the treated individuals have healed oral mucosal lesions. At the end of the treatment, this percentage reached 90%. In the remaining three cases only the pathological condition persists, but the symptoms are improved compared to the beginning of the treatment, at least significantly improving the quality of life and restoring a normal, diverse diet.

Example 3

Two patients with sore throats (sore throats) were not relieved with analgesics or other topical medications. The composition of example 1 in a 15ml sachet was diluted 1: 4 with water and the patient was then treated with it. The solution was kept in the mouth for about one minute, during which time it was used to rinse the mouth to make good contact with the throat tissue. The solution was then discarded. Within ten minutes, the patient had a significant improvement in sore throat symptoms, and this relief could last for hours.

Claims (7)

1. A pharmaceutical composition for the treatment of inflammation of the oral mucosa comprising as active ingredients 0.01-5% hyaluronic acid, 0.01-3% glycyrrhetinic acid and 1-20% polyvinylpyrrolidone, based on the total weight of the composition, in admixture with excipients and adjuvants suitable for topical administration.

2. The composition of claim 1, wherein the excipients and adjuvants are selected from the group consisting of viscosity increasing agents, surfactants, stabilizer-preservatives, flavoring agents, fragrances, sweeteners, bioadhesive agents and co-solvents.

3. The composition of claim 1, wherein the excipients and adjuvants are selected from the group consisting of cellulose derivatives, acrylic or methacrylic acid polymers or copolymers, ethylene or propylene glycol, polyethoxylated hydrogenated castor oil, EDTA, sodium benzoate, sodium or potassium sorbate, dextrin, sodium saccharin and aspartame.

4. A composition as claimed in any one of claims 1 to 3, which contains at least one of an antibacterial/disinfectant agent, a fungicide, an analgesic, an anti-inflammatory agent, an emollient and a local anaesthetic.

5. The composition of claim 1, having the following percentage composition:

hyaluronic acid sodium salt 0.1

Glycyrrhetinic acid 0.06

PVP 9.0

Maltodextrin 6.00

Propylene glycol 2.94

Potassium sorbate 0.3

Sodium benzoate 0.3

Hydroxyethyl cellulose 1.5

Hydrogenated castor oil PEG-400.27

EDTA disodium 0.1

Benzalkonium chloride 0.5

Fragrance 0.16

Saccharin sodium 0.1

Purified water 78.44.

6. Use of hyaluronic acid, glycyrrhetinic acid and polyvinylpyrrolidone for the preparation of a medicament for the treatment of oral mucosal inflammation.

7. The use of claim 6, wherein the oral mucosal inflammation is mucositis or stomatitis.