AU664504B2

AU664504B2 - Polymeric bio-erodible delivery system for the periodontal pocket

Info

Publication number: AU664504B2
Application number: AU52336/93A
Authority: AU
Inventors: Rohinton Toddywala
Original assignee: Colgate Palmolive Co
Current assignee: Colgate Palmolive Co
Priority date: 1992-12-11
Filing date: 1993-12-10
Publication date: 1995-11-16
Anticipated expiration: 2013-12-10
Also published as: DE4342842A1; AU5233693A; GB2274586A; GB9325292D0; CA2111136A1; GB2274586B; FR2699076A1

Description

66 4m,

U

-1-

AUSTRALIA

Patents Act 1990 COLGATE-PALMOLIVE COMPANY

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Invention Title: "Polymeric bio-erodible delivery system for the periodontal pocket" c The following statement is a full description of this invention including the best method of performing it known to us:- Background of the Invention The present invention relates to an improved article and method for medication delivery or more particularly to an improved drug release article suitable for delivering a medicament directly into the periodontal pocket of a patient. It is known in the art to deliver active agents to the periodontal pocket for periodontal therapy or inflammation reduction. In this regard it is known to incorporate antibacteriil or anti-inflammatory material into thin, monolithic strips for insertion into the periodontal pocket. In some instances, direct application of a C medication to an affected area is more desirable than systemic treatment via ingestion. Systemic treatment usually involves a :drug of higher dose than is necessary compared- to local application. This situation can be significant for patients with allergic tendencies or side effects to the required active agent.

Also, systemic therapy provides a high treatment dose vhich attenuates quickly and must be repeated every few hours.

Periodontal strips are known and are advantageous since they can be positioned directly on the affected area thus providing a relatively high dose of active agent targeted to a small region 0 with little active agent being transferred to the rest of the patient's body. The strip, once inserted by a dental professional, provides a corntinuous application of the active agent over a number of days. It has been a problem in the art to tailor the dosage release to the particular active agent to be used. Known monolithic periodontal strips sometimes exhaust the active ingredient prematurely. In this regard, Addy, et al The Development and in Vitro Evaluation of Acrylic Strips and Dialysis Tubing for Local Drug Delivery, J. Periodontol. (1982) SVol. 52, pgs 693-699 shows and evaluates monolithic acrylic strips for drug delivery. Higashi, et al, Local Ofloxacin Delivery Using A Controlled Release Insert (PT-01) in the Human Periodontal Pocket, J. Periodontol. Res. (1990) Vol. 25, pgs. shows a monolithic periodontal insert comprising ofloxacin and I0 hydroxypropylcellulose. Lindhe, et al Local Tetracycline Delivery Using Hollow Fiber Devices In PeriodQntal Therapy, J.

Clinical Periodontology (1979) Vol. 6, pgs 141-149 shows the periodontal administration of tetracycline via hollow fibers.

U.S. patent 4,975,271 shows the placement of a'chemotherapeutic '7 agent into the periodontal pocket together with a skin penetration enhancer. U.S. patent 4,965,262 shows the local administration of drug containing gels and tapes to the gingiva.

EP application 0 430 474 Al shows treatment of the oral cavity S: with polylactide/glycolide devices. U.S. patent 4,981,693 shows C a composition having a polymer admixed with a therapeutically active ingredient. The mixture is cast into a sheet, dried and formed into strips for placement into the periodontal pocket.

Two-layered laminated films are shown with layers of different polymers having dissimilar solubilities, and each layer ha= an active ingredient. A three layered structure is not considered where a center layer has an active ingredient in admixture with a polymer, and where the polymer appears on outer layers without a drug component, U.S. patents 4,900,.552 and U.S. 5,047,244 show a multilayered trilayer laminate film for drug delivery, Before use, protective layers are stripped off and the useful structure Sis a medication containing layer which does not have a covering, an insoluble barrier layer and an adhesive layer which allows adhesion to the inside of a patient's cheek. This structure is not bio-erodjible. U.S. Patent 4,889,720 shows a dosage release structure for oral rather than periodontal administration. The Sdesign has an adhesive layer, barrier layer and drug containing layer. A drug release controlling layer surrounds the edges at *its sides thus blocking drug emission out of the side edges.

U.S. patent 3,854,480 shows a drug release system where a drug containing composition is encapsulated within'a polymeric :z membrane and the drug permeates through the polymeric membrane over time. unlike the present invention, the sides of the structure are not open and the polymeric membrane must specifically be non-soluble and non-erodible by body fluids.

U.S. patent 5,084,267 shows a device for drug administration ~O within the periodontal pocket. This shows a non-layered, monolithic structure. U.S. patent 4,517,173 shows a mucous .et membrane adhering film having a drug containing layer, water soluble layer and a non-water soluble layer to discharge drugs into the mouth on a time release basis. Japanese patent c T JP4059723 shows an adhesive film comprising a water soluble, drug containing polymeric layer and a drug controlling layer on one or both sides of it.

It has been found that one can improve upon these prior inventions by providing a strip which gives a continuous dose of Sactive agent, which is slowly released over an extended period of time, usually 7-10 days. The structure according to this invention has a drug containing layer which is a mixture of a drug and a bio-erodible polymer. This layer is covered on its top and bottom surfaces, but not on its sides, by a bio-erodible Spolymer layer. There are no intermediary layers such as oe adhesives or plastic films, once placed in the periodontal pocket of a patient, a dose of active agent diffuses out of the uncovered sides of the drug containing layer. *Over time, the balance is provided to the patient by diffusion of the drug l b through the top and bottom layers.

0. As distinguished from prior art periodontal drug delivery systems Swhich initially release a major portion or "burst" of the drug, e.g. 70-80% release of the drug, in the first 24-48 hours after insertion, the periodontal dosage form of the present invention SR provides a continuous, slow release of the drug, releasing only about 20-30% of the drug in the first 24-48 hours after insertion into the periodontal pocket. Large initial bursts of drug are considered to be disadvantageous as depletion of the drug may occur before the full period for treatment has expired without fulillentof the treatment objectives.

*see Brief Description of the Drawings Figure 1 shows a schematic representation of a three layered periodontal strip according to the invention.

Figure 2 shows a schematic representation of a monolithic periodontal strip according to the prior art and which was subjected to comparative testing.

Figure 3 shows a comparison of the release of metronidazole, tetracycline, flurbiprofen and chlorhexidin from trilayer laminate chips.

I

Figure 4 shows a comparison of the release of metronidazole from a monolithic chip and a trilaminate chip.

Figure 5 shows seven day release study results. of metronidazole and flurbiprofen in a trilayer laminate chip.

Figure 6 shows an extended metronidazole study results from an acrylic chip vs. Eudragit S100.

*1II I Figure 7 shows the release of metronidazole from chips laminated with different drug contents within each layer.

Summary of the Invention The invention provides a periodontal dosage form suitable for delivery of an active ingredient into a periodontal pocket which comprises: an active ingredient containing layer having top and bottom surfaces, and side edges around the periphery thereof wherein said side edges are substantially free of applied coverings; said layer comprising an admixture of the active ingredient and a physiologically acceptable, drug diffusible polymer composition which is bio-erodible in the environment of the periodontal 10 pocket? and S" a polymeric layer positioned directly on each of said top and bottom surfaces in the absence of intermediary layers, said polymeric layer comprising a physiologically acceptable, bioerodible, polymer composition capable of diffusing an active ingrediere therethrough from the active ingredient containing layer when the dosage form is positioned in a periodontal pocket.

The invention also provides a method for delivery of an active ingredient into a periodontal pocket which comprises i) providing a periodontal dosage form suitable comprising :O 0 an active ingredient containing layer having top and bottom surfaces, and side edges around the periphery thereof wherein said side edges are substantially free of applied coverings; said layer comprising an admixture of the active ingredient and a physiologically acceptable, drug diffusible polymer composition which is bio-erodible in the environment of the periodontal pocket; and a polymeric layer positioned directly on each of said top and Sbottom surfaces in the absence of intermediary layers, said polymeric layer comprising a physiologically acceptable, bioerodible, polymer composition capable of diffusing an active ingredient therethrough from the active ingredient containing layer when the dosage form is positioned in a periodontal pocket; h1 and ii) positioning the periodontal dosage form in a periodontal pocket; and iii) causing the diffusion of part of the active ingredient directly into the periodontal pocket via the side edges of the '5 active ingredient containing layer; and thereafter iv) causing the diffusion of an additional part of the active ingredient into the periodontal pocket through the top and bottom surfaces and through the polymeric layers.

In use the drug is first released from the sides of the multilayer chip. Thereafter, to be released from the top or bottom layers of the chip, the drug must first diffuse through empty polymeric layers whereby the release of the drug from the chip is maintained in a slow, continuous manner with the absence of any initial bursts of the drug.

Detailed Description of the Preferred Embodiment In the practice of the present invention, one prepares an active ingredient containing polymeric layer, which is broadly composed of a drug component, a physiologically acceptable, bio-erodible, polymer, and optionally, but preferably a physiologically acceptable plasticizer. This active ingredient containing layer is shown as 4 in Figure 1. Within the context of this invention, as distinguished from biodegradability which is a chemical degradation of a polymer into a different compound of reduced molecular weight, bio-erodibility means a change of a physical 0 state of a compound rather than chemical change. Within the context of this invention, a drug diffusible polymer composition 9 is one which is capable of diffusing an active' ingredient therethrough. These polymer and active ingredient components are blended in a solvent composition, formed into a sheet film and 5 dried. on top on this active ingredient containing layer 4 is applied a second polymeric layer 2 which also comprises a physiologically acceptable, bio-erodible, and optionally, but preferably a physiologically acceptable plasticizer. These ingredients are blended in a solvent composition, coated in the 0 form of a sheet film on the active ingredient containing layer and dried. Another such polymeric layer 6 is similarly formed on the other side of the active ingredient containing layer 4 to form the three membered laminate construction shown in Figure 1.

Strips or tablets of this structure may be cut out to the desired -I size and shape. Importantly, the sides of the active component containing layer 4 are not covered in any way so that when the structure is placed in a periodontal pocket, the active component can diffuse out of the sides of the active component containing 3 layer 4, as shown by the arrows in Figure 1.

Physiologi'lly acceptable, bio-erodible, polymers nonexclusively include copolymers of acrylic acid, methacrylic acid and/or esters thereof, such as methyl acrylate/methacrylic acid copolymer, methyl methacrylate/methacrylic acid copolymer, and 1O phthalate containing polymers including cellulose acetate phthalate, polyvinyl acetate phthalate and hydroxy propyl methyl cellulose phthalate.

The polymers listed above :an be prepared so as to have a desired solubility in the periodontal environment by, for example, 1 5 adjusting the degree of polymerization. Accordingly, a polymer tailored to erode at the pH of the periodontal pocket can be determined as desired by selecting a single polymer from the above-listed polymers or by blending two or more of these polymers.

The most preferred polymers are methylmethacrylate/methacrylic acid copolymers having the trademark designation Eudragit S100 and Eudragit L100 available commercially from Rohn Haas. Such copolymers have the structural formula: COOH COOCH 3 Jn where n is selected to provide a mean molecular weight in the range of from about 125,000 to about 150,000. Eudragit S100 has an acid to ester ratio of about 2:1 and Eudragit LlOO has an acid to ester ratio of about 1:1.

.7Active ingredients include any therapeutic material suitable for *the treatment of periodontal conditions. These non-exclusively *.:include germicidal, antimicrobial, anti- infl1ami'atory, collagenase :inhibiting, and plaq-ue solubilizing agents. Examples include germicides, such a~r chlorhexidine, glyceryl iodide, phenol, 1 0 benzalkconiun chloride, cetylpyridinium chloride, and the like; antimicrobial agents, such as ampicillin, tetracycline, benzylpenicillin, clindamycin, cefalexin, erythromycin, chioramphenicol, sanguinaria, metronidazole, doxycycline, minocyclinef triclosan, ciprofloxacin, ofloxac.n and the like: ~anti-inflammatory agents, such as ibuprofen, indomethacin, ketoprof en, mefenamic acid, antipyrine, flurbiproten, prednisolone, dexamethasone, triamcinolone acetonide, and the.

like; plaque solubilizing agents, such as dextranase, protease, amylase and the like: and collagenase inhibitors obtained from 12 the extraction of crude drugs, such as gambir-catechu. The most preferred active ingredients are metronidazole, tetracycline, chlorhexidine and flurbiprofen.

Plasticizers non-exclusively include glycerin, propylene glycol, castor oil and dibutyl phthalate. The layers may include one or more of pharmaceutically acceptable preservatives, pH regulating agents, base materials for preparing film or ointment, lubricants and/or stabiizers.

The active ingredient, polymer and plasticizer are preferably 6 combined via a solution including a solvent such as deionized water, acetone, methanol and isopropanol. The active ingredient .containing layer may be prepared by mixing one or more active o.

o ingredients with a polymer and/or plasticizer and forming the resultant mixture into a homogeneous solid material in the form of film, sheet or bar by casting or coating onto a substrate with subsequent drying. The polymer layer composition is similarly formed by casting, coating or laminating onto one side of the active ingredient containing layer with subsequent drying, if necessary. This is then repeated on the other side of the active ~0O ingredient containing layer to form a three membered laminate construction. The solid composition of the invention in the form of film, sheet or bar can be prepared in different sizes.

Convenient sizes may be from about 0.3 mm to about 0.8 mm in overall thickness, from about 1 mm to about 4 mm in overall width, and from about 7 mm to about 10 mm in overall length.

The active ingredient containing layer may be from about 0.1 mm to about 0.4 mm in thickness, from about 1 mm to about 4 mm in width, and from about 7 mm to about 10 mm in length. Each Spolymeric layer may be from about 0.1 mm to about 0.3 mm in thickness, from about 1 mm to about 4 mm in width, and from about 7 mm to about 10 mm in length. However, these dimensions are not critical and any convenient size or shape may be made depending on several factors, such as severity of the disease, and the width and depth of the locus to be applied. The structure of the invention is applied to the periodontal pocket by insertion.

09 The active ingredient component is preferably present in the active ingredient containing layer in an amount of from about to about 20 by weight of the dry layer. A more preferred I1 range is from about 5 to about 20 and most preferably from about 10 to about 15 SThe bio-erodible polymer component is preferably present in the active ingredient containing layer in an amount of from about to about 95 by weight of the dry layer. A more preferred 40 range is from about 70 I to about 90 and most preferably from about 75 to about 85 The plasticizer ingredient component is preferably present in the active ingredient containing layer, when one is used, in an amount of from about 5 to about 20 by weight of the dry layer. A more preferred range is from about 10 to about 20 and most preferably from about 10 to about 15 The bio-erodible polymer component is preferably present in the polymeric layer in an amount of from about 65 to about 100 by weight of the dry layer. A more preferred range is from about to about 90 4 and most preferably from about 75 to about The plasticizer ingredient component is preferably present in the I polymeric layer, when one is used, in an amount of from about 0 to about 20 by weight of the dry layer. A more preferred range is from about 10 I to about 20 and most preferably from about 10 to about 15 The solvent components may be used in any convenient amount for forming the layered structure and which can subsequently be substantially removed. Any other of the above mentioned optional ingredients are present in minor amounts. Each of said polymeric layers and said active ingredient containing layer is erodible at o a pH normally present in a periodontal pocket, i.e. in the range of from about 6.0 to about 8.0, and particularly from about to about 7.4.

The following non-limiting example serves to illustrate the invention.

EXAMPLE I A. LAMINATE COMPONENTS SThe polymer used in this example was Eudragit 5100.

The plasticizer was dibutyl phthalate.

9 A-ctive Ingredient *~.The active ingredients used included antimicrobial agents 10 ietronidazole, tetracycline, chiorhexidine andflurbiprofen, a non-steroidal anti-inflammatory agent.

Solvents The solvents used for the polymer solution were a 50:50 acetone: :isopropanol mixture.

B. Preparationi of Eudracrit S1OO Polymer Solutions The active ingredient was incorporated in the polymer solit~ion in which had been dissolved the dibutyl phthalate plasticizer and was mixed until the active ingredient was either dissolved in solution or was uniformly dispersed. The resultant polymer cO solution had the following composition: Component by Weicht Solvent Active ingredient Eudragit S100 Dibutyl phthalate Preparation of Trilayer Laminate Using Eudraqit S100 Polymer Solution Prepared in B.

A backing membrane was taped to a metal sheet with the external side up. Polymer solution prepared in B. was applied to the membrane. A metallic bar with a wire coiled around it having a S* 1 wire thickness of 0.51 microns was pulled down the backing membrane, creating an even and thick, uniform film layer on the membrane which was allowed to air dry. To prepare additional layers, this step was repeated for lamination on top of the first layer. The first layer containing the active ingredient was firm 3 but not completely dry (usually about 15-20 minutes) when additional layers were applied which did not contain active ingredient. The total thickness of the trilayer laminate was 0.21 mm. The thickness of the laminate chip containing chlorhexidine was 0.31 mm. The laminated sheets were cut into

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10 ix1 cm squares with a scalpel and 1 cm template to form chips for evaluation of drug release.

D. Drur -Eytraction fromn Chins, The trilayer laminate chips prepared in C. were weighed out and then placed in a vial. 10 ml of pH 7.4 phosphate buffer were added to the vial. The vial was then placed in a shaking water S bath (44 RPM) at 37 0 C. Upon complete dissolution of the laminated chip, a I ml sample was transferred to a microcentrifuge tube. The sample was centrifuged at 8000 RPM for approximately 15 minutes. 50 microliters of the supernatant was diluted with 950 ml of fresh phosphate buffer solution. Either SHPLC (for metronidazole and flurbiprofen) or UlV assay (for tetracycline and chlorhexidine) was used to determine the concentration of the active agent released into the buffered solution. All studieas were carried out in triplicate.

0 0* 6. The composition of tbe laminated chips and their physical '3properties are summarized in Table I below. Thie results of a 24 0*90* hour study are recorded in the graph of Figure 3.

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Table I DRUG CONJTENT 0-10-0% Metronidazole outer Layers 0% Metronidazole Middle Layer 10% Metronidazole PHYSICAL PROPERTIES Clear, Strong and Elastic 0-10-01 Flurbiprofen 5 outer Layers Drug Middle Layer -10t Drug Clear, Strong and Elastic 0-10-0% Tetracycline outer Layers 0% Drug Middle Layer 10% Drug Yellow, Strong and Elastic io0-10-0% Chiorhexidine Outer Layers 0% Drug Middle Layer lo%*Drugj White clurups many bubbles Reference to Figure 3 indicates that the release profile of metronidazole, flurbiprofen and tetracycline were similar in indicating continuous, slow release of the active ingredient with the exception of chiorhexidine which was erratic for the first two hours of exposure possibly due to difficulty in dissolving chiorhexidine in the polymer solution.

For purposes of comparison, a 24 hour study following the procedure of Example I was repeated with the exception that the trilayer laminate chip containing 0-10-0% metronidazole of Example I was compared to a monolayer chip of the same thickness containing 15% dibutyl phthalate and 10% metronidazole. The results of this study are recorded in the graph of Figure 4.

Reference to Figure 4 indicates that the monolithic chip released 90% of its metronidazole content within about 9 hours whereas in that same period of time less than 30% of the metronidazole had tO been released from the trilayer laminate.

EXAMPLE-II

c A seven day study was performed using 0-10-0% metronidazole (0% etronidazole in outer layers, 10% metronidazole in the middle layer) and 0-10-0% flurbiprofen flurbiprofen in two outer layers, 10% flurbiprofen in the middle layer) trilayer chips following the same procedure as in Example I. The results of this study are recorded in the graph in Figure 5. The results in the graph in Figure 5 show a release profile of metronidazole and flurbiprofen indicating slow and continuous release of these active ingredients from the chip over the seven day period, less 4L than 30% of the active ingredient being released during the initial 24 hour period of chip exposure.

EXAMPLE III The procedure of Example II was repeated using a trilayer 0-10-0% metronidazole Eudragit S100 Chip. For purposes of comparison, the procedure was repeated except a single acrylic chip composed of a polymethyl methacrylate/polyethylmethacrylate co-polymer containing 10% metronidazole was evaluated. The composition and physical properties of the two chips are summarized below: Drug Content Polymer Plasticizer Physical Content Used Attributes 0-10-0% Metronidazole Eudragit Dibutyl Bio-erodible Chips 5100 Phthalate Clear, Strong and Elastic Metronidazole Polymethyl None Non-biodegradable methacrylate/ chips, clear, polyethyl strong and elastic S* p Samples were taken during the first 24 hours and then taken once a day for the remainder of the seven day exposure. The results were recorded in the graph in Figure 6. The results indicate l 1 that the Eudragit Sl00 chip had a slight burst phase up until 12 hours, and then the release of metronidazole was steady. The monolithic acrylic chip released 50% of the drug within 24 hours and released 90% of the drug within 48 hours. The Eudragit S100 chip on the other hand released approximately 10-15% of the drug c0 in the first day and only 65-70% of the drug in seven days indicating a significant reduction of the burst phase and a steady release over 7 days.

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EXAMPLE IV The procedure of Example I was repeated with the exception a 0-10-0% trilayer Eudragit SIOO metronidazole chip was compared with trilayer metronidazole chips in which the outer layers had incorporated therein 51G or lot metronidazole.

The composition and physical properties of these chips are summarized below.

D1RUG CONTENT PHYSICAL PROPERTIES 0-10-0% Metronidazole Trilayer Chips Outer Layers 0% Metronidazole Clear, Strong and Elastic Middle Layer 10t Metronidazole 10 5-10-5% Metronidazole Trilayer Chips Outer Layers 5% Metronidazole Clear, Strong and Elastic Middle Layer 10% Metronidazole 10-10-10% Metronidazole Trilayer Chips Outer Layers 10% Metronidazole Clear, Strong anid Elastic 0 Middle Layer 10% Metronidazole The metronidazole release over a 24 hour period from the chips is summzarized in the graph of Figure 7. Tlhe results summarized in the graph in Figure 7 indi.cate the 5-10-5% and 10-10-10% metronidazole trilayer chips had similar release E7 profiles marked by a large initial burst phase. Also these chips completely dissolved within 24 hours. By way of contrast, the 0-10-0% metronidazole trilayer chip indicated steady release throughout the 24 hour timer period and did not completely ***dissolve.

Claims

1. A periodontal dosage form suitable for delivery of an active ingredient into a periodontal pocket which comprises: an active ingredient containing layer having top and bottom surfaces, and side edges around the periphery thereof wherein E said side edges are substantially free of applied coverings: said layer comprising an admixture of the active ingredient and a physiologically acceptable, drug diffusible polymer composition bio-erodible in the environment of the periodontal pocket: and 9 a polymeric layer positioned directly on each of said top and bottom surfaces in the absence of intermediary layers, said polymeric layer comprising a physiologically acceptable, bio- erodible, polymer composition capable of diffusing an active ingredient therethrough from the active ingredient containing layer when the dosage form is positioned in a peric ontal pocket. .9

2. The dosage form of claim 1 wherein said active ingredient is selected from the group consisting of germicidal, antimicrobial, anti-inflammatory, collagenase inhibiting, and plaque solubilizing agents.

3. The dosage form of claim 1 wherein said active ingredient is 2o selected from the group consisting of metronidazole, tetracycline, chlorhexidine, flurbiprofen, glyceryl iodide, phenol, benzalkonium chloride, cetylpyridinium chloride, ampicillin, tetracycline, benzylpenicillin, clindamycin, cefalexin, erythromycin, chioramphenicol, sanguinaria, doxycycline, minocycline, triclosan, ciprofloxan, ofloxacin, ibuprofen, indomethacin, ketoprofen, mefenamic acid, antipyrine, prednisolone, dexamethasone, triamcinolone acetonide, prostaglandin, dextranase, protease, amylase and gambir-catechu.

4. The dosage form of claim 1 wherein said physiologically acceptable, bio-erodible, polymer composition is selected from the group consisting of copolymers of acrylic acid, mnethacrylic acid and/or esters thereof, and phthalate containing polymers. The dosage form of claim 4 wherein the polymer composition is a methyl methacrylate/methacrylic acid copolymer.

6. The dosage form of claim 1 wherein each of said polymeric layers is formed on said top and bottom surfaces of said active I~ingredxin-t containing layer by coating, lamination or casting.

7. The dosage form of claim 1 wherein each of said polymeric layers and said active ingredient containing layer is erodible at a pH in the range of from about 6.0 to about

8. The dosage form of claim 1 wherein each of said polymeric ZClayers and said active ingredient containing layer is erodible at a pH in the range of from about 7.0 to about 7.4.

9. The dosage form of claim 1 wherein at least one of the active ingredient containing layer and the polymeric layer further comprises a physiologically acceptable plasticizer. The dosage form of claim 1 wherein at least one of said active ingredient containing layer and said polymeric layers further comprises a physiologically acceptable, bio-erodible, plasticizer selected from the group consisting of glycerin, propylene glycol, castor oil and dibutyl phthalate.

11. The dosage form of claim 10 wherein the plasticizer is oo dibutyl phthalate.

12. The dosage form of claim 1 wherein the active ingredient containing layer comprises: a) from about 1 to about 20 4 by weight of the layer of an active ingredient; and b) from about 65 to about 95 by weight of the layer of a physiologically acceptable, bio-erodible polymer; and c) from about 5 to about 20 by weight of the layer of a physiologically acceptable plasticizer.

13. The dosage form of claim 1 wherein the active ingredient 2' containing layer comprises: a) from about 10 to about 15 t by weight of the layer of an active ingredient; and b) from about 75 to about a5 by weight of the layer of a physiologically acceptable, bio-erodible, polymer; and Sc) from about 10 t to about 15 by weight of the layer of a physiologically acceptable plasticizer.

14. The dosage form of claim 1 wherein the polymeric layer comprises *o a) from about 65 to about 100 by weight of the layer of a 10 physiologically acceptable, bio-erodible, non-biodegradable polymer: and 0 b) from about 0 to about 20 by weight of the layer of a physiologically acceptable plasticizer. 0* The dosage form of claim 1 wherein at least one of said :5 active ingredient containing layer and said polymeric layers further comprises one or more of components selected from the group consisting of pharmaceutically acceptable preservatives, pH regulating agents, ointments, lubricants, solvents and stabilizers.

16. A method for delivery of an active ingredient into a periodontal pocket which comprises i) providing a periodontal dosage form suitable comprising an active ingredient containing layer having top and bottom surfaces, and side edges around the periphery thereof wherein said side edges are substantially free of applied coverings; said layer comprising an admixture of the active ingredient and a physiologically acceptable, drug diffusible polymer composition bio-erodible in the environment of the periodontal pocket; and a polymeric layer positioned directly on each of said top and bottom surfaces in the absence of intermediary layers, said polymeric layer comprising a physiologically acceptable, bio- 0 erodible, polymer composition capable of diffusing an active S* ingredient therethrough from the active ingredient containing layer when the dosage form is positioned in a periodontal pocket; and ii) positioning the periodontal dosage form in",a periodontal pocket; and iii) causing the diffusion of part of the active ingredient directly into the periodontal pocket via the side edges of the active ingredient containing layer; and thereafter iv, causing the diffusion of an additional part of the active O ingredient directly into the periodontal pocket through the top and bottom surfaces and through the polymeric layers.

17. The method of claim 16 wherein said active ingredient is selected from the group consisting of germicidal, antimicrobial, anti-inflammatory, collagenase inhibiting and plaque solubilizing agents.

18. The method of claim 16 wherein said active ingredient is selected from the group consisting of metronidazole, tetracycline, chiorhexidine, flurbiprofen, glyceryl iodide, phenol, berizalkonium. chloride, cetylpyridinium. chloride, tetracycline, benzylpenicillin, clindamycin, cefalexin, erythromycin, chioramphenicol, sanguinaria, doxycycline, minocycline, triclosan, ciprofloxan, ofloxacin, ibuprofen, indomethacin, ketoprofen, mefenamic acid, antipyrine, prednisolone, dexamethasone, triamcinolone acetonide, dextranase, protease, amylase and gambir-catechu.

19. The method of claim 2.6 wherein said physiologically acceptable, bio-erodible, polymer composition -is selected from the group consisting of copolymers of acrylic acid, methacrylic acid and/or esters thereof and phthalate containing polymers. S2n. The method of claim 19 wherein the polymer composition isz a methyl methacrylate/methacrylic acid copolymer.

21. The method of claim 16 wherein each of said polyi.aric layers is formed on said top and bottom surfaces of said active ingredient containing layer by coating, lamination or casting. AZO 22. The method of claim 16 wherein each of said polymeric layers I and said active ingredient containing layer is erodible at a pH in the range of from about 6.0 to about

23. The method of claim 16 wherein each of said polymeric layers and said active ingredient containing layer is erodible at a pH Sin the range of from about 7.0 to about 7.4.

24. The method of claim 16 wherein at least one of the active ingredient containing layer and the polymeric layer further comprises a physiologically acceptable plasticizer.

25. The method of claim 16 wherein at least one of said active 10 ingredient containing layer and said polymeric layers further comprises a physiologically acceptable, bio-erodible, plasticizer is selected from the group consisting of glycerin, propylene glycol, castor oil and dibutyl phthalate.

26. The method of claim 16 wherein the active ingredient 15 containing layer comprises: a) from about 1 t to about 20 by weight of the layer of an active ingredient; and b) from about 65 to about 95 by weight of the layer of a 0 physiologically acceptable, bio-erodible, polymer: and S "0 c) from about 5 to about 20 by weight of the layer of a physiologically acceptable plasticizer. oO oo oo oooo

27. The method of claim 16 wherein the active ingredient containing layer comprises: a) from about 10 1 to about 15 by weight of the layer of an active ingredient: and b) from about 75 to about 85 by weight of the layer of a physiologically acceptable, bio-erodible, polymer: and c) from about 10 to about 15 by weight of the layer of a physiologically acceptable plasticizer.

28. The method of claim 16 wherein the polymeric layer comprises !0 a) from about 65 to about 100 1 by weight of the layer of a physiologically acceptable, bio-erodible polymer; and b) from about 0 to about 20 by weight of the layer of a physiologically acceptable plasticizer.

29. The method of'claim 16 wherein at least one of said active 15 ingredient containing layer and said polymeric layers further comprises one or more of components selected from the group consisting of pharmaceutically acceptable preservatives, pH regulating agents, ointments, lubricants, solvents and stabilizers. DATED THIS 10 DAY OF DECEMBER 1993 COLGATE-PALMOLIVE COMPANY Patent Attorneys for the Applicant:- F.B.RICE CO.