CA2065156A1 - Intragingival delivery systems for treatment of periodontal disease - Google Patents
Intragingival delivery systems for treatment of periodontal diseaseInfo
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- CA2065156A1 CA2065156A1 CA002065156A CA2065156A CA2065156A1 CA 2065156 A1 CA2065156 A1 CA 2065156A1 CA 002065156 A CA002065156 A CA 002065156A CA 2065156 A CA2065156 A CA 2065156A CA 2065156 A1 CA2065156 A1 CA 2065156A1
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- 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
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- Health & Medical Sciences (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
A polymeric controlled delivery system is provided for use in treating periodontal disease. The delivery system in a variety of forms is placed directly in the infected gingival tissue where the chemotherapeutic agent is slowly released into the tissue and into the infected periodontal pocket by means of the gingival crevicular fluid originating in the gingival tissue.
Description
WO 92/1~07182 o ~ r; 1 eJ ~ PCr/US90/03762 XNTRAGINGIV~II DELIVERY 8YSTEM~; l?OR
TRi~:AT~ENT OF PERIODONT~L DISEASE
Bacl,cqround of the Invention Periodontal disease or gum disease as it is often called can be defined as an infection and inflamma-tion of the gingiva or gums and loss of underlying al~Qolar bone support. There are varying -lo lçvels of seYerity of the disease. The mildest cases are clinically termed gingivitis (inflamed and bleeding gums). ~ior~ severe cases are clinically known as periodon-ci-Lis and can involve loss of bone support.
Gingivitis is reversible and can orten be eliminated with a thorough dental prophylaxis followed by improved personal oral hygiene proc~dures. If gingivitis is not controlled, th2 disease often progresses into periodontitis.
Periodontitis is not only characterized by bacterial infection~and inflammation, it is also accompanies by the formation of periodontal pockets (spaces between the teeth and gums) and bone deterioration which can lead to tooth loss.
Periodontitis is recurring, progressive, and episodic.
There is no cure at this time. Effective treatment is to apply prof2ssional intervention to halt disease progression.
Professional inte`rvention may involve surgical or nonsurgical procedures. Nonsurgical treatment consists of periodic professional scaling, root planing, and soft tissue curettage, in combination with conscientious home care by brushing and flossing on the part of the patient. Surgical treatment involves gingivectomy and flap surgery to recontour the soft and hard tissue around the diseased areas.
In recent years, it has become increasingly recogni~ed that control of periodontitis may be possible with the use of antimicrobial agents delivered to the infected site. Systemic antibiotics taken orally or ~! 40 intramuscularly have been successfully used, but due to .
. , ~
TRi~:AT~ENT OF PERIODONT~L DISEASE
Bacl,cqround of the Invention Periodontal disease or gum disease as it is often called can be defined as an infection and inflamma-tion of the gingiva or gums and loss of underlying al~Qolar bone support. There are varying -lo lçvels of seYerity of the disease. The mildest cases are clinically termed gingivitis (inflamed and bleeding gums). ~ior~ severe cases are clinically known as periodon-ci-Lis and can involve loss of bone support.
Gingivitis is reversible and can orten be eliminated with a thorough dental prophylaxis followed by improved personal oral hygiene proc~dures. If gingivitis is not controlled, th2 disease often progresses into periodontitis.
Periodontitis is not only characterized by bacterial infection~and inflammation, it is also accompanies by the formation of periodontal pockets (spaces between the teeth and gums) and bone deterioration which can lead to tooth loss.
Periodontitis is recurring, progressive, and episodic.
There is no cure at this time. Effective treatment is to apply prof2ssional intervention to halt disease progression.
Professional inte`rvention may involve surgical or nonsurgical procedures. Nonsurgical treatment consists of periodic professional scaling, root planing, and soft tissue curettage, in combination with conscientious home care by brushing and flossing on the part of the patient. Surgical treatment involves gingivectomy and flap surgery to recontour the soft and hard tissue around the diseased areas.
In recent years, it has become increasingly recogni~ed that control of periodontitis may be possible with the use of antimicrobial agents delivered to the infected site. Systemic antibiotics taken orally or ~! 40 intramuscularly have been successfully used, but due to .
. , ~
2 ~ 136 PCT/US90/03762 the concern about allergic responses, the development of resistance, and the treatment of the whole person rather than the specific infection site, their use is recommended only in the severest or pe-iodontal cases.
Treatm2n~ by mouLh ~^ins_ a-.~ c~-h~ ~ icall~
applied oral medicinal agents 'LO p2ne~La.- into the periodontal pocket where cney 2re -neeaed ~rrigTacion OL
the pockets with these agencs has snGwn ,ome e:r.eccs on gingivitis, but the short tim2 of e.c?os;ire with ; lO irrigation solutions and the .~pid r~.~o;al o~ any therapeutic agent by tha out-iia--d flow o^ ~he crevicular fluid make this type of tre3tmen-t inerrec i~e wilh severe cases of periodontitis.
Th~ ~ost r3c~t ~-^0p~ 2 '~
periodontitis with the local deliv2r~ OL
chemotherapeutic agents have involved the placement of these agents directly into the periodontal pocket.
These include the cellulose hollow fibers loaded with tretacycline described in U.S. Patent No. 4,175,326 to Goodson, the ethylcellulose films loaded with metronidazole described in U.S. Patent No. 4,568,535 to Loesche, the absorbable putty-like material described in ; U.S. Patent No. 4,568,536 to Xronenthal, the ethylene vinyl acetate fibers loaded with telracycline descrlbed in the European patent application No. 84401985.1 to Goodson, and the biodegradable microspheres and matrix ~ described in U.S. Patant No. 4,6~5,~3 to Jernberq. Ail ;! of these delivery systems involve placing the product directly into the periodontal pocket.
~ 30 Although the space between the gingival tissue `~ and the tooth in periodontal disease is called a pocket, it is really only a potential space in which bacteria can grow. The insertion of a delivery system within this potential space is more di~ficult than the simple ;~ 35 placement of a material within a well-de~ined pocket.
Moreover, the shape of the pocke_ or po.ential space is not regular, but often contoured based upon the shape of : ~
~.,, ... - - : . .
.
-~092/00718 2 ?3~ PCT/US90/03762 the tooth and the extent of the disease. Thus, placement of a film or fiber within the pocket requires careful fitting to fill the pocket but not extend beyond the gingival margin. Any material ext~nding outside the pocket will be remoYed by no~ al 3-a.~ y~jlene procedures unless the material is either adhered to the tissue or tooth or covered by a periodontal dressing.
In addition to the retention problems associated with normal dental care, ;_he outwa~d flo~ of crevicular fluid and the mecha~lcal acLio~ OL the teeth and the gums during eatinq maV cause ;nos~ mat2ri als placed within the periodon~al poc1cet to be expelled in a relatively short time. It is -~ell Xnown that carbon particles placed wiLhin a periodGn~al pock2l are all displaced within a few hours. Because of these retention problems, most periodontal delivery systems for chemotherapeutic agents are either adhesively bound to the tooth-or the tissue within the pocket. However, adhesion to a wet surface such as that within the pock'et is extremely difficult and normally the adhesion deteriorates rapidly. Thus, retention within the pocket is short-lived.
` The other solution to reLention of a delivery system within the pocket is to use a periodontal dressing to cover the pocket. Periodontal dressings are also adhesives and their adhesions to wet surfaces such as a tooth or gum tissue is dirficult; and most periodontal dressings do not adhere long within the mouth. In addition, they are uncomfortable to the wearer and they tend to collect food particles and bacteria.
Because of these problems with proper placement , ~ of a local delivery system within the periodontal pocket .: .
and the retention of the system ror sufficient~time to kill all of the periodontal pathogens, there is a need ` for a ~etter delivery system to aeliver cnemoiherapeutic agents to the site of infection. Moreover, recent .
.
WO92/00718 ~O~ 6 PCT/US90/03762 research indicates that the bacteria often responsible for periodontal disease exist not only in the periodontal pock~t but also within the gingival tissue.
This is espPcially true for localized juvenile periodontitis. The only ~.tay to treat ~his form of periodoncal disaase has been to administer systemic antibiotics ~hich can attack the bacterial infection within che gingival tissue itself. Several researchers have recen~ly sho~n that the bacteria responsible for periodontal di32ase have also been found in the tissue of ~atients with normal adult periodontitis.
Thus, delivery systems containing chPmothe~ap2utic agents when plac-d within the periooncal poc1~2-t will kill the bacteria there, but lS these agsnts ~ill not penetrate the gingival tissue to destroy the bacteria located intragingivally. These bacteria subsequently repopulate the periodontal pocket after the chemotherapeutic agent has been totally released or exhausted. There is therefore a need for a local delivery system that will destroy not only the periodontal pathogens within the periodontal pocket but also within the gingival tissues.
S~MMARY OF T~E PRES~NT INVENTION
The present invention relates to the use of ~ controlled release systems for the delivery of ;~ chemotherapeutic agents to localized sites in the mouth for the-treatment of periodontal disease. The method of treatment involves the placement of a polymeric delivery system directly into the gingival tissue that is infected rather than into the periodontal pocket that is formed ~etween the infected tissue and the tooth.
~` The polymeric delivery system may consist of microspheres, microcapsules, liposomes, fibers, rods, films, or spheres. They may be iabricated from either `~ biodegradable or nonbiodegradable polymers, although delivery sys~ems fabricated from biodegradable polymers - . ~
: ~ , : - ' . . ' ` .
.
2~51~ ~
~092/00718 PCT/US90/03762 are preferred because they do not require removal after the chemotherapeutic agent has been released. Also preferred are the delivery systems in the form of ; mic osp-~es, microcapsules, nano-particles, and liposomes which can be injected directly into the gingival tissue. Liquid polymeric systems that can be injected -nto tha gingival tissue to form solid implants are also preferred delivery systems.
~,~1nen injected into the gingival tissue, the poly-meris delivery systems release the bioactive agent directly into the inrected tissue. The bioactive agent is released by diffusion or dissolution from the polymer or i, h~ pol~..er is bioerodible the agent can be released as the polymeric device erodes or biodegrades.
The release of the agent creates a high concentration of active material within the gingival tissue. If the agent released is antimicrobial, the local concentration is sufficient to destroy the bacteria causing the infection. If the agent is an anti-inflammatory drug, the concentration is sufficient to reduce the i inflammation within the tissue. Because the gingival crevicular fluid in the periodontal pocket is formed from serum from within the gingival tissue, the active agent is transported to the periodontal pocket as the serum flows out of the tissue. If the active agent is an antimicrobial, the intragingival deli~ery system can achieve concentrations of drug sufficient to kill the bacteria both within the tissue as well as in the . .~
periodontal pocket.
This system provides a significant advantage over delivery systems placed within the periodontal pocket where the outward flow or crevicular fluid tends to remove the active agent from the pocket as it is released. This loss of active agent has been alleviated to some extent by the placement of periodontal dressings over the opening of the pocket or the use of adhesives or sutures to close the pocket. Because of the outward . , .
.
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~ w092/00718 2 ~ ~ ~ 1 5 ~ PCT/US90/03762 flow of the crevicular fluid and the poor penetration of most active agents into tissue, the drugs released into the periodontal pocket Irom a delivery syst~m plac~d within the pocket or outside thé pock2'~ are unable to S achieve an efL^ectiv2 concen,ra?_ O~ .lrlg w ;:.~in .a~
infected gingival tissue.
In addition to achie~ing e rfeccit/o concentrations of the activ2 ag~n_ '~tiChl a ~he glngi~al tissue and the periodontal pOC~2'5, the intra-3ingi~al delivery system describ2d in LhO -p _sen~ invanticn provides a reliable mêthOd iO~ -ce~2n; ion o~ Lhe deiive:rv system at the site of infection. The del very sysLom is retained by the gingival tissue -ntll _ ia su~-gically removed or the ~oly~er nas deg adê. ~e ng loca-~ëd within the tissue, the intragingival dslivery syste~
; (unlike a periodontal poc~et delivery system) is not .~ subject to untimely removal by the gingival crevicular ~ fluid or the normal dental hygiene procedures such as `~ brushing, flossing, or rinsing. Also, the location of the delivery system within the gingival tissue does not interfere with the reattachment of tissue to the tooth once the bacteria have been destroyed or the inflammation has been eliminated. A periodontal pock2t delivery system prevents tissue reattachment unless it is removed or unless the delivery system degrades in a . short.time. An added advantage of the intragingival delivery system of this invention is that its retention and non-interference properties allow the active agent to be delivered for much longer times than those ~; 30 possible with a periodontal-pocket-delivery system.
. Thus, instead of the normal 5-14 days of delivery with a periodontal-pocket-delivery system, times of 1-6 months for delivery of bioactive agent can be achieved. This extended delivery time can be used to prevent reinfection of the site.
. .
~ ~VO 92t00718 2 " ~ p~/Us90,03762 . .
DETAILED DESCRIPTION OF q!~IE I~EN~rION
The present invention relates to a method for treatiny periodontal diseasa by the us~ OI an intragingival polymeric controll~d deliv_-y system. The polymeric delivQry system in ~he -~r --~ ~ crospheres, microcapsules, nanoparticles, oL liposomes are injected directly into the in~2ct2d ginglYal ti~su3 t~nere -chey release an active agent such as an an'cimic-L-obic or antibiotic to destroy bacceria or an anti-inIlammatory agent to eliminate in~la~maLion. i~he L~r3LaLLed delivery ~system consis ts of a biodegLad2bl~ pol ~leL suc;~ that the delivery system does not r~quire removal once the drug has been dep~eted. The ~ol~..eris dQllver~ s~ystem can ~ also be in the 90rm OL a ~lber~ '~'''m~ or rod ~,ihich ls -~ ) 15 surgically placed wi~hin the gingival tissue, buc the preferred systems are those ~hich can be injected into the tissue. A liquid polymeric system that forms a solid implant that forms a solid implant after injection into the tissue is preferred.
~`~ 20 Although nonbiodegradable polymers can be used in this application, the biodegradable polymers are preferred because they do not require removal after drug ~; depletion. Examples of biodegradabl~ polymers which can be used in this application are polylactldes, ~; 25 polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, ` polyketals, polycarbonates, polyorthocarbonates, `~ polyphosphazenes, polyhydroxybutyrates, 30 polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, hydroxycellulose, methylcellulose, chitln, chitosan, gela~in, collagen, and copolymers, terpolymers, or 35 combinations or mixtures o~ tne above ma-terials. It is understood by thos2 skilled ln the art that the degradation times of the polymers can be adjusted by .~ ~
-, ' ~ ~o 92~00718 2 .~ J ~ PCT/US90/03762 their composition, their molecular weights, catalysts, and the surface areas of the polymers.
The term drug or bioactive agent as used hsrein includes, without limitation, physiologically or pharmacologically active substances that act locally or systamically in the body. Representative drugs and biologically active agents to be used in this application include antimicrobials, antibiotics, anti-inflammoratory agents, anti-infectives, peptide drugs, lo ~rotein drugs, bone and tissue growth factors, ~:
~` analg~sics, antigens, biological response modifiers, vaccines, and the benzophenanthridine alkaloids. To ~`~ those skilled in the art, other drugs or bioactive agen~s tha can ~e releas2d in an aqueous environment can be utilized in the described intragingival delivery ~; system. Also, various forms of the drugs or bioactive : `;
` agents may be used. These include, without limitation, forms such as uncharged molecules, molecular complexes, salts, ethers, esters, amides, etc., which are biologi~ally activated when injected into the body.
The amount of drug or bioactive agent incorporated into the intragingival delivery system ~; depends upon the desired release profile, the concentration of drug required for a biological effect, and the length of time that the drug has to be released for treatment. There is no critical upper limit on the amount of drug incorporated into the delivery system - except for the local tissue irritation or the toxicity of the drug. The lower limit of drug incorporated into the delivery system is dependent simply upon the activity of the drug and the length of time needed for treatment.
With certain drugs and polymers, the drug will be released by diffusion from the polymer matrix. The rate of release will be described by Fick's Law of Diffusion for polymeric systems. If the matrix is a monolithic ~vice, the release rate will be first-order .
.:
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W092/00718 PCT/US90tO3762 in which there is a burst of drug initially followed by a gradually declining rate. If a reservoir device is used, the release rate will be zero-order in which there is a constant rate of release until the drug has been depleted. For other drugs and polymer, the drug will be released by simple dissolution in which the loading of drug and the porosity of the polymeric delivery system will control the rate of delivery. For other drugs, the release will depend upon the degradation rate of the polymer. The molecular weight of these drugs are so `~ hi~h that they will not diffuse through the matrix polymer and the only way for them to be released is for the pol~mer to erode or fragment due to biodegradation.
~ The drug and ths polymer can be blended ! 15 together using a variety of methods. The intimacy of mixing, particle size, and particle shape can be varied according to the intended use. ~igh homogeneity can be ; obtained by mixing the components in the molten state, cooling and grinding the resulting solid. The same type of homogeneity can be achieved if both components are dissolved in a common solvent, the solvent removed to give a film, and the film ground into a powder. These particles can be sieved to-obtain the desired particle size for injection and for drug release. These particles as prepared constitute a monolithic delivery system in which~the drug is distributed within the polymer matrix. As such the rate of release will be first order.
However, the particles can be converted to reservoir systems by coating them with a layer of polymer which serves as a rate-controlling membrane.
~he particles can be coated by several methods including spray drying, fluid-bed coating, or microencapsulation.
Although microencapsulation can be used to coat drug/polymer particles already formed, it can also be used directly to form microspheres or microcapsules ; containing drug using a variety of methods known to .
W O 92/00718 2 ~ V ~1~ P ~ /US90/03762 '`
those skilled in the art. These include solvent evaporation, phase separation, interfacial polymerization, hot melt, and spray drying. The type of polymer used for the c~ating, the uniformity of the coating, tho rh71'~ SS o'r^ ~12 ---2tl~ ~d tho sizo of the microspher2s or mic-ocapsule~s can ~2 used to control r the relaa3e o:c drug.
O~h~r small -3a.ticle. .~hich ca~ be used for injection include liposcmes. Thes2 arug deliv~ry rorms are formed by er.ca-?sulating ~/arious drugs in lipid bylayers. The liposom~s ~o;...ed a-e exLr_m21y small and ~; can be injected oasily into 'che body or the blood stream. The other p2rt~cles o- micrccapsules a_e injected as -luid _USp~nS7l 31:S ~rO`7l. ~yringes into ~ 15 subcutaneous or muscular ,issue. Water or aqueous ;~ solutions of sodium chloride or sodium carboxymethyl cellulose can be used for these injections. Oils such as sesame or peanut may also be used for injection. If , the polymer is soluble in a biocompatible solvent that once injected into the body disperses and leaves the polymer to form a solid, then the drug also dissolved or -~ dispersed in the polymer solution may be injected directly into the body to form a solid implant. Also, if the polvmer is injected into the body as a liquid prepolymer and then polymerizes further or crosslinks to form a solid, then the drug dispersed in the liquid prepolymer can be injected to form a solid implant.
For the other implants which are solids as formed, then a surgical incision or the use of a trochar is needed for implantation. These solid implants may be in the form of fibers, films, rods, cylinders, and pellets. The fibers can be formed by melt extrusion if the drug is stable at the melt-spinning temperature or by solution spinning where polymer is soluble in a solvent that is compatibl2 with the drug. Rods and cylinders can be formed by ~he same method or they can be formed by injection molding or compression molding.
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Pellets can also be formed by compression molding or injection molding.
D~T~ 3 ~C~ TO.~.l 0~ ~S~L~S
Tha following examplQs arQ set lorth as representativ2 oi Lne present in~enLion. TAese examples are not to be construed as limiting the scope of the invention as tnes2 and ocner ~quivalenc em~odiments will be appar~nt in ~ 2W of the ~-es~nt dis~losur2 and accompanyiny cl2ims.
- .,;
? ï .r. 1 Poly(DL~lactide)~DL-PLAj witn an inherent viscosity of 0.26 dL/g ~nd a Lheoretical molecular weight of apprcximat31y 10,00~ daltons was prepar~d by the ring-opening polymerization of DL-lactide using lauryI alcohol as the initiator and stannous chloride as ~; the catalyst. The polymer was dissolved in N-methyl-2-pyrrolidone to gi~e a 74% by weight solution.
`' 20 Sanguinarine hydrochloride as an orange powder was added to the polymer solution to give a 5% by weight dispersion of the drug in the polymer solution. The dispersion when addad to watar or saline solution formad a deep orange-colored solid ~rQCi pitatQ Y~hich reloasod the active drug over a period of two weeks.
EX~PLE 2 ~thoxydihydrosanguinarine, the ethoxy estar of sanguinarine, was added to the same DL-PLA solution as described in Example 1 to give a 5% by weight solution of th~o drug. The light brown solution when injected into water or a saline solution gave a slightly orange-colored solid precipitate which releasPd the drug as sanguinarine over a period of two wee~s.
: ~
-~ . . . .
WO 92/00718 ~ 5 PCT/US90/03762 ~
The two formulations described in Example 1 and 2 were place in l-mL disposable syringes fitted with 21 gauge, 1.5-inch needles. Each formulation was then injected into the gingival tissue of healthy ~eagle dogs with artificially-created periodontal poc~ets. ThP
` needle was placed so that the formulation penetrated through ~he ,issue into the periodontal pocket. As the formulation was forced from the syrings, it filled up the pocket with a rapidly solidifying mass. The naedl~
was then withdrawn from the injection site while maintaining a flow of liquid. In this manner, both the periodontal pocket and the injection site in the gingival tissue were filed with the solid implant.
After several days, the material in the periodontal pocket had been completely dislodged. However, the material in the tissue injection site was still visible.
There were no signs of irritation or inflammation at the injection sites.
Tetracycline hydrochloride was added to the same DL-PLA solution as described in Example 1 to give a 5~ by weight dispersion of drug in the solution. AftAr standing overnight, the drug had dissolved completely into the polymer solution to give a light yellow solution. When injected into an aqueous or saline solution, the polymer coagulated to form a solid which slowly released tetracycline over a time of several weeks.
Poly(DL lactide-co-glycolide) was prepared by the ring-opening polymerization of a mixture af DL-lactide and glycolide using lauryl alcohol as theinitiator and stannous chloride as the catalyst. The proportions of the two monomers were adjusted so that :
: ~ .
0 92/00718 PC~r/US90/03762 the final copolymer (DL-PLG) had a 50:50 ratio of the two monomers as determined by nuclear magnetic resonance spectrophotometry. The initiator was also adjusted to give a copolymer with a theoretical molecular weight of 1500 daltons. The copolymer was dissolved in N-methyl-2-pyrrolidone to give a 70% by weight polymer solution.
Tetracycline as the free base was added to the polymer solution to give a 2.4% by weight solution of the drug in the polymer solution. The light yellow solution when added to water or saline formed a solid matrix as the polymer coagulated. The drug was released from the polymeric matrix over a period of two weeks.
:;~
~; 15 Tetracycline hydrochloride was added to the same DL-PLG solution as described in Example 5 to give a 2% by weight dispersion. After standing overnight, the drug dissolved completely in the polymer solution. The solid that formed when the solution was added to water or saline released the drug at a controlled rate for a time of two wee~s.
DLA-PT~ with an inherent viscosity of 0.26 dL/g and a theoretical molecular weight of approximately lO,000 daltons was dissolved in methylene chloride to give a clear viscous solution. To this polymer solution was added ethoxydihydrosanguinarine which dissolved to give a light brown solution with 5% by weight of drug.
The solution of polymer and drug was poured into a shallow dish and the methylene chloride evaporated to form a homogenous film. The dry film was then ground to give small particles of polymer/drug which could be suspended in an aqueous injection vehicle and injected directly into tissue using a standard syringe and needle.
,: :
WO92/00718 2 ~ ~ 5 ~ PCT/US90/03762 , Sanguinarine chlorido was added to the same DL-- PLA solution as described in Example 7 to give a 5% by weight dispersion. The dispersion was poured into a shallow dish and th2 m2chylene chloride evaporated to form a .ilm wlth t.~2 pa~-_lcl-s o_ d-uy dlsp2rsed uniformly within the ~ol~,~ner matrix. The film was then ground to yi-ve s."all ~d~-tiCl_s OL PO ~y~.ner/'druy ~-hich could ~e sus~endod ln an a~lOUS injection ~Jehicle and injected di:-~s-ly int~ u~ using a ,ta..~ard sy~ing2 and nee~le.
' : ' ' , :
. ~`~ ' .
. .
.
: ~i :`
-~ '
Treatm2n~ by mouLh ~^ins_ a-.~ c~-h~ ~ icall~
applied oral medicinal agents 'LO p2ne~La.- into the periodontal pocket where cney 2re -neeaed ~rrigTacion OL
the pockets with these agencs has snGwn ,ome e:r.eccs on gingivitis, but the short tim2 of e.c?os;ire with ; lO irrigation solutions and the .~pid r~.~o;al o~ any therapeutic agent by tha out-iia--d flow o^ ~he crevicular fluid make this type of tre3tmen-t inerrec i~e wilh severe cases of periodontitis.
Th~ ~ost r3c~t ~-^0p~ 2 '~
periodontitis with the local deliv2r~ OL
chemotherapeutic agents have involved the placement of these agents directly into the periodontal pocket.
These include the cellulose hollow fibers loaded with tretacycline described in U.S. Patent No. 4,175,326 to Goodson, the ethylcellulose films loaded with metronidazole described in U.S. Patent No. 4,568,535 to Loesche, the absorbable putty-like material described in ; U.S. Patent No. 4,568,536 to Xronenthal, the ethylene vinyl acetate fibers loaded with telracycline descrlbed in the European patent application No. 84401985.1 to Goodson, and the biodegradable microspheres and matrix ~ described in U.S. Patant No. 4,6~5,~3 to Jernberq. Ail ;! of these delivery systems involve placing the product directly into the periodontal pocket.
~ 30 Although the space between the gingival tissue `~ and the tooth in periodontal disease is called a pocket, it is really only a potential space in which bacteria can grow. The insertion of a delivery system within this potential space is more di~ficult than the simple ;~ 35 placement of a material within a well-de~ined pocket.
Moreover, the shape of the pocke_ or po.ential space is not regular, but often contoured based upon the shape of : ~
~.,, ... - - : . .
.
-~092/00718 2 ?3~ PCT/US90/03762 the tooth and the extent of the disease. Thus, placement of a film or fiber within the pocket requires careful fitting to fill the pocket but not extend beyond the gingival margin. Any material ext~nding outside the pocket will be remoYed by no~ al 3-a.~ y~jlene procedures unless the material is either adhered to the tissue or tooth or covered by a periodontal dressing.
In addition to the retention problems associated with normal dental care, ;_he outwa~d flo~ of crevicular fluid and the mecha~lcal acLio~ OL the teeth and the gums during eatinq maV cause ;nos~ mat2ri als placed within the periodon~al poc1cet to be expelled in a relatively short time. It is -~ell Xnown that carbon particles placed wiLhin a periodGn~al pock2l are all displaced within a few hours. Because of these retention problems, most periodontal delivery systems for chemotherapeutic agents are either adhesively bound to the tooth-or the tissue within the pocket. However, adhesion to a wet surface such as that within the pock'et is extremely difficult and normally the adhesion deteriorates rapidly. Thus, retention within the pocket is short-lived.
` The other solution to reLention of a delivery system within the pocket is to use a periodontal dressing to cover the pocket. Periodontal dressings are also adhesives and their adhesions to wet surfaces such as a tooth or gum tissue is dirficult; and most periodontal dressings do not adhere long within the mouth. In addition, they are uncomfortable to the wearer and they tend to collect food particles and bacteria.
Because of these problems with proper placement , ~ of a local delivery system within the periodontal pocket .: .
and the retention of the system ror sufficient~time to kill all of the periodontal pathogens, there is a need ` for a ~etter delivery system to aeliver cnemoiherapeutic agents to the site of infection. Moreover, recent .
.
WO92/00718 ~O~ 6 PCT/US90/03762 research indicates that the bacteria often responsible for periodontal disease exist not only in the periodontal pock~t but also within the gingival tissue.
This is espPcially true for localized juvenile periodontitis. The only ~.tay to treat ~his form of periodoncal disaase has been to administer systemic antibiotics ~hich can attack the bacterial infection within che gingival tissue itself. Several researchers have recen~ly sho~n that the bacteria responsible for periodontal di32ase have also been found in the tissue of ~atients with normal adult periodontitis.
Thus, delivery systems containing chPmothe~ap2utic agents when plac-d within the periooncal poc1~2-t will kill the bacteria there, but lS these agsnts ~ill not penetrate the gingival tissue to destroy the bacteria located intragingivally. These bacteria subsequently repopulate the periodontal pocket after the chemotherapeutic agent has been totally released or exhausted. There is therefore a need for a local delivery system that will destroy not only the periodontal pathogens within the periodontal pocket but also within the gingival tissues.
S~MMARY OF T~E PRES~NT INVENTION
The present invention relates to the use of ~ controlled release systems for the delivery of ;~ chemotherapeutic agents to localized sites in the mouth for the-treatment of periodontal disease. The method of treatment involves the placement of a polymeric delivery system directly into the gingival tissue that is infected rather than into the periodontal pocket that is formed ~etween the infected tissue and the tooth.
~` The polymeric delivery system may consist of microspheres, microcapsules, liposomes, fibers, rods, films, or spheres. They may be iabricated from either `~ biodegradable or nonbiodegradable polymers, although delivery sys~ems fabricated from biodegradable polymers - . ~
: ~ , : - ' . . ' ` .
.
2~51~ ~
~092/00718 PCT/US90/03762 are preferred because they do not require removal after the chemotherapeutic agent has been released. Also preferred are the delivery systems in the form of ; mic osp-~es, microcapsules, nano-particles, and liposomes which can be injected directly into the gingival tissue. Liquid polymeric systems that can be injected -nto tha gingival tissue to form solid implants are also preferred delivery systems.
~,~1nen injected into the gingival tissue, the poly-meris delivery systems release the bioactive agent directly into the inrected tissue. The bioactive agent is released by diffusion or dissolution from the polymer or i, h~ pol~..er is bioerodible the agent can be released as the polymeric device erodes or biodegrades.
The release of the agent creates a high concentration of active material within the gingival tissue. If the agent released is antimicrobial, the local concentration is sufficient to destroy the bacteria causing the infection. If the agent is an anti-inflammatory drug, the concentration is sufficient to reduce the i inflammation within the tissue. Because the gingival crevicular fluid in the periodontal pocket is formed from serum from within the gingival tissue, the active agent is transported to the periodontal pocket as the serum flows out of the tissue. If the active agent is an antimicrobial, the intragingival deli~ery system can achieve concentrations of drug sufficient to kill the bacteria both within the tissue as well as in the . .~
periodontal pocket.
This system provides a significant advantage over delivery systems placed within the periodontal pocket where the outward flow or crevicular fluid tends to remove the active agent from the pocket as it is released. This loss of active agent has been alleviated to some extent by the placement of periodontal dressings over the opening of the pocket or the use of adhesives or sutures to close the pocket. Because of the outward . , .
.
.. .
~ w092/00718 2 ~ ~ ~ 1 5 ~ PCT/US90/03762 flow of the crevicular fluid and the poor penetration of most active agents into tissue, the drugs released into the periodontal pocket Irom a delivery syst~m plac~d within the pocket or outside thé pock2'~ are unable to S achieve an efL^ectiv2 concen,ra?_ O~ .lrlg w ;:.~in .a~
infected gingival tissue.
In addition to achie~ing e rfeccit/o concentrations of the activ2 ag~n_ '~tiChl a ~he glngi~al tissue and the periodontal pOC~2'5, the intra-3ingi~al delivery system describ2d in LhO -p _sen~ invanticn provides a reliable mêthOd iO~ -ce~2n; ion o~ Lhe deiive:rv system at the site of infection. The del very sysLom is retained by the gingival tissue -ntll _ ia su~-gically removed or the ~oly~er nas deg adê. ~e ng loca-~ëd within the tissue, the intragingival dslivery syste~
; (unlike a periodontal poc~et delivery system) is not .~ subject to untimely removal by the gingival crevicular ~ fluid or the normal dental hygiene procedures such as `~ brushing, flossing, or rinsing. Also, the location of the delivery system within the gingival tissue does not interfere with the reattachment of tissue to the tooth once the bacteria have been destroyed or the inflammation has been eliminated. A periodontal pock2t delivery system prevents tissue reattachment unless it is removed or unless the delivery system degrades in a . short.time. An added advantage of the intragingival delivery system of this invention is that its retention and non-interference properties allow the active agent to be delivered for much longer times than those ~; 30 possible with a periodontal-pocket-delivery system.
. Thus, instead of the normal 5-14 days of delivery with a periodontal-pocket-delivery system, times of 1-6 months for delivery of bioactive agent can be achieved. This extended delivery time can be used to prevent reinfection of the site.
. .
~ ~VO 92t00718 2 " ~ p~/Us90,03762 . .
DETAILED DESCRIPTION OF q!~IE I~EN~rION
The present invention relates to a method for treatiny periodontal diseasa by the us~ OI an intragingival polymeric controll~d deliv_-y system. The polymeric delivQry system in ~he -~r --~ ~ crospheres, microcapsules, nanoparticles, oL liposomes are injected directly into the in~2ct2d ginglYal ti~su3 t~nere -chey release an active agent such as an an'cimic-L-obic or antibiotic to destroy bacceria or an anti-inIlammatory agent to eliminate in~la~maLion. i~he L~r3LaLLed delivery ~system consis ts of a biodegLad2bl~ pol ~leL suc;~ that the delivery system does not r~quire removal once the drug has been dep~eted. The ~ol~..eris dQllver~ s~ystem can ~ also be in the 90rm OL a ~lber~ '~'''m~ or rod ~,ihich ls -~ ) 15 surgically placed wi~hin the gingival tissue, buc the preferred systems are those ~hich can be injected into the tissue. A liquid polymeric system that forms a solid implant that forms a solid implant after injection into the tissue is preferred.
~`~ 20 Although nonbiodegradable polymers can be used in this application, the biodegradable polymers are preferred because they do not require removal after drug ~; depletion. Examples of biodegradabl~ polymers which can be used in this application are polylactldes, ~; 25 polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, ` polyketals, polycarbonates, polyorthocarbonates, `~ polyphosphazenes, polyhydroxybutyrates, 30 polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, hydroxycellulose, methylcellulose, chitln, chitosan, gela~in, collagen, and copolymers, terpolymers, or 35 combinations or mixtures o~ tne above ma-terials. It is understood by thos2 skilled ln the art that the degradation times of the polymers can be adjusted by .~ ~
-, ' ~ ~o 92~00718 2 .~ J ~ PCT/US90/03762 their composition, their molecular weights, catalysts, and the surface areas of the polymers.
The term drug or bioactive agent as used hsrein includes, without limitation, physiologically or pharmacologically active substances that act locally or systamically in the body. Representative drugs and biologically active agents to be used in this application include antimicrobials, antibiotics, anti-inflammoratory agents, anti-infectives, peptide drugs, lo ~rotein drugs, bone and tissue growth factors, ~:
~` analg~sics, antigens, biological response modifiers, vaccines, and the benzophenanthridine alkaloids. To ~`~ those skilled in the art, other drugs or bioactive agen~s tha can ~e releas2d in an aqueous environment can be utilized in the described intragingival delivery ~; system. Also, various forms of the drugs or bioactive : `;
` agents may be used. These include, without limitation, forms such as uncharged molecules, molecular complexes, salts, ethers, esters, amides, etc., which are biologi~ally activated when injected into the body.
The amount of drug or bioactive agent incorporated into the intragingival delivery system ~; depends upon the desired release profile, the concentration of drug required for a biological effect, and the length of time that the drug has to be released for treatment. There is no critical upper limit on the amount of drug incorporated into the delivery system - except for the local tissue irritation or the toxicity of the drug. The lower limit of drug incorporated into the delivery system is dependent simply upon the activity of the drug and the length of time needed for treatment.
With certain drugs and polymers, the drug will be released by diffusion from the polymer matrix. The rate of release will be described by Fick's Law of Diffusion for polymeric systems. If the matrix is a monolithic ~vice, the release rate will be first-order .
.:
' 2 ~
W092/00718 PCT/US90tO3762 in which there is a burst of drug initially followed by a gradually declining rate. If a reservoir device is used, the release rate will be zero-order in which there is a constant rate of release until the drug has been depleted. For other drugs and polymer, the drug will be released by simple dissolution in which the loading of drug and the porosity of the polymeric delivery system will control the rate of delivery. For other drugs, the release will depend upon the degradation rate of the polymer. The molecular weight of these drugs are so `~ hi~h that they will not diffuse through the matrix polymer and the only way for them to be released is for the pol~mer to erode or fragment due to biodegradation.
~ The drug and ths polymer can be blended ! 15 together using a variety of methods. The intimacy of mixing, particle size, and particle shape can be varied according to the intended use. ~igh homogeneity can be ; obtained by mixing the components in the molten state, cooling and grinding the resulting solid. The same type of homogeneity can be achieved if both components are dissolved in a common solvent, the solvent removed to give a film, and the film ground into a powder. These particles can be sieved to-obtain the desired particle size for injection and for drug release. These particles as prepared constitute a monolithic delivery system in which~the drug is distributed within the polymer matrix. As such the rate of release will be first order.
However, the particles can be converted to reservoir systems by coating them with a layer of polymer which serves as a rate-controlling membrane.
~he particles can be coated by several methods including spray drying, fluid-bed coating, or microencapsulation.
Although microencapsulation can be used to coat drug/polymer particles already formed, it can also be used directly to form microspheres or microcapsules ; containing drug using a variety of methods known to .
W O 92/00718 2 ~ V ~1~ P ~ /US90/03762 '`
those skilled in the art. These include solvent evaporation, phase separation, interfacial polymerization, hot melt, and spray drying. The type of polymer used for the c~ating, the uniformity of the coating, tho rh71'~ SS o'r^ ~12 ---2tl~ ~d tho sizo of the microspher2s or mic-ocapsule~s can ~2 used to control r the relaa3e o:c drug.
O~h~r small -3a.ticle. .~hich ca~ be used for injection include liposcmes. Thes2 arug deliv~ry rorms are formed by er.ca-?sulating ~/arious drugs in lipid bylayers. The liposom~s ~o;...ed a-e exLr_m21y small and ~; can be injected oasily into 'che body or the blood stream. The other p2rt~cles o- micrccapsules a_e injected as -luid _USp~nS7l 31:S ~rO`7l. ~yringes into ~ 15 subcutaneous or muscular ,issue. Water or aqueous ;~ solutions of sodium chloride or sodium carboxymethyl cellulose can be used for these injections. Oils such as sesame or peanut may also be used for injection. If , the polymer is soluble in a biocompatible solvent that once injected into the body disperses and leaves the polymer to form a solid, then the drug also dissolved or -~ dispersed in the polymer solution may be injected directly into the body to form a solid implant. Also, if the polvmer is injected into the body as a liquid prepolymer and then polymerizes further or crosslinks to form a solid, then the drug dispersed in the liquid prepolymer can be injected to form a solid implant.
For the other implants which are solids as formed, then a surgical incision or the use of a trochar is needed for implantation. These solid implants may be in the form of fibers, films, rods, cylinders, and pellets. The fibers can be formed by melt extrusion if the drug is stable at the melt-spinning temperature or by solution spinning where polymer is soluble in a solvent that is compatibl2 with the drug. Rods and cylinders can be formed by ~he same method or they can be formed by injection molding or compression molding.
., ' - ' .
~. - , ~.
.;, . .
2 ~
Pellets can also be formed by compression molding or injection molding.
D~T~ 3 ~C~ TO.~.l 0~ ~S~L~S
Tha following examplQs arQ set lorth as representativ2 oi Lne present in~enLion. TAese examples are not to be construed as limiting the scope of the invention as tnes2 and ocner ~quivalenc em~odiments will be appar~nt in ~ 2W of the ~-es~nt dis~losur2 and accompanyiny cl2ims.
- .,;
? ï .r. 1 Poly(DL~lactide)~DL-PLAj witn an inherent viscosity of 0.26 dL/g ~nd a Lheoretical molecular weight of apprcximat31y 10,00~ daltons was prepar~d by the ring-opening polymerization of DL-lactide using lauryI alcohol as the initiator and stannous chloride as ~; the catalyst. The polymer was dissolved in N-methyl-2-pyrrolidone to gi~e a 74% by weight solution.
`' 20 Sanguinarine hydrochloride as an orange powder was added to the polymer solution to give a 5% by weight dispersion of the drug in the polymer solution. The dispersion when addad to watar or saline solution formad a deep orange-colored solid ~rQCi pitatQ Y~hich reloasod the active drug over a period of two weeks.
EX~PLE 2 ~thoxydihydrosanguinarine, the ethoxy estar of sanguinarine, was added to the same DL-PLA solution as described in Example 1 to give a 5% by weight solution of th~o drug. The light brown solution when injected into water or a saline solution gave a slightly orange-colored solid precipitate which releasPd the drug as sanguinarine over a period of two wee~s.
: ~
-~ . . . .
WO 92/00718 ~ 5 PCT/US90/03762 ~
The two formulations described in Example 1 and 2 were place in l-mL disposable syringes fitted with 21 gauge, 1.5-inch needles. Each formulation was then injected into the gingival tissue of healthy ~eagle dogs with artificially-created periodontal poc~ets. ThP
` needle was placed so that the formulation penetrated through ~he ,issue into the periodontal pocket. As the formulation was forced from the syrings, it filled up the pocket with a rapidly solidifying mass. The naedl~
was then withdrawn from the injection site while maintaining a flow of liquid. In this manner, both the periodontal pocket and the injection site in the gingival tissue were filed with the solid implant.
After several days, the material in the periodontal pocket had been completely dislodged. However, the material in the tissue injection site was still visible.
There were no signs of irritation or inflammation at the injection sites.
Tetracycline hydrochloride was added to the same DL-PLA solution as described in Example 1 to give a 5~ by weight dispersion of drug in the solution. AftAr standing overnight, the drug had dissolved completely into the polymer solution to give a light yellow solution. When injected into an aqueous or saline solution, the polymer coagulated to form a solid which slowly released tetracycline over a time of several weeks.
Poly(DL lactide-co-glycolide) was prepared by the ring-opening polymerization of a mixture af DL-lactide and glycolide using lauryl alcohol as theinitiator and stannous chloride as the catalyst. The proportions of the two monomers were adjusted so that :
: ~ .
0 92/00718 PC~r/US90/03762 the final copolymer (DL-PLG) had a 50:50 ratio of the two monomers as determined by nuclear magnetic resonance spectrophotometry. The initiator was also adjusted to give a copolymer with a theoretical molecular weight of 1500 daltons. The copolymer was dissolved in N-methyl-2-pyrrolidone to give a 70% by weight polymer solution.
Tetracycline as the free base was added to the polymer solution to give a 2.4% by weight solution of the drug in the polymer solution. The light yellow solution when added to water or saline formed a solid matrix as the polymer coagulated. The drug was released from the polymeric matrix over a period of two weeks.
:;~
~; 15 Tetracycline hydrochloride was added to the same DL-PLG solution as described in Example 5 to give a 2% by weight dispersion. After standing overnight, the drug dissolved completely in the polymer solution. The solid that formed when the solution was added to water or saline released the drug at a controlled rate for a time of two wee~s.
DLA-PT~ with an inherent viscosity of 0.26 dL/g and a theoretical molecular weight of approximately lO,000 daltons was dissolved in methylene chloride to give a clear viscous solution. To this polymer solution was added ethoxydihydrosanguinarine which dissolved to give a light brown solution with 5% by weight of drug.
The solution of polymer and drug was poured into a shallow dish and the methylene chloride evaporated to form a homogenous film. The dry film was then ground to give small particles of polymer/drug which could be suspended in an aqueous injection vehicle and injected directly into tissue using a standard syringe and needle.
,: :
WO92/00718 2 ~ ~ 5 ~ PCT/US90/03762 , Sanguinarine chlorido was added to the same DL-- PLA solution as described in Example 7 to give a 5% by weight dispersion. The dispersion was poured into a shallow dish and th2 m2chylene chloride evaporated to form a .ilm wlth t.~2 pa~-_lcl-s o_ d-uy dlsp2rsed uniformly within the ~ol~,~ner matrix. The film was then ground to yi-ve s."all ~d~-tiCl_s OL PO ~y~.ner/'druy ~-hich could ~e sus~endod ln an a~lOUS injection ~Jehicle and injected di:-~s-ly int~ u~ using a ,ta..~ard sy~ing2 and nee~le.
' : ' ' , :
. ~`~ ' .
. .
.
: ~i :`
-~ '
Claims (16)
1. A pharmaceutical composition for controlled delivery of a chemotherapeutic agent to a localized site in infected gingival tissue of the mouth for of a patient having periodontal disease, comprising a polymeric delivery system formed from the chemotherapeutic agent in mixture with a polymer.
2. A pharmaceutical composition in accordance with claim 1 in which said delivery is accomplished by insertion with a syringe apparatus.
3. A pharmaceutical composition in accordance with claim 1 in which said delivery is accomplished with a trochar or a surgical incision.
4. A pharmaceutical composition in accordance with claim 1 in which said chemotherapeutic agent is selected from an antimicrobial, antibiotic, anti-inflammatory, anti-infective, peptide, protein, growth factor, antigen, biological response modifier, or vaccine.
5. A pharmaceutical composition in accordance with claim 1 in which said polymer is biodegradable.
6. A pharmaceutical composition in accordance with claim 2 in which the delivery system is selected from microspheres, microcapsules, nanoparticles, liposomes, and other small particles.
7. A polymeric composition in accordance with claim 2 in which the delivery system comprises a polymer solution containing a drug dissolved or dispersed in said solution and which solidifies to form a solid implant after injection into said tissue/
8. A polymeric composition in accordance with claim 2 in which the delivery system comprises a drug dissolved or dispersed in a liquid prepolymer that polymerizes or crosslinks to form a solid implant after injection into said tissue.
9. A polymeric composition in accordance with claim 3 in which said polymeric delivery system is in the form of a fiber, film, rod, cylinder, or pellet.
10. A polymeric composition in accordance with claim 4 in which the drug is selected from tetracycline, chlorhexidine, metronidazole, minocycline, clindamycin, sanguinarine, sanguinarine acetate, ethoxydihydrosanguinarine, sanguirubine, sanguilutine, chelirubine, chelerythrine, chelilutine, acetylsalicyclic acid, acetaminophen, ibuprofen, flurbiprofen, ketanserin, bone morphogenetic protein, fibronectin, fibrololast growth factor, platelet derived growth factor, transforming growth factor, and endothelial cell growth factor.
11. A polymeric composition in accordance with claim 5 in which said biodegradable polymer is selected from the group consisting of polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, hydroxycellulose, methylcellulose, gelatin, collagen, and copolymers, terpolymers, or combinations or mixtures of the above materials.
12. A pharmaceutical composition in accordance with claim 1, wherein said agent is selected from the group consisting of sanguinarine hydrochloride, ethoxydihydrosanguinarine, sanguinarine acetate, chlorhexidine diacetate, chlorhexidine gluconate, tetracycline, and tetracycline hydrochloride; and wherein said polymer is selected from the group consisting of poly(DL-lactide) and poly(DL-lactid-co-glycolide).
13. A pharmaceutical composition in accordance with claim 1, wherein said agent is present in said polymer at a concentration in the range of about 1 to 80% by weight.
14. A pharmaceutical composition in accordance with claim 1, wherein said agent is present in said polymer at a concentration in the range of about 10 to 40% by weight.
15. A pharmaceutical composition in accordance with claim 12, wherein said agent and said polymer are present in a liquid carrier.
16. A pharmaceutical composition in accordance with claim 15, wherein said liquid carrier comprises a solvent for said agent and said polymer.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US1990/003762 WO1992000718A1 (en) | 1990-07-03 | 1990-07-03 | Intragingival delivery systems for treatment of periodontal disease |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2065156A1 true CA2065156A1 (en) | 1992-01-04 |
Family
ID=22220935
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002065156A Abandoned CA2065156A1 (en) | 1990-07-03 | 1990-07-03 | Intragingival delivery systems for treatment of periodontal disease |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0489743A1 (en) |
| CA (1) | CA2065156A1 (en) |
| WO (1) | WO1992000718A1 (en) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU663328B2 (en) * | 1991-06-21 | 1995-10-05 | Genetics Institute, Llc | Pharmaceutical formulations of osteogenic proteins |
| US5384333A (en) * | 1992-03-17 | 1995-01-24 | University Of Miami | Biodegradable injectable drug delivery polymer |
| FR2691360B1 (en) * | 1992-05-20 | 1995-06-30 | 3P Agence Conseil | PHARMACEUTICAL COMPOSITIONS PARTICULARLY FOR THE TREATMENT OF PERIODONTAL POCKETS AND METHOD OF MANUFACTURE. |
| GB9211268D0 (en) * | 1992-05-28 | 1992-07-15 | Ici Plc | Salts of basic peptides with carboxyterminated polyesters |
| DK0676948T3 (en) * | 1992-12-16 | 2000-09-04 | Colgate Palmolive Co | Oral anti-plaque, anti-gingivitis, anti-caries composition |
| US5423337A (en) * | 1994-03-24 | 1995-06-13 | Ahlert; Gary | Medicated dental floss |
| CA2187355C (en) * | 1994-04-08 | 2009-10-13 | Richard L. Dunn | An adjunctive polymer system for use with medical device |
| KR960016882A (en) * | 1994-11-01 | 1996-06-17 | 강재헌 | Sustained-release biodegradable preparations for the treatment of periodontitis |
| US5607686A (en) * | 1994-11-22 | 1997-03-04 | United States Surgical Corporation | Polymeric composition |
| US5736152A (en) * | 1995-10-27 | 1998-04-07 | Atrix Laboratories, Inc. | Non-polymeric sustained release delivery system |
| PT949905E (en) * | 1996-12-20 | 2001-12-28 | Alza Corp | DELAYED EFFECT INJECTABLE GEL COMPOSITION AND PROCESS FOR THEIR PREPARATION |
| KR100508229B1 (en) | 1997-03-18 | 2005-08-17 | 선스타 가부시키가이샤 | Composition for forming solid particles |
| EP1344538A1 (en) | 2002-03-14 | 2003-09-17 | Degradable Solutions AG | Porous biodegradable implant material and method for its fabrication |
| US8163030B2 (en) | 2004-05-06 | 2012-04-24 | Degradable Solutions Ag | Biocompatible bone implant compositions and methods for repairing a bone defect |
| US8865198B2 (en) | 2010-10-25 | 2014-10-21 | Dexcel Pharma Technologies Ltd. | Method for treating a periodontal disease |
| US9498612B2 (en) | 2013-03-14 | 2016-11-22 | Hallux, Inc. | Method of treating infections, diseases or disorders of nail unit |
| DE102016101280A1 (en) | 2016-01-26 | 2017-07-27 | Frank Bröseler | Pharmaceutical composition |
| CN116172983A (en) * | 2022-12-13 | 2023-05-30 | 首都医科大学附属北京朝阳医院 | Tooth Zhou Sai treatment film and manufacturing process thereof |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4774091A (en) * | 1983-10-14 | 1988-09-27 | Sumitomo Pharmaceuticals Company, Ltd. | Long-term sustained-release preparation |
| JPS60184027A (en) * | 1984-03-01 | 1985-09-19 | Lion Corp | Preventive and remedy for periodontosis |
| US4780320A (en) * | 1986-04-29 | 1988-10-25 | Pharmetrix Corp. | Controlled release drug delivery system for the periodontal pocket |
| IL86802A0 (en) * | 1987-06-30 | 1988-11-30 | Vipont Pharma | Drug delivery devices |
| JP2670680B2 (en) * | 1988-02-24 | 1997-10-29 | 株式会社ビーエムジー | Polylactic acid microspheres containing physiologically active substance and method for producing the same |
| US4938763B1 (en) * | 1988-10-03 | 1995-07-04 | Atrix Lab Inc | Biodegradable in-situ forming implants and method of producing the same |
| IE61346B1 (en) * | 1988-11-02 | 1994-11-02 | Genentech Inc | A permeable material to fit around the teeth or gums of a mammal |
-
1990
- 1990-07-03 EP EP90911129A patent/EP0489743A1/en not_active Withdrawn
- 1990-07-03 CA CA002065156A patent/CA2065156A1/en not_active Abandoned
- 1990-07-03 WO PCT/US1990/003762 patent/WO1992000718A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0489743A1 (en) | 1992-06-17 |
| WO1992000718A1 (en) | 1992-01-23 |
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