Field of invention

The present invention relates to the stable pharmaceutical compositions containing benzydamine hydrochloride as an anti-inflammatory agent, an quaternary ammonium compound of antiseptics, a local anesthetic agent and optionally zinc salt.

Background of the invention

Most sore throats are caused cold and viruses. Some sore throats can be caused by infection by bacteria. Antibiotics is rarely required in some cases. Viral sore throats, on the other hand, do not respond to antibiotics, and therefore management of the symptoms is required until the virus has been eliminated by the body.

Sore throat products are available as lozenges, sprays, gargles, and, most recently, pain strips that are applied directly to the tongue, providing immediate pain relief. These agents usually contain anesthetics, such as benzocaine and dyclonine hydrochloride, which provide temporary relief. Other products available contain local antiseptics, such as cetylpyridinium chloride, hexylresorcinol, and/or menthol or camphor. Some products also may contain phenol.

Benzydamine is a locally acting anesthetic and analgesic drug. It is used for gingivitis, stomatitis, glossitis apthous ulcers, dental surgery and oral ulceration due to radiation therapy, pharyngitis, tonsillitis, post tonsillectomy radiation or intubation mucositis.

Benzydamine has analgesic, antipyretic, and anti-inflammatory effects. Benzydamine hydrochloride is painkiller medicine utilized to relieve mild to moderate pain and inflammation in a particular area. If it directly applied to the affected area, it can be very effective. Benzydamine also works by preventing the formation of prostaglandins.

It is used to reduce post-surgical and post-traumatic pain and edema and to promote healing. It is also used topically in treatment of rheumatic diseases and inflammation of the mouth and throat.

Several clinical studies suggest that topically applied benzydamine is effective in attenuating a variety of inflammatory conditions including oral mucositis induced by antineoplastic radiation or chemotherapy.

The preparation of benzydamine is described in US 3318905. Chemical name is 3-[(1-Benzyl- 1H-indazol-3-yl)oxy]-N,N-dimethyl-1-propanamine. There have been proposals to use benzydamine in mouth washes in many sources.

l Antiseptics can be used for handwashing, pre-operative skin disinfection, mucous membrane disinfection, preventing and treating infected wounds and burns, treating mouth and throat infections.

Antiseptics can be classified according to their chemical structure. Commonly used antiseptic groups are alcohols, quaternary ammonium compounds, chlorhexidine and other diguanides, antibacterial dyes, chlorine and hypochlorites, inorganic iodine compounds, metals, peroxides and permanganates, halogenated phenol derivatives and quinolone derivatives. Cetylpyridinium chloride is a member of quaternary ammonium compounds.

Cetylpyridinium, chemical name is 1-Hexadecylpyridinium, is a cationic bactericidal surfactant used as a topical antiseptic for skin. Cetylpyridinium chloride can be purchased in two forms: cetylpyridinium chloride and cetylpyridinium chloride monohydrate. Cetylpyridinium chloride is commonly used in oral rinses for cleaning mouth and treating throat or mouth infections and teething problems.

Cetylpyridinium chloride is a cationic quaternary ammonium compound that is known to have antibacterial properties and helps fight plaque and gingivitis. Cetylpyridinium chloride has a combination of antibacterial and anti-fungal activity.

Cetylpyridinium is a topical antiseptic for skin, wounds, mucous membranes, instruments. It is used in solutions or lozenges for the treatment of minor infections of the mouth and throat depending antiseptic properties.

Benzydamine Cetylpyridinium Lidocaine

Local anesthetics have been used in the aim of having a local analgesic effect, including absence of pain sensation for many years. Local anesthetics can be used for acute and chronic pain, also industry of surgery, podiatry and dentistry.

Lidocaine, chemical name is (1 E)-2-(Diethylamino)-N-(2,6-dimethylphenyl)ethanimidic acid, is also called xylocaine or lignocaine.

Zinc is a metal that is called an "essential trace element" because very small amounts of zinc are necessary for human health. It can be used for boosting the immune system, treating the common cold and recurrent ear infections, and preventing lower respiratory infections. Also zinc is used for malaria and other diseases caused by parasites.

Zinc salts is applied to the skin for treating acne, aging skin, herpes simplex infections, and to speed wound healing. Zinc preparation can be sprayed in the nostrils for treating the common cold.

EP 0812193 relates to the oral hygiene compositions containing an anti-inflammatory agent; benzydamine and a anti-microbial agent; cetyl pyridinium chloride and having improved antimicrobial activity. This document is relevant to provide an effective antiseptic, anti-inflammatory and analgesic treatment for microbial infections in suitable forms of the gum, mouth and throat. According to this document, composition of the invention may contain benzydamine and cetyl pyridinium chloride in the ratio (by weight) of from 10:1 to 1 :10.

EP0759739 describes a method of adding chemotherapeutic preparations including cetylpyridinium chloride and lidocaine to dental containing several bundles comprising multiple fibres.

According to EP2570123, there is provided the use of one or more anti-bacterial compounds including cetylpyridinium chloride and lidocaine for the preparation of a medicament wherein the one or more anti-bacterial compounds exhibits an anaesthetic effect.

Summary of the invention

The present invention provides pharmaceutical formulations comprising active ingredients combination characterized by 1.) good stability properties, 2.) controlling the release of the active ingredient according to desired therapeutical needs, and finally 3.) simple and also competitive manufacturing process.

The major subject of the present invention is to provide a formulation which has resistant against physical and environmental conditions and also have a high bioavailability.

Pharmaceutical composition, characterized in that it comprises:

a) Benzydamine or pharmaceutical acceptable salt thereof as nonsteroidal antiinflammatory agent,

b) a quaternary ammonium compound of antiseptic,

c) a local anesthetic agent,

d) optionally a zinc salt,

We have now surprisingly found that benzydamine, lidocaine and also a zinc salt may be effectively combined with cetylpyridinium chloride, comparing with single activity of benzydamine and with an enhancement of the activity of cetylpyridinium chloride and other compounds, so as to provide an effective antiseptic, anti-inflammatory and analgesic treatment. Detailed description of the invention

This invention is related to a pharmaceutical product that contains a local anesthetic called lidocaine or its salts, which relieves pain and irritation; and nonsteroidal anti-inflammatory agent called benzydamine or its salts in anti-inflammatory treatment for the relief of painful inflammatory conditions of the mouth; and an antiseptic called cetylpyridinium chloride, which kills bacteria and helps prevent infection.

A preferred embodiment according to the present invention relates to a pharmaceutical composition, characterized in that it comprises:

a) active ingredient selected from nonsteroidal anti-inflammatory agents is benzydamine hydrochloride,

b) active ingredient selected from quaternary ammonium compound of antiseptics is cetylpyridinium chloride,

c) active ingredient selected from local anesthetic agents is lidocaine,

d) optionally a zinc salt,

in combination with at least one pharmaceutically acceptable excipient.

Benzydamine may be used as a pharmaceutically acceptable salt thereof, for example benzydamine hydrochloride.

Cetylpyridinium may be used as a pharmaceutically acceptable salt thereof, for example cetylpyridinium chloride.

In this invention, the term " zinc" means a compound including, but not limited to; zinc,zinc acetate, zinc bromide, zinc caprylate, zinc carbonate, zinc chloride, zinc citrate, zinc formate, zinc hexafluorosilicate, zinc iodate, zinc iodide, zinc iodide-starch, zinc lactate, zinc nitrate, zinc oleate, zinc oxalate, zinc oxide, calamine (zinc oxide with a small proportion of ferric oxide), zinc p-phenolsulfonate, zinc propionate, zinc salicylate, zinc silicate, zinc stearate, zinc sulfate, zinc sulfide, zinc tarmate, zinc tartrate, zinc valerate, zinc ethylenebis(dithiocarbamate), poly(zinc acryfate) or a combination thereof and their pharmaceutically acceptable salts.

The formulation according to the present invention may be in the form of lozenge and other solid oral dosage forms or liquid oral dosage forms. The preferred dosage form according to the present invention is the solid dosage form, preferably a tablet or lozenge form.

Lozenges are the most commonly used OTC products for the treatment of sore throat pain. There are 3 main types: lozenges with a weak topical anesthetic, lozenges with menthol, and unmeditated lozenges.

Pharmaceutical composition of the present invention may comprise one or more pharmaceutically acceptable excipient(s). Pharmaceutically acceptable excipients comprise, but are not limited to, fillers, disintegrants, binders, lubricants, glidants, sweeteners, aromatic agents, preservatives, coloring agents, and the mixtures thereof, to facilitate the physical formulation of various dosage forms like orally disintegrating tablets, chewable tablets and suspensions (including dry powders or granules for suspension).

A preferred embodiment according to the present invention provides a method for preparing pharmaceutical granules in wet granulation, comprising the steps of

a. Benzydamine hydrochloride, an quaternary ammonium compound of antiseptics, a local anesthetic agent, optionally a zinc salt and excipients are mixed with a binder solution comprising PVP, ethanol or water or a combination thereof,

b. after wet granulation process, next steps are fluid bed drying, sieving and finally blend is obtained,

c. obtained blend is mixed with sweetener or flavour agents,

d. lubricating the final blend of step c,

e. compressing the mixture into tablets.

A further preferred embodiment according to the present invention provides a method for preparing pharmaceutical granules in wet granulation, comprising the steps of

a. benzydamine HCI, cetylpyridinium chloride, lidocaine and optionally a zinc salt and excipients are mixed with a binder solution comprising PVP, ethanol or water or a combination thereof, b. after wet granulation process, next steps are fluid bed drying, sieving and finally blend is obtained,

c. obtained blend is mixed with sweetener or flavour agents,

d. lubricating the final blend of step c,

e. compressing the mixture into tablets.

Compositions of this invention may be used in therapy or as a prophylatic against microbial infections accompanied by irritation, such as skin infections. In particular, composition can be used for oral application: as an antiseptic, anti-inflammatory and analgesic treatment of gums, mouth and throat, especially for treatment of plaque, gingivitis and periodontitis, denture irritation. It is useful for treating sore or bacteria infected throat, cough-irritated sore throat, and other oral ailments wherein the source of irritation is partly or wholly derived from microbial infection. It may be used for painful inflammatory conditions of the mouth and throat including pharyngitis (eg following tonsillectomy), aphthous ulcers, aspecific odontostomatoligic affections, glossitis and stomatitis, and teeting troubles, pain and may be used before and/or after dental extractions.

Examples

The manufacturing method of Examples 1 and 2 are described below:

1. Intra-granular powders are weighed and mixed, and optionally a zinc salt is added in a pharmaceutically effective amount.

2. Binder solution is prepared by adding PVP K30 to water, 3. Dry mix of Step 1 is granulated with binder of step 2 and granules are dried.

4. Then dried granules are shifted through 1.0 mm mesh.

5. According to yield, extragranular materials are weighed and shifted and added to dried shifted granules and blended for 5 min.

6. Then lubricant is weighed and shifted and added to above step and lubricated for 3 min and finally resulting powder is compressed.