PHARMACEUTICAL COMPOSITIONS

Abstract: Novel pharmaceutical compositions of matter are disclosed for use in eliciting a topical anesthetic and antimicrobial response, preferably for oral health care purposes, said compositions comprising dyclonine hydro­ chloride and phenol. When used in combination, dyclonine hydrochloride and phenol provide an improved antimicro­ bial response.

Description: This invention is directed to pharmaceutical compositions containing dyclonine hydrochloride (HCl) and phenol. Dyclonine HCl, chemically denoted as 3-piperidino-4′-butoxypropiophenone hydrochloride, is a well known anesthetic/analgesic agent for topical use on the mucous membranes of the mouth and throat (see Federal Register, Vol. 47, No. 101, Proposed Rules, pages 22810-13, 1982). Oral pharmaceutical compositions of dyclonine HCl commercially available in the United States include and aqueous liquid spray containing 0.1% dyclonine HCl and solid lozenges containing 1.2 mg dyclonine HCl per lozenge for children and 3.0 mg per lozenge for adults (see Physicians' Desk Reference for Non-prescription Drugs, 8th Ed., 1987, pages 518-9). The benefit of dyclonine HCl is that it provides long acting topical anesthetic relief. The use of certain acids, particularly citric acid, to stabilize dyclonine HCl in anesthetic lozenges is reported in US-A-4,139,627. In addition to its anesthetic/analgesic properties, dyclonine HCl is known to possess antimicrobial activity. In this regard, US-A-2,868,689 discloses stabilized aqueous preparations of dyclonine HCl (0.1-58) having topical anesthetic and antimicrobial action, the stabilization aspect being provided by the addition of chlorobutanol (0.1-0.5%). It is noted, for purposes of the subject invention, that phenol was specifically identified in US-A-2, 868, 689 as being an unsatisfactory stabilizer (column 1, lines 60-61). Phenol is a known topical anesthetic, which has been used to treat minor sore mouth and sore throat pain. The mode of action, fast acting but not long lasting, is that it desensitizes sensory nerve receptors present in the mucous membranes of the throat and oral cavity to exert its local anestheticeffect. Previous dosage forms of administration have included lozenges containing 32.5 mg phenol per lozenge and aqueous solutions of 1.4% phenol for use as a mouthwash, rinse or gargle, which is expelled from the oral cavity after use, and as a throat spray (see Physicians' Desk Reference for Non-prescription Drugs, 8th Ed., 1987, pages 654-5). In addition to its anesthetic activity, phenol is known to possess antimicrobial activity. It has now been found that the combined action of dyclonine HCl and phenol in pharmaceutical compositions containing an effective topical anesthetic and antimicrobial amount of each active results in producing an enhanced antimicrobial effect beyond that which might be expected from the mere additive effect of the two actives. Without being bound to such explanation, it would seem, in view of the antimicrobial activity of each active, that said antimicrobial enhancement results from co-potentiation between the two, that is, by each active potentiating the antimicrobial activity of the other. According to the invention, there is provided a liquid pharmaceutical composition of matter for oral health care use arid having enhanced antimicrobial action comprising an aqueous-based orally acceptable pharmaceutical carrier having incorporated therein from 0.05 to 2.0 w/v percent of dyclonine hydrochloride and from 1.0 to 1.4 w/v percent of phenol, said composition having a pH of from 3 to 4. The subject invention provides a pharmaceutical composition of matter for oral health care use which not only provides relief of pain in irritated mucous membranes of the mouth and throat, but also provides enhanced antimicrobial activity. As used herein, the term "oral" includes the throat and oral cavity with contiguous mucosal tissues. Accordingly, the composition of this invention has beneficial application in treating, for example, 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 has been found that the composition of this invention possesses antimicrobial action that is greater than the sum of that possessed by dyclonine HCl or phenol when used alone. The enhanced antimicrobial action between dyclonine HCl and phenol is demonstrated in the following type experiment using Staphylococcus aureus, a gram-positive bacterium. METHODOLOGY A five millimeter (ml) aliquot of the test formulation is dispensed into a clean 18 mm borosilicate glass test tube for the undiluted sample. Dilutions of the test formulation are prepared using sterile deionized water. The inoculum suspension is prepared from an overnight growth of the challenge organism on appropriate media. In the case of S. aureus , Soybean Casein Digest Agar (SCDA) is used. SCDA contains 15 grams/liter (g/L) Soybean Casein Digest Broth and 15 g/L agar. One liter of the medium is autoclaved at 15 psi and 121 C for 30-40 minutes and approximately 25 ml per plate are poured into sterile disposable 100 x 15 mm polystyrene Petri dishes. Surface growth from the overnight culture is transferred from the plate using a sterile wire loop to 6 ml of 0.85% sterile saline in a test tube. The suspension is adjusted to an optical density at 540 nanometers (OD₅₄₀) of 0.5 as read in a Spectronic 20 spectrophotometer. This OD₅₄₀ is equivalent to approximately 5 x 10⁸ colony forming units (cfu)/ml for S. aureus . The inoculum size is confirmed by serial dilution of the inoculum into Letheen broth and by plating dilutions onto SCDA using a spread plate technique. At time zero 0.05 ml of a suspension of the challenge organism is inoculated into each tube and the contents mixed to yield a level of about 5 x 10⁶ cfu/ml. At given time intervals 0.1 ml aliquots are removed from each test sample and plated onto SCDA. All plates are incubated at 30 C in a convection incubator for 48 hours at which time colonies are counted and cfu/ml are calculated and recorded. The enhanced antimicrobial effect of phenol and dyclonine HCl in aqueous pharmaceutical preparations is illustrated in Table I by the indicated test results obtained in accordance with the Methodology. The "Base Vehicle" and other test products are described hereinafter in Example 1. The Staphylococcus organism used is S. aureus ATCC 6538 (ATCC = American Tissue Culture Collection). In this particular experiment, the actual OD₅₄₀ reading was 0.43 and the actual inoculum size was 5.7 x 10⁶ cfu/ml. The symbol "P" represents phenol, and the symbol "D" represents dyclonine hydrochloride. The numerical symbols indicate the recorded cfu/ml at the indicated time interval as follows: Test results shown that the Base Vehicle itself has very little antimicrobial effectiveness. Complete kill (0 = <10 cfu/ml) is only seen after 5 minutes at full strength (1x) concentration. Test product containing 1.4% phenol shows complete kill by 30 seconds at full strength concentration and a two-fold dilution (1/2x). However, a four-fold dilution (1/4x) shows less antimicrobial effectiveness with a count of 10-100 cfu/ml being recorded even after 5 minutes. Test product containing 0.1% dyclonine HCl shows some activity at full strength with complete kill by 3 minutes. However, no activity is recorded at either two-fold or four-fold dilutions. Test product with both 1.4% phenol and 0.1% dyclonine HCl shows complete kill by 30 seconds at full strength, two-fold dilution and four-fold dilution. At the four-fold dilution, the combination product has a faster onset of action than either of the single entity products. The test results demonstrate that the two actives together have more than an additive effect on the antimicrobial activity of the formulations. Test product containing both 1.0% phenol and 0.1% dyclonine HCL shows a similar effect. With 1.0% phenol alone, diluted four-fold, a 1001-10,000 cfu/ml count is observed after 5 minutes; and the four-fold dilution of dyclonine HCl alone shows no effect. In contrast, the four-fold dilution of the combination of the two actives shows complete kill by 5 minutes. It is thus shown that marked enhancement exists since the two actives when acting in combination, each in a certain concentration for a certain time and under certain conditions on a fixed number of microorganisms, decrease the number to a lower level than did either of the actives acting alone at the concentration in which it was present in the combination and under the same conditions. In addition to the aforementioned S. aureus similar evidence of enhancement between the two actives may be observed against other bacterial organisms such as, for example, Pseudomonas aeruginosa , Hemophilus influenza and Neisseria meningitidis ; and the yeast, Candida albicans . The present invention thus provides a novel pharmaceutical composition of matter for oral health care use, wherein it is sought to elicit an antimicrobial response. In addition, the combination of the two actives provides the benefit of both faster acting topical anesthetic activity attributable to the phenol and longer acting topical anesthetic activity attributable to the dyclonine HCl, particularly for the relief of sore throat or mouth conditions requiring antimicrobial treatment. Said composition comprises the two essential active ingredients, dyclonine hydrochloride and phenol, in admixture with a pharmaceutically acceptable carrier. In preparing the pharmaceutical compositions of the present invention, the dyclonine HCl and phenol are incorporated into a liquid pharmaceutically acceptable carrier according to conventional pharmaceutical practices. The carrier is an aqueous-based pharmaceutically acceptable carrier, that is, one wherein the entire or predominant solvent content is water. As noted in US-A-2,868,689, however, dyclonine HCl demonstrates instability in such water-containing preparations and, accordingly, the use of an acid stabilizer for dyclonine HCl will serv to prolong and enhance shelf life. The pH of the subject compositions utilizing an aqueous-based orally acceptable pharmaceutical carrier is from 3 to 4 and, preferably, from 3.2 to 3.6. To provide and maintain the subject compositions at such pH levels, acid buffers consistent with conventional pharmaceutical practices are generally utilized such as, for example, citrate and phosphate buffers. As noted previously, stabilized aqueous pharmaceutical compositions containing dyclonine HCl are heretofore known as, for example, in US-A-2,868,689. Accordingly, in a stable liquid pharmaceutiral composition for oral health care use comprising an aqueous-based orally acceptable pharmaceutical carrier having incorporated therein an effective topical anesthetic and antimicrobial amount of dyclonine HCl, the present invention provides the improvement comprising the incorporation therein of the herein mentioned amounts of phenol. In liquid preparations for oral health care purposes, it is common practice to include such product enhancing optional additives as colorants, flavorants and co-solvents, which additives may affect the total solubility of the two actives in the final product. Accordingly, such a liquid composition of this invention having an aqueous-based orally acceptable pharmaceutical carrier has from 0.05 to 2.0 weight/volume (w/v) percent of dyclonine HCl and from 1.0 to 1.4 w/v percent of phenol incorporated into said carrier. The compositions of this invention may optionally contain one or more other known therapeutic agents, particularly those commonly utilized in oral health care preparations, such as, for example, other agents having local anesthetic or antimicrobial activity. Other optional ingredients which are non-therapeutic and well known to the pharmacist's art may also be included in amounts generally known for such ingredients, for example, natural or artificial sweeteners, flavoring agents and colorants to provide a palatable and pleasant looking final product; ethyl alcohol, propylene glycol and glycerin as co-solvents; and other typical pharmaceutically acceptable ingredients commonly employed in compositions of this type. The following examples illustrate the Base Vehicle and test products utilized in the experiments herein reported and also illustrate embodiments of the present invention. The foregoing formulation represents the herein mentioned Base Vehicle, which is an aqueous-based orally acceptable pharmaceutical carrier without either the dyclonine HCl or the phenol. To this Base Vehicle, 1.0% and 1.4% w/v of phenol (P) are added to provide the herein mentioned two respective test products with phenol as the sole active; and 0.1% w/v of dyclonine HCl (D) is added to provide the herein mentioned test product with dyclonine HCl as the sole active. In addition, both phenol and dyclonine HCl are added to the Base Vehicle in the indicated percentages to provide the herein mentioned two respective test products with both P and D as combined actives, i.e., two respective embodiments of the compositions of this invention. EXAMPLE 2 The antimicrobial effectiveness of combined phenol and dyclonine HCl on the yeast microorganism, Candida albicans , is demonstrated in Table II, the indicated test results being obtained in accordance with the previously described Methodology with the following modifications. The OD₅₄₀ of 0.5 is approximately equivalent to 5 x 10⁷ cfu/ml for C. albicans . In this particular experiment, the actual OD₅₄₀ was 0.63 and the actual inoculum size was 1.8 x 10⁵. The particular microorganism is C. albicans ATCC 10231. Other indicated symbols are as previously denoted. As shown in the tabulated data, neither 0.1% dyclonine HCl alone nor 1.0% phenol alone show activity at two-fold dilution; and 1.4% phenol alone at this dilution shows slight activity at 3 to 5 minutes. In contrast, the combination of the two actives with 1.0% phenol at the same dilution shows a marked increase in organism kill at 3 minutes and complete kill at 5 minutes; and the combination with 1.4% phenol at the same dilution shows a marked increase in organism kill at 1 minute and complete kill at 3 minutes.

Claims: 1. A liquid pharmaceutical composition of matter for oral health care use and having enhanced antimicrobial action comprising an aqueous-based orally acceptable pharmaceutical carrier having incorporated therein from 0.05 to 2.0 w/v percent of dyclonine hydrochloride and from 1.0 to 1.4 w/v percent of phenol, said composition having a pH of from 3 to 4. 2. The composition of Claim 1 wherein the pH is from 3.2 to 3.6 3. A liquid pharmaceutical composition of matter for oral health care use and having enhanced antimicrobial action comprising an aqueous-based orally acceptable pharmaceutical carrier having incorporated therein about 0.1 w/v percent of dyclonine hydrochloride and from 1.0 to 1.4 w/v percent of phenol, said composition having a pH of 3.4.

Inventors: KELLEHER, WILLIAM JOSEPH, MOYE, JEANNE OLORE, SORRENTINO, JAMES VINCENT
Applicants: RICHARDSON-VICKS, INC.
Application year: 1988
Main classification: A61K31
IPC codes: A61P31, A61K9, A61K31, A61K47