WO1988003021A2

WO1988003021A2 - Treatment of gingivitis with ibuprofen or flurbiprofen

Info

Publication number: WO1988003021A2
Application number: PCT/US1987/002587
Authority: WO
Inventors: Charles M. Hall; Herbert G. Johnson; Steven Offenbacher
Original assignee: The Upjohn Company
Priority date: 1986-10-22
Filing date: 1987-10-13
Publication date: 1988-05-05
Also published as: JPH02500189A; KR880701547A; AU8320387A; EP0321505A1; WO1988003021A3

Abstract

Method of treating gingivitis using ibuprofen of flurbiprofen or a pharmaceutically acceptable salt or a C1 to C6 alkyl ester thereof.

Description

TREATMENT OF GINGIVITIS WITH IBUPROFEN OR FLURBIPROFEN FIELD OF INVENTION

This invention teaches a method for inhibiting, preventing and/or treating gingivitis. BACKGROUND OF INVENTION

Gingivitis describes inflammation of the gingivae, characterized by swelling, redness, influx of inflammatory cells, edema in the tissue, change of normal contours, and bleeding. Gingival pockets from tissue swelling and loss of attachment not involving bone are usually present. Gingivitis may be either acute or chronic, with emissions and exacerbations. General causes include hypovitaminosis, blood dyscrasias, allergic reactions, endocrine disturbances, such as diabetes mellitus, drugs such as diphenylhydantoin or the heavy metals, chronic debilitating disease or local factors such as dental calculus or plaque, food impaction, or faulty dental restorations and dental hygiene.

The inhibition, prevention and treatment of gingivitis has varied little over the past two decades and consists primarily of establishing good oral hygiene, eliminating subgingival calculus and faulty dental restorations and maintaining a periodontal environment that is easily kept clean by the patient. This therapy is not only long and expensive, but it never truly ends. In some cases, gingivectomy for the removal of hypertrophied tissue will be required. Clearly, new modes of therapy are needed to substitute and augment current prophylaxis procedures.

R.I. Vogel, et al., J. Periodontol. 54, 247-251 (1984), has demonstrated that a topically applied steroidal anti-inflammatory drug, fluocinonide, will suppress plague-induced gingivitis. In this study, however, a nonsteroidal anti-inflammatory drug, sulindac, had no significant effect on experimentally produced gingival inflammation according to the variables measured in the study. In another study, R.I. Vogel, et al., J. Clin. Periodontal. 13, 139-144 (1986), the topically applied nonsteroidal anti-inflammatory drug, 2-(3-(1,1- dimethyl)-5-methoxyphenyl)oxazolo(4,5b)pyridine was found to inhibit both alveolar bone resorption and gingival inflammation. Other investigators have shown nonsteroidal anti-inflammatory drugs may be used to treat periodontal disease. R.C. Williams, et al., Science 227, 640-642 (1985), reports the effect of flurbiprofen on alveolar bone resorption in the beagle dog. I.M. tfaite, et al., J. of Periodontal Research 16, 100-118 (1981), reports on the periodontal status of subjects receiving nonsteroidal anti-inflammatory drugs. R.S. Feldman, et al., J. Clin. Periodontal. 10, 131-136 (1983), suggests chronic ingestion of aspirin or aspirin together with indomethacin inhibited aveolar bone loss. Other references which report the effect of indomethacin on bone resorption associated with periodontal disease include: M. Weaks-Dybvig, et al., J. Periodontal Research 17, 90-100 (1982); S. Nyman, et al., J. Periodontol. 50, 450-461 (1979); and J.J. Lasfargues, et al., J. Periodontal Research 18, 110-117 (1983). SUMMARY OF INVENTION

This invention teaches a method for the inhibition, prevention and/or treatment of gingivitis in a patient which comprises administering to said patient a compound, wherein said compound comprises ibuprofen, flurbiprofen, a pharmaceutically acceptable salt thereof, or a C₁ to C₆ alkyl ester thereof, in an amount effectively inhibiting preventing or treating gingivitis. This invention also provides a composition useful in inhibiting, preventing or treating gingivitis comprising a quantity of a compound, wherein said compound comprises ibuprofen, flurbiprofen, a pharmaceutically acceptable salt thereof, or a C₁ to C₆ alkyl ester thereof, said quantity being effective in inhibiting, preventing or treating gingivitis and a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

Ibuprofen and flurbiprofen are known anti-inflammatory agents that possess analgesic and antipyretic activities. Ibuprofen is α- methyl-4-(2-methylpropyl)benzeneacetic acid (Structure I) and is prepared as described in U.S. patent 3,228,831. Flurbiprofen is 2- fluoro-α-methyl[1,1'-biphenyl}-4-acetic acid (Structure II) and is prepared as described in U.S. patent 3,755,427.

The method of the present invention comprises administration of ibuprofen or flurbiprofen or a pharmaceutically acceptable salt or C₁ to C₆ alkyl ester of said compounds for the inhibition, prevention or treatment of gingivitis. Pharmaceutically acceptable salts of ibuprofen or flurbiprofen useful in practicing the present invention are aluminum salts (see, e.g., U.S. 4,361,580 and U.S. 4,145,440), alkali metal salts such as potassium or sodium, alkaline earth salts such as calcium or magnesium, or amine salts such as t-butyl amine. Representative C₁ to C₆ alkyl esters of ibuprofen or flurbiprofen useful in practicing the present invention include the methyl, ethyl, npropyl, isopropyl, n-butyl, tert-butyl, pentyl, etc., esters. In practicing the method of the present invention ibuprofen, flurbiprofen, a salt thereof or an ester thereof is administered orally, topically, or buccally to the patient. The patient to be treated is any mammal, such as dogs, cats, horses, cattle, rats, mice, monkeys or humans. Although the compounds are effective when administered intravenously this obviously is a less preferred method of administration. However, the injection of the compounds directly into the gum by subdermal implantation represent suitable means of administering ibuprofen or flurbiprofen to achieve inhibition, prevention or treatment of gingivitis. The compounds may also be administered transdermally. Suitable forms of oral administration include tablets, capsules, pills, powders, granules, solutions or suspensions. Suitable solid unit dosage forms may also be compounded as a sustained release formulation. Sterile aqueous solutions or suspensions are also suitable for injection in practicing the method of the present invention. Suitable formulations for buccal administration include slow dissolving tablets, troches, chewing gum, gels, pastes or powders, e.g., to be applied to the gums. Suitable topical forms of administration include gels, pastes, mouthwashes or rinses, or adhesive patches containing the compound.

The quantity of ibuprofen or flurbiprofen effective in inhibiting, preventing and/or treating gingivitis varies over a wide range depending on the method of administration and type of patient. The oral dosage range in humans for ibuprofen varies from about 25 mg to 2000 mg per day per patient and preferably from 50 to 800 ag, and for flurbiprofen the range varies from about 1 mg to 500 mg per day per patient and preferably from 5 to 50 mg. The topical dosage range in humans for flurbiprofen varies from about 1.0 mg per unit dose to 50.0 mg per unit dose. When the pH of the topical application is controlled to allow maximum absorption by the gingival tissues the preferred topical dosage range in humans varies from about 1.0 mg per unit dose to 5.0 mg per unit dose. The topical dosage range for ibuprofen is from about 20 mg per unit dose to 500 mg per unit dose and preferably from 10 mg to 100 mg per unit dose. Typically a topical application would be applied from 1 to 3 times daily.

Compositions suitable for use in the present invention are formulated using conventional pharmaceutical carriers. For example, solid dosage forms typically will contain lubricants such as stearic acid or magnesium stearate and fillers such as lactose, sucrose, cornstarch, or perhaps disintegrating agents such as alginic acid. Injectable solutions or suspensions may contain sterile liquids such as water or oils with surfactants as needed. Sustained release formulations may be prepared as generally described in U.S. 4,389,393 and U.S. 3,065,143. Representative examples of compositions useful in practicing the method of the present invention are set forth hereinbelow.

The patient to be treated is one which possesses signs of gingivitis. The gingiva of the patient is generally characterized by having severe inflammation with marked redness and edema, ulceration, and a tendency to bleed spontaneously. Additionally, the presence of subgingival calculus and an accumulation of soft deposits within the gingival pockets are characteristic of more advanced stages. Reports indicate periodontal disease, including but not limited to gingivitis, is endemic in the population over age 35 in the United States, thus individuals in this class would most particularly benefit from the invention described herein.

The utility of the present invention is demonstrated in a six month study using the rhesus monkey, Macacca mulatta. In the study 24 adult ovariectomized female Macca mulatta monkeys were divided into three groups for study. Animals were screened and selected on the basis of pre-existent incipient periodontitis. Following screening, the animals were anaesthetized with 2-(2-chlorophenyl)-2- (methylamino)-cyclohexanone (Ketamine) and given an initial oral examination. This examination included assessments of plaque accumulation, redness, edema, suppuration, bleeding on probing and Ramfjord attachment loss level measurements. At each examination, the buccal surfaces of the maxillary first molars, first premolars, central incisors, mandibular central incisors, second bicuspids and first molars were scored. For each clinical index three sites were monitored on each tooth, the mesiobuccal, buccal and distobuccal. After initial examinations, animals were ranked according to increas ing mean attachment loss. Starting from the top of this ranked list, animals were taken in trios and randomly assigned into one of the three groups. Thus, each of the eight monkeys within a group had a disease-matched cohort in each of the other two groups and each group had comparable disease level at baseline. Two groups were treated with flurbiprofen as administered via osmotic mini-pump at levels of 0.266 μg/kg/day and 7.1 μg/kg/day resulting in 14 day blood levels of 0.22 μg/ml and 3.5 μg/ml, respectively. The low dosage group had one pump each which was replaced every four weeks. The high dosage group had two pumps replaced every two weeks. The vehicle was 0.1M TRIS, pH = 8.0. Sham pumps were not used.

At the onset of drug testing a split-mouth approach was used. Silk ligatures (3-0) were placed on the right side around the cementoenamel junction of teeth #3, 5, 8, 25, 29 and 30. The animals were simultaneously placed on a soft diet to promote plaque retention. Subsequently, the right side was monitored for ligature-induced periodontitis and the left side for spontaneous (soft chow-induced) periodoncitis. Examinations were performed at 0, 1, 2, 4, 8, 12, 18 and 24 weeks. The results are set forth in the following Table 1 and indicate that flurbiprofen significantly affected the condition of the gingival tissue when examined for change in redness.

Table II provides a statistical analysis of the data outlined in Table I. The mean ridit for the low dose and high dose groups gives an approximation of the probability that a randomly selected individual from a group has a value indicating less redness than a randomly selected individual from the control group. A mean ridit value less than 0.50 indicates that more than half the time a randomly selected subject from a treated group will have less redness than a randomly selected subject from the control group. The odds therefore give the probability that a treated subject will experience less redness than the control group.

The following examples provide illustrative compositions useful in practicing the present invention. In each example where flurbiprofen has been used, ibuprofen in an appropriate amount could be substituted therefor to give a composition useful in practicing the invention.

Example 1 Mouthwash Composition

Flurbiprofen 5.00 gm

Methylparaben 0.75 gm

Propylparaben 0.25 gm Saccharin 1.50 gm

Ascorbic acid 1.00 gm

Orange oil flavor 1.00 gm

FDC orange dye 0.75 gm

Sucrose 200.00 gm Deionized water, qs 1000.00 ml

The saccharin, ascorbic acid, orange flavor, dye, and parabels are dissolved in 600 ml of deionized water. The flurbiprofen is mixed with the sucrose and the mixture dispersed in the aqueous solution. Sufficient deionized water is added to make 1000 ml of the composition, containing 5 mg per ml or 25 mg per teaspoonful of active ingredient. Example 2 Chewing Gum

Pieces of uncoated chicle chewing gum of tablet-like shape weighing about one gram each are used as starters for the coating process. A coating of sucrose is first applied, using a syrup (80% sucrose solution) and the usual coating pan. A finely powdered highly hydrogenated castor oil is dusted on the sucrose covered starters. The second coating step in the application is a dispersion of micronized flurbiprofen and benzocaine (10:1) in absolute ethanol. Successive applications are made until 10 mg of flurbiprofen and 1 mg of benzocaine have been deposited on each piece. Thereafter, a second dusting of the hydrogenated castor oil is applied. A final finishing coating of sucrose solution is applied containing flavor and color. Advantageously, a polishing coat of wax is added. The foregoing chewing gum composition is chewed in the mouth to provide the slow release of flurbiprofen for the topical treatment. Example 3 Toothpaste

Flurbiprofen 5% Magnesium aluminum silicate 1.0% Dicalcium phosphate 47.0%

Sodium carboxymethylcellulose 0.5% Mint flavor 4.0% Sodium lauryl sulfate 2.0%

Benzoic acid 0.1%

Water 40.4%

Add all ingredients slowly to the water while stirring and then pass the mixture through a roller mill. Example 4 Hard Gelatin Capsules

One thousand two-piece hard gelatin capsules for oral use, each capsule containing 50 mg of flurbiprofen, are prepared from the following:

Flurbiprofen 50 gm Lactose 100 gm

Cornstarch 20 gm

Talc 20 gm

Magnesium stearate 2 gm

The flurbiprofen (finely divided by means of an air micronizer) is added to the other finely powdered ingredients, mixed thoroughly and then encapsulated in the usual manner.

Using the procedure above, capsules are similarly prepared containing flurbiprofen in 25, 75, and 100 mg amounts by substituting 25, 75, and 100 gm of flurbiprofen for the 50 gm used above. Example 5 Soft Gelatin Capsules

One-piece soft gelatin capsules for oral use, each containing 25 mg of flurbiprofen (finely divided by means of an air micronizer) are prepared by first suspending the compound in 0.5 ml of corn oil to render the material capsulatable and then capsulating in the above manner.

Example 6 Tablets

One thousand tablets , each containing 100 mg of flurbiprofen are prepared from the following types and amounts of ingredients : Flurbiprofen micronized 100 gm Lactose 75 gm

Cornstarch 50 gm

Magnesium stearate 4 gm

Light liquid petrolatum 5 gm The flurbiprofen (finely divided by means of an air micronizer) is added to the other ingredients and then thoroughly mixed and slugged. The slugs are broken down by forcing through a number sixteen screen. The resulting granules are then compressed into tablets each tablet containing 100 mg of flurbiprofen.

Using the procedure above, tablets are similarly prepared containing flurbiprofen in 25 mg and 50 mg amounts by substituting 25 gm and 50 gm of flurbiprofen for the 100 gm used above. Example 7 Oral Suspension One thousand ml of an aqueous suspension for oral use, containing in each teaspoonful (5 ml) dose, 100 mg of flurbiprofen, sodium salt is prepared from the following types and amounts of ingredients: Flurbiprofen, sodium salt micronized 20 gm Citric acid 2 gm

Benzoic acid 1 gm

Sucrose 400 gm

Cellulose, microcrystalline 10 gm Lemon oil 2 gm Polysorbate 80 5 gm

Deionized water, qs 1000 ml

The citric acid, benzoic acid, sucrose, cellulose, lemon oil and polysorbate 80 are dispersed in sufficient water to make 850 ml of suspension. The flurbiprofen sodium salt (finely divided by means of an air micronizer) is stirred into the syrup until uniformly distributed. Sufficient water is added to make 1000 ml. Example 8

A sterile aqueous solution for parenteral (i.v.) injection, containing in one liter, 150 mg of flurbiprofen, sodium salt is prepared from the following types and amounts of Ingredients:

Flurbiprofen, sodium salt 150 mg

Water for injection, qs 1000 mg

To the sterile solution is added sterilized flurbiprofen, sodium salt and filled into sterile containers sealed. Example 9 Oral Topical Paste

Flurbiprofen, aluminum salt micronized 5.0%

Sodium carboxymethylcellulose 3.0% Pectin 3.0%

Gelatin 3.0%

Sodium saccharin 0.5%

Polysorbate 80 0.5% Cherry flavor 0.1%

Water 84.9%

Heat water to 50ºC and add, while stirring, polysorbate 80, and all other ingredients. Pass through a colloid mill, then stir until cool. Example 10 Sustained Release Tablet

The following formulation is representative of a 100 mg sustained release formulation useful in practicing the present invention. The 100 mg sustained release formulation may be used in place of other dosage unit forms which contain 50 mg of active ingredients for administration, for example, twice a day.

(a) Flurbiprofen milled 100 .0 mg

(b) Lactose USP hydrous bolted 95 .0 mg

(c) Pregelatinized starch NF 10 .5 mg

(d) Purified water USP, qs (e) Methocel K 15M-premium 95 .0 mg

(f) Colloidal silicon dioxide NF 1 .0 mg

(g) Magnesium stearate NF 2 .5 mg (h) Hydroxypropyl methylcellulose

2910 USP 15 CPS 10 .0 mg (i) Film coat concentrate white FC-100-PC 2 .0 mg

(j ) Purified water USP, qs ad Ingredients (a) to (d) are blended, granulated, wet screened, and dried, then mixed with ingredients (e) to (g) and coated with ingredients (h) to (j).

The following are representative of additional sustained release formulations. Example 11 Flurbiprofen tablet

For a tablet to be administered once per day 50 mg of flurbiprofen is combined with the following excipients to provide release of active ingredient over a 24 hour period:

22.7 mg of hydroxypropyl methylcellulose 2208 USP, 15000 cps 0.5 mg of colloidal silicon dioxide NF 2.5 mg of magnesium stearate NF, powder food grade Example 12 Ibuprofen tablet

For a tablet to be administered once per day 400 mg of ibuprofen is combined with the following excipients to provide release of active ingredient over a 24 hour period:

120 mg of hydroxypropyl cellulose 2208 USP, 100 cps

77 mg of microcrystalline cellulose NF, coarse grade 1.3 mg of colloidal silicon dioxide, NF

To provide a tablet which releases 400 of ibuprofen over a 12 hour period in addition to the above listed excipients the active ingredient is combined with 80 mg of hydroxypropyl methylcellulose 2208 USP, 100 cps.

INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(51) International Patent Classification (11) International Publication Number: WO 88/ 03 A61K 31/19, 31/215 A3 (43) International Publication Date: 5 May 1988 (05.05.

(21) International Application Number : PCT/US87/02587 (72) Inventors; and

(75) Inventors/ Applicants (for US only) : HALL, Charles,

(22) International Filing Date: 13 October 1987 (13.10.87) [US/US]; 3835 Ruthin Road, Kalamazoo, MI 49 (US). JOHNSON, Herbert, G. [US/US]; 829 Be shire Street, Kalamazoo, MI 49007 (US). OFF

(31) Priority Application Number: 921,990 BACHER, Steven [US/US]; 4478 Woodland Fo Drive, Stone Mountain, GA 30083 (US).

(32) Priority Date: 22 October 1986 (22.10.86)

(74) Agent: JAMESON, William, G.; Patent Law Dep

(33) Priority Country : US ment, The Upjohn Company, Kalamazoo, MI 49 (US).

(60) Parent Application or Grant

(63) Related by Continuation (81) Designated States: AT (European patent), AU, BE (

US 921,990 (CON) ropean patent), CH (European patent), DE (Eu

Filed on 22 October 1986 (22.10.86) pean patent), DK, FI, FR (European patent), (European patent), IT (European patent), JP, KR, (European patent), NL (European patent), NO,

(71) Applicant (for all designated States except US): THE (European patent), US. UPJOHN COMPANY [US/US]; 301 Henrietta Street, Kalamazoo, MI 49001 (US). Published

With international search report.

Before the expiration of the time limit for amending claims and to be republished in the event of the receipt amendments.

(88) Date of publication of the international search report:

30 June 1988 (30.06.

(54) Title: TREATMENT OF GINGIVITIS WITH IBUPROFEN OR FLURBIPROFEN

(57) Abstract

Method of treating gingivitis using ibuprofen of flurbiprofen or a pharmaceutically acceptable salt or a C_[ to C₆ kyl ester thereof.

Claims

1. A method for the inhibition, prevention or treatment of gingivitis in a patient which comprises administering to said patient a compound, wherein said compound comprises ibuprofen, flurbiprofen, a pharmaceutically acceptable salt thereof, or a C₁ to C₆ alkyl ester thereof, in an amount effectively inhibiting, preventing or treating gingivitis.

2. The method of claim 1 wherein the compound is ibuprofen, a pharmaceutically acceptable salt thereof or a C₁ to C₆ alkyl ester thereof.

3. The method of claim 1 wherein the compound is flurbiprofen, a pharmaceutically acceptable salt thereof or a C₁ to C₆ alkyl ester thereof.

4. A method of for the inhibition of gingivitis in accordance with Claim 1.

5. A method of for the prevention of gingivitis in accordance with Claim 1.

6. A method for the treatment of gingivitis in accordance with Claim 1.

7. A composition useful in inhibiting, preventing or treating gingivitis comprising a quantity of a compound, wherein said compound comprises ibuprofen, flurbiprofen, a pharmaceutically acceptable salt thereof, or a C₁ to C₆ alkyl ester thereof, said quantity being effective in inhibiting, preventing or treating gingivitis and a pharmaceutically acceptable carrier.

8. The composition of claim 4 which is suitable for oral administration.

9. The composition of claim 4 which is suitable for topical administration.

10. The composition of claim 4 which is suitable for sustained release.

11. The composition of claim 4 which is suitable for buccal administration.