JP2009242348A - Pharmaceutical composition for preventing repeated infection - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical composition which exhibits sustained bactericidal effect by being adhered to and kept resident at a lesion for a definite time and used for preventing repeated infection in the respiratory organ. <P>SOLUTION: This invention provides a pharmaceutical composition for the oropharynx containing water, a quaternary ammonium bactericide, a polyhydric alcohol, hydroxypropylcellulose, hypromellose, and polyvinylpyrrolidone and used for the prevention of repeated infection in the respiratory organ. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to an oropharyngeal pharmaceutical composition used for the treatment or prevention of inflammatory diseases such as infections and bronchitis, in particular for the prevention of recurrent infections.

  The respiratory tract is divided into three areas: 1) upper respiratory tract (nasal vestibule, nasal cavity, pharynx, larynx), 2) lower respiratory tract (trachea, bronchi, bronchiole, terminal bronchus) and 3) alveoli. The upper respiratory tract in direct contact with it becomes an entry route for microorganisms that cause infections, and causes not only upper respiratory tract infections such as the pharynx but also lower respiratory tract infections (for example, bronchitis, pneumonia, etc.).

  A “repetitive infection” that repeats infection frequently is known, and in the case of respiratory infections, particularly lower respiratory tract infections, repeated infections caused by the same bacteria and various pathogenic bacteria have been reported. If the infection defense mechanism is damaged in the oral cavity, pharynx, bronchus, or alveoli, the defense mechanism against long-term colonization of the pathogenic bacteria from the temporary attachment or colonization of the pharyngeal epithelium is weakened, resulting in infection. It is considered that one of the causes of repeated infection is that the disease is easily established (Non-patent Document 1).

  Conventionally, “gargle” has been used as a means of preventing infectious diseases. When gargles with tap water, some of the bacteria in the oral cavity and pharynx are removed due to physical effects. The bactericidal effect is not sufficient. In addition, gargles having a bactericidal effect have been conventionally used (Patent Documents 1 and 2, etc.), but the effects are temporary, and the preventive effect of infectious diseases is not always sufficient, and better gargle There is a need for agents.

On the other hand, a composition containing a quaternary ammonium fungicide such as cetylpyridinium chloride has been known as a composition for treating oral diseases such as stomatitis and periodontitis (Patent Document 3).
JP-A-9-151127 JP 2000-169378 A JP-A-7-126133 Pharma Medica, Volume 9, Issue 4, 1991

  Since pharmaceutical compositions such as gargles used for the prevention of infectious diseases have a temporary bactericidal effect, it has been necessary to frequently gargle to obtain a sufficient effect. However, frequent repetition of gargle itself has an adverse effect on the mucous membrane of the oral cavity, causing the condition of the pharynx and oral cavity to deteriorate, and rather has an adverse effect on the defense mechanism against infections inherent in the living body. There was concern.

  Moreover, when using fat and oil as a component from the viewpoint of improving the adherence of the drug to the affected area and the sustainability of the bactericidal effect, it is necessary to use a surfactant in order to maintain the uniformity of the solution. However, the addition of the surfactant has a problem that the effect of the bactericidal component, particularly the quaternary ammonium type bactericidal agent is lowered.

  The object of the present invention is to provide a pharmaceutical composition for the oropharynx that is used to continuously exert a bactericidal effect and suppress throat discomfort over a long period of time by attaching and retaining the drug on the affected area for a certain period of time. Is to provide things. A further object of the present invention is to provide a pharmaceutical composition that is used to prevent repetitive infections in the respiratory tract by exerting a bactericidal effect continuously by attaching and retaining a drug on an affected area for a certain period of time. It is.

As a result of intensive studies for solving the above problems, the present inventor has found a good effect on a novel pharmaceutical composition containing a specific component and completed the present invention.
According to one aspect of the present invention, there is provided a pharmaceutical composition for the oropharynx comprising water, a quaternary ammonium fungicide, a polyhydric alcohol, hydroxypropylcellulose, hypromellose, and polyvinylpyrrolidone.

  According to another aspect of the present invention, the oral cavity used for preventing recurrent infections of respiratory infections, comprising water, a quaternary ammonium fungicide, a polyhydric alcohol, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone. A pharmaceutical composition for the pharynx is provided.

  The “repeated infection of respiratory infection” referred to in the present specification is not particularly limited as long as it is a frequently repeated respiratory infection, for example, an external factor is temporarily established in the pharyngeal epithelium, As a result, long-term colonization is facilitated due to factors such as a decrease in the physical strength of the patient, which means a state in which the cycle of persistent infection, decreased physical strength, and new infection is repeated. Examples of the external factor of the repeated infection include bacteria and viruses.

  Examples of the quaternary ammonium fungicide used in the present invention include cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, and decalinium chloride. Preferably, cetylpyridinium chloride or benzalkonium chloride is used. used. The usage amount of the quaternary ammonium fungicide is not particularly limited as long as it is a pharmaceutically acceptable usage amount. From the viewpoint of bactericidal power and safety, for example, 0.001 to 1% by weight, preferably 0 An amount of 0.001 to 0.5 wt%, more preferably 0.001 to 0.05 wt% can be used.

  The polyhydric alcohol used in the present invention is not particularly limited as long as it can be used as a solvent in a pharmaceutical preparation. For example, propylene glycol, glycerin, sorbitol, ethylene glycol and mannitol, particularly glycerin, propylene glycol, Ethylene glycol and the like can be mentioned, and propylene glycol is preferably used from the viewpoint of excellent adhesion and usability of the oropharyngeal pharmaceutical composition. Although the usage-amount of the said polyhydric alcohol is not specifically limited, For example, the quantity of 3-25 weight%, Preferably, 5-10 weight% can be used. By using it within this range, particularly preferable adhesion can be realized.

  The hydroxypropylcellulose, hypromellose and polyvinylpyrrolidone used in the present invention are not particularly limited as long as they can be used in pharmaceutical preparations. Examples of hydroxypropylcellulose include hydroxypropylcellulose listed in the Japanese Pharmacopoeia (for example, HPC-SSL, SL, L, M, and H (all Nippon Soda Co., Ltd.)) and the like, and a pharmaceutical composition for oropharynx HPC-H is preferably used because it can provide suitable adhesion and retention as a product. HPC-H has a viscosity value of 1000 to 4000 mPa · s at 20 ° C. of an aqueous solution having an HPC concentration of 2%.

  Examples of hypromellose (hydroxypropylmethylcellulose) are those having a substitution degree of 1800 to 3000, and specifically, those having a substitution degree of 2208, a substitution degree of 2906, and a substitution degree of 2910. Preferably, those having a substitution degree of 2910 are used because they provide adhesion and retention properties suitable as a pharmaceutical composition. Examples of polyvinyl pyrrolidone include povidone (for example, polyvidone, polyvinyl pyrrolidone, polyvinyl pyrrolidone K25, polyvinyl pyrrolidone K30, polyvinyl pyrrolidone K90, etc.) listed in the Japanese Pharmacopoeia. Polyvinyl pyrrolidone K90 is preferably used because it can be provided with a retention property.

The water used for this invention is not specifically limited, For example, distilled water, deionized water, etc. can be used.
In one embodiment of the above aspect of the present invention, the composition contains water, a quaternary ammonium fungicide, a polyhydric alcohol, hydroxypropyl cellulose, hypromellose, and polyvinylpyrrolidone, and has a viscosity at 25 ° C. of 2 to 50 cP, preferably 3 to 40 cP, and more preferably 5 to 25 cP. Thereby, the pharmaceutical composition for oral pharynx which has suitable adhesiveness, retention property, and bactericidal power, is excellent in long-term stability, and has a good feeling of use.

  Here, the viscosity can be measured by a usual method, for example, using a Brooklyn viscometer (BROOK FIELD, PROGRAMMABLE, DV-II + VISCOMETER, etc.) and a spindle (BROOK FIELD, UL / Y ADAPTER) Can be measured by reading the numerical value (cP) with the number of rotations of the spindle adjusted so that the conductivity is about 10%.

  The viscosity of the pharmaceutical composition of the present invention can be adjusted by increasing or decreasing the amount of each component of the pharmaceutical composition, particularly the amount of hydroxypropylcellulose, hypromellose and polyvinylpyrrolidone. Hydroxypropyl cellulose, hypromellose and polyvinylpyrrolidone are each 0.01 to 5% by weight, preferably 0.02 to 10% by weight, depending on the amount of other components, particularly the presence or absence of optional components having thickening properties. The amount can be appropriately increased or decreased within the range of 3% by weight, more preferably 0.03 to 1% by weight, and still more preferably 0.05 to 0.5% by weight. For example, when hydroxypropylcellulose H, hypromellose substitution degree 2910, and polyvinylpyrrolidone K90 are used, 0.05 to 0.2% by weight, preferably 0.1 to 0.2% by weight, should be used. Can do. When used within this range, a pharmaceutical composition for oral pharynx having suitable adhesion, retention and bactericidal power, excellent long-term stability and good usability is provided.

  In one embodiment of the above aspect of the invention, 0.001 to 1 wt% quaternary ammonium fungicide, 3 to 25 wt% polyhydric alcohol, 0.01 to 5 wt% hydroxypropylcellulose, 0 There is provided a pharmaceutical composition for oropharynx used for the prevention of recurrent infections of respiratory infections, comprising 0.01-5% by weight hypromellose and 0.01-5% by weight polyvinylpyrrolidone. When used within this range, a pharmaceutical composition for oral pharynx having suitable adhesion, retention and bactericidal power, excellent long-term stability and good usability is provided.

The pharmaceutical composition of the present invention can also be used as a mouthwash. That is, according to one aspect of the present invention, the following invention is provided:
(1) A mouthwash for oropharynx containing water, quaternary ammonium fungicide, polyhydric alcohol, hydroxypropylcellulose, hypromellose and polyvinylpyrrolidone.

(2) The gargle described in the present specification having a viscosity at 25 ° C. of 2 to 50 cP.
(3) 0.001-1 wt% quaternary ammonium fungicide, 3-25 wt% polyhydric alcohol, 0.01-5 wt% hydroxypropylcellulose, 0.01-5 wt% hypromellose The gargle described herein, comprising 0.01 to 5 wt% polyvinylpyrrolidone.

  (4) The gargle described in the present specification, wherein the quaternary ammonium fungicide is selected from cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, and decalinium chloride.

(5) The gargle described in the present specification, wherein the polyhydric alcohol is selected from propylene glycol, glycerin, sorbitol, ethylene glycol and mannitol.
In one embodiment of the above aspect of the present invention, the fat / oil contained in the component is, for example, 5% by weight or less, preferably 3% by weight or less, and more preferably not blended. A defined pharmaceutical composition is provided. Moreover, in another aspect of the present invention, there is provided a pharmaceutical composition as defined herein, wherein the surfactant contained as an optional component is, for example, 0.1% by weight or less, preferably not blended. The pharmaceutical composition of the present invention is excellent in the adhesion and retention of the drug to the affected area, and has a low surfactant content that hinders the effect of the quaternary ammonium fungicide, or a surfactant. Since it does not contain substantially, it is excellent also in sterilization power.

  Here, fats and oils added as optional components are not particularly limited as long as they are fats and oils that can be used in pharmaceutical preparations, particularly oropharynx, such as olive oil, squalane, isopropyl myristate, palmitic acid. A general term for substances consisting of glycerin esters of fatty acids, such as isopropyl, cetyl palmitate, diethyl sebacate, cetanol, stearyl alcohol, behenyl alcohol, silicone oil, waxes, etc. Is “oil”.

  Here, the surfactant to be added as an optional component is not particularly limited as long as it is a surfactant that can be used for pharmaceutical preparations, particularly the oropharynx. Sorbitan fatty acid ester, sucrose fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene alkylphenyl ether, polyoxyethylene polyoxypropylene glycol, fatty acid polyethylene glycol, fatty acid polyoxyethylene sorbitan, and fatty acid alkanolamide), and anionic surface activity Agents (eg, alkyl benzene sulfonates, alkyl sulfates, oil sulfate esters, polyoxyethylene alkyl ether phosphates, and polyoxyethylene alkyl phenyl ether phosphates) Etc., and the like.

  The pharmaceutical composition of the present invention can be prepared by a usual method. Furthermore, the pharmaceutical composition of the present invention may contain conventional additives such as antioxidants, preservatives, pH adjusters, fragrances, flavoring agents, solvents, colorants and the like as necessary.

  Here, examples of the antioxidant include dibutylhydroxytoluene (BHT), propyl gallate, butylhydroxyanisole (BHA), α-tocopherol, citric acid, ascorbic acid and the like. Examples of the preservative include sodium benzoate, p-hydroxybenzoate ester, sorbic acid and the like. Examples of the pH adjuster include edible organic acids such as citric acid, malic acid, tartaric acid, acetic acid, succinic acid, lactic acid and fumaric acid; inorganic acids such as hydrochloric acid and phosphoric acid; and salts thereof (for example, sodium salts) , Potassium salts, etc.). Examples of the corrigent include l-menthol, peppermint water, peppermint oil, eucalyptus oil, fennel oil, sucrose, glucose, fructose, lactose hydrate, D-sorbitol, D-mannitol, xylitol, licorice extract, saccharin sodium hydrate Products, dipotassium glycyrrhizinate, acesulfame potassium, aspartame and the like. Examples of the solvent include ethanol. Examples of the colorant include Blue No. 1.

  According to another aspect of the present invention, a composition used for the preparation of the pharmaceutical composition of the present invention by adding water, comprising a quaternary ammonium fungicide, a polyhydric alcohol, hydroxypropyl cellulose, There is provided such a composition comprising hypromellose and polyvinylpyrrolidone. The amount of water to be added is not particularly limited, and for example, water may be added to dilute 1.2 to 500 times in volume ratio. The composition may contain additional solvents to maintain component uniformity.

  The pharmaceutical composition of the present invention can be used as a mouthwash or mouthwash in the same manner as a normal mouthwash or mouthwash, and the amount used at one time is, for example, 10 to 100 mL, preferably 10 About 50 mL. The pharmaceutical composition of the present invention may be used once or a plurality of times a day, for example, about 5 to 6 times a day. Since the pharmaceutical composition of the present invention has good retention in the affected area, it may be used at intervals of about once every 5 to 8 hours, for example, and is preferably used before going to bed.

  The pharmaceutical composition of the present invention is characterized in that it is durable, safely exhibits bactericidal activity, and is effective in preventing repeated infections in respiratory infections (eg, upper respiratory tract, lower respiratory tract, etc.). Have. Furthermore, the pharmaceutical composition of the present invention is excellent in storage stability and exhibits sufficient bactericidal activity even when used after long-term storage.

  EXAMPLES Hereinafter, although the preferable Example of this invention is described in detail, this invention is not limited to these Examples. In addition, the percentage shown in this specification means weight% unless there is particular mention.

[Examples 1 to 40]
Using the reagent of Table 1, according to a conventional method, the composition (Examples 1-40 and Comparative Examples 1-18) which has a composition of Tables 2-4, and 100 mL of each were prepared.

[Test Example 1]
The following tests were conducted to evaluate the adhesion, retention, and bactericidal power of each composition, and to measure the viscosity.

Evaluation of adhesion It was evaluated by a sensory test by 15 people. Gargle was performed using each composition, and the feeling of adhesion to the throat immediately after gargle was evaluated. A case where the drug was found to be present around the pharynx was evaluated as ◯, a case where the drug could not be felt, and a case where the drug could be felt but uncomfortable was evaluated as x.

Retention property test A part (1 mL) of each composition was dropped on a glass plate, left as it was for 7 hours under a constant condition of 23 ° C. and low humidity, and then the flowability was evaluated by tilting the glass plate by 45 °. . When fluidity was maintained, it was evaluated as ◯, and when it was dry, it was evaluated as ×.

Bactericidal activity test
Use Staphylococcus aureus (NBRC 12732), Escherichia coli (NBRC 3972), Pseudomonas aeruginosa (NBRC13275), and Streptococcus pyogenes (ATCC 19615) (obtained from the National Institute of Biotechnology and Genetic Resources (NBRC), respectively) And tested. The bacteria were enriched in pure culture and then suspended in a nutrient broth so as to have a turbidity of McFarland No. 0.5 to prepare a bacterial solution. Put the test composition (9.9 mL) in a sterilized test tube, add 0.1 mL of the bacterial solution, sample after 30 seconds and 60 seconds, serially dilute, and culture in agar medium. Was measured. Based on the number of bacteria obtained, the antibacterial activity value is calculated based on the test method defined in JIS Z 2801 antibacterial test method. When all four bacterial species became ○ by 60 seconds, it was judged that there was a bactericidal effect.

Viscosity measurement test Using Brooklyn viscometers (BROOK FIELD, PROGRAMMABLE, DV-II + VISCOMETER, etc.) and spindle (BROOK FIELD, UL / Y ADAPTER), put 16mL of sample in the spindle attachment, conductivity at 25 ℃ The numerical value (cP) was read by adjusting the number of rotations of the spindle so as to be about 10%, and the first decimal place was rounded off to obtain the viscosity value.

Tables 9 and 10 below show the results of the adhesion test, the retention test, and the bactericidal activity test for the compositions of Examples and Comparative Examples.

  The compositions of Examples 1 to 40 were good in all of adhesion, retention, and bactericidal power. Further, even when the compositions of Examples 1 to 40 were allowed to stand at 40 ° C. for 6 months and at 50 ° C. for 1 month, they did not change in quality and were excellent in stability. Furthermore, when actually used, it exhibited a sterilizing effect continuously, and was excellent in suppressing the throat discomfort over a long period of time.

  On the other hand, it was confirmed that compositions (Comparative Examples 1 to 17) not containing at least one of hydroxypropylcellulose, hypromellose, and polyvinylpyrrolidone have problems in adhesion and retention.

  Here, the composition of hydroxypropylcellulose, hypromellose and polyvinylpyrrolidone was adjusted to prepare a composition having a viscosity of 1 cp in Example 7 and a composition having a viscosity of 55 cp in Example 36, respectively. When compared with 36, the compositions of Examples 7 and 36 were superior in adhesion and retention. In particular, the examples having a viscosity of 5 to 25 cP have appropriate adhesion and retention as a gargle and, when actually used, exert a sterilizing effect continuously and cause discomfort in the throat over a long period of time. Excellent suppression effect.

In the examples, the same result was obtained when propylene glycol was changed to glycerin or sorbitol.
[Test Example 2]
In order to evaluate the repeated infection improvement effect of each composition, the following tests were conducted.

Tests for Cold Patients Four cold patient groups were prepared for each group, and each group was designated as the administration group of Example 1, Comparative Example 9, Comparative Example 10, Comparative Example 11 and Comparative Example 18. Each patient gargled twice a day using the test substance. The number of days until remission of cold symptoms such as throat discomfort, fever, and malaise due to subjective symptoms was confirmed. The results for each group are shown in Table 11 below.

In the examples, since the number of days until symptom remission was obviously shortened, it was confirmed that the pharmaceutical composition of the present invention was excellent in repeated infection improvement effect.
[Prescription example]
According to the formulation examples described in Tables 12 and 13, pharmaceutical compositions for oropharynx were prepared.

Claims (7)

  A pharmaceutical composition for the oropharynx comprising water, a quaternary ammonium fungicide, a polyhydric alcohol, hydroxypropylcellulose, hypromellose and polyvinylpyrrolidone.   The pharmaceutical composition according to claim 1, which is used for prevention of repeated infections of respiratory infections.   The pharmaceutical composition according to claim 1 or 2, wherein the viscosity at 25 ° C is 2 to 50 cP.   0.001 to 1 wt% quaternary ammonium fungicide, 3 to 25 wt% polyhydric alcohol, 0.01 to 5 wt% hydroxypropylcellulose, 0.01 to 5 wt% hypromellose; The pharmaceutical composition according to any one of claims 1 to 3, comprising from 01 to 5% by weight of polyvinylpyrrolidone.   The pharmaceutical composition according to any one of claims 1 to 4, wherein the quaternary ammonium fungicide is selected from cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, and decalinium chloride.   The pharmaceutical composition according to any one of claims 1 to 5, wherein the polyhydric alcohol is selected from propylene glycol, glycerin, sorbitol, ethylene glycol and mannitol.   The pharmaceutical composition according to any one of claims 1 to 6, which is used as a mouthwash.