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EP-3834815-B1 - TOPICAL AQUEOUS PHARMACEUTICAL COMPOSITIONS OF FLURBIPROFEN AND CHLORHEXIDINE

EP3834815B1EP 3834815 B1EP3834815 B1EP 3834815B1EP-3834815-B1

Inventors

  • Cifter, Ümit
  • TÜRKYILMAZ, Ali
  • MUTLU, ONUR

Dates

Publication Date
20260506
Application Date
20130816

Claims (12)

  1. An oral topical aqueous pharmaceutical composition comprising on a weight basis, (i) between 0,01 to 4,75% flurbiprofen or pharmaceutically acceptable salts thereof; (ii) between 0.01 to 4.0% chlorhexidine or salts thereof; (iii) from 0.05 to 1.0% eucalyptus oil.
  2. The composition according to claim 1, wherein the pH of the solution is between 6 and 7.
  3. The composition according to claim 1, comprising on a weight basis, (i) between 0,01 to 4,75% flurbiprofen or pharmaceutically acceptable salts thereof; (ii) between 0.01 to 4.0% chlorhexidine or salts thereof; (iii) between 0.05 to 1.0% eucalyptus oil; (iv) sodium hydroxide in a sufficient amount to adjust the pH of the solution to between 6 and 7.
  4. The composition according to claims 1, further comprising at least one solvent in an amount of from 5 to 40 % by weight of the total composition.
  5. The composition according to claim 4, wherein the solvent is selected from ethyl alcohol, glycerin and sorbitol.
  6. The composition according to claims 1, further comprising at least one sweetening agent in an amount of from 0.1 to 15.0% by weight of the total composition.
  7. The composition according to claim 6, wherein the sweetening agent is selected from saccharine sodium and sorbitol.
  8. The composition according to claims 1, further comprising at least one surfactant in an amount of from 0.1 to 5.0% by weight of the total composition.
  9. The composition according to claim 8, wherein the surfactant is polyoxyl 40 hydrogenated castor oil.
  10. The composition according to any of the preceding claims, comprising on a weight basis: (i) between 0,05 to 2,5% flurbiprofen or pharmaceutically acceptable salts thereof; (ii) between 0.02 to 3.0% chlorhexidine or salts thereof; (iii) between 0,05 to 1,0% eucalyptus oil; (iv) between 0,1 to 2,5% sodium hydroxide (v) between 5 to 20 % sorbitol; (vi) between 0,1 to 0,5% saccharine sodium; (vii) between 5 to 25% glycerin; (viii) between 0.1 to 5% polyoxyl 40 hydrogenated castor oil; (ix) between 5 to 15 % ethyl alcohol
  11. The composition according to any one of the preceding claims, wherein said composition is in the form of a mouthwash, mouth rinse or spray.
  12. The composition according to any one of the preceding claims, for use in the treatment of periodontal diseases and non-specific epidermal and muco-epidermal infections and inflammation.

Description

Field of the Invention The present invention relates to stable topical aqueous pharmaceutical compositions comprising flurbiprofen or pharmaceutically acceptable salts thereof and chlorhexidine or salts thereof. More particularly, the present invention relates to a stable oral topical aqueous pharmaceutical composition of this combination having desired levels of dissolution rate, solubility, enhanced taste and absorption from mucosal surface, comprising mint oil or eucalyptus oil and wherein the pH of the solution is between 6 to 7. Background of the Invention Flurbiprofen is a well-known non-steroidal anti-inflammatory drug which has analgesic and anti-inflammatory activities. It is used in muscle-skeletal and joint disorders such as ankylosing spondylitis, osteoarthritis and rheumatoid arthritis, in soft-tissue disorders such as sprains and strains and for postoperative pains. Its chemical structure is illustrated with Formula I given below. Flurbiprofen is mostly administrated orally. One disadvantage of the oral administration of flurbiprofen comprising compositions is that the patient is likely to experience unpleasant side effects, including gastrointestinal irritation. The use of flurbiprofen in treating local pains and inflammations may cause a problem especially for those who have gastrointestinal system disorders. It is possible to develop various locally-administrable topical forms of flurbiprofen, in order to avoid the systemic side-effects thereof. Another disadvantage of flurbiprofen is that it is practically insoluble in water. This makes it difficult to prepare its aqueous solutions. Chlorhexidine is an antiseptic and disinfectant effective against a wide variety of bacteria, fungi and some viruses. It is used clinically in various preparations for disinfecting purposes such as oral rinses and skin cleansers. It is often used in mouthwash designed for reducing dental plaque and oral bacteria and to treat and prevent gingivitis. Its chemical structure is illustrated with Formula II given below. Chlorhexidine is a strong base and is most stable in the form of salts such as the digluconate and dihydrochloride. The most commonly used derivative is the digluconate salt because of its higher water-solubility. Chlorhexidine and its derivatives have the disadvantage that they stain the teeth with repeated use and have a bitter taste. Thus there is a need to increase the water solubility of chlorhexidine and its derivatives and to mask the bitter taste of these compounds so that they can be more incorporated into the aqueous based compositions to decrease the level of staining the teeth significantly and find greater acceptability to the user. PCT patent application WO 95/04520 describes the use of chlorhexidine and a non-steoridal anti-inflammatory agent for the treatment of epidermal and muco-epidermal tissue. Non-steoridal anti-inflammatory agent is stated to include flurbiprofen. However this document does not describe a specific formulation for this combination. A Canadian patent application CA 2275049-A1 describes a needle-like device adapted for insertion in a root canal and pulp chamber of a tooth of the patient, comprising chlorhexidine and another biological active agent wherein the biological active agent consisting of flurbiprofen and some other agents. However it does not describe a topical aqueous formulation of this combination. A Japanese patent document JP 8268854 discloses a composition containing an acidic non-steroidal anti-inflammatory agent, a cationic antimicrobial agent, a tetracy cline antibiotic and an inorganic acid for use in oral cavities. Flurbiprofen and chlorhexidine are stated for non-steroidal anti-inflammatory agent and cationic antimicrobial agent respectively. This composition further comprises an antibiotic and an acid. This document does not disclose the specific combination of flurbiprofen and chlorhexidine. In addition to this, the composition described in JP 8268854 contains an acid which decreases the solubility of flurbiprofen and thus dissolution and the extent of penetration into the muco-epidermal and epidermal tissue decreases. Accordingly, for the treatment of periodontal diseases and muco-epidermal and epidermal inflammation and infection there arises the need of an oral topical aqueous composition comprising flurbiprofen and chlorhexidine which optimizes the delivery of them through the oral mucosal surface. Summary of the Invention It is therefore an object of the present invention to provide an oral topical aqueous pharmaceutical composition of flurbiprofen or pharmaceutically acceptable salts thereof and chlorhexidine or pharmaceutically acceptable salts thereof having desired levels of dissolution rate, solubility enhanced taste and absorption from mucosal surface. The inventors of the present invention have discovered that by using an alkalizing agent the pH of the solution is adjusted to pH 6-7 thus the solubility of flurbiprofen is increased