Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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
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WO92/00718 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
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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
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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
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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
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~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
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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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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.
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~ ~VO 92t00718 2 " ~ p~/Us90,03762
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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
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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
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` 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
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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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092/00718 PCT/US90/03762
11
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.
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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.
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WO 92/00718 ~ 5 PCT/US90/03762 ~
12
EXAMPLE 3
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.
EXAMPLE 4
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.
- EXAMPLE 5
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
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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.
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EXAMPLE 6
~; 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.
EXAMPLE 7
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.
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WO92/00718 2 ~ ~ 5 ~ PCT/US90/03762 ,
14
EXAMPLE 8
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.
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