CA1309345C - Controlled release drug delivery system for the periodontal pocket - Google Patents
Controlled release drug delivery system for the periodontal pocketInfo
- Publication number
- CA1309345C CA1309345C CA000535738A CA535738A CA1309345C CA 1309345 C CA1309345 C CA 1309345C CA 000535738 A CA000535738 A CA 000535738A CA 535738 A CA535738 A CA 535738A CA 1309345 C CA1309345 C CA 1309345C
- Authority
- CA
- Canada
- Prior art keywords
- drug
- delivery system
- periodontal pocket
- microparticles
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K6/00—Preparations for dentistry
- A61K6/15—Compositions characterised by their physical properties
- A61K6/17—Particle size
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K6/00—Preparations for dentistry
- A61K6/30—Compositions for temporarily or permanently fixing teeth or palates, e.g. primers for dental adhesives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K6/00—Preparations for dentistry
- A61K6/60—Preparations for dentistry comprising organic or organo-metallic additives
- A61K6/69—Medicaments
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0063—Periodont
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
Abstract
ABSTRACT
A controlled release drug delivery system for placement in the periodontal pocket. The system comprises a plurality of drug-containing microparticles or microcapsules, between 10 and 500 microns in size, suspended in a pharmaceutically acceptable carrier medium, and is capable of maintaining an effective level of drug in the periodontal pocket for a period of 1 to 30 days.
A controlled release drug delivery system for placement in the periodontal pocket. The system comprises a plurality of drug-containing microparticles or microcapsules, between 10 and 500 microns in size, suspended in a pharmaceutically acceptable carrier medium, and is capable of maintaining an effective level of drug in the periodontal pocket for a period of 1 to 30 days.
Description
1 3'`93~5 CONTROLLED RELEASE DRUG DELIVERY
SYSTEM FOR THE PERIODONTAL POCKET
BACKGROUND OF ~E INVENTION
Field of the Invention Thi6 invention relates to a controlled release ~yetem of drug delivery to the periodontal pocket. Such a 6ystem can be u~ed to treat any periodontal disease, 6uch a6 gingivitis, pyorrhea alveolari6 and other related disorders.
PescriDtion of the Prior Art Periodontal disease, with car$es, i~ the most important cau6e of 1088 of teeth. It is well establiEhed that bacteria are directly involved in both the onset and progres6ion of periodontal disease.
See for example J. Slots, "Subgingival Microflora and Periodont~l Disea6e," J. Clin. Periodontal. 6, 315 (1979) and S.S. Socran~ky, "Microbiology of Periodontal Disease - Precent Status ~nd Future Con6ideration6," J. Periodontol. 48, 497 (1977). Thi~
~5 has led to the wide6pread use of antibiotics in the treatment of periodontal disease, and particularly to the u6e of tetr2cycline, since æiqnificantly h~gher levels of tetracycline are found in gingival fluid than in blood after admini6tration of ~ingle or multiple oral dose6. ~J.M. Gordon et al., ~Sensitive A6say for Measuring Tetracycline Levels in Cingival Crevice Fluid,~ Anti~icrob. Agent~ Chemother. 17, 193 1 3~93~5 (1980), J.M. Gordon et al., "concentratlons of Tetracycl~ne in Human G$ngival Fluid aftQr 81ngle Doses," J. Clln. Periodontol. 8, 117 (1981) and J.M.
Gordon et al., ~Tetracycline: Levels Achiovable ln Gingival Crevice Fluid and in vltro Effect on Subgingival Organism6. Part 1. Concentrat~on6 in Crevicul~r Fluid after Repeated Dose6, n J. Periodontol. 52, 609 (1981).) However the typical effective tetracycline oral dose of one gram per day for 30 days can lead to 6eriou6 side effects. It has been estimated that the dose 6hould be of the order of one hundred time6 smaller to avoid these effect6. A
more 6atisfactory approach then is to administer the antibiotic topically using a controlled release device to sus~nin an effective dose for the reguired length o$ ti~e. Because the drug is delivered locally, a much reduced dose will 6uffice for effective therapy, and harmful side effect6 can be reduced or eliminated.
Long lasting drug delivery 6ystems pre6ently u6ed in the oral cavity fall broadly into two groups; either troches, pa6tilles or tablets which adhere to the oral mucosa in some way, or drug containing strips or dosage form6 which are attached to the gums, teeth or other interior surface of the mouth. A good example of the former category i6 U.S. Patent No. 4,039,653.
This patent disclo6e6 a 6u6tained relea6e tablet coated with a pharmaceutically acceptable oral adhe6ive, which 1~ placed in an upper coner of the mouth and i6 capable of di6pensing an odor-mas~ing agent, local anesthetic or other medicat$on ln a 6ustained fa6hion for period6 of up to twelv- hour6.
U.S. Patent No. 4,250,163 di6clo6e6 a method of administering a broad range of medications to the oral cavity by means of a water-~wellable and muco~a-adhe6ive polymeric matrix, which can be ln the form of 1 3!~q345 a tablet, powder or granules and which i~ effective for times of the order of a few hours. AB can be seen from these and other examples, such as U.S. Patent~
No. 4,226,848, 4,369,172 and 4,0S9,686, such troches S and tablets are normally effective for period~ of hours rather than day6, and a course of treatment lasting one month would require the use of numerous tablets. Furthermore they are lnappropriate to the treatment of periodontal di~ease because the drug is released lnto the 6aliva or oral mucosa, and doe6 not penetrate the periodontal pocket to any 6ignificant extent. ~uccal tapes, ~trips and forms suffer from the 6ame disadvantages. For example, the buccal dosage form disclosed in U.S. Patent No. 3,972,995 was found to be effective without leaking, if not wrinkled or dislodged by the teeth, for about one hour only.
This highlights another disadvantage of existing methods of dispensing drugs for oral therapy; they may slip or be dislodged by the tongue or teeth, may be uncomfortable to a greater or lesser degree, and may interfere with the normal oral functions to some extent. Recent dQvelopments in the art are directed toward delivering the therapeutic agent directly to the periodontal pocket, in some caseC in a controlled release formulation. Gordon et al. have described the use of a drug-filled polymer hollow fiber. (J.M.
Goodson et al., NPeriodontal Therapy by Local Delivery of Tetracycline," J. Clin. Periodontol. 6, 83 (1979), J. Lindhe et al., "Local Tetracycline Delivery Using Hollow Fiber Devices in Periodontal Therapy, H J. Clin.
Periodontol. 6, 141 (1979) and R.L. Dunn t al., "Monolithic Fibers for Controlled Delivery of Tetracycline, n in Proc. Ninth Int. Symposium on Controlled Release of Bioactive Material~, Ft.
Lauderdale, FL, July (1982).) This device is tied around a tooth and qently pressed below the m~rgin of 1 3"?3~5 the ging~va ~o that lt resides in the perlodontal pocket, and i6 capable of delivering an effective dose of 2.5 microgram6 o$ tetracycline per day per periodontal pocket for A prolonged period of a week or more. Similar result6 have been obtained by Coventry and Newman (J. Coventry and H.N. Newman, ~Experimental U6e of a Slow Relea6e Device employing Chlorhexidine Gluconate in Area6 of Acute Periodontal Infla~mation,"
J. Clin. Periodontol. 9, 129 (1982)) and Addy et al.
(M. Addy et al., ~The Development and in vitro Evaluation of Acrylic Strip6 and Dialy~i6 Tubing for Local Drug Delivery," J. Peridontol. 53, 693 (1982)) using acrylic 6trips lmm or more long, impregnated with chlorhexidine, tetracycline or metronidazole, which were in6erted into the periodontal pocket with tweezer6. Such a fitrip, formed from ethylcelluloge impregnated with metronidazole, $8 di6closed by Loesche in U.S. Patent No. 4,568,538 (February 1986).
Another ~trip, employing a water 601uble polymer of a particular elasticity and vi6c08ity, i~ disclosed by Suzuki et al. in U.S. Patent No. 4,569,837. Although the6e devices may be able to dispen6e an appropriate drug for a time ~pan of a week or more, they are inappropriate to wide6pread u6e becausQ they are difficult and time con6uming to apply and may be di610dged by the patient during normal oral functiong.
The drug relea6ing microparticle system that i6 propo6ed below overcomes all of the6e previou6 difficulties, and provide6 a drug formulation which i6 ea6ily applied and capable of delivering ~ntibiotic6 or other drug6 reliably to the periodontal pocket for ~ prolonged period of time, without interfering in any way with the normal oral function6.
1 3'`93~, 5 SUMMARY OF THE INVENTION
This invention is a controlled release drug delivery system for placement in the periodontal pocket. The system comprises microparticles or microcapsules, hereinafter referred to as microparticles, suspended in a pharmaceutically acceptable carrier medium. The microparticles are between 10 and 500 microns in size, and consist of an active agent dispersed within or encapsulated by a rate-controlling polymer matrix.
Thus, the invention provides a controlled release drug delivery system for placement in the periodontal pocket, comprising:
(a) a plurality of discrete microparticles, between 10 and 500 microns in size, consisting of a drug-containing biodegradable polymer and the drug dispersed therein, and (b) a fluid suspending medium for the said microparticles;
the said drug delivery system remaining active in the periodontal pocket for a period of between one and 30 days.
Microparticles of this specification can be prepared by a variety of well-established technigues, for example solvent evaporation, coacervation or spray-drying. The active agent may be one of a broad spectrum of drugs, including, but not limited to, antibiotics, anti-inflammatory agents, local anesthetics and so on. The polymer matrix may be chosen from a range of medically suitable materials and varied to provide the required release rate for the drug involved. Embodiments employing biodegradable polymers can limit the life of the microparticles to a month or two and prevent microparticle entrapment in the periodontal pocket A~ 4 1 3"~3~5 for excessive periods of time.
The carrier medium may be an aqueous solution, paste or gel. In general the properties required are that it should be pharmaceutically acceptable (non-toxic and non-allergenic), promote good adhesion in the periodontal pocket, and have a high permeability for the active agent involved. A preferred embodiment of the invention employs a thermally gelling polymer such as Pluronic~ F127 from BASF Wyandotte. In aqueous solution this polymer is a free-flowing fluid at room temperature, but gels rapidly above 30~. Embodiments of the invention are introduced into the periodontal 1 3r'931~ 5 pockets of the patient by a denti¢t or phy6ician using a 6yringe and a fine rubber tube. The ~y6t-m then re6ides ln the pocket, unfalt by the patient and reliably delivering a ~teady dose of the chosen medication.
An ob;ect of the invention is to provide a 6y6tem to deliver a drug or other active Agent to the periodontal pocket at a steady do6age level which can be ustained for a period of day~ or week6.
Another ob~ect of th~ invention i~ that the 6aid sy~tem 6hould be comfortable in u6e, 6hould not interfere with the normal oral functions and 6hould not be easily di610dged by the patient.
A further object i8 that the 6aid sy6tem ~hould be capable of insertion in a 6imple manner, and ~hould not require the u6e of undue time or exceptional experti6e on the part of the denti6t or physician involved.
Other ob~ect~ and advantage6 of the present invention will be apparent from the following description.
BRIEF DESCRIPTION QF THE DRAWINGS
Fig. lA ~how6 the normal human gingival 6ulcus.
Fig. lB 6hows the effect of periodontal disea6e, where the 6ulcus ha6 deepened to form ~ periodontal pocket.
Fig. 2 i6 a graphic repre6entation of the gelling 2S characteri6tic6 of aqueous PluronicF127 ~olution6.
Fig. 3 6how6 the 601vent ovaporation techn$gue u6ed to prepare microparticle6.
1 3"q3~ 5 Fig. 4 i6 a graphic repre6entation of the in vitro drug relea6e rate of tetracycline from polysulfone microparticle~.
Fig. 5 i6 a graphic representation of the in vitro drug relea6e rate of flurbiprofen from ethylcellulo6e particles.
DETAILED ~ESCRIPTION OF THE INVENTION
~Active agent" as u6ed herein broadly includes any composition or compound of matter which when di6pen6ed in the cho6en environment of u6e produce6 a predetermined, beneficial and u6eful re6ult.
"Drug" a6 u6ed herein broadly includes physiologically or pharmacologically active 6ub6tance6 for producing a localized effect at the admini6tration site or a 6y6temic effect at a ~ite remote from the admini6tration site.
Referring now to Fig. 1, Fig. lA 6how6 the normal human gingival ~ulcu6. The alveolar bone cre6t 1 i6 undamaged. The depth from the crown 2 to the epithelial attachment 3 i~ around 2 or 3 mm. Between the crown 2 and the free gingiva 4 i6 the healthy gingival ~ulCU6 5. In contra6t Fig. lB show6 the effect of periodontal di6ea6e. The alveolar bone cre6t 1 ha6 been eroded; the depth from the crown 2 to the epithelial attachment 3 has increa6ed con6ider2bly, and the normal sulcus has deepened to form a periodontal pocket 6.
Suitable drug6 whlch can be admini6tered in the drug delivery ffy6tem of the pre6ent invention include but are in no way limited to antibacterial agents 6uch as thimerosal, chloramine, boric acid, phenol, iodoform, 1 ) , 3 ~,:
chlorhexidine and other oral antiseptics, ~-lactam antibiotic6, for example cefoxitin, n-formamidoyl thienamycin and other thienamycin derivatives, tetracyclines, chloramphenicol, neomycin, gramicidin, kanamycin, amikac~n, 6i6micin and tobramycin; anti-inflammatory ~teroids ~uch a6 corti60ne, hydrocorti60ne, beta-methasone, dexametha60ne, fluocortolone, predni~olone, triamcinolone and the like; non-~teroidal anti-inflammatory drugs including flurbiprofen, lbuprofen, lndomethacin, piroxicam, naproxen, antipyrine, phenylbutazone and a6pirin for example; plague di6solving substances, for example ly60zyme chloride or amyla6e; and local anesthetic6 such as lidocaine, procaine, benzocaine, xylocaine and 60 on.
The sy6tem comprises a plurality of microparticles or microcap6ules between 10 and 500 microns in ~ize, 6uspended in a pharmaceutically acceptable carrier.
Microparticle6 in this context are defined a6 re6ervoir sy6tem6 in which a simple reservoir of active agent iB ~urrounded by a membrane ~hell;
microparticle6 are 6mall monolithic entitie~ in which the active agent i8 randomly di6per6ed through the particle matrix. Many practical formulation6 fall between the6e two definition6; for example microcap6ule6 often agglomerate during the microencapsulation process, while the 6ize of the active agent particle6 contained in ~ microparticle 6y6tem i6 often of the ~ame order a6 the size of the microparticles themselves. In the following discus6ion then, Nmicroparticle" will be defined to ~ean microparticle, microcapsule or any intermediate form. Variou6 physical and chemical method6 ~or preparing microparticle6 have been developed over the pa6t twenty year6 and the technology i6 well 7 L ~
establi6hed and well documented. See for example Patrick B. Deasy, Microencap6ulation and Related Drug Proces6es, Marcel Dekker Inc., New York, 1984. The more important method6 are de6cribed below, and depending on the chemical and phy6ical propertie6 of the desired embodiment, any of these could be used to prepare the microparticles.
Coacervation wa6 the fir6t microencap6ulation technique and remains one of the most widely u6ed.
Coacervation usually involve6 four 6tep6. Fir6t a di6per6ion or emulsion of the active agent i6 prepared in an agueou6 polymer solution. Secondly, the polymer i6 cau6ed to precipitate BlOWly by ~ome means:
addition of a non-601vent, cooling, change of pH or ionic strength, or addition of an incompatible polymer solution for example. Under the6e conditions, most polymer6 initially precipitate a6 a highly 6wollen liquid polymer pha6e, th~6 phenomenon being known a6 coacervation. During the precipitation, the liquid phase coat~ the di6per6ed active agent droplet6.
Finally the microparticles thus formed are ~eparated from the eolvent/non-solvent mixture, dried and 6ieved into different size ~raction~. Most industrial coacervation proce6ses u6e agueou6 ~olution~ of gelatin and other water ~oluble polymer6 ~nd can only encap6ulate hydrophobic, water in601uble agents di6601ved in an organic solvent. However the proce6s can be inverted by u6ing organic-601vent-601uble polymer6 with organic-601vent-insoluble active agent6 di6solved in an ~queou6 solu~ion. Since many drugs are at lea6t moder~tely water 601uble, thi6 ~akes the proce~6 appropriate to the preparation of microencap6ulated pharmaceutical~. For example ethylcellulose ha6 been used to prepare microparticles containing a6pirin, indomethacin, paracetamol, 1 3"934~
theophylline and vitam~ns among others. The main disadvantage of the coacervatlon technigue i~ that it requires considerable skill to produce particles with consistent properties, since the particle 6ize8 and wall thickness may vary widely.
Interfacial polymerization occur6 when two reactiqe monomer6, each in different immiscible liquid6, are brought into contact. The monomers are able to react only at the interface of the two 601ution~, where a polymer film form6. When one ~olution i6 dispersed in the other, the polymer film formed encapsulates the disper~e pha6e. Thi~ procaB8 iB not widely used for the commercial preparation of pharmaceuticals because of various practical problems; toxicity of remaining unreacted monomer, drug degradation a a re6ult of reaction with the monomer, high permeability of the encapsulating polymer to the active agent involved, fragility of the capeules produced and non-biodegradability of the particles amongst others.
However extensive reasearch work has been done on the coating of high-molocular-weight biological material6 such a6 enzymes with polyamides, and recently McGinity et al. have successfully encapsulated caffeine, 60dium salicylate, theophylline and other drugs ln a nylon coated particle by this technique. (J.W. McGinity et al., nInfluences of matrices on nylon-encapsulAted pharmaceutical6," J. Pharm. Sci. 70, 372-37S (1981).) Solvent evaporation is another technique which is appropriate for the encapsulaton of a water-soluble drug. Firfit the polymer matrix material 1~ di~olved in an organic ~olvent. Adding the active agent, dissolved in water, nnd emulsifying, produces a water-in-oil emul~ion. This emulsion is re-emul6i~ied in an aqueous ~olution, forming a water-in-oil-in-water 1 3''9345 emul~ion. Thi6 final aqueous eolution usually contains a polymer ~uch as gelatin, to prevent aggregation. The Bolvent iB then removed under reduced pres6ure to form a hard outer wall to the particle6. Hydrophobic agent~ may a1B0 be prepared by ~olvent evaporation, but in thi~ ca6e the procedure i6 modified by fir6t preparing an oil-in-water emul6ion of the agent. This proce6~ ha6 been used for example by Wakiyama et al. to prepare microparticle6 of butam~en, tetracaine, and dibucaine, where the polymer material used was polyalactic acid in a 601ution of methylene chloride, methyl acetate or ethyl acetate.
(N. Wakiyama et al., "Preparation and evaluation in vitro of polylactic acid microspheres containing local ane6thetics," Chem. Pharm. Bull. 29, 3363-68 (1981).) Recently Ko;ima et al. used the 601vent evaporation technique to enclose various local ane~thetics in polycarbonate microsphere6: Eustained drug-release time6 measured in hundreds of hour6 resulted. (Chem.
Pharm. Bull. 32, 2795-2802 (1982).) Finally a number of simple phy6ical technigues can be u6ed to prepare microp~rticles, and 6pray drving, for example, 16 widely u6ed in the preparation of food or pharmaceutical flavors. Spray dried particles are le66 sati6factory for preparing drugs however, a6 the particles tend to be non-uniform and the coating porous, cau6ing the active agent to di6perse too rapidly for a controlled-relea6e application. However several penicillin6 have been microencapsulated in ethylcellulose in this way. See ~or instance U.S.
Patent No. 4,016,254 (April 1977).
The polymer matrix material chosen should be pharmaceutically acceptable, 601uble in a variety of suitable ~olvents and available in different grade6 to 1 3r93/l5 enable the release rate of the active agent to be controlled. Cellulose acetate and ethyl cellulose have A good record of acceptability ln ~edical applications. Polystyrene, poly6ulfone ~nd polycarbonate are possible choices for use with antibiotics such as tetracycline. Exper$ments described in the Examples below showed that tetracycline release from poly6ulfone and polystryene was extremely 810w, and that polycarbonate release values were much more satisfactory; however different results could well be obtained with different drug6.
Biodegradable polymers ~uch a6 the lactic-glycolic acid copolymer6 from Hexel Corporation of Hayward, California offer a distinct advantage, in that they lS have been found to biodegrade over a period of 4 to 12 weeks, and thu6 could prevent particles becoming trapped in the periodontal pocket indefinitely. Work on the u6e! of such polymers for controlled release drug di6pensing ha~ been carried out by 6everal researchers. (For example, D.A. Wood, Int. J.
Pharmaceut. 7, l (1980).) A paper of Setterstrom et al. in Polym. Mater. 8ci. Eng., 53, 620-626 (1985) de6cribes the use of ampicillin microencap6ulated in poly~DL-lactide-co-glycolide) for topical application to wound6; effective levels of antibiotic are detectable At the wound slte for at least ~ourteen day~. The ~ize of the microparticles should be limited to between lO and 500 microns. Very 6mall particles with consi6tent properties are dif~icult to prepare and they may wash out of the periodontal pocket rather easily. Particles larger than 500 micron~ may be too large to deliver with ~yringe and rubber tube and may be uncomfortable or irritating to the gingival membranes.
1 3"q-~45 The theory of drug release from 601id microsphere6 was developed by ~iguchi (T. Hlguchi, J. Pharm. ~ci. 52, 1145 (1963)). The relea6e i~ controlled by the equation 2 [ [ ~t ]2/3 Mt ) 3P-t Mt/M0 i~ the fraction of total drug released after time t from a particle of radius rO. The drug permeability in the matrix i~ P and the drug loading i5 Co~ This equation can be u6~d to limit further the ~ize of the microparticles, and to select an appropriate drug loading, ~o that the desired do6age level and relea~e rate for the cho6en e~bodiment is obtained.
The carrier medium used to contain the microparticles must conform to eeveral requirement~. First it ~hGuld be biocompatible, non-toxic ~nd non-allergenic.
Secondly it should have a low solubility but a high permeability for the dug in question. A low 601ubility i~ nece6sary to minimize leaching of the drug fron the microparticle during 6torage. ~igh permeability i~ required in order that the drug be well conducted from the microparticle to the mucous membrane6. Thirdly it ~hould promote good adhesion of the microparticles in the periodontal pocket, and la6t it ~hould have an appropriate v~sco6ity for the intended use. The choice of medically ~cc~ptable carrier6 i~ very wide and can include amongst other~, water, aqueou6 ~olutlon~, 6yrups, alcohol~, glycerine, mineral oil, vegetable oils, ~ynthetic mucilage-like ~ubstance6 ~uch ~6 polyvinyl alcohol, carboxymethylcellulose and BO on. Further examples ? ~ 4 ^`
which may be mentioned are the water soluble polymers li6tad by Suzuki et al. ln U.S. Pat. No. 4,S69, 837, col. 4, llnes 9 through 21. Simple saline solutione and similar aqueous ~olutions can be u6ed, but may be wa6hed out o~ the periodontal pocket rather guickly and easlly. A preferred alternative i6 one of the thicker, viecou6 media ~uch a6 carboxymethylcellulo6e.
In general, the more viecou6 the medium, the better it will adhere in the periodontal pocket; however highly vi6cous carriers may be difficult to insert with a syringe and rubber tube and con6equently may not spread through the pocket to any u6eful extent. An e6pecially preferred form then is a thermally gelling polymer, 6uch as tho6e vehicles di6clo6ed by Krezanowski in U.S. Patent No. ~,188,373. The Pluronic~ serie~ of polyoxypropylene-polyoxyethylene copolymer6, marketed by BASF Wyandotte, Par6ippany, New Jer6ey, conta~n6 several 6uitable example6. The6e polymere are compatible with many commonly used pharmaceutical materials, and have been approved by the FDA for medical u6e. The Pluronic eeries can be obtained in a range of molecular weights and compo6itions; thus the carrier formulation may be tailored for optimum performance in the environment of the lnvention. F~g. 2 shows graphically the gelling temperature of aqueous PluronicF127 solution~ of different concentrations. Because of hydrogen bonding, the viscosity of the eolutions increasee greatly with temperature. Pluronic concentration6 of 20 wt% have ideal characteri6ticQ, being free-flowing fluids at room temperature, but gelling rapidly at 30C or above. Thus these eolutions are amenable to delivery by the ~yringe/rubber tube method, but quickly take on the nece6sary visco6ity for good adhesion and durability once resident within the periodontal pocket. Optionally, a eelf-gelling 1 3nq34~
preparation such as those disclo6ed by Caslav~ky et al., in U.S. Patent No. 4,563,351 (Jan. 1986~ could be u6ed for the carrier medium.
Polycarbonate was used to prepare microparticles by the 601vent evaporation proces~. The drug used was tetracycline fr¢e ba~e (TFB). The aqueous phase was saturated with TFB before starting a microparticle preparation run. In this way migration of the TFB
into the aqueous phase during particle formation was minimized, and it wa6 possible to encapsulate 70 to 100% of the TFB u~ed. Fig. 3 6hows the apparatus used to prepare the microparticles. Known amount6 of TF~
and polycarbonate dissolved in methylene chloride were added to the aqueous pha~e 7 containing polyvinyl alcohol (PVA) and 3ppm n-octanol. The PVA is an emulsifier and the n-octanol an anti-foaming agent.
Air was continuou61y passed over the ~olution by means of the vacuum pump 8. A stirrer 9 driven by a motor 10 kept the 601utlon 6tirred and aa the methylene chloride evaporated, the Qmulsion droplet~ 11 ~olidified. The micropartlclee thus formed were separated from the aqueous solution, dried and sieved to obtain three size factions; 50-110 microns, 110-210 microns and 210-500 microns. The in vitro drug release rate was mea6ured by di6persing a known amount of microparticlQs in a volume of agueous saline solution (0.9~ NaCl). The dispersion was 6tlrred and kept at a temperature of 37~C. Samples were periodically removed and diluted and their antibiotic concentration determined by W spectrophotometry. The total tetracycline content of the microparticles was determined in a similar way by dissolving a known amount of microparticle~ and mea~uring the antibiotic concentratlon. The presence of the matrix poly~er in the 601ution does not interfere with the W
measurements. A typical re6ult i6 shown by the upper curve in Fig. 4. The initial relea6e rate was high for a couple of hours, then remained fairly steady until it tapered off at time6 in exces6 of 25 hour6.
Drug loading6 between 18 and 35wt% were u6ed. The release curve6 for the three 6ize fraction6 were closely bunched, and lt appeared that the 6ize of the microparticles i8 relatively unimportant a~ far a~ the drug kinetic6 are concerned but 6hould be limited rather by the practical con6ideration6 of ea6e of manufacture, convenience of in~ertion and comfort in use. ~hese experiment6 6howed that microparticle6 made of polycarbonate containing 18 to 35wt%
tetracycline and ranging in size from 50 to 500 micron6 were capable of delivering tetracycline in a 6u6tained fa6hion for period6 of about 25 hour6.
Since the periodontal pocket iB 6mall and it~ fluid exchange rate 610w, the flow of gingival fluid in a ~ingle periodontal pocket being of the order of 10 microliters per hour, thi6 in vitro relea6e rate i6 estimated to corre6pond to an in vivo release period of the order o~ 10 to 20 day6.
The method as de6cribed in Example 1 wa6 u6ed to prepare microparticle6. Polysulfone was cho6en a6 the matrix material: the drug u6ed wa6 ~FB. A typical relea6e curve is shown in Fig. 4. A6 can be seen the drug release rate was very ~low, only a ~mall fraction of the totAl drug loading having been relea6ed after 24 hour6. Although too ~low to be within the parameters for optimum treatment of periodontal di6ea6e, this combination of drug and matrix would be appropriate to embodiment~ of the invention calling for a very ~mall dosage level over a long ~me period.
I ~"'S4-) ~ XAMPLE 3 A ~eries of flurb~profen microcapsules sultable for use in a periodontal formulation was prepared by the solvent evaporation method. Varying ~mounts of ilurbiprofen were dissolved in ethylcellulose (medium ethoxy, vi3co~ity 100 (Dow Chemical Co., Midland, MI)) in MeC12 601ution. Fifteen ml of thi6 ~olution were emul6ified in 600 ml of aqueous 60 bloom gelatin (.25%
as an emulsifier) being stirred at 500 rpm. ~wo drops of octanol were also added to eliminate any foam. The MeC12 was allowed to evaporate at 30C. After 55 minutes the stirrer was shut off and the mixture was allowed to ~ettle. The hollow cap6ules floating on the surface were decanted and the remaining capsules were collected on fine filter paper using a buchner funnel. The capsules were then placed in a foil dish in a dehumidifying cabinet. The drug release rates of the ethylcellulose cApsules with varying drug contents were measured. These result~ are shown in Figure 5.
The flurbiprofen content of various batche6 of 2 0 miCroCap8UleB iB also shown on thi~ figure. As ~hown, the microcapsule delive n rate can be varied over a wide range by varying the drug to polymer ratio in the microcapsules.
SYSTEM FOR THE PERIODONTAL POCKET
BACKGROUND OF ~E INVENTION
Field of the Invention Thi6 invention relates to a controlled release ~yetem of drug delivery to the periodontal pocket. Such a 6ystem can be u~ed to treat any periodontal disease, 6uch a6 gingivitis, pyorrhea alveolari6 and other related disorders.
PescriDtion of the Prior Art Periodontal disease, with car$es, i~ the most important cau6e of 1088 of teeth. It is well establiEhed that bacteria are directly involved in both the onset and progres6ion of periodontal disease.
See for example J. Slots, "Subgingival Microflora and Periodont~l Disea6e," J. Clin. Periodontal. 6, 315 (1979) and S.S. Socran~ky, "Microbiology of Periodontal Disease - Precent Status ~nd Future Con6ideration6," J. Periodontol. 48, 497 (1977). Thi~
~5 has led to the wide6pread use of antibiotics in the treatment of periodontal disease, and particularly to the u6e of tetr2cycline, since æiqnificantly h~gher levels of tetracycline are found in gingival fluid than in blood after admini6tration of ~ingle or multiple oral dose6. ~J.M. Gordon et al., ~Sensitive A6say for Measuring Tetracycline Levels in Cingival Crevice Fluid,~ Anti~icrob. Agent~ Chemother. 17, 193 1 3~93~5 (1980), J.M. Gordon et al., "concentratlons of Tetracycl~ne in Human G$ngival Fluid aftQr 81ngle Doses," J. Clln. Periodontol. 8, 117 (1981) and J.M.
Gordon et al., ~Tetracycline: Levels Achiovable ln Gingival Crevice Fluid and in vltro Effect on Subgingival Organism6. Part 1. Concentrat~on6 in Crevicul~r Fluid after Repeated Dose6, n J. Periodontol. 52, 609 (1981).) However the typical effective tetracycline oral dose of one gram per day for 30 days can lead to 6eriou6 side effects. It has been estimated that the dose 6hould be of the order of one hundred time6 smaller to avoid these effect6. A
more 6atisfactory approach then is to administer the antibiotic topically using a controlled release device to sus~nin an effective dose for the reguired length o$ ti~e. Because the drug is delivered locally, a much reduced dose will 6uffice for effective therapy, and harmful side effect6 can be reduced or eliminated.
Long lasting drug delivery 6ystems pre6ently u6ed in the oral cavity fall broadly into two groups; either troches, pa6tilles or tablets which adhere to the oral mucosa in some way, or drug containing strips or dosage form6 which are attached to the gums, teeth or other interior surface of the mouth. A good example of the former category i6 U.S. Patent No. 4,039,653.
This patent disclo6e6 a 6u6tained relea6e tablet coated with a pharmaceutically acceptable oral adhe6ive, which 1~ placed in an upper coner of the mouth and i6 capable of di6pensing an odor-mas~ing agent, local anesthetic or other medicat$on ln a 6ustained fa6hion for period6 of up to twelv- hour6.
U.S. Patent No. 4,250,163 di6clo6e6 a method of administering a broad range of medications to the oral cavity by means of a water-~wellable and muco~a-adhe6ive polymeric matrix, which can be ln the form of 1 3!~q345 a tablet, powder or granules and which i~ effective for times of the order of a few hours. AB can be seen from these and other examples, such as U.S. Patent~
No. 4,226,848, 4,369,172 and 4,0S9,686, such troches S and tablets are normally effective for period~ of hours rather than day6, and a course of treatment lasting one month would require the use of numerous tablets. Furthermore they are lnappropriate to the treatment of periodontal di~ease because the drug is released lnto the 6aliva or oral mucosa, and doe6 not penetrate the periodontal pocket to any 6ignificant extent. ~uccal tapes, ~trips and forms suffer from the 6ame disadvantages. For example, the buccal dosage form disclosed in U.S. Patent No. 3,972,995 was found to be effective without leaking, if not wrinkled or dislodged by the teeth, for about one hour only.
This highlights another disadvantage of existing methods of dispensing drugs for oral therapy; they may slip or be dislodged by the tongue or teeth, may be uncomfortable to a greater or lesser degree, and may interfere with the normal oral functions to some extent. Recent dQvelopments in the art are directed toward delivering the therapeutic agent directly to the periodontal pocket, in some caseC in a controlled release formulation. Gordon et al. have described the use of a drug-filled polymer hollow fiber. (J.M.
Goodson et al., NPeriodontal Therapy by Local Delivery of Tetracycline," J. Clin. Periodontol. 6, 83 (1979), J. Lindhe et al., "Local Tetracycline Delivery Using Hollow Fiber Devices in Periodontal Therapy, H J. Clin.
Periodontol. 6, 141 (1979) and R.L. Dunn t al., "Monolithic Fibers for Controlled Delivery of Tetracycline, n in Proc. Ninth Int. Symposium on Controlled Release of Bioactive Material~, Ft.
Lauderdale, FL, July (1982).) This device is tied around a tooth and qently pressed below the m~rgin of 1 3"?3~5 the ging~va ~o that lt resides in the perlodontal pocket, and i6 capable of delivering an effective dose of 2.5 microgram6 o$ tetracycline per day per periodontal pocket for A prolonged period of a week or more. Similar result6 have been obtained by Coventry and Newman (J. Coventry and H.N. Newman, ~Experimental U6e of a Slow Relea6e Device employing Chlorhexidine Gluconate in Area6 of Acute Periodontal Infla~mation,"
J. Clin. Periodontol. 9, 129 (1982)) and Addy et al.
(M. Addy et al., ~The Development and in vitro Evaluation of Acrylic Strip6 and Dialy~i6 Tubing for Local Drug Delivery," J. Peridontol. 53, 693 (1982)) using acrylic 6trips lmm or more long, impregnated with chlorhexidine, tetracycline or metronidazole, which were in6erted into the periodontal pocket with tweezer6. Such a fitrip, formed from ethylcelluloge impregnated with metronidazole, $8 di6closed by Loesche in U.S. Patent No. 4,568,538 (February 1986).
Another ~trip, employing a water 601uble polymer of a particular elasticity and vi6c08ity, i~ disclosed by Suzuki et al. in U.S. Patent No. 4,569,837. Although the6e devices may be able to dispen6e an appropriate drug for a time ~pan of a week or more, they are inappropriate to wide6pread u6e becausQ they are difficult and time con6uming to apply and may be di610dged by the patient during normal oral functiong.
The drug relea6ing microparticle system that i6 propo6ed below overcomes all of the6e previou6 difficulties, and provide6 a drug formulation which i6 ea6ily applied and capable of delivering ~ntibiotic6 or other drug6 reliably to the periodontal pocket for ~ prolonged period of time, without interfering in any way with the normal oral function6.
1 3'`93~, 5 SUMMARY OF THE INVENTION
This invention is a controlled release drug delivery system for placement in the periodontal pocket. The system comprises microparticles or microcapsules, hereinafter referred to as microparticles, suspended in a pharmaceutically acceptable carrier medium. The microparticles are between 10 and 500 microns in size, and consist of an active agent dispersed within or encapsulated by a rate-controlling polymer matrix.
Thus, the invention provides a controlled release drug delivery system for placement in the periodontal pocket, comprising:
(a) a plurality of discrete microparticles, between 10 and 500 microns in size, consisting of a drug-containing biodegradable polymer and the drug dispersed therein, and (b) a fluid suspending medium for the said microparticles;
the said drug delivery system remaining active in the periodontal pocket for a period of between one and 30 days.
Microparticles of this specification can be prepared by a variety of well-established technigues, for example solvent evaporation, coacervation or spray-drying. The active agent may be one of a broad spectrum of drugs, including, but not limited to, antibiotics, anti-inflammatory agents, local anesthetics and so on. The polymer matrix may be chosen from a range of medically suitable materials and varied to provide the required release rate for the drug involved. Embodiments employing biodegradable polymers can limit the life of the microparticles to a month or two and prevent microparticle entrapment in the periodontal pocket A~ 4 1 3"~3~5 for excessive periods of time.
The carrier medium may be an aqueous solution, paste or gel. In general the properties required are that it should be pharmaceutically acceptable (non-toxic and non-allergenic), promote good adhesion in the periodontal pocket, and have a high permeability for the active agent involved. A preferred embodiment of the invention employs a thermally gelling polymer such as Pluronic~ F127 from BASF Wyandotte. In aqueous solution this polymer is a free-flowing fluid at room temperature, but gels rapidly above 30~. Embodiments of the invention are introduced into the periodontal 1 3r'931~ 5 pockets of the patient by a denti¢t or phy6ician using a 6yringe and a fine rubber tube. The ~y6t-m then re6ides ln the pocket, unfalt by the patient and reliably delivering a ~teady dose of the chosen medication.
An ob;ect of the invention is to provide a 6y6tem to deliver a drug or other active Agent to the periodontal pocket at a steady do6age level which can be ustained for a period of day~ or week6.
Another ob~ect of th~ invention i~ that the 6aid sy~tem 6hould be comfortable in u6e, 6hould not interfere with the normal oral functions and 6hould not be easily di610dged by the patient.
A further object i8 that the 6aid sy6tem ~hould be capable of insertion in a 6imple manner, and ~hould not require the u6e of undue time or exceptional experti6e on the part of the denti6t or physician involved.
Other ob~ect~ and advantage6 of the present invention will be apparent from the following description.
BRIEF DESCRIPTION QF THE DRAWINGS
Fig. lA ~how6 the normal human gingival 6ulcus.
Fig. lB 6hows the effect of periodontal disea6e, where the 6ulcus ha6 deepened to form ~ periodontal pocket.
Fig. 2 i6 a graphic repre6entation of the gelling 2S characteri6tic6 of aqueous PluronicF127 ~olution6.
Fig. 3 6how6 the 601vent ovaporation techn$gue u6ed to prepare microparticle6.
1 3"q3~ 5 Fig. 4 i6 a graphic repre6entation of the in vitro drug relea6e rate of tetracycline from polysulfone microparticle~.
Fig. 5 i6 a graphic representation of the in vitro drug relea6e rate of flurbiprofen from ethylcellulo6e particles.
DETAILED ~ESCRIPTION OF THE INVENTION
~Active agent" as u6ed herein broadly includes any composition or compound of matter which when di6pen6ed in the cho6en environment of u6e produce6 a predetermined, beneficial and u6eful re6ult.
"Drug" a6 u6ed herein broadly includes physiologically or pharmacologically active 6ub6tance6 for producing a localized effect at the admini6tration site or a 6y6temic effect at a ~ite remote from the admini6tration site.
Referring now to Fig. 1, Fig. lA 6how6 the normal human gingival ~ulcu6. The alveolar bone cre6t 1 i6 undamaged. The depth from the crown 2 to the epithelial attachment 3 i~ around 2 or 3 mm. Between the crown 2 and the free gingiva 4 i6 the healthy gingival ~ulCU6 5. In contra6t Fig. lB show6 the effect of periodontal di6ea6e. The alveolar bone cre6t 1 ha6 been eroded; the depth from the crown 2 to the epithelial attachment 3 has increa6ed con6ider2bly, and the normal sulcus has deepened to form a periodontal pocket 6.
Suitable drug6 whlch can be admini6tered in the drug delivery ffy6tem of the pre6ent invention include but are in no way limited to antibacterial agents 6uch as thimerosal, chloramine, boric acid, phenol, iodoform, 1 ) , 3 ~,:
chlorhexidine and other oral antiseptics, ~-lactam antibiotic6, for example cefoxitin, n-formamidoyl thienamycin and other thienamycin derivatives, tetracyclines, chloramphenicol, neomycin, gramicidin, kanamycin, amikac~n, 6i6micin and tobramycin; anti-inflammatory ~teroids ~uch a6 corti60ne, hydrocorti60ne, beta-methasone, dexametha60ne, fluocortolone, predni~olone, triamcinolone and the like; non-~teroidal anti-inflammatory drugs including flurbiprofen, lbuprofen, lndomethacin, piroxicam, naproxen, antipyrine, phenylbutazone and a6pirin for example; plague di6solving substances, for example ly60zyme chloride or amyla6e; and local anesthetic6 such as lidocaine, procaine, benzocaine, xylocaine and 60 on.
The sy6tem comprises a plurality of microparticles or microcap6ules between 10 and 500 microns in ~ize, 6uspended in a pharmaceutically acceptable carrier.
Microparticle6 in this context are defined a6 re6ervoir sy6tem6 in which a simple reservoir of active agent iB ~urrounded by a membrane ~hell;
microparticle6 are 6mall monolithic entitie~ in which the active agent i8 randomly di6per6ed through the particle matrix. Many practical formulation6 fall between the6e two definition6; for example microcap6ule6 often agglomerate during the microencapsulation process, while the 6ize of the active agent particle6 contained in ~ microparticle 6y6tem i6 often of the ~ame order a6 the size of the microparticles themselves. In the following discus6ion then, Nmicroparticle" will be defined to ~ean microparticle, microcapsule or any intermediate form. Variou6 physical and chemical method6 ~or preparing microparticle6 have been developed over the pa6t twenty year6 and the technology i6 well 7 L ~
establi6hed and well documented. See for example Patrick B. Deasy, Microencap6ulation and Related Drug Proces6es, Marcel Dekker Inc., New York, 1984. The more important method6 are de6cribed below, and depending on the chemical and phy6ical propertie6 of the desired embodiment, any of these could be used to prepare the microparticles.
Coacervation wa6 the fir6t microencap6ulation technique and remains one of the most widely u6ed.
Coacervation usually involve6 four 6tep6. Fir6t a di6per6ion or emulsion of the active agent i6 prepared in an agueou6 polymer solution. Secondly, the polymer i6 cau6ed to precipitate BlOWly by ~ome means:
addition of a non-601vent, cooling, change of pH or ionic strength, or addition of an incompatible polymer solution for example. Under the6e conditions, most polymer6 initially precipitate a6 a highly 6wollen liquid polymer pha6e, th~6 phenomenon being known a6 coacervation. During the precipitation, the liquid phase coat~ the di6per6ed active agent droplet6.
Finally the microparticles thus formed are ~eparated from the eolvent/non-solvent mixture, dried and 6ieved into different size ~raction~. Most industrial coacervation proce6ses u6e agueou6 ~olution~ of gelatin and other water ~oluble polymer6 ~nd can only encap6ulate hydrophobic, water in601uble agents di6601ved in an organic solvent. However the proce6s can be inverted by u6ing organic-601vent-601uble polymer6 with organic-601vent-insoluble active agent6 di6solved in an ~queou6 solu~ion. Since many drugs are at lea6t moder~tely water 601uble, thi6 ~akes the proce~6 appropriate to the preparation of microencap6ulated pharmaceutical~. For example ethylcellulose ha6 been used to prepare microparticles containing a6pirin, indomethacin, paracetamol, 1 3"934~
theophylline and vitam~ns among others. The main disadvantage of the coacervatlon technigue i~ that it requires considerable skill to produce particles with consistent properties, since the particle 6ize8 and wall thickness may vary widely.
Interfacial polymerization occur6 when two reactiqe monomer6, each in different immiscible liquid6, are brought into contact. The monomers are able to react only at the interface of the two 601ution~, where a polymer film form6. When one ~olution i6 dispersed in the other, the polymer film formed encapsulates the disper~e pha6e. Thi~ procaB8 iB not widely used for the commercial preparation of pharmaceuticals because of various practical problems; toxicity of remaining unreacted monomer, drug degradation a a re6ult of reaction with the monomer, high permeability of the encapsulating polymer to the active agent involved, fragility of the capeules produced and non-biodegradability of the particles amongst others.
However extensive reasearch work has been done on the coating of high-molocular-weight biological material6 such a6 enzymes with polyamides, and recently McGinity et al. have successfully encapsulated caffeine, 60dium salicylate, theophylline and other drugs ln a nylon coated particle by this technique. (J.W. McGinity et al., nInfluences of matrices on nylon-encapsulAted pharmaceutical6," J. Pharm. Sci. 70, 372-37S (1981).) Solvent evaporation is another technique which is appropriate for the encapsulaton of a water-soluble drug. Firfit the polymer matrix material 1~ di~olved in an organic ~olvent. Adding the active agent, dissolved in water, nnd emulsifying, produces a water-in-oil emul~ion. This emulsion is re-emul6i~ied in an aqueous ~olution, forming a water-in-oil-in-water 1 3''9345 emul~ion. Thi6 final aqueous eolution usually contains a polymer ~uch as gelatin, to prevent aggregation. The Bolvent iB then removed under reduced pres6ure to form a hard outer wall to the particle6. Hydrophobic agent~ may a1B0 be prepared by ~olvent evaporation, but in thi~ ca6e the procedure i6 modified by fir6t preparing an oil-in-water emul6ion of the agent. This proce6~ ha6 been used for example by Wakiyama et al. to prepare microparticle6 of butam~en, tetracaine, and dibucaine, where the polymer material used was polyalactic acid in a 601ution of methylene chloride, methyl acetate or ethyl acetate.
(N. Wakiyama et al., "Preparation and evaluation in vitro of polylactic acid microspheres containing local ane6thetics," Chem. Pharm. Bull. 29, 3363-68 (1981).) Recently Ko;ima et al. used the 601vent evaporation technique to enclose various local ane~thetics in polycarbonate microsphere6: Eustained drug-release time6 measured in hundreds of hour6 resulted. (Chem.
Pharm. Bull. 32, 2795-2802 (1982).) Finally a number of simple phy6ical technigues can be u6ed to prepare microp~rticles, and 6pray drving, for example, 16 widely u6ed in the preparation of food or pharmaceutical flavors. Spray dried particles are le66 sati6factory for preparing drugs however, a6 the particles tend to be non-uniform and the coating porous, cau6ing the active agent to di6perse too rapidly for a controlled-relea6e application. However several penicillin6 have been microencapsulated in ethylcellulose in this way. See ~or instance U.S.
Patent No. 4,016,254 (April 1977).
The polymer matrix material chosen should be pharmaceutically acceptable, 601uble in a variety of suitable ~olvents and available in different grade6 to 1 3r93/l5 enable the release rate of the active agent to be controlled. Cellulose acetate and ethyl cellulose have A good record of acceptability ln ~edical applications. Polystyrene, poly6ulfone ~nd polycarbonate are possible choices for use with antibiotics such as tetracycline. Exper$ments described in the Examples below showed that tetracycline release from poly6ulfone and polystryene was extremely 810w, and that polycarbonate release values were much more satisfactory; however different results could well be obtained with different drug6.
Biodegradable polymers ~uch a6 the lactic-glycolic acid copolymer6 from Hexel Corporation of Hayward, California offer a distinct advantage, in that they lS have been found to biodegrade over a period of 4 to 12 weeks, and thu6 could prevent particles becoming trapped in the periodontal pocket indefinitely. Work on the u6e! of such polymers for controlled release drug di6pensing ha~ been carried out by 6everal researchers. (For example, D.A. Wood, Int. J.
Pharmaceut. 7, l (1980).) A paper of Setterstrom et al. in Polym. Mater. 8ci. Eng., 53, 620-626 (1985) de6cribes the use of ampicillin microencap6ulated in poly~DL-lactide-co-glycolide) for topical application to wound6; effective levels of antibiotic are detectable At the wound slte for at least ~ourteen day~. The ~ize of the microparticles should be limited to between lO and 500 microns. Very 6mall particles with consi6tent properties are dif~icult to prepare and they may wash out of the periodontal pocket rather easily. Particles larger than 500 micron~ may be too large to deliver with ~yringe and rubber tube and may be uncomfortable or irritating to the gingival membranes.
1 3"q-~45 The theory of drug release from 601id microsphere6 was developed by ~iguchi (T. Hlguchi, J. Pharm. ~ci. 52, 1145 (1963)). The relea6e i~ controlled by the equation 2 [ [ ~t ]2/3 Mt ) 3P-t Mt/M0 i~ the fraction of total drug released after time t from a particle of radius rO. The drug permeability in the matrix i~ P and the drug loading i5 Co~ This equation can be u6~d to limit further the ~ize of the microparticles, and to select an appropriate drug loading, ~o that the desired do6age level and relea~e rate for the cho6en e~bodiment is obtained.
The carrier medium used to contain the microparticles must conform to eeveral requirement~. First it ~hGuld be biocompatible, non-toxic ~nd non-allergenic.
Secondly it should have a low solubility but a high permeability for the dug in question. A low 601ubility i~ nece6sary to minimize leaching of the drug fron the microparticle during 6torage. ~igh permeability i~ required in order that the drug be well conducted from the microparticle to the mucous membrane6. Thirdly it ~hould promote good adhesion of the microparticles in the periodontal pocket, and la6t it ~hould have an appropriate v~sco6ity for the intended use. The choice of medically ~cc~ptable carrier6 i~ very wide and can include amongst other~, water, aqueou6 ~olutlon~, 6yrups, alcohol~, glycerine, mineral oil, vegetable oils, ~ynthetic mucilage-like ~ubstance6 ~uch ~6 polyvinyl alcohol, carboxymethylcellulose and BO on. Further examples ? ~ 4 ^`
which may be mentioned are the water soluble polymers li6tad by Suzuki et al. ln U.S. Pat. No. 4,S69, 837, col. 4, llnes 9 through 21. Simple saline solutione and similar aqueous ~olutions can be u6ed, but may be wa6hed out o~ the periodontal pocket rather guickly and easlly. A preferred alternative i6 one of the thicker, viecou6 media ~uch a6 carboxymethylcellulo6e.
In general, the more viecou6 the medium, the better it will adhere in the periodontal pocket; however highly vi6cous carriers may be difficult to insert with a syringe and rubber tube and con6equently may not spread through the pocket to any u6eful extent. An e6pecially preferred form then is a thermally gelling polymer, 6uch as tho6e vehicles di6clo6ed by Krezanowski in U.S. Patent No. ~,188,373. The Pluronic~ serie~ of polyoxypropylene-polyoxyethylene copolymer6, marketed by BASF Wyandotte, Par6ippany, New Jer6ey, conta~n6 several 6uitable example6. The6e polymere are compatible with many commonly used pharmaceutical materials, and have been approved by the FDA for medical u6e. The Pluronic eeries can be obtained in a range of molecular weights and compo6itions; thus the carrier formulation may be tailored for optimum performance in the environment of the lnvention. F~g. 2 shows graphically the gelling temperature of aqueous PluronicF127 solution~ of different concentrations. Because of hydrogen bonding, the viscosity of the eolutions increasee greatly with temperature. Pluronic concentration6 of 20 wt% have ideal characteri6ticQ, being free-flowing fluids at room temperature, but gelling rapidly at 30C or above. Thus these eolutions are amenable to delivery by the ~yringe/rubber tube method, but quickly take on the nece6sary visco6ity for good adhesion and durability once resident within the periodontal pocket. Optionally, a eelf-gelling 1 3nq34~
preparation such as those disclo6ed by Caslav~ky et al., in U.S. Patent No. 4,563,351 (Jan. 1986~ could be u6ed for the carrier medium.
Polycarbonate was used to prepare microparticles by the 601vent evaporation proces~. The drug used was tetracycline fr¢e ba~e (TFB). The aqueous phase was saturated with TFB before starting a microparticle preparation run. In this way migration of the TFB
into the aqueous phase during particle formation was minimized, and it wa6 possible to encapsulate 70 to 100% of the TFB u~ed. Fig. 3 6hows the apparatus used to prepare the microparticles. Known amount6 of TF~
and polycarbonate dissolved in methylene chloride were added to the aqueous pha~e 7 containing polyvinyl alcohol (PVA) and 3ppm n-octanol. The PVA is an emulsifier and the n-octanol an anti-foaming agent.
Air was continuou61y passed over the ~olution by means of the vacuum pump 8. A stirrer 9 driven by a motor 10 kept the 601utlon 6tirred and aa the methylene chloride evaporated, the Qmulsion droplet~ 11 ~olidified. The micropartlclee thus formed were separated from the aqueous solution, dried and sieved to obtain three size factions; 50-110 microns, 110-210 microns and 210-500 microns. The in vitro drug release rate was mea6ured by di6persing a known amount of microparticlQs in a volume of agueous saline solution (0.9~ NaCl). The dispersion was 6tlrred and kept at a temperature of 37~C. Samples were periodically removed and diluted and their antibiotic concentration determined by W spectrophotometry. The total tetracycline content of the microparticles was determined in a similar way by dissolving a known amount of microparticle~ and mea~uring the antibiotic concentratlon. The presence of the matrix poly~er in the 601ution does not interfere with the W
measurements. A typical re6ult i6 shown by the upper curve in Fig. 4. The initial relea6e rate was high for a couple of hours, then remained fairly steady until it tapered off at time6 in exces6 of 25 hour6.
Drug loading6 between 18 and 35wt% were u6ed. The release curve6 for the three 6ize fraction6 were closely bunched, and lt appeared that the 6ize of the microparticles i8 relatively unimportant a~ far a~ the drug kinetic6 are concerned but 6hould be limited rather by the practical con6ideration6 of ea6e of manufacture, convenience of in~ertion and comfort in use. ~hese experiment6 6howed that microparticle6 made of polycarbonate containing 18 to 35wt%
tetracycline and ranging in size from 50 to 500 micron6 were capable of delivering tetracycline in a 6u6tained fa6hion for period6 of about 25 hour6.
Since the periodontal pocket iB 6mall and it~ fluid exchange rate 610w, the flow of gingival fluid in a ~ingle periodontal pocket being of the order of 10 microliters per hour, thi6 in vitro relea6e rate i6 estimated to corre6pond to an in vivo release period of the order o~ 10 to 20 day6.
The method as de6cribed in Example 1 wa6 u6ed to prepare microparticle6. Polysulfone was cho6en a6 the matrix material: the drug u6ed wa6 ~FB. A typical relea6e curve is shown in Fig. 4. A6 can be seen the drug release rate was very ~low, only a ~mall fraction of the totAl drug loading having been relea6ed after 24 hour6. Although too ~low to be within the parameters for optimum treatment of periodontal di6ea6e, this combination of drug and matrix would be appropriate to embodiment~ of the invention calling for a very ~mall dosage level over a long ~me period.
I ~"'S4-) ~ XAMPLE 3 A ~eries of flurb~profen microcapsules sultable for use in a periodontal formulation was prepared by the solvent evaporation method. Varying ~mounts of ilurbiprofen were dissolved in ethylcellulose (medium ethoxy, vi3co~ity 100 (Dow Chemical Co., Midland, MI)) in MeC12 601ution. Fifteen ml of thi6 ~olution were emul6ified in 600 ml of aqueous 60 bloom gelatin (.25%
as an emulsifier) being stirred at 500 rpm. ~wo drops of octanol were also added to eliminate any foam. The MeC12 was allowed to evaporate at 30C. After 55 minutes the stirrer was shut off and the mixture was allowed to ~ettle. The hollow cap6ules floating on the surface were decanted and the remaining capsules were collected on fine filter paper using a buchner funnel. The capsules were then placed in a foil dish in a dehumidifying cabinet. The drug release rates of the ethylcellulose cApsules with varying drug contents were measured. These result~ are shown in Figure 5.
The flurbiprofen content of various batche6 of 2 0 miCroCap8UleB iB also shown on thi~ figure. As ~hown, the microcapsule delive n rate can be varied over a wide range by varying the drug to polymer ratio in the microcapsules.
Claims (12)
1. A controlled release drug delivery system for placement in the periodontal pocket, comprising:
(a) a plurality of discrete microparticles, between 10 and 500 microns in size, consisting of a drug-containing biodegradable polymer and the drug dispersed therein, and (b) a fluid suspending medium for the said microparticles;
the said drug delivery system remaining active in the periodontal pocket for a period of between one and 30 days.
(a) a plurality of discrete microparticles, between 10 and 500 microns in size, consisting of a drug-containing biodegradable polymer and the drug dispersed therein, and (b) a fluid suspending medium for the said microparticles;
the said drug delivery system remaining active in the periodontal pocket for a period of between one and 30 days.
2. The delivery system of claim 1, wherein the drug is selected from the group comprising antimicrobial drugs, anti-inflammatory drugs and local anesthetics.
3. The delivery system of claim 1, wherein the drug is an antibiotic.
4. The delivery system of claim 1, wherein the drug is chosen from the group comprising tetracycline, its compounds and derivatives.
5. The delivery system of claim 1, wherein the drug is chosen from the group comprising chlorhexidine, its compounds and derivatives.
6. The delivery system of claim 1, wherein the drug is flurbiprofen.
7. The delivery system of claim 1, wherein the said drug-containing polymer is chosen from the group comprising cellulose acetate, ethylcellulose, polystyrene, polysulfone, polycarbonate and the lactic-glycolic acid co-polymers.
18a
18a
8. The delivery system of Claim 1, wherein the said drug-containing polymer is polycarbonate.
9. The delivery system of Claim 1, wherein the said drug-containing polymer is chosen from the group of lactic-glycolic acid co-polymers.
10. The delivery system of Claim 1, wherein the said microparticles are between 10 and 500 microns in size.
11. The delivery system of Claim 1, wherein the fluid suspending medium has a viscosity of at least 1000 centipoise.
12. The delivery system of Claim 1, wherein the fluid suspending medium is a thermally gelling fluid, the said fluid having a sol/gel transition temperature between 25 and 40°C and being a free-flowing liquid below the transition temperature and a thickened non-flowing gel above the transition temperature.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US856,961 | 1986-04-29 | ||
| US06/856,961 US4780320A (en) | 1986-04-29 | 1986-04-29 | Controlled release drug delivery system for the periodontal pocket |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1309345C true CA1309345C (en) | 1992-10-27 |
Family
ID=25324860
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000535738A Expired - Fee Related CA1309345C (en) | 1986-04-29 | 1987-04-28 | Controlled release drug delivery system for the periodontal pocket |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US4780320A (en) |
| EP (1) | EP0244118B1 (en) |
| JP (1) | JP2698353B2 (en) |
| AU (1) | AU614061B2 (en) |
| CA (1) | CA1309345C (en) |
| DE (1) | DE3787829T2 (en) |
| DK (1) | DK219287A (en) |
| MX (1) | MX167175B (en) |
| NO (1) | NO177125C (en) |
| NZ (1) | NZ219948A (en) |
Families Citing this family (136)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62223112A (en) * | 1986-03-25 | 1987-10-01 | Rooto Seiyaku Kk | Remedy for periodontosis |
| US5500228A (en) * | 1987-05-26 | 1996-03-19 | American Cyanamid Company | Phase separation-microencapsulated pharmaceuticals compositions useful for alleviating dental disease |
| US5013553A (en) * | 1987-06-30 | 1991-05-07 | Vipont Pharmaceutical, Inc. | Drug delivery devices |
| US5175000A (en) * | 1987-06-30 | 1992-12-29 | Vipont Pharmaceutical, Inc. | Free amine benzophenanthridine alkaloid compositions |
| US4843099A (en) * | 1987-07-20 | 1989-06-27 | Colgate-Palmolive Company | Device and composition for treatment of the gums |
| US5632727A (en) * | 1988-10-03 | 1997-05-27 | Atrix Laboratories, Inc. | Biodegradable film dressing and method for its formation |
| US4938763B1 (en) * | 1988-10-03 | 1995-07-04 | Atrix Lab Inc | Biodegradable in-situ forming implants and method of producing the same |
| US5324520A (en) * | 1988-12-19 | 1994-06-28 | Vipont Pharmaceutical, Inc. | Intragingival delivery systems for treatment of periodontal disease |
| US5236355A (en) * | 1988-12-22 | 1993-08-17 | American Cyanamid Company | Apparatus for the treatment of periodontal disease |
| ATE111729T1 (en) * | 1988-12-22 | 1994-10-15 | American Cyanamid Co | PHASE SEPARATION MICRO-ENCAPSULATED MEDICINAL COMPOSITION TO REDUCE DENTAL DISEASE. |
| EP0374531B1 (en) * | 1988-12-22 | 1994-05-04 | American Cyanamid Company | Method for the treatment of periodontal disease by sustained delivery of a therapeutic agent to the periodontal pocket, composition of matter therefor and apparatus for the administration thereof |
| US5007790A (en) * | 1989-04-11 | 1991-04-16 | Depomed Systems, Inc. | Sustained-release oral drug dosage form |
| US5324519A (en) * | 1989-07-24 | 1994-06-28 | Atrix Laboratories, Inc. | Biodegradable polymer composition |
| US5487897A (en) * | 1989-07-24 | 1996-01-30 | Atrix Laboratories, Inc. | Biodegradable implant precursor |
| US5077049A (en) * | 1989-07-24 | 1991-12-31 | Vipont Pharmaceutical, Inc. | Biodegradable system for regenerating the periodontium |
| US5143934A (en) * | 1990-11-21 | 1992-09-01 | A/S Dumex (Dumex Ltd.) | Method and composition for controlled delivery of biologically active agents |
| US5198220A (en) * | 1989-11-17 | 1993-03-30 | The Procter & Gamble Company | Sustained release compositions for treating periodontal disease |
| US4997830A (en) * | 1990-02-07 | 1991-03-05 | The Research Foundation Of State University Of New York | Pharmaceutical composition for the treatment of periodontitis |
| US5464609A (en) * | 1990-03-16 | 1995-11-07 | The Procter & Gamble Company | Use of ketorolac for treatment of oral diseases and conditions |
| AU629316B2 (en) * | 1990-04-11 | 1992-10-01 | Flora Inc. | Periodontal disease treatment system |
| USRE37950E1 (en) | 1990-04-24 | 2002-12-31 | Atrix Laboratories | Biogradable in-situ forming implants and methods of producing the same |
| US5290271A (en) * | 1990-05-14 | 1994-03-01 | Jernberg Gary R | Surgical implant and method for controlled release of chemotherapeutic agents |
| US5059123A (en) * | 1990-05-14 | 1991-10-22 | Jernberg Gary R | Periodontal barrier and method for aiding periodontal tissue regeneration |
| US5197882A (en) * | 1990-05-14 | 1993-03-30 | Gary R. Jernberg | Periodontal barrier and method for aiding periodontal tissue regeneration agents |
| CA2065156A1 (en) * | 1990-07-03 | 1992-01-04 | Richard L. Dunn | Intragingival delivery systems for treatment of periodontal disease |
| US5620700A (en) * | 1990-10-30 | 1997-04-15 | Alza Corporation | Injectable drug delivery system and method |
| WO1992007555A1 (en) * | 1990-10-30 | 1992-05-14 | Alza Corporation | Drug delivery system and method |
| US5770588A (en) * | 1991-02-11 | 1998-06-23 | The Research Foundation Of State University Of New York | Non-antibacterial tetracycline compositions of the prevention and treatment of root caries |
| BR9206408A (en) * | 1991-08-23 | 1994-11-22 | Gillette Canada | Oral brush, extended release matrix, process for releasing an antimicrobial agent from an oral brush and for releasing an antimicrobial agent in an animal's mouth and an oral wear indicator brush |
| US5340581A (en) * | 1991-08-23 | 1994-08-23 | Gillette Canada, Inc. | Sustained-release matrices for dental application |
| US5906834A (en) * | 1992-06-15 | 1999-05-25 | The Gillette Company | Color changing matrix as wear indicator |
| US5211939A (en) * | 1991-09-13 | 1993-05-18 | Gillette Canada | Method for desensitizing teeth |
| US5250288A (en) * | 1991-09-13 | 1993-10-05 | Gillette Canada, Inc. | Method for desensitizing teeth |
| WO1993005680A1 (en) * | 1991-09-13 | 1993-04-01 | Gillette Canada Inc. | Polymeric particles for dental applications |
| AU704007B2 (en) * | 1991-09-13 | 1999-04-01 | Gillette Canada Inc. | Toothbrushes |
| US5364634A (en) * | 1991-11-08 | 1994-11-15 | Southwest Research Institute | Controlled-release PH sensitive capsule and adhesive system and method |
| DE4140183C2 (en) * | 1991-12-05 | 1995-12-21 | Alfatec Pharma Gmbh | Retard form for a medicine containing flurbiprofen |
| DE4140184C2 (en) * | 1991-12-05 | 1995-12-21 | Alfatec Pharma Gmbh | Acute form for a medicine containing flurbiprofen |
| EP0560014A1 (en) * | 1992-03-12 | 1993-09-15 | Atrix Laboratories, Inc. | Biodegradable film dressing and method for its formation |
| EP0633907A1 (en) * | 1992-03-30 | 1995-01-18 | Alza Corporation | Additives for bioerodible polymers to regulate degradation |
| WO1993019739A1 (en) * | 1992-03-30 | 1993-10-14 | Alza Corporation | Viscous suspensions of controlled-release drug particles |
| US5700485A (en) * | 1992-09-10 | 1997-12-23 | Children's Medical Center Corporation | Prolonged nerve blockade by the combination of local anesthetic and glucocorticoid |
| US5922340A (en) | 1992-09-10 | 1999-07-13 | Children's Medical Center Corporation | High load formulations and methods for providing prolonged local anesthesia |
| EP0659073B1 (en) * | 1992-09-10 | 2001-12-19 | Children's Medical Center Corporation | Biodegradable polymer matrices for sustained delivery of local anesthetic agents |
| US5242910A (en) * | 1992-10-13 | 1993-09-07 | The Procter & Gamble Company | Sustained release compositions for treating periodontal disease |
| US5447725A (en) * | 1993-06-11 | 1995-09-05 | The Procter & Gamble Company | Methods for aiding periodontal tissue regeneration |
| EP0707465A4 (en) * | 1993-07-08 | 1997-04-16 | Cygnus Therapeutic Systems | Monolithic matrix transdermal delivery system |
| WO1995022308A1 (en) * | 1994-02-17 | 1995-08-24 | The Oralife Group, Inc. | Method for the diagnosis and reduction of dental caries |
| US5502092A (en) * | 1994-02-18 | 1996-03-26 | Minnesota Mining And Manufacturing Company | Biocompatible porous matrix of bioabsorbable material |
| JPH09511666A (en) * | 1994-04-08 | 1997-11-25 | アトリックス・ラボラトリーズ・インコーポレイテッド | Ancillary polymer systems for use in medical devices |
| PT754032E (en) * | 1994-04-08 | 2002-05-31 | Atrix Lab Inc | LIQUID COMPOSITIONS FOR DIFFUSE |
| US5725869A (en) * | 1994-06-20 | 1998-03-10 | Zeneca Limited | Microsphere reservoirs for controlled release application |
| US5616315A (en) * | 1994-10-13 | 1997-04-01 | Gillette Canada Inc. | Particles including degradable material and anti-microbial agent |
| US5660817A (en) * | 1994-11-09 | 1997-08-26 | Gillette Canada, Inc. | Desensitizing teeth with degradable particles |
| US5607686A (en) * | 1994-11-22 | 1997-03-04 | United States Surgical Corporation | Polymeric composition |
| US5779471A (en) * | 1995-03-08 | 1998-07-14 | Gillette Canada Inc. | Delivery of substance to the mouth |
| AU706541B2 (en) | 1995-06-09 | 1999-06-17 | Euro-Celtique S.A. | Formulations and methods for providing prolonged local anesthesia |
| US5747060A (en) * | 1996-03-26 | 1998-05-05 | Euro-Celtique, S.A. | Prolonged local anesthesia with colchicine |
| SE9601421D0 (en) * | 1996-04-12 | 1996-04-12 | Astra Ab | New composition |
| US5939047A (en) * | 1996-04-16 | 1999-08-17 | Jernberg; Gary R. | Local delivery of chemotherapeutic agents for treatment of periodontal disease |
| AU713276B2 (en) * | 1996-05-23 | 1999-11-25 | Samyang Corporation | Locally administrable, biodegradable and sustained-release pharmaceutical composition for periodontitis and process for preparation thereof |
| AU733867B2 (en) | 1996-06-24 | 2001-05-31 | Euro-Celtique S.A. | Methods for providing safe local anesthesia |
| US6046187A (en) * | 1996-09-16 | 2000-04-04 | Children's Medical Center Corporation | Formulations and methods for providing prolonged local anesthesia |
| US5972389A (en) * | 1996-09-19 | 1999-10-26 | Depomed, Inc. | Gastric-retentive, oral drug dosage forms for the controlled-release of sparingly soluble drugs and insoluble matter |
| US5918609A (en) * | 1996-10-24 | 1999-07-06 | Gillette Canada Inc. | Particulate modified elastomeric flosses |
| US5941256A (en) * | 1996-12-24 | 1999-08-24 | Gillette Canada Inc. | Dental hygiene article |
| ES2130969B1 (en) * | 1997-02-24 | 2000-02-16 | Univ Valencia Estudi General | BIOMEMBRANES FOR EXTEMPORANEOUS ENCAPSULATION OF TETRACAINE. |
| KR100508229B1 (en) | 1997-03-18 | 2005-08-17 | 선스타 가부시키가이샤 | Composition for forming solid particles |
| FR2764514B1 (en) * | 1997-06-13 | 1999-09-03 | Biopharmex Holding Sa | IMPLANT INJECTED IN SUBCUTANEOUS OR INTRADERMAL WITH CONTROLLED BIORESORBABILITY FOR REPAIR OR PLASTIC SURGERY AND AESTHETIC DERMATOLOGY |
| AU739384B2 (en) * | 1997-07-02 | 2001-10-11 | Euro-Celtique S.A. | Prolonged anesthesia in joints and body spaces |
| US6123957A (en) * | 1997-07-16 | 2000-09-26 | Jernberg; Gary R. | Delivery of agents and method for regeneration of periodontal tissues |
| US6153210A (en) * | 1997-08-14 | 2000-11-28 | Periodontix, Inc. | Use of locally delivered metal ions for treatment of periodontal disease |
| US7846919B2 (en) * | 1998-02-10 | 2010-12-07 | Dermex Pharmaceuticals, Llc | Chelated 8-hydroxyquinoline and use thereof in a method of treating epithelial lesions |
| US7128927B1 (en) | 1998-04-14 | 2006-10-31 | Qlt Usa, Inc. | Emulsions for in-situ delivery systems |
| US6451335B1 (en) | 1998-07-02 | 2002-09-17 | Euro-Celtique S.A. | Formulations and methods for providing prolonged local anesthesia |
| US6153225A (en) * | 1998-08-13 | 2000-11-28 | Elan Pharma International Limited | Injectable formulations of nanoparticulate naproxen |
| US6165506A (en) * | 1998-09-04 | 2000-12-26 | Elan Pharma International Ltd. | Solid dose form of nanoparticulate naproxen |
| US8226598B2 (en) | 1999-09-24 | 2012-07-24 | Tolmar Therapeutics, Inc. | Coupling syringe system and methods for obtaining a mixed composition |
| DE19957918A1 (en) | 1999-11-25 | 2001-06-13 | Ulrich Doht | Disinfectant cleaner for cleaning and care and process for its manufacture |
| US6352711B1 (en) | 1999-11-30 | 2002-03-05 | Phillip Campbell | Lesion and ulcer medication |
| US6555125B2 (en) | 1999-11-30 | 2003-04-29 | Phillip Campbell | Lesion and ulcer medication |
| US6503894B1 (en) | 2000-08-30 | 2003-01-07 | Unimed Pharmaceuticals, Inc. | Pharmaceutical composition and method for treating hypogonadism |
| US6887493B2 (en) * | 2000-10-25 | 2005-05-03 | Adi Shefer | Multi component controlled release system for oral care, food products, nutraceutical, and beverages |
| US6589562B1 (en) | 2000-10-25 | 2003-07-08 | Salvona L.L.C. | Multicomponent biodegradable bioadhesive controlled release system for oral care products |
| US6565873B1 (en) * | 2000-10-25 | 2003-05-20 | Salvona Llc | Biodegradable bioadhesive controlled release system of nano-particles for oral care products |
| US6726898B2 (en) | 2000-11-17 | 2004-04-27 | Gary R. Jernberg | Local delivery of agents for disruption and inhibition of bacterial biofilm for treatment of periodontal disease |
| US6576226B1 (en) | 2000-11-17 | 2003-06-10 | Gary R. Jernberg | Local delivery of agents for disruption and inhibition of bacterial biofilm for treatment of periodontal disease |
| US6610274B1 (en) * | 2000-12-22 | 2003-08-26 | Wallace J. Gardner | Anti-inflammatory composition comprising tetracycline |
| US20040029842A1 (en) * | 2001-12-18 | 2004-02-12 | Gardner Wallace J. | Triglyceride lowering, common cold and pneumonia prevention composition comprising tetracycline, and methods of treating or preventing diseases using same |
| JP4202656B2 (en) * | 2002-02-19 | 2008-12-24 | サンスター株式会社 | Topical sustained-release ointment |
| US7074426B2 (en) * | 2002-03-27 | 2006-07-11 | Frank Kochinke | Methods and drug delivery systems for the treatment of orofacial diseases |
| US20040001889A1 (en) | 2002-06-25 | 2004-01-01 | Guohua Chen | Short duration depot formulations |
| JP4865330B2 (en) | 2002-12-13 | 2012-02-01 | デュレクト コーポレーション | Oral drug delivery system |
| US20050079187A1 (en) * | 2003-10-14 | 2005-04-14 | Gardner Wallace J. | Composition, kit and method for reducing plaque formation, tooth decay and incidence of caries |
| PL2351555T3 (en) * | 2004-02-23 | 2017-06-30 | Euro-Celtique S.A. | Abuse resistance opioid transdermal delivery device |
| US20080019927A1 (en) * | 2004-06-07 | 2008-01-24 | Jie Zhang | Compositions and methods for dermally treating neuropathy with minoxidil |
| US20070189978A1 (en) * | 2004-06-07 | 2007-08-16 | Jie Zhang | Compositions and methods for dermally treating musculoskeletal pain |
| US20070196323A1 (en) * | 2004-06-07 | 2007-08-23 | Jie Zhang | Polyvinyl alcohol-containing compositions and methods for dermal delivery of drugs |
| US8907153B2 (en) | 2004-06-07 | 2014-12-09 | Nuvo Research Inc. | Adhesive peel-forming formulations for dermal delivery of drugs and methods of using the same |
| US20070196457A1 (en) * | 2004-06-07 | 2007-08-23 | Jie Zhang | Two or more volatile solvent-containing compositions and methods for dermal delivery of drugs |
| US20070196452A1 (en) * | 2004-06-07 | 2007-08-23 | Jie Zhang | Flux-enabling compositions and methods for dermal delivery of drugs |
| US20070196453A1 (en) * | 2004-06-07 | 2007-08-23 | Jie Zhang | Two or more non-volatile solvent-containing compositions and methods for dermal delivery of drugs |
| US8741332B2 (en) * | 2004-06-07 | 2014-06-03 | Nuvo Research Inc. | Compositions and methods for dermally treating neuropathic pain |
| US20070190124A1 (en) * | 2004-06-07 | 2007-08-16 | Jie Zhang | Two or more solidifying agent-containing compositions and methods for dermal delivery of drugs |
| US8741333B2 (en) | 2004-06-07 | 2014-06-03 | Nuvo Research Inc. | Compositions and methods for treating dermatitis or psoriasis |
| US20070196293A1 (en) * | 2004-06-07 | 2007-08-23 | Jie Zhang | Compositions and methods for treating photo damaged skin |
| US20070196325A1 (en) * | 2004-06-07 | 2007-08-23 | Jie Zhang | Compositions and methods for dermally treating infections |
| ES2378671T3 (en) | 2004-09-17 | 2012-04-16 | Durect Corporation | Prolonged local anesthetic composition containing SAIB |
| US8940311B2 (en) * | 2004-10-21 | 2015-01-27 | Tae-Hong Lim | In situ controlled release drug delivery system |
| WO2006096893A2 (en) * | 2005-03-10 | 2006-09-14 | Marx Management Cc | Dental barrier composition |
| WO2007002041A2 (en) * | 2005-06-21 | 2007-01-04 | Foster Corporation | Drug-filled polymer films |
| US20070027105A1 (en) | 2005-07-26 | 2007-02-01 | Alza Corporation | Peroxide removal from drug delivery vehicle |
| PT1937276E (en) | 2005-10-12 | 2013-02-21 | Besins Healthcare Luxembourg | Improved testosterone gel and method of use |
| US20070280972A1 (en) * | 2006-04-25 | 2007-12-06 | Zars, Inc. | Adhesive solid gel-forming formulations for dermal drug delivery |
| EP2046360A4 (en) * | 2006-06-30 | 2011-01-26 | Piramal Life Sciences Ltd | Herbal compositions for the treatment of diseases of the oral cavity |
| EP2117521B1 (en) | 2006-11-03 | 2012-06-27 | Durect Corporation | Transdermal delivery systems comprising bupivacaine |
| WO2009088414A2 (en) | 2007-12-06 | 2009-07-16 | Durect Corporation | Oral pharmaceutical dosage forms |
| WO2009120889A2 (en) * | 2008-03-26 | 2009-10-01 | Alltranz Inc. | Abuse deterrent transdermal formulations of opiate agonists and agonist-antagonists |
| US20090311335A1 (en) * | 2008-06-12 | 2009-12-17 | Scott Jenkins | Combination of a triptan and an nsaid |
| GB0818473D0 (en) | 2008-10-08 | 2008-11-12 | Probio Nutraceuticals As | Composition |
| US20100260844A1 (en) | 2008-11-03 | 2010-10-14 | Scicinski Jan J | Oral pharmaceutical dosage forms |
| CN102272055B (en) * | 2008-11-20 | 2013-11-27 | 水威视国际公司 | Antimicrobial device and materials for fluid treatment |
| US9012477B2 (en) * | 2009-01-06 | 2015-04-21 | Nuvo Research Inc. | Method of treating neuropathic pain |
| US8481678B2 (en) * | 2009-03-30 | 2013-07-09 | E I Du Pont De Nemours And Company | Peptide-based tooth whitening reagents |
| US9693976B2 (en) | 2010-01-14 | 2017-07-04 | Crescita Therapeutics Inc. | Solid-forming local anesthetic formulations for pain control |
| DE102010033048A1 (en) * | 2010-08-02 | 2012-02-02 | Katz Biotech Ag | Use of a microencapsulated food substrate |
| WO2012061547A1 (en) * | 2010-11-05 | 2012-05-10 | The Research Foundation Of State University Of New York | System and method for differentially timed local delivery of a combination pharmaceutical preparation for oral therapy |
| WO2013142482A1 (en) | 2012-03-20 | 2013-09-26 | Particle Dynamics International, Llc | Gelling agent-based dosage form |
| US20150044147A1 (en) * | 2013-02-18 | 2015-02-12 | King Abdullah International Medical Research Center | Composition for management of periodontal disease |
| JP2016514024A (en) | 2013-03-14 | 2016-05-19 | ハラックス，インコーポレイテッド | How to treat nail infections, diseases or disorders |
| EP2983468A4 (en) | 2013-03-15 | 2016-09-07 | Durect Corp | Compositions with a rheological modifier to reduce dissolution variability |
| CN104784152B (en) * | 2014-01-20 | 2017-10-24 | 洛阳惠中兽药有限公司 | A kind of Thiamphenicol micro-capsule and preparation method and application |
| DE102016101280A1 (en) * | 2016-01-26 | 2017-07-27 | Frank Bröseler | Pharmaceutical composition |
| CN108498854B (en) * | 2018-04-27 | 2021-06-15 | 温州医科大学附属第二医院（温州医科大学附属育英儿童医院） | Expanded sponge loaded with nano slow-release drug micelles and silver-loaded microspheres and preparation method and application thereof |
| EP3982929A4 (en) * | 2019-04-18 | 2023-06-07 | Board of Regents of the University of Nebraska | Hydrogel drug delivery composition |
| WO2021146215A1 (en) | 2020-01-13 | 2021-07-22 | Durect Corporation | Sustained release drug delivery systems with reduced impurities and related methods |
Family Cites Families (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3185625A (en) * | 1961-11-08 | 1965-05-25 | Brown Ethan Allan | Injectionable substances |
| US3934001A (en) | 1965-12-07 | 1976-01-20 | Lever Brothers Company | Oral compositions containing germicidally active plastic powders |
| FR2077696B1 (en) * | 1970-02-06 | 1973-03-16 | Synthelabo | |
| US4039653A (en) * | 1974-01-23 | 1977-08-02 | Defoney, Brenman, Mayes & Baron | Long-acting articles for oral delivery and process |
| JPS5138412A (en) * | 1974-09-24 | 1976-03-31 | Nippon Kayaku Kk | Kokoseizai no seiho |
| US3972995A (en) * | 1975-04-14 | 1976-08-03 | American Home Products Corporation | Dosage form |
| US4188373A (en) * | 1976-02-26 | 1980-02-12 | Cooper Laboratories, Inc. | Clear, water-miscible, liquid pharmaceutical vehicles and compositions which gel at body temperature for drug delivery to mucous membranes |
| US4138477A (en) * | 1976-05-28 | 1979-02-06 | Colgate Palmolive Company | Composition to control mouth odor |
| US4585651A (en) * | 1978-10-17 | 1986-04-29 | Stolle Research & Development Corporation | Active/passive immunization of the internal female reproductive organs |
| GB2042888B (en) * | 1979-03-05 | 1983-09-28 | Teijin Ltd | Preparation for administration to the mucosa of the oral or nasal cavity |
| US4292028A (en) * | 1979-07-13 | 1981-09-29 | Arthur Barr | Cosmetic breath freshener and palate coolant composition and method of use |
| US4622244A (en) * | 1979-09-04 | 1986-11-11 | The Washington University | Process for preparation of microcapsules |
| US4369172A (en) * | 1981-12-18 | 1983-01-18 | Forest Laboratories Inc. | Prolonged release therapeutic compositions based on hydroxypropylmethylcellulose |
| US4434153A (en) * | 1982-03-22 | 1984-02-28 | Alza Corporation | Drug delivery system comprising a reservoir containing a plurality of tiny pills |
| SE8203953D0 (en) * | 1982-06-24 | 1982-06-24 | Astra Laekemedel Ab | PHARMACEUTICAL MIXTURE |
| US4568535A (en) * | 1982-08-06 | 1986-02-04 | Loesche Walter J | Composition for periodontal administration |
| US4597960A (en) * | 1983-04-19 | 1986-07-01 | Cohen Edgar C | Microencapsulated astringent hemostatic agents and methods of use |
| ES8601706A1 (en) * | 1983-05-16 | 1985-11-16 | Merck & Co Inc | Drug delivery system utilizing thermosetting gels. |
| JPS59222406A (en) * | 1983-06-01 | 1984-12-14 | Teijin Ltd | Pharmaceutical preparation for remedying periodontosis and its preparation |
| JPS60100516A (en) * | 1983-11-04 | 1985-06-04 | Takeda Chem Ind Ltd | Preparation of sustained release microcapsule |
| US4568538A (en) | 1984-02-23 | 1986-02-04 | International Flavors & Fragrances Inc. | Flavoring with norbornyl pyridine derivatives |
| US4650665A (en) * | 1985-02-08 | 1987-03-17 | Ethicon, Inc. | Controlled release of pharmacologically active agents from an absorbable biologically compatible putty-like composition |
| US4568536A (en) * | 1985-02-08 | 1986-02-04 | Ethicon, Inc. | Controlled release of pharmacologically active agents from an absorbable biologically compatible putty-like composition |
| JPS62223112A (en) * | 1986-03-25 | 1987-10-01 | Rooto Seiyaku Kk | Remedy for periodontosis |
-
1986
- 1986-04-29 US US06/856,961 patent/US4780320A/en not_active Expired - Fee Related
-
1987
- 1987-04-10 NZ NZ219948A patent/NZ219948A/en unknown
- 1987-04-14 DE DE87303275T patent/DE3787829T2/en not_active Expired - Fee Related
- 1987-04-14 EP EP87303275A patent/EP0244118B1/en not_active Revoked
- 1987-04-27 AU AU72112/87A patent/AU614061B2/en not_active Ceased
- 1987-04-28 MX MX006257A patent/MX167175B/en unknown
- 1987-04-28 NO NO871774A patent/NO177125C/en unknown
- 1987-04-28 CA CA000535738A patent/CA1309345C/en not_active Expired - Fee Related
- 1987-04-29 DK DK219287A patent/DK219287A/en not_active Application Discontinuation
- 1987-04-30 JP JP62107935A patent/JP2698353B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| MX167175B (en) | 1993-03-08 |
| DE3787829D1 (en) | 1993-11-25 |
| DE3787829T2 (en) | 1994-05-11 |
| EP0244118B1 (en) | 1993-10-20 |
| AU614061B2 (en) | 1991-08-22 |
| NO871774D0 (en) | 1987-04-28 |
| EP0244118A1 (en) | 1987-11-04 |
| US4780320A (en) | 1988-10-25 |
| JP2698353B2 (en) | 1998-01-19 |
| DK219287D0 (en) | 1987-04-29 |
| JPS6327422A (en) | 1988-02-05 |
| NO177125B (en) | 1995-04-18 |
| NZ219948A (en) | 1988-11-29 |
| NO177125C (en) | 1995-07-26 |
| DK219287A (en) | 1987-10-30 |
| NO871774L (en) | 1987-10-30 |
| AU7211287A (en) | 1987-11-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1309345C (en) | Controlled release drug delivery system for the periodontal pocket | |
| US4919939A (en) | Periodontal disease treatment system | |
| AU613298B2 (en) | Topical delivery system | |
| US5500228A (en) | Phase separation-microencapsulated pharmaceuticals compositions useful for alleviating dental disease | |
| US6692769B1 (en) | Sustained-release particles | |
| JP3253072B2 (en) | Drug delivery excipient suspended in non-aqueous perfluorinated carrier | |
| KR0167078B1 (en) | Sustained release oral drug dosage form | |
| JP3233638B2 (en) | Method for producing freeze-dried drug dosage forms | |
| JP3286315B2 (en) | Compositions and methods for controlled release of soluble actives | |
| EP0257915A1 (en) | Pharmaceutical formulations comprising microcapsules | |
| JP2626248B2 (en) | Capsule | |
| US20020122828A1 (en) | Hybrid porous materials for controlled release | |
| AU629316B2 (en) | Periodontal disease treatment system | |
| EP1498116A1 (en) | Method of manufacturing chemical-containing composite particles | |
| CA2006106C (en) | Improved phase separation-microencapsulated pharmaceutical compositions useful for alleviating dental disease | |
| EP0608306B1 (en) | Peroral drug delivery system | |
| JPH045227A (en) | Gum disease treating system | |
| JPS61263633A (en) | Water soluble dry capsule | |
| CA2271571C (en) | Improved phase separation-microencapsulated pharmaceutical compositions useful for alleviating dental disease | |
| CA2012665A1 (en) | Periodontal disease treatment system | |
| JPS6258333B2 (en) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |