United States Patent 19 11 Patent Number: 4,919,939 Baker 45 Date of Patent: Apr. 24, 1990 54 PERIODONTAL DISEASE TREATMENT 52 U.S. C. .................................... 424/493; 424/486; SYSTEM 424/497 58) Field of Search ............... 424/493, 489, 484, 490, 75 Inventor: Richard W. Baker, Palo Alto, Calif. 424/486, 497 73 Assignee: Pharmetrix Corporation, Menlo Primary Examiner-Nancy A. B. Swisher Park, Calif. Attorney, Agent, or Firm-A. J. Castro; J. Farrant 21 Appl. No.: 216,802 (57) ABSTRACT A controlled release drug delivery system for place 22) Filed: Jul. 8, 1988 ment in the periodontal pocket, gingival sulcus, tooth socket, wound or other cavity within the mouth. The Related U.S. Application Data system incorporates drug-containing microparticles in a 63) Continuation-in-part of Ser. No. 856,961, Apr. 29, fluid carrier medium, and is effective in the environ 1986, Pat. No. 4,780,320. ment of use for up to 30 days. (51) Int. Cl. ............................................. A6L 15/03 47 Claims, 3 Drawing Sheets U.S. Patent Apr. 24, 1990 Sheet 1 of 2 4,919,939 Polycarbonate TETRACYCLINE 15 RELEASE FROM 100 mg PARTICLES (mg) O Polysulfone O FIG. 1 TIME (hrs) Flurbiprofen 50% TOTAL DRUG RELEASED PER 200 mg 40% PARTICLES (mg) 30% O 20 40 60 80 100 1G. 2 RELEASE TIME (hrs) U.S. Patent Apr. 24, 1990 Sheet 2 of 2 4,919,939 100 Microcapsules with 30% 80 tetracycline hydrochloride 60. % Tetracycline hydrochloride released 40 Microcapsules with 5% tetracycline hydrochloride 20 O 5 10 15 20 25 Time (hrs) FIGURE 3 4,919,939 1. 2 4,226,848, 4,369,172 and 4,059,686, such troches and PERIODONTAL DISEASE TREATMENT SYSTEM tablets are normally effective for periods of hours rather than days, and a course of treatment lasting one month CROSS REFERENCE TO RELATED would require the use of numerous tablets. Furthermore APPLICATIONS they are inappropriate to the treatment of periodontal This application is a continuation-in-part of U.S. pa disease because the drug is released into the saliva or oral mucosa, and does not penetrate the periodontal tent application Ser. No. 856,961, filed April 29, 1986 pocket to any significant extent. Buccal tapes, strips and now U.S. Pat. No. 4,780,320. forms suffer from the same disadvantages. For example, FIELD OF THE INVENTION 10 the buccal dosage form disclosed in U.S. Pat. No. This invention relates to a controlled release drug 3,972,995 was found to be effective without leaking, if delivery system for use in the mouth, and particularly to not wrinkled or dislodged by the teeth, for about one systems for placement in the periodontal pocket to treat hour only. This highlights another disadvantage of ex periodontal disease. isting methods of dispensing drugs for oral therapy; 15 they may slip or be dislodged by the tongue or teeth, BACKGROUND OF THE INVENTION may be uncomfortable to a greater or lesser degree, and Periodontal disease, with caries, is the most important may interfere with the normal oral functions to some cause of loss of teeth. It is well established that bacteria extent. Recent developments in the art are directed are directly involved in both the onset and progression toward delivering the therapeutic agent directly to the of periodontal disease. See for example J. Slots, "Sub 20 periodontal pocket, in some cases in a controlled release gingival Microflora and Periodontal Disease,' J. Clin, formulation. Gordon et al. have described the use of a Periodontal. 6, 315 (1979) and S. S. Socransky, "Micro drug-filled polymer hollow fiber. (J. M. Goodson et al., biology of Periodontal Disease-Present Status and "Periodontal Therapy by Local Delivery of Tetracy Future Considerations,” J. Periodontol. 48, 497 (1977). cline,' J. Clin. Periodontol. 6, 83 (1979), J. Lindhe et al., This has led to the widespread use of antibiotics in the 25 "Local Tetracycline Delivery Using Hollow Fiber De treatment of periodontal disease, and particularly to the vices in Periodontal Therapy," J. Clin. Periodontol. 6, use of tetracycline, since significantly higher levels of 141 (1979) and R. L. Dunn et al.,"Monolithic Fibers for tetracycline are found in gingival fluid than in blood Controlled Delivery of Tetracycline,' in Proc. Ninth after administration of single or multiple oral doses. (J. M. Gordon et al., "Sensitive Assay for Measuring Tet-330 Int, Symposium on Controlled Release of Bioactive Mate racycline Levels in Gingival Crevice Fluid,' Antimi rials, Ft. Lauderdale, Fl., July (1982).) This device is crob. Agents Chemother. 17, 193 (1980), J. M. Gordon et tied around a tooth and gently pressed below the mar al., "Concentrations of Tetracycline in Human Gingival gin of the gingiva so that it resides in the periodontal Fluid after Single Doses,” J. Clin. Peridontol. 8, 117 pocket, and is capable of delivering an effective dose of (1981) and J. M. Gordon et al., "Tetracycline: Levels 35 2.5 micrograms of tetracycline per day per periodontal Achievable in Gingival Crevice Fluid and in vitro Ef pocket for a prolonged period of a week or more. Simi fect on Subgingival Organisms. Part 1. Concentrations lar results have been obtained by Coventry and New in Crevicular Fluid after Repeated Doses,” J. Periodon man (J. Coventry and H. N. Newman, "Experimental tol. 52, 609 (1981).) However, the typical effective tetra Use of a Slow Release Device employing Chlorhexi cycline oral dose of one gram per day for 30 days can dine Gluconate in Areas of Acute Periodontal Inflam lead to serious side effects. It has been estimated that the mation,” J. Clin. Periodontol. 9, 129 (1982)) and Addy et dose should be of the order of one hundred times al. (M. Addy et al., "The Development and in vitro smaller to avoid these effects. A more satisfactory ap Evaluation of Acrylic Strips and Dialysis Tubing for proach then is to administer the antibiotic topically Local Drug Delivery,” J. Periodontol. 53, 693 (1982)) using a controlled release device to sustain an effective 45 using acrylic strips 1 mm or more long, impregnated dose for the required length of time. Because the drug is with chlorhexidine, tetracycline or metronidazole, delivered locally, a much reduced dose will suffice for which were inserted into the periodontal pocket with effective therapy, and harmful side effects can be re tweezers. Such a strip, formed from ethylcellulose im duced or eliminated. pregnated with metronidazole, is disclosed by Loesche Long lasting drug delivery systems presently used in 50 in U.S. Pat. No. 4,568,538. Another strip, employing a the oral cavity fall broadly into two groups; either tro water soluble polymer of a particular elasticity and ches, pastilles or tablets which adhere to the oral mu viscosity, is disclosed by Suzuki et al. in U.S. Pat. No. cosa in some way, or drug containing strips or dosage 4,569,837. Although these devices may be able to dis forms which are attached to the gums, teeth or other pense an appropriate drug for a time span of a week or interior surface of the mouth. A good example of the 55 more, they are inappropriate to widespread use because former category is U.S. Pat. No. 4,039,653. This patent they are difficult and time consuming to apply and may discloses a sustained release tablet coated with a phar be dislodged by the patient during normal oral func maceutically acceptable oral adhesive, which is placed tions. in an upper corner of the mouth and is capable of dis U.S. patent application Ser. No. 856,961, copending pensing an odor-masking agent, local anaesthetic or 60 with the present invention, provides a novel controlled other medication in a sustained fashion for periods of up release system that can deliver antibiotics or other to twelve hours. U.S. Pat. No. 4,250,163 discloses a drugs in the periodontal pocket for a prolonged period method of administering a broad range of medications of time, without interfering in any way with normal oral to the oral cavity by means of a water-swellable and functions. mucosa-adhesive polymeric matrix, which can be in the 65 The present invention provides for the controlled form of a tablet, powder or granules and which is effec delivery of a range of agents that are efficacious in the tive for times of the order of a few hours. As can be seen treatment of periodontal disease and other gingival or from these and other examples, such as U.S. Pat. Nos. oral problems. 4,919,939 3 4. It is another object of the invention to provide a SUMMARY OF THE INVENTION controlled release drug delivery system that is self-re This invention is a controlled release drug delivery taining in the periodontal pocket. system that can be placed in the periodontal pocket. It is another object of the invention to provide a The system is particularly useful in control and treat controlled release drug delivery system that can pene ment of periodontal disease, but can also be used for trate throughout the periodontal pocket. controlled delivery at the affected site for post-opera It is another object of the invention to provide a tive pain, inflammation or bleeding, or for treatment of controlled release drug delivery system for the peri other local diseases of the oral cavity or systemic dis odontal pocket or the oral cavity that does not interfere eases with oral manifestations. The system offers a 10 with normal oral functions, and is not easily dislodged major advantage over systemic therapy, in that the by the patient. useful therapeutic dose of many drugs is found to be one It is another object of the invention to provide a or two orders of magnitude less than the corresponding controlled release drug delivery system for use in the oral dose, thereby avoiding all or many of the side ef periodontal pocket, gingival sulcus or other localized fects associated with long-term oral delivery of antibiot 15 oral site, where the drug delivery is controlled by diffu ics, antiinflammatories, or other potent drugs.