CA2212165A1 - Method and device for administering analgesics - Google Patents
Method and device for administering analgesicsInfo
- Publication number
- CA2212165A1 CA2212165A1 CA002212165A CA2212165A CA2212165A1 CA 2212165 A1 CA2212165 A1 CA 2212165A1 CA 002212165 A CA002212165 A CA 002212165A CA 2212165 A CA2212165 A CA 2212165A CA 2212165 A1 CA2212165 A1 CA 2212165A1
- Authority
- CA
- Canada
- Prior art keywords
- analgesic
- matrix body
- neuraxis
- animal
- polymeric
- 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.)
- Abandoned
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Classifications
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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
- A61K9/0085—Brain, e.g. brain implants; Spinal cord
Abstract
A device and method is disclosed for continuously administering an analgesic to the neuraxis of an organism. The device comprises a polymeric matrix body loaded with the analgesic. The body is implanted in the neuraxis where the analgesic diffuses into the neuraxis.
Description
WO 96/2433iO PCT~US96~a~753 METHOD AND DEV~CE FOR ADMI~ ;~ING ANALGESICS
Te~1~ CAI Field This invention relates to a device and method for A~ analgesics to the 5 neuraxis of an ol~al~i~ . More specifically, this invention relates to the long term release of an ~nAlgPeic from a bioco...l.A~ e polymeric matrix device i...~ d into the central nervous system of a human patient or other warm blooded animal.
Bac~uu~d Art Constant or chronic pain is a ei~nificAnt medical 1,r~'- , for P~AIII1~1e in tPrminAI
cancer patiel1ts. Many of the drugs, such as the opioid class of ~n~l~oi~.e, used to treat severe chronic pain act on rec~Lc,ls found in the neuraxis. By "neuraxis" as used herein is meant any region oftissue that c~ s the spin~l cord, brain or central nervous system.
The current regimen for ileaL~ of these patients is systemic ~lminietration of 15 lelaLi~e;ly high doses of ~n~lgeoi~e by for ~x~ni.le oral, slh~ A,-Puus, intr~mllec~llAr, illLl~v~ )us and related routes on a daily or continuous basis. Oral ~ n;"~ lion of a~
~nAl~eic is prob'~ nAtic because the patient ~ iellces high ~y~ c concentration of drug at the time of ingP..etion follo~wed by a gradual decrease in systemic conc~ ion of the drug until the next dose is ;..~ d Other methods of systernic ~ Lion are pl-b'-m~ti~
20 because they rnay be invasive, for example p1~PmPnt of an i~ v~llu~ls catheter for continllous ~l~l...;..;.~l.~Lion of the AnAIgçeic In either case, however, the ~n~lgPcic is disLlil,uled equally throughout the body af[er being A~l...;..:~i~.~d systPm:~Ally and diffuses across the b]ood brain barrilsr into the n~ul~xis to its central site of action, blocking pain mP~:~Ag~ to ~he brain. The cost for treating these patients is high from a hospital care as well 25 as from a phzlrrnA~ellticAl standpoint since many patients must be IllA;/~lA;llPd in the hospital to continue their pain treatment ,~gim~l, of high doses of the analgesic. Ful~helmore, side effects related to the systemic a-l...;~;xl~ _Lion of high doses of, for example, opioids include ~ sedation"~)haloly depressiion, nausea, c~ ion and vomiting. These side effects are well do~.. ~.. lecl in product labeling and the literature and dekact greatly from the already 30 col.,~ ,ll ised quality of life o:Fthese patients.
More lec~..Lly, trAn.~clPrrnAl patches have been developed as a means for efficiently delivering an~gesics to patiel1ts on a continuous basis. A patch is loaded with an An~lge~ic =
such as fentanyl and is att~rhPd to the pali~ 's skin by means of typically an a&esive. The ~n~lgP~ic diffuses out of the patch and crosses the patient's skin, where it is absorbed by the body. Patients may be ~ uil~d to wear a number of patches to obtain ~-leclu~te tLc;la~uLic l~onSe, as the ~n~lf~.eic site of action is in the ll~;u~xiS. Wbile less i. v~iv~: than other 5 a~l...;..;~il~Lion techn~ Pe listed above, systemic side effects l~ulLill~, from high levels of ~n~lgP~ic in the body are still a ~i nifir~nt medical plobl~ and cnnfin le to co.~ u~se patient quality of life.
AlLt;lllaLi~,~,ly, spinal ~ l;nn (LlLlaLl,ecal or epidural) of centrally acting iqn~ irs via an e~tprn~li7p~d spinal catheter, a spinal catheter cc.l~l~P~ilerl to an external 10 infileion pump, a spinal caLLcLel connPc;ted to a fully ;~ ed infusion pump and other related systems has been shown to be th~,a~uLically ~ ;L vt; for the l,~aL~e"L of chronic pain. To reduce systemic side effects caused by l~l~Li~v~ly high dosage systemic delivery, direct spinal delivery of the ~n~lgP~ic is pl~r~lled. In this way, drug is deLv~ d in a col~P-.I~aLed manner and at low doses to its specific site of action on ,~cel,Lo,~ in the 15 n~ x;~, 1ll;ll;lll;~;l~ systemic side effects as outlined above. Spinal catheter pl~rPmP.nt and infil~inn pump use, while shown to be highly t;~Livt;"~c;sellL a therapy ~ l;v~;; that is r~laLiv~ly ~ siv~ and illvas;ve to implant. These therapies also present w-vith risk of spinal infectinn such as mPningitic since the blood-brain barrier has been co~ loll~ised and drug is delivered to the lle~ul~iS from an external source such as a drug pump.
Recent r~se~-,L has also d~ al~d that living cells that produce natural analge~irs can be P.nr~pslll~ted into a silicone sheath and ;...~ .led into the central nervous system. It has not been PSI ~ l .Pd whether these cells produce LL~ uLic qll~ntitiPs of anal~eQ;~s while in vivo or how long the encapsulated cells will remain viable. Doses of analgesic that the cells produce in many in~t~nres can not be controlled and external stimuli, for c~ nicotine, 25 may change cell viability p~l~Lel~. Finally, potential for infection in the neuraxis if one of these modules were to rupture has not been chara~P.ri7P,A
The present invention provides an alL~lllaLive means for achieving continuous central nervous system ~Amini~tration of an ~n~lg~ic into the neuraxis via ill~lav~lll.;clllar, epidural, intrathecal and related routes for those ~ chronic pain and is directed to solving one or 30 more ofthe problems noted above. The invention compri~Pc an ~nalgP~sic caî~ying device and its method of use"n~ ing ;,~ l;on, which releases the ~n~l~P~ic in a continuous and sll~t~in~ release manner The device consists of a biocom~al~ e polymer matrix body -WO 96124331) PCI~/US96101753 loaded with an ~n~lgf cir such that a slow, plrrél~bly col~l release of the ~n~ ç~ic is provided. The polymer matrix ~ub~Ll~lrv may be constructed of any of a number of biostable or biodegradable polymers t~at act as the carrier matrix for the ~n~l~e~if . Ideally, l~el~euLic levels ofthe :ln~lgf Q;~ will be de]ivered over the long term, i.e., one month to one year. Two 5 plerelled ~n~ fri~~ arefentanyl and ~,.r~."~ ;l opioids about 100 to 500 and 1000 to 5000 times, lrv~e~,lively, more potent than ~ull~Liue. Plrvrel~ly the method of the invention ~I".;.,i~ the 51n~1~?r;'' illLl~lvr~ rly, intrathecally, epidurally, or by other related routes to the neuraxis. The illLl~LLec2~ route ûf ~1.,,;,~;~;1. ;ll;f~n is prerelled 10 Diclosure of Invention With this invention it is reco~i7çd for the first time that increased cost-elIer Live and cimrlif ity of the ~ Lion of ~n~lgf cics directly to the central nervous system, i.e., ~eul~ially, may be ~cc~ pli.~ d by means of a polymer matrix body loaded with an~n~lg~cic and made available for fliffilcion from the matrix into the biologic ne.~ x;~i 15 f ll~r~ rllL.
Brief Description of Dl~whl~ s Figure 1 is a view of a side matrix body made from a bioc~.,..p~ polymer cn"~ 3n~1~r;c in the int,erstic- s thereo~
Figures la, lb and lc show ~ le configurations.
Figure 2 is a view of a plerelled shape ofthe matrix body for retrieval purposes.
Figure 3 is a s~ ...z~ showing the spinal column and d~mn~ Lill~ the lumbar ; " ,l ,1" . " ;~ ~ ;r)n of an ~n~lg~cic loaded matrix body by ejection of same from a needle. Figure 4 is a more detailed showing of the matrix body in the needle of Figure 3 and a method of 25 delivery of same into the body ellvilol~llrllL.
Figure 5 is a graph ~ JWil1g e~ lcs of fentanyl elution from polyul,eLl~le over time as the percent of the total fentanyl available.
~ Figure 6 is a graph ~LL~w"lg fentanyl elution from silicone over time as the percent of the total fentanyl available.
Figure 7 is a graph sh~wing sample m~trices in terms of effective dose in micrograms per day as ~ ed from a matrix body accor&g to the invention.
CA 022l2l65 l997-os-05 . 4 Figures 8, 9 and 10 are graphs showing the amount of fentanyl delivered as a percent of the total amount of fentanyl bonded with several sample matrix ger" "~l~ ;
Best Mode for Carryin~ Out the Llv~lLion Turning now to the ~ wi~gs, which disclose ~ les of various drug delivery devices and methods accolding to the invention, one embodiment of the device is in~ir~ted in Figure 1 at 10. Device 10 co",l";.cP~ a polymeric matrix body 12 made of a biostable or biodegradable polymer loaded with an ~n~l~Qi~ such as fentanyl. Device 10 can be used for the cnntinlloll~ ~l. ";.~ Lion of the ~n~lgP~ic to the neuraxis of an anim~l body. Device 10 10 delivers an ~n~lgP~ic by elution of the ~n~l~P~ic from the matrix polymer body 12 in a fluid ~U~IO~ ,t;llL at a gradual manner with the drug being delivered at a controlled and continuous rate over a prc lr nged period of time. The analgesic elutes from the matrix body 12 due to the pP.rmP~tinn of water and lipids from the ~l~L~l~Lilial fluid through the polymer matrix. This pPrm~tinn solubilizes the ~n~l~Qi~ to allow release from the matrix body 12. Various 15 factors such as geomPtry~ size, m~tPri~l and pore size all affect pPrmP~hility of the polymer matrix body 12 and l~ulL~lL elution rates ofthe ~n~lg~ric to the neuraxis.
Figure la shows a cylinder cnnfi~lration for body 12a of device 10 with rounded ends for easing pl~rP.mPnt and retrieval. Figure lb shows a cylinder confi~lration for body 12b of device 10 formed from a rolled-up sheet of polymer m~tPri~l Figure lc shows a 20 cylinder co"r,~ Lion for body 12c of device 10 in the form of a hollow tube, cn"~;.;";.,~ a 4u~Lily of an ~n~lg~ic 16. The ~n~lgP~ic 16 may be dispersed within the polymer. Many other confi~lrations will be al~p~llL to those f~miliar with this art.
,~tt~rhrd to body 12 by any suitable means of cn~ ;nn such as a&esive or fusion is a tether 14 of such a length as to allow for retrieval of device 10 at any time following 25 ;",~ ;nn thereof into the neuraxis region of an animal body. The tether 14 may be of any known bioc-"~ ]c m~tPri~l such as nylon as is generally used in surgery.
Figure 2 illu~Ll~Les a preferred confi~lration of body 12 in which the p~ llal end thereof, i.e., the end to which tether 14 is ~tt~rh~d is tapered for f~rilit~ting retrieval. '' The polymer utilized for making up the matrix body 12 of device 10 may be any 30 suitable biocc~ le polymer, whether biostable or biodegradable.
Biostable polymers that may be utilized include silicone, polyult;ll~e~ polyether urethane, polyether urethane urea, poly ~?, polyacetal, polyester, poly ethylene-WO 96124330 ~CI/IJS96~(1I753 chloluLlinuoIoethylene, poly tetrafluoroethylene (Pl~ or "Teflon~"), styrene b~t~ n~
rubber, polyethylene, poly~,r~ylene, poly~h~llylene oxide-poly~yl~l~e~ poly-a-chloro-p-xylene, polylll~L}lyl~llL~lle, polysulfone and other related biostable polymers. Presently, polyul~ll~e is a plert;ll~d biostable polymeric matrix m~t~.n~l for body 12, but many of the 5 above listed polymers may be useful for this applic~tirm Biodegradable polymers that may be utilized include poly~y~Lides, cyclodestrans,poly lactic-glycolic acid, polyorthoesters, n-vinyl alcohoL polyethylene oxide/polyethylene le~ te, polyglycolic ac,id, polylactic acid and other related bioabsoll,abl~ polymers. In the event a bliodegradable polymer is used as the matrix body 12, the tether 14 may or may 10 notbeutilizedsincep~ J~ I;on_ aybeacceptable.
The ~n~l~Fi~ 16 loaded into the polymer matrix body 12 may be from one of any number of ~,1asses of ~n~l~PQ;~ that have been shown to act c~ lly on specific pain lt:Cel~Ol~ in the n~llr~e Potential drug classes include ~n~ ir~, typically called opioids, tha~t act on opioid pain l~ce;~Lul:i. F,X;~ le~ of such opioid ~n~l~PQ;~s are ...~ e, fentanyl, 15 ~"r-."~"il ~llfPnt~nil, hyJlu~l~ul~ olle, mPpPri(1inP; mP.th~ )nP; I)u~ Gl~l 'e, DADL, l~uLul~ ol and related opioids. O~er puLellLial drug classes include ~n~lg~ s that act on non-opioid pain leceptol~. One such group of ~n~l~c;~s that act on non-opioid pain t;Ct;~lOl:i are alpha-2 adre~ ic leC~Ol a~nietq such as rlr~n:~in~ l;..P, ST-91, mPdetom: linP; ~lpymp(letomirlinp and related alpha-2 adr~ ic ~nnictc Another group of 20 ~n~lgPr;~s are NMDA le:c~Lor ~nt~gt)nicte such as d~ LLol~ , Ifenprodil, MK-801 and related NMDA ~nt~goniete Yet another group of ~n~lg~Q;~s are som~tost~tin analogs such as Octreotide, Sandostatin, Vapreotide, Lanreotide and related ~eom~tost~tin ~n~logc Finally, other ~n~lg~Q;~ ,e may be used that act on non-opioid pain lec~lol~ such as ketorûlac, super oxide rliqmllt~e~; b?lelOfen~ c~lritonin~ St;lulCJl~, vasoactive ;~IP~I;II~1 polypeptide, bombesin, 25 omega-conopeptides and related non-opioid ~n~lgPr;~ e The list is not intPnrled to be c~ mplet~, but rather to demonetrate the broad potential and fe~eihility of the invention to act on a number of central pain lec~Lol~, even though not all agents may be readily used to ~ construct a device of clinically viable size. The preferred ~n~lgP.eic pl~selllly is the opioid fentanyl that is about 100 to 500 times more potent than morphine and is well characteri7~d in 30 the neuraxis or ~Itl~rn~tively ~"r~."~il that is about 1000 to 5000 times more potent than morphine.
Anal~esic Loadin~ 6 The ~n~lgRxic 16 _ay be loaded into the polymer matriX body 12 by a number of terhn~ R.~ The choice of loading te ~ e for a particular ~n~lgRcirlpolymer ~trix/device y,~r~ y will be dependent on a number of factors in-hltli~ drug/polymer/solvent 5 cc~...p~l;l.il;ly, desired fin~l col~c~..L,~Lion of ~n~lgecic 16 in the polymer _atrix body 12, x;~ y of the process, desired final ~ÇC.I~ y of the device 10 and ~t;r~lc~d elution char~ct~o.rictics of the ~ device 10. As c r I , a few loading te~ hn:que options are listed as follows. The list is not intPnllRd to be c~ l.'cte or limhin~ but r~ther to serve as fc well ~lnrlP.rctood by anyone skilled in the art.
The ~n~lgR~* 16 _ay be loaded into the polymer body 12 by means of dispersion loading. D;. ~ n loa&g is the t c ' que of loading a powdered Xul~-xL~ce into a polymer by stir- xing it into the polymer precure or sohltinn to ~ke a dispersion of the two m~t.~.ri~l.c The powder is not dissolved by the polymer s(~' ltinn in dispersion loading. The polymer is soli~ifiRcl by curing or solvent ~v~ulilLio~ and a homogel~euus blend of ~n~lgRcir 15 16 in the polymer is achieved. The ~n~lgesir. 16 has not reacted with the polymer but rather is cL~lxed within the i ~ LiLi~l spaces ofthe cured polymer. The conccllLlaLion of drug that can be loaded into the polymer is limited only by the physical iLILegliLy of the resul~ing polymer m--atrix body 12. Dispersion mixjng is a standard te~hni~lLue for loading dl ~.n~ c~ nR into polymeric lead tips to create steroid eluting leads.
The dispersion loading method is the pl~rt;lled method of cu......... l,inillg ~n~lgRcic 16 with the polymeric matrix body 12 because the method allows for a fairly high p~ ge of ~n~lgRcir. 16 to be added to the polymer to form matrix body 12. The pel~ llL~ge of ~n~lg~.cic 16 added to the polymer to form matriX body 12 is pl~r~l~ly from 10% to 80% by weight.
This percentage has been found to ,~ ;,. the hlLe~iLy of the polymer ~ubsLlaL~ in body 12.
25 A higher loading conc~..L~Lion of ~n~lgRcic~ 16 allows for the design of a smaller device 10 for clinical use and p1~cP.mPnt in the ncul~is.
The dispersion loading method also allows the body 12 to be formed into optimal genmPtries prior to cure of the polymer or for body 12 to be extruded as a tube or other geoll~Lly. Finally, solvent cu. . ~ l ;l .ilily between the polymer of body 12 and the ~n~lgRcic 16 30 is not a factor.
AlL~lllaLi~ly, solvent swelling can be used to combine the ~n~lgt?cic 16 with the polymeric matrix body 12. This method is particularly useful where a pl~rl.~",ed polymer body 12 is imtroduced into a solution of the ~n~ eic 16 in a solvent that acts as a ~wellillg agent for the polymer body 12. The body 12, while ~ llhl~,, absorbs the solvent along with the dissolved ~n~l~.eic 16 until a steady state is achieved. The polymer body 12 is then allowed to dry with the solvent ev~ul~Liu~ from the sample and the ~n~l~,r~ei~. 16 l~t behind 5 in the body 12. As the body 12 dries, it returns from its swelled state to its original g~om~.try and size. Solubility of the ~n~l~e.eic 16 in the sollltion limits the possible collc~ lion of drug that can be introduced by this te~ e. Even so, the te~LL~ ue is well known and has been used sllcc~.efillly to load antLmicrobials into poly_er m~tric~e, (See, for c~lc, U.S.
PatentNo. 4,gl7,686).
Solution loading is silnilar to ~ el~;on loading except that the ~n~l~.ei~, 16 or clrug must be solu.ble in the polymer solvent. The cured polymer body 12 then inr.llld~ the dissolved ~n~'lg~.~is 16 or drug in its matrix.
Finally, the method Oi-lc~SelvOll loading may be used to comhin~ the ~n~lg~Qir 16 with the body 12. This method cc~ es loading pure drug or ~n~ eir, 16 inside a hollow tube 15 and sealing the ends ofthe tube to form the body 12. The ~n~l~eic 16 then diffuses through thepolymertubingwall of body 12.
Althoughthe configllration ofthe device 10 rnay be varied in-~.hl-lin~,r for ~ ,..pl~.
rods, rolled up sheets, buttons, discs, tubes, rnicrospheres and fibers, the plesell~y pler~lled c~ nfi~lration is a small tube or rod of polymer the size and shape of a grain of rice which may 20 be readily introduced into 1he intrathecal space via a 14 gauge needle. Final product confi~lration rnay be r~l ~. ;c~l ~ed by any of the rOl'èg,Oi~ ter~n:qlles More specifically, srmall device sizes typically less than 0.10 inches in r~i~rnPt~r are co..~ ,l,.led for the preferred method of ~ lion co.-.l..;.~;.~gr the simple lurnbar ~ulleLule te~ m~ e. This technique is illu~ ed with reference to Figure 3 wll~leill a needle 25 20, preferably fourteen (14) gauge or smaller in size is inserted between the vel lel~l~e 30 into the epidural space 32 or the intrathecal space 36 in the known lumbar ~-lllcLule te-hni~
The ara~hnni~ layer is shown at 34 and the spinal cord at 38.
Needle 20, as is best shown in Figure 4, cnnt~in~ the device 10 to be ;~pl~ ed Needle 20 also contains a pusher rod or cylinder 22 that is used to eject device 10 from 30 needle 20 for ;..~pl~ lion Plerel~bly, as shown, pusher rod or cylinder 22 is hollow so as to readily accommodate tether 14 whereupon removal of needle 20 and pusher rod 22 leaves the led device 10 in place with the tether 14 ~ r.ll~l;ll~, thel~iul~l. Tether 14 pl~rel~ly CA 022l2l65 lss7-os-05 wo 96/24330 PCT/US96/01753 extends away from the body 10 and l~ e,c under the skin but outside the spinal cord so that tether 14 is easily ~çc~ le when retrieval is desired. To retrieve body 12, the needle 20 is simply inserted over the tether 14 and moved to body 12. Tether 14 is then used to draw the body 12 into the needle 20 and the body 12 is removed with the needle 20.
AlLel~Lively, the co. .. l)il-~d ~n~l~Qie/polymer matrix body 12 may be ~tt~hPd to the end of a ~L~d~d spinal caLlleleL by any suitable means such that the outer ~ of the device 10 equals the outer ~ . of the catheter. The device/catheter system may then be introduced into the desired location in the spinal column by the sL~da ~1 lumbar ~e~
Le~ using ~L~d~-l needles and plocedu.ès. The system may be retrieved in the same 10 manner as a ~l~d~d spinal callleLer is leLlieved today as is well understood by those skilled in the art.
Prerel~ly~ ;",pl~ l;on of the device 10 will occur in the ilLl~lLecal space as opposed to the epidural space. This is because less ~n~lge~i~ 16 is le~luiled for t;~eLiv~;
control of chronic pain when device 10 is introduced to the illLlaLllec~l space as COlll~al ed to 15 the epidural space. As already in-lir~tet1, the te~hr:q~l~c described herein may also be used for i".pl,...l;.l;nn of device 10 into a brain ventricle.
Table I shown hèléillb~l~ w provides an ~ .lc of the device size le~lulle~.-ellLs for providing a minim~l SiX month dose of fentanyl to acc~ l . chronic pain control in a more or less typical .~ihl~tinn involving i lLl~Lllecal ~-1. . .;I . il . ~Lion.
TABLE I
DRUG NEEDS
Intrathecal fentanyl dosage: 0.1 to 0.3 mg/day Using ~ ~ -' dose for 6 months ~..,..;..g polymer and drug d~n~iti~s _ 1 g/cm3 or 1 mg/mm3 0.1 mg/day x 180 days x 1 mm3/mg = 18.0 mm3 fentanyl to be delivered DEVICE SIZE
Assume 20% lo~-linp~, and 50% a~ in 6 months 18.0 mm3 of active fentanyl = 180.0 mm3 of device 0.1 mm3 actives/mm3 inactives Device of volume 180.0 mm3 or 0.18 cm3:
WO 96124330 r ~, l / U ~6101753 ~ Cube, 0.56 cm on-a-side --Cylinder, D = 1.8 mm, L = 70 mm (2.8 in) Detailed Deslcriphon of Ex~.l,lcs The :following PX~mrle~. are set forth as le~lesell~Livc of the spirit of the present invenlion. These ~.~Qmp'-~ are not to be construed as limiting the scope of the illvcllLio4 as these and other fim~it)n~lly equivalent methods and devices will be readily appal~l.L to those skilled in the art. Studies to date have focused on developing and char~ a feasible polymLer mahix ~ul,~Ll~Le for body 12 that will elute QnQl~esi~ 16 continllollqly and over the long term, i.e., one month to one year. In patients or ~nimQle near zero order release kinehcs for the duralion of the imp]iant are plcrcllcd because stable drug concc~ Lions may be ..~ ;"ed in the neuraxis. Zero order release kinehcs means that over hme, the amount of drug ~ ,ased by the polymer matrix remain~ at a l.,laliwly co~ lll rate. For ~ ~ , for an implant having a useful duration of several months, ~Lth zero order release kinP.ti~.~, the amoullt of dnlg released fromL tbLe polymer mat~x on day 30 will be the same as the amount of drug released from the nnahix on day 5. FiT~lly, the ~n~l~e~i~ loaded polymer mLatrix body 12 must be ~I~,;T;,,,l)le, biocc""p~ le and of a ~ec~ y and size that is easily ;",pl~"~ le and removable in the llcul~iS.
For ~le following ~ ,1e~, fentanyl citrate was chosen as the ~l~rt;ll~d ~n~ e~ic 16 because it has a centrally acting mode of effect, is 100 times more potent than "~ol~ e, and is a stable anld well c~ cL~ ed opioid ~n~l~Qir Fentanyl citrate powder was purchased from USPC Inc., Rockville, Maryland. Polymer substrate m~t~ri~le tested in~ ded medical grade silicone ~ ,ha~ed from Rehau Corp., Leesburg, ~lrginia, (Trade name Pc~llmerlic SI2000) and PellethanLe bra~d polyult;ll~ e of dulu~~L~l 80A purchased from Dow ~h~mic~l Midland, Michig~n Polyulc~ e adhesive was prepared by heat press moltling PPllP,tll~nP- pellets into film and dissolving the film in dilllcLllyl ~cet~mi-le (DMAC) solvent.
Initial studies i-l~ntifiPd a polymer matrix, developed an c~;Liv~ te~' q~le forloading fentarLyl into the matrix as (~ ed earlier, and con~alcd the in vifro release kinetics of fentanyl from various m~trires Also described are studies c~ r~ g the effect of fentanyl release as a fi~n~inn of polymer type, matrix porosity, drug conr~"l~Lion and device shape.
All s~mrles vvere placed into a phosphate buffered saline solution and were ~ d at 37C. Eluate samples were pu:lled at various time points for analysis by standard high plc~ c liquid cLlc~lography (HPLC) techniques, with samples being cc~ hlt;d against a ~ dard fentanyl co~ Lion curve. Fx~ pl~.s are ~ ecl as follows:
This ~le evaluates the release kinetics of the ~n~lgPqic fentanyl from r~l~liv~ly nonporous polyul~Llla~e matrix samples 1 and 2 over time. Data is shown in Figure 5. The samples l and 2 are also cu~d to ~ ;v~ silicone carrier matrix samples 3 and 4 shown in Figure 6 and ~ c~ ed in Fx~mple 2.
Polyult;lL~le samples 1 and 2 in Figure 5 were pl~ed by the di~ ioll le~ 4~le 10 l~ ecl earlier and well understood by those skilled in the art. Polyul~Ll~e used was pP.lleth~nP 80A. S~ 1 and 2 were loaded with a 10% fentanyl powder and were pl~t;d in a film confi~ration applux;...~ y three quarter inches long by one quarter inch wide by .015 inches thick. Sr~ 1 and 2 were placed in ~ dald ph~srh~te bu~ ;d sc l-~fi~ n (PBS) and allowed to elute drug for 60 days at 37C.
Figure 5 shows the amount of fentanyl delivered as a percent of the total amount of fentanyl loaded into the sample, i.e., ~;~.. l~l;v~ elution. Release kinetics are nearly zero order, with the amount of drug being deliv~l~d on day 50 nearly equal to the amount of drug being delivered on day 10.
Figure 7 pl~sellls the data for the first 28 days as rnicrograms per day of fentanyl 20 delivered from the matrix by sarnples 1 and 2. Following a first day bolus, the sarnples both eluted drug at h~p~l~x;-~ .ly 30 micrograms per day, h~plux~l~ly one third to one tenth the effective intrathecal dose required for human clinical use. Results for both samples were cc l~ for each tirne point as well as over tirne.
This ~ lc evaluates the release kinetics of the ~n~l~;Pcic fentanyl from silicone matrix sarnples 3 and 4 over tirne. The sarnples 3 and 4 were also col~aled to ~ l;ve polyul~Lllalle carrier m~tPri~l samples 1 and 2 as described in Example 1 above.Silicone sarnples 3 and 4 in Figure 6 were prepared by the dispersion technique 30 ~liecu~ed earlier and well understood by those skilled in the art. S~mr'es 3 and 4 were loaded with a 10% fentanyl powder and were prepared in a film confi~-ration a~p-u~Lely one inch long by one half inch wide by .020 inches thick. Samples were placed in ~d~d ph~ sl h~te l~u~led sol ltic~n (l'BS) and allowed to elute drug for 60 days at 37C.
Figure 6 shows the amount of fentanyl delivered as a percent of the initial total ~ amount of fentanyl loaded into the sample, i.e., c -m -l~tive elution. In contrast to the 5 polyult;Ll~e samples 1 and 2~ silicone samples 3 and 4 provide a bolus release of fentanyl on day one followed by decl~; drug release ~ Llel. Results of both silicone samples 3 and 4 were Cr~ .I for each time point as well as over time.
This e/~ CO~ eS the effect of di~ fentanyl loading cr~ Lions on release kinetics using a l~laLivl~ly non~ol~,us polyul~;ll~e film.
Polyu~ ~e samples 5 and 6 in Figure 8 were p,~d by the dispersion terhn:qlle iq~;~ls~ed earlier. Polyu~ e used was Pellethane 80~ S~mpl-~ 5 and 6 were loaded with 10% fentanyl powder and 25~,/o fentanyl powder, lc;s~e-;Lively by weight and prepared in a film 15 c~."l~ Lion a~plux;~ ly one quarter inch wide by one quarter inch long by 0.01 inches thick. S~mpl-s 5 and 6 were placed in ~L~d~d phosphate bu~fered solution (PBS) and allowed to elulte drug for 60 days at 37C.
Figure 8 shows the l,l l . .~ ;v~ amount of fentanyl delivered as a percent of the total amount of fentanyl loaded into the s~ The graph shows that the higher the 20 C~ lion offentanyl loaded into the sample, the greater the release rate ofthe ~n~lgPoi~
The 25% fentanyl loaded sample 6 e~ibits nearly zero order release kinetics over the first 30 days, with dnlg elution rates tailing offfrom day 30 to day 60.
This ~Y~ plc cO--l~aleS release kinetics of a nurnber of fentanyl loading concentrations from a l~,ldLiv~ly porous polyul~ e pellet.
Polyu.~ e samples 7, 8 and 9 in Figure 9 were p~ d by the dispersion ~echn:qlle ~ ecl earlier. Polyu~ e used was PP.IIP.t~l~nP 80A as in the previousPY~mplec, bul: the polymer samples were allowed to cure in a high humidity en~ e,lL
30 rather than in a vacuum. Casting the polyul~ll~e film in a high humidity e~ ol~c~
created a phase inversion allowing the polyurethane to pler.;p;l;.le and cure in a ~ liv~ly porous fashio:n. Samples 7, 8 and 9 ~,vere loaded with 10% fentanyl powder, 25% fentanyl powder, and 40% fentanyl powder, le~e~;LIv~ly by weight, and were pl~al~d as pellets aE~ x;~ y one halfinch long by 0.05 inches wide by 0.03 inches thick. The samples were placed in standard phosphate buffered sollltion and allowed to elute drug for 60 days at 37C.
Figure 9 shows the amount of fentanyl delivered as a percent of the t.otal amount of 5 fentanyl loaded into the s~mplee The graph shows that the higher the CO~ Lion of drug loaded into the sample, the greater the release rate. All samples suggest a large ~n~lge.~ic bolus is delivered on day one, followed by de~a~ g ~n~l~P.eic elution t~l~r~[lel.
This ~ .le cc~ s effects of gec,.. ~l~y of a sample on release kinrtire Polymer matrix m~tP.ri~l and fentanyl loading cr,nr.~.ntration are held c~ n~li ..1 polyulc~LLalle samples 10 and 11 in Figure 10 were pl~ d by the dispersion J~ ue .~ sed earlier. Polyul~LI~e used was p~ th~n~ 80A. S~nnrles 10 and 11 wereloaded with 10% fentanyl powder and were prep~ed as a film and a tube, le;*Je~;Li~ ly.
15 Tubing sample 11 was p~e~d applu~aL~ly one eighth inches in outer ,l;~ with awall th:-.kn~e.e of 0.005 inches and one quarter inch in length. Film sample 10 was ~l~a.~d ap~l.J,~;",s.l~.ly one quarter inch wide by one quarter inch long by 0.01 inches thick. S~mpl~e 10 and 11 were placed in standard phnsrh~te bu~l~d sC~1-lti~n and allowed to elute drug for 60 days at 37C.
Figure 10 shows the amount offentanyl deliv~l~d as a percent ofthe total amount of fentanyl loaded into the s~mrlle The samples provide coll~ .ll drug release over 60 days, with the tube geo ~ y r~lea~ll.g a greater amount offentanyl and at a greater rate.
The above FY~"~ and r1i~rlosllre are int~n-led to be illu~L.~Liv~ and not e~rh~llstive.
These 1~! rt~s and description will suggest rnany viqri~tion~ and ~ l;v~s to one of 25 oldi~y skill in this art. All these ~ "~l;v~s and v~ri~tion~ are int~nrled to be inrJlltled within the scope of the ~tt~rh~d claims. Those familiar with the art may recognize other equivalents to the specific embodirnents cl~er.rihçd herein which equivalents are also int~.ntled to be enct mp -~ed by the claims ~ rh~d hereto. The ~ Jlcs cl~o.m~-n~rate that an o~Lil..u", geometry and ~n~lg~ic loading rnay be prepared to allow for nearly zero order 30 release kinetics (straight line) oftherapeutic ~lluullL~ of an ~n~lg~ic over a period oftirne, for ,lc one month to one year.
=
Te~1~ CAI Field This invention relates to a device and method for A~ analgesics to the 5 neuraxis of an ol~al~i~ . More specifically, this invention relates to the long term release of an ~nAlgPeic from a bioco...l.A~ e polymeric matrix device i...~ d into the central nervous system of a human patient or other warm blooded animal.
Bac~uu~d Art Constant or chronic pain is a ei~nificAnt medical 1,r~'- , for P~AIII1~1e in tPrminAI
cancer patiel1ts. Many of the drugs, such as the opioid class of ~n~l~oi~.e, used to treat severe chronic pain act on rec~Lc,ls found in the neuraxis. By "neuraxis" as used herein is meant any region oftissue that c~ s the spin~l cord, brain or central nervous system.
The current regimen for ileaL~ of these patients is systemic ~lminietration of 15 lelaLi~e;ly high doses of ~n~lgeoi~e by for ~x~ni.le oral, slh~ A,-Puus, intr~mllec~llAr, illLl~v~ )us and related routes on a daily or continuous basis. Oral ~ n;"~ lion of a~
~nAl~eic is prob'~ nAtic because the patient ~ iellces high ~y~ c concentration of drug at the time of ingP..etion follo~wed by a gradual decrease in systemic conc~ ion of the drug until the next dose is ;..~ d Other methods of systernic ~ Lion are pl-b'-m~ti~
20 because they rnay be invasive, for example p1~PmPnt of an i~ v~llu~ls catheter for continllous ~l~l...;..;.~l.~Lion of the AnAIgçeic In either case, however, the ~n~lgPcic is disLlil,uled equally throughout the body af[er being A~l...;..:~i~.~d systPm:~Ally and diffuses across the b]ood brain barrilsr into the n~ul~xis to its central site of action, blocking pain mP~:~Ag~ to ~he brain. The cost for treating these patients is high from a hospital care as well 25 as from a phzlrrnA~ellticAl standpoint since many patients must be IllA;/~lA;llPd in the hospital to continue their pain treatment ,~gim~l, of high doses of the analgesic. Ful~helmore, side effects related to the systemic a-l...;~;xl~ _Lion of high doses of, for example, opioids include ~ sedation"~)haloly depressiion, nausea, c~ ion and vomiting. These side effects are well do~.. ~.. lecl in product labeling and the literature and dekact greatly from the already 30 col.,~ ,ll ised quality of life o:Fthese patients.
More lec~..Lly, trAn.~clPrrnAl patches have been developed as a means for efficiently delivering an~gesics to patiel1ts on a continuous basis. A patch is loaded with an An~lge~ic =
such as fentanyl and is att~rhPd to the pali~ 's skin by means of typically an a&esive. The ~n~lgP~ic diffuses out of the patch and crosses the patient's skin, where it is absorbed by the body. Patients may be ~ uil~d to wear a number of patches to obtain ~-leclu~te tLc;la~uLic l~onSe, as the ~n~lf~.eic site of action is in the ll~;u~xiS. Wbile less i. v~iv~: than other 5 a~l...;..;~il~Lion techn~ Pe listed above, systemic side effects l~ulLill~, from high levels of ~n~lgP~ic in the body are still a ~i nifir~nt medical plobl~ and cnnfin le to co.~ u~se patient quality of life.
AlLt;lllaLi~,~,ly, spinal ~ l;nn (LlLlaLl,ecal or epidural) of centrally acting iqn~ irs via an e~tprn~li7p~d spinal catheter, a spinal catheter cc.l~l~P~ilerl to an external 10 infileion pump, a spinal caLLcLel connPc;ted to a fully ;~ ed infusion pump and other related systems has been shown to be th~,a~uLically ~ ;L vt; for the l,~aL~e"L of chronic pain. To reduce systemic side effects caused by l~l~Li~v~ly high dosage systemic delivery, direct spinal delivery of the ~n~lgP~ic is pl~r~lled. In this way, drug is deLv~ d in a col~P-.I~aLed manner and at low doses to its specific site of action on ,~cel,Lo,~ in the 15 n~ x;~, 1ll;ll;lll;~;l~ systemic side effects as outlined above. Spinal catheter pl~rPmP.nt and infil~inn pump use, while shown to be highly t;~Livt;"~c;sellL a therapy ~ l;v~;; that is r~laLiv~ly ~ siv~ and illvas;ve to implant. These therapies also present w-vith risk of spinal infectinn such as mPningitic since the blood-brain barrier has been co~ loll~ised and drug is delivered to the lle~ul~iS from an external source such as a drug pump.
Recent r~se~-,L has also d~ al~d that living cells that produce natural analge~irs can be P.nr~pslll~ted into a silicone sheath and ;...~ .led into the central nervous system. It has not been PSI ~ l .Pd whether these cells produce LL~ uLic qll~ntitiPs of anal~eQ;~s while in vivo or how long the encapsulated cells will remain viable. Doses of analgesic that the cells produce in many in~t~nres can not be controlled and external stimuli, for c~ nicotine, 25 may change cell viability p~l~Lel~. Finally, potential for infection in the neuraxis if one of these modules were to rupture has not been chara~P.ri7P,A
The present invention provides an alL~lllaLive means for achieving continuous central nervous system ~Amini~tration of an ~n~lg~ic into the neuraxis via ill~lav~lll.;clllar, epidural, intrathecal and related routes for those ~ chronic pain and is directed to solving one or 30 more ofthe problems noted above. The invention compri~Pc an ~nalgP~sic caî~ying device and its method of use"n~ ing ;,~ l;on, which releases the ~n~l~P~ic in a continuous and sll~t~in~ release manner The device consists of a biocom~al~ e polymer matrix body -WO 96124331) PCI~/US96101753 loaded with an ~n~lgf cir such that a slow, plrrél~bly col~l release of the ~n~ ç~ic is provided. The polymer matrix ~ub~Ll~lrv may be constructed of any of a number of biostable or biodegradable polymers t~at act as the carrier matrix for the ~n~l~e~if . Ideally, l~el~euLic levels ofthe :ln~lgf Q;~ will be de]ivered over the long term, i.e., one month to one year. Two 5 plerelled ~n~ fri~~ arefentanyl and ~,.r~."~ ;l opioids about 100 to 500 and 1000 to 5000 times, lrv~e~,lively, more potent than ~ull~Liue. Plrvrel~ly the method of the invention ~I".;.,i~ the 51n~1~?r;'' illLl~lvr~ rly, intrathecally, epidurally, or by other related routes to the neuraxis. The illLl~LLec2~ route ûf ~1.,,;,~;~;1. ;ll;f~n is prerelled 10 Diclosure of Invention With this invention it is reco~i7çd for the first time that increased cost-elIer Live and cimrlif ity of the ~ Lion of ~n~lgf cics directly to the central nervous system, i.e., ~eul~ially, may be ~cc~ pli.~ d by means of a polymer matrix body loaded with an~n~lg~cic and made available for fliffilcion from the matrix into the biologic ne.~ x;~i 15 f ll~r~ rllL.
Brief Description of Dl~whl~ s Figure 1 is a view of a side matrix body made from a bioc~.,..p~ polymer cn"~ 3n~1~r;c in the int,erstic- s thereo~
Figures la, lb and lc show ~ le configurations.
Figure 2 is a view of a plerelled shape ofthe matrix body for retrieval purposes.
Figure 3 is a s~ ...z~ showing the spinal column and d~mn~ Lill~ the lumbar ; " ,l ,1" . " ;~ ~ ;r)n of an ~n~lg~cic loaded matrix body by ejection of same from a needle. Figure 4 is a more detailed showing of the matrix body in the needle of Figure 3 and a method of 25 delivery of same into the body ellvilol~llrllL.
Figure 5 is a graph ~ JWil1g e~ lcs of fentanyl elution from polyul,eLl~le over time as the percent of the total fentanyl available.
~ Figure 6 is a graph ~LL~w"lg fentanyl elution from silicone over time as the percent of the total fentanyl available.
Figure 7 is a graph sh~wing sample m~trices in terms of effective dose in micrograms per day as ~ ed from a matrix body accor&g to the invention.
CA 022l2l65 l997-os-05 . 4 Figures 8, 9 and 10 are graphs showing the amount of fentanyl delivered as a percent of the total amount of fentanyl bonded with several sample matrix ger" "~l~ ;
Best Mode for Carryin~ Out the Llv~lLion Turning now to the ~ wi~gs, which disclose ~ les of various drug delivery devices and methods accolding to the invention, one embodiment of the device is in~ir~ted in Figure 1 at 10. Device 10 co",l";.cP~ a polymeric matrix body 12 made of a biostable or biodegradable polymer loaded with an ~n~l~Qi~ such as fentanyl. Device 10 can be used for the cnntinlloll~ ~l. ";.~ Lion of the ~n~lgP~ic to the neuraxis of an anim~l body. Device 10 10 delivers an ~n~lgP~ic by elution of the ~n~l~P~ic from the matrix polymer body 12 in a fluid ~U~IO~ ,t;llL at a gradual manner with the drug being delivered at a controlled and continuous rate over a prc lr nged period of time. The analgesic elutes from the matrix body 12 due to the pP.rmP~tinn of water and lipids from the ~l~L~l~Lilial fluid through the polymer matrix. This pPrm~tinn solubilizes the ~n~l~Qi~ to allow release from the matrix body 12. Various 15 factors such as geomPtry~ size, m~tPri~l and pore size all affect pPrmP~hility of the polymer matrix body 12 and l~ulL~lL elution rates ofthe ~n~lg~ric to the neuraxis.
Figure la shows a cylinder cnnfi~lration for body 12a of device 10 with rounded ends for easing pl~rP.mPnt and retrieval. Figure lb shows a cylinder confi~lration for body 12b of device 10 formed from a rolled-up sheet of polymer m~tPri~l Figure lc shows a 20 cylinder co"r,~ Lion for body 12c of device 10 in the form of a hollow tube, cn"~;.;";.,~ a 4u~Lily of an ~n~lg~ic 16. The ~n~lgP~ic 16 may be dispersed within the polymer. Many other confi~lrations will be al~p~llL to those f~miliar with this art.
,~tt~rhrd to body 12 by any suitable means of cn~ ;nn such as a&esive or fusion is a tether 14 of such a length as to allow for retrieval of device 10 at any time following 25 ;",~ ;nn thereof into the neuraxis region of an animal body. The tether 14 may be of any known bioc-"~ ]c m~tPri~l such as nylon as is generally used in surgery.
Figure 2 illu~Ll~Les a preferred confi~lration of body 12 in which the p~ llal end thereof, i.e., the end to which tether 14 is ~tt~rh~d is tapered for f~rilit~ting retrieval. '' The polymer utilized for making up the matrix body 12 of device 10 may be any 30 suitable biocc~ le polymer, whether biostable or biodegradable.
Biostable polymers that may be utilized include silicone, polyult;ll~e~ polyether urethane, polyether urethane urea, poly ~?, polyacetal, polyester, poly ethylene-WO 96124330 ~CI/IJS96~(1I753 chloluLlinuoIoethylene, poly tetrafluoroethylene (Pl~ or "Teflon~"), styrene b~t~ n~
rubber, polyethylene, poly~,r~ylene, poly~h~llylene oxide-poly~yl~l~e~ poly-a-chloro-p-xylene, polylll~L}lyl~llL~lle, polysulfone and other related biostable polymers. Presently, polyul~ll~e is a plert;ll~d biostable polymeric matrix m~t~.n~l for body 12, but many of the 5 above listed polymers may be useful for this applic~tirm Biodegradable polymers that may be utilized include poly~y~Lides, cyclodestrans,poly lactic-glycolic acid, polyorthoesters, n-vinyl alcohoL polyethylene oxide/polyethylene le~ te, polyglycolic ac,id, polylactic acid and other related bioabsoll,abl~ polymers. In the event a bliodegradable polymer is used as the matrix body 12, the tether 14 may or may 10 notbeutilizedsincep~ J~ I;on_ aybeacceptable.
The ~n~l~Fi~ 16 loaded into the polymer matrix body 12 may be from one of any number of ~,1asses of ~n~l~PQ;~ that have been shown to act c~ lly on specific pain lt:Cel~Ol~ in the n~llr~e Potential drug classes include ~n~ ir~, typically called opioids, tha~t act on opioid pain l~ce;~Lul:i. F,X;~ le~ of such opioid ~n~l~PQ;~s are ...~ e, fentanyl, 15 ~"r-."~"il ~llfPnt~nil, hyJlu~l~ul~ olle, mPpPri(1inP; mP.th~ )nP; I)u~ Gl~l 'e, DADL, l~uLul~ ol and related opioids. O~er puLellLial drug classes include ~n~lg~ s that act on non-opioid pain leceptol~. One such group of ~n~l~c;~s that act on non-opioid pain t;Ct;~lOl:i are alpha-2 adre~ ic leC~Ol a~nietq such as rlr~n:~in~ l;..P, ST-91, mPdetom: linP; ~lpymp(letomirlinp and related alpha-2 adr~ ic ~nnictc Another group of 20 ~n~lgPr;~s are NMDA le:c~Lor ~nt~gt)nicte such as d~ LLol~ , Ifenprodil, MK-801 and related NMDA ~nt~goniete Yet another group of ~n~lg~Q;~s are som~tost~tin analogs such as Octreotide, Sandostatin, Vapreotide, Lanreotide and related ~eom~tost~tin ~n~logc Finally, other ~n~lg~Q;~ ,e may be used that act on non-opioid pain lec~lol~ such as ketorûlac, super oxide rliqmllt~e~; b?lelOfen~ c~lritonin~ St;lulCJl~, vasoactive ;~IP~I;II~1 polypeptide, bombesin, 25 omega-conopeptides and related non-opioid ~n~lgPr;~ e The list is not intPnrled to be c~ mplet~, but rather to demonetrate the broad potential and fe~eihility of the invention to act on a number of central pain lec~Lol~, even though not all agents may be readily used to ~ construct a device of clinically viable size. The preferred ~n~lgP.eic pl~selllly is the opioid fentanyl that is about 100 to 500 times more potent than morphine and is well characteri7~d in 30 the neuraxis or ~Itl~rn~tively ~"r~."~il that is about 1000 to 5000 times more potent than morphine.
Anal~esic Loadin~ 6 The ~n~lgRxic 16 _ay be loaded into the polymer matriX body 12 by a number of terhn~ R.~ The choice of loading te ~ e for a particular ~n~lgRcirlpolymer ~trix/device y,~r~ y will be dependent on a number of factors in-hltli~ drug/polymer/solvent 5 cc~...p~l;l.il;ly, desired fin~l col~c~..L,~Lion of ~n~lgecic 16 in the polymer _atrix body 12, x;~ y of the process, desired final ~ÇC.I~ y of the device 10 and ~t;r~lc~d elution char~ct~o.rictics of the ~ device 10. As c r I , a few loading te~ hn:que options are listed as follows. The list is not intPnllRd to be c~ l.'cte or limhin~ but r~ther to serve as fc well ~lnrlP.rctood by anyone skilled in the art.
The ~n~lgR~* 16 _ay be loaded into the polymer body 12 by means of dispersion loading. D;. ~ n loa&g is the t c ' que of loading a powdered Xul~-xL~ce into a polymer by stir- xing it into the polymer precure or sohltinn to ~ke a dispersion of the two m~t.~.ri~l.c The powder is not dissolved by the polymer s(~' ltinn in dispersion loading. The polymer is soli~ifiRcl by curing or solvent ~v~ulilLio~ and a homogel~euus blend of ~n~lgRcir 15 16 in the polymer is achieved. The ~n~lgesir. 16 has not reacted with the polymer but rather is cL~lxed within the i ~ LiLi~l spaces ofthe cured polymer. The conccllLlaLion of drug that can be loaded into the polymer is limited only by the physical iLILegliLy of the resul~ing polymer m--atrix body 12. Dispersion mixjng is a standard te~hni~lLue for loading dl ~.n~ c~ nR into polymeric lead tips to create steroid eluting leads.
The dispersion loading method is the pl~rt;lled method of cu......... l,inillg ~n~lgRcic 16 with the polymeric matrix body 12 because the method allows for a fairly high p~ ge of ~n~lgRcir. 16 to be added to the polymer to form matrix body 12. The pel~ llL~ge of ~n~lg~.cic 16 added to the polymer to form matriX body 12 is pl~r~l~ly from 10% to 80% by weight.
This percentage has been found to ,~ ;,. the hlLe~iLy of the polymer ~ubsLlaL~ in body 12.
25 A higher loading conc~..L~Lion of ~n~lgRcic~ 16 allows for the design of a smaller device 10 for clinical use and p1~cP.mPnt in the ncul~is.
The dispersion loading method also allows the body 12 to be formed into optimal genmPtries prior to cure of the polymer or for body 12 to be extruded as a tube or other geoll~Lly. Finally, solvent cu. . ~ l ;l .ilily between the polymer of body 12 and the ~n~lgRcic 16 30 is not a factor.
AlL~lllaLi~ly, solvent swelling can be used to combine the ~n~lgt?cic 16 with the polymeric matrix body 12. This method is particularly useful where a pl~rl.~",ed polymer body 12 is imtroduced into a solution of the ~n~ eic 16 in a solvent that acts as a ~wellillg agent for the polymer body 12. The body 12, while ~ llhl~,, absorbs the solvent along with the dissolved ~n~l~.eic 16 until a steady state is achieved. The polymer body 12 is then allowed to dry with the solvent ev~ul~Liu~ from the sample and the ~n~l~,r~ei~. 16 l~t behind 5 in the body 12. As the body 12 dries, it returns from its swelled state to its original g~om~.try and size. Solubility of the ~n~l~e.eic 16 in the sollltion limits the possible collc~ lion of drug that can be introduced by this te~ e. Even so, the te~LL~ ue is well known and has been used sllcc~.efillly to load antLmicrobials into poly_er m~tric~e, (See, for c~lc, U.S.
PatentNo. 4,gl7,686).
Solution loading is silnilar to ~ el~;on loading except that the ~n~l~.ei~, 16 or clrug must be solu.ble in the polymer solvent. The cured polymer body 12 then inr.llld~ the dissolved ~n~'lg~.~is 16 or drug in its matrix.
Finally, the method Oi-lc~SelvOll loading may be used to comhin~ the ~n~lg~Qir 16 with the body 12. This method cc~ es loading pure drug or ~n~ eir, 16 inside a hollow tube 15 and sealing the ends ofthe tube to form the body 12. The ~n~l~eic 16 then diffuses through thepolymertubingwall of body 12.
Althoughthe configllration ofthe device 10 rnay be varied in-~.hl-lin~,r for ~ ,..pl~.
rods, rolled up sheets, buttons, discs, tubes, rnicrospheres and fibers, the plesell~y pler~lled c~ nfi~lration is a small tube or rod of polymer the size and shape of a grain of rice which may 20 be readily introduced into 1he intrathecal space via a 14 gauge needle. Final product confi~lration rnay be r~l ~. ;c~l ~ed by any of the rOl'èg,Oi~ ter~n:qlles More specifically, srmall device sizes typically less than 0.10 inches in r~i~rnPt~r are co..~ ,l,.led for the preferred method of ~ lion co.-.l..;.~;.~gr the simple lurnbar ~ulleLule te~ m~ e. This technique is illu~ ed with reference to Figure 3 wll~leill a needle 25 20, preferably fourteen (14) gauge or smaller in size is inserted between the vel lel~l~e 30 into the epidural space 32 or the intrathecal space 36 in the known lumbar ~-lllcLule te-hni~
The ara~hnni~ layer is shown at 34 and the spinal cord at 38.
Needle 20, as is best shown in Figure 4, cnnt~in~ the device 10 to be ;~pl~ ed Needle 20 also contains a pusher rod or cylinder 22 that is used to eject device 10 from 30 needle 20 for ;..~pl~ lion Plerel~bly, as shown, pusher rod or cylinder 22 is hollow so as to readily accommodate tether 14 whereupon removal of needle 20 and pusher rod 22 leaves the led device 10 in place with the tether 14 ~ r.ll~l;ll~, thel~iul~l. Tether 14 pl~rel~ly CA 022l2l65 lss7-os-05 wo 96/24330 PCT/US96/01753 extends away from the body 10 and l~ e,c under the skin but outside the spinal cord so that tether 14 is easily ~çc~ le when retrieval is desired. To retrieve body 12, the needle 20 is simply inserted over the tether 14 and moved to body 12. Tether 14 is then used to draw the body 12 into the needle 20 and the body 12 is removed with the needle 20.
AlLel~Lively, the co. .. l)il-~d ~n~l~Qie/polymer matrix body 12 may be ~tt~hPd to the end of a ~L~d~d spinal caLlleleL by any suitable means such that the outer ~ of the device 10 equals the outer ~ . of the catheter. The device/catheter system may then be introduced into the desired location in the spinal column by the sL~da ~1 lumbar ~e~
Le~ using ~L~d~-l needles and plocedu.ès. The system may be retrieved in the same 10 manner as a ~l~d~d spinal callleLer is leLlieved today as is well understood by those skilled in the art.
Prerel~ly~ ;",pl~ l;on of the device 10 will occur in the ilLl~lLecal space as opposed to the epidural space. This is because less ~n~lge~i~ 16 is le~luiled for t;~eLiv~;
control of chronic pain when device 10 is introduced to the illLlaLllec~l space as COlll~al ed to 15 the epidural space. As already in-lir~tet1, the te~hr:q~l~c described herein may also be used for i".pl,...l;.l;nn of device 10 into a brain ventricle.
Table I shown hèléillb~l~ w provides an ~ .lc of the device size le~lulle~.-ellLs for providing a minim~l SiX month dose of fentanyl to acc~ l . chronic pain control in a more or less typical .~ihl~tinn involving i lLl~Lllecal ~-1. . .;I . il . ~Lion.
TABLE I
DRUG NEEDS
Intrathecal fentanyl dosage: 0.1 to 0.3 mg/day Using ~ ~ -' dose for 6 months ~..,..;..g polymer and drug d~n~iti~s _ 1 g/cm3 or 1 mg/mm3 0.1 mg/day x 180 days x 1 mm3/mg = 18.0 mm3 fentanyl to be delivered DEVICE SIZE
Assume 20% lo~-linp~, and 50% a~ in 6 months 18.0 mm3 of active fentanyl = 180.0 mm3 of device 0.1 mm3 actives/mm3 inactives Device of volume 180.0 mm3 or 0.18 cm3:
WO 96124330 r ~, l / U ~6101753 ~ Cube, 0.56 cm on-a-side --Cylinder, D = 1.8 mm, L = 70 mm (2.8 in) Detailed Deslcriphon of Ex~.l,lcs The :following PX~mrle~. are set forth as le~lesell~Livc of the spirit of the present invenlion. These ~.~Qmp'-~ are not to be construed as limiting the scope of the illvcllLio4 as these and other fim~it)n~lly equivalent methods and devices will be readily appal~l.L to those skilled in the art. Studies to date have focused on developing and char~ a feasible polymLer mahix ~ul,~Ll~Le for body 12 that will elute QnQl~esi~ 16 continllollqly and over the long term, i.e., one month to one year. In patients or ~nimQle near zero order release kinehcs for the duralion of the imp]iant are plcrcllcd because stable drug concc~ Lions may be ..~ ;"ed in the neuraxis. Zero order release kinehcs means that over hme, the amount of drug ~ ,ased by the polymer matrix remain~ at a l.,laliwly co~ lll rate. For ~ ~ , for an implant having a useful duration of several months, ~Lth zero order release kinP.ti~.~, the amoullt of dnlg released fromL tbLe polymer mat~x on day 30 will be the same as the amount of drug released from the nnahix on day 5. FiT~lly, the ~n~l~e~i~ loaded polymer mLatrix body 12 must be ~I~,;T;,,,l)le, biocc""p~ le and of a ~ec~ y and size that is easily ;",pl~"~ le and removable in the llcul~iS.
For ~le following ~ ,1e~, fentanyl citrate was chosen as the ~l~rt;ll~d ~n~ e~ic 16 because it has a centrally acting mode of effect, is 100 times more potent than "~ol~ e, and is a stable anld well c~ cL~ ed opioid ~n~l~Qir Fentanyl citrate powder was purchased from USPC Inc., Rockville, Maryland. Polymer substrate m~t~ri~le tested in~ ded medical grade silicone ~ ,ha~ed from Rehau Corp., Leesburg, ~lrginia, (Trade name Pc~llmerlic SI2000) and PellethanLe bra~d polyult;ll~ e of dulu~~L~l 80A purchased from Dow ~h~mic~l Midland, Michig~n Polyulc~ e adhesive was prepared by heat press moltling PPllP,tll~nP- pellets into film and dissolving the film in dilllcLllyl ~cet~mi-le (DMAC) solvent.
Initial studies i-l~ntifiPd a polymer matrix, developed an c~;Liv~ te~' q~le forloading fentarLyl into the matrix as (~ ed earlier, and con~alcd the in vifro release kinetics of fentanyl from various m~trires Also described are studies c~ r~ g the effect of fentanyl release as a fi~n~inn of polymer type, matrix porosity, drug conr~"l~Lion and device shape.
All s~mrles vvere placed into a phosphate buffered saline solution and were ~ d at 37C. Eluate samples were pu:lled at various time points for analysis by standard high plc~ c liquid cLlc~lography (HPLC) techniques, with samples being cc~ hlt;d against a ~ dard fentanyl co~ Lion curve. Fx~ pl~.s are ~ ecl as follows:
This ~le evaluates the release kinetics of the ~n~lgPqic fentanyl from r~l~liv~ly nonporous polyul~Llla~e matrix samples 1 and 2 over time. Data is shown in Figure 5. The samples l and 2 are also cu~d to ~ ;v~ silicone carrier matrix samples 3 and 4 shown in Figure 6 and ~ c~ ed in Fx~mple 2.
Polyult;lL~le samples 1 and 2 in Figure 5 were pl~ed by the di~ ioll le~ 4~le 10 l~ ecl earlier and well understood by those skilled in the art. Polyul~Ll~e used was pP.lleth~nP 80A. S~ 1 and 2 were loaded with a 10% fentanyl powder and were pl~t;d in a film confi~ration applux;...~ y three quarter inches long by one quarter inch wide by .015 inches thick. Sr~ 1 and 2 were placed in ~ dald ph~srh~te bu~ ;d sc l-~fi~ n (PBS) and allowed to elute drug for 60 days at 37C.
Figure 5 shows the amount of fentanyl delivered as a percent of the total amount of fentanyl loaded into the sample, i.e., ~;~.. l~l;v~ elution. Release kinetics are nearly zero order, with the amount of drug being deliv~l~d on day 50 nearly equal to the amount of drug being delivered on day 10.
Figure 7 pl~sellls the data for the first 28 days as rnicrograms per day of fentanyl 20 delivered from the matrix by sarnples 1 and 2. Following a first day bolus, the sarnples both eluted drug at h~p~l~x;-~ .ly 30 micrograms per day, h~plux~l~ly one third to one tenth the effective intrathecal dose required for human clinical use. Results for both samples were cc l~ for each tirne point as well as over tirne.
This ~ lc evaluates the release kinetics of the ~n~l~;Pcic fentanyl from silicone matrix sarnples 3 and 4 over tirne. The sarnples 3 and 4 were also col~aled to ~ l;ve polyul~Lllalle carrier m~tPri~l samples 1 and 2 as described in Example 1 above.Silicone sarnples 3 and 4 in Figure 6 were prepared by the dispersion technique 30 ~liecu~ed earlier and well understood by those skilled in the art. S~mr'es 3 and 4 were loaded with a 10% fentanyl powder and were prepared in a film confi~-ration a~p-u~Lely one inch long by one half inch wide by .020 inches thick. Samples were placed in ~d~d ph~ sl h~te l~u~led sol ltic~n (l'BS) and allowed to elute drug for 60 days at 37C.
Figure 6 shows the amount of fentanyl delivered as a percent of the initial total ~ amount of fentanyl loaded into the sample, i.e., c -m -l~tive elution. In contrast to the 5 polyult;Ll~e samples 1 and 2~ silicone samples 3 and 4 provide a bolus release of fentanyl on day one followed by decl~; drug release ~ Llel. Results of both silicone samples 3 and 4 were Cr~ .I for each time point as well as over time.
This e/~ CO~ eS the effect of di~ fentanyl loading cr~ Lions on release kinetics using a l~laLivl~ly non~ol~,us polyul~;ll~e film.
Polyu~ ~e samples 5 and 6 in Figure 8 were p,~d by the dispersion terhn:qlle iq~;~ls~ed earlier. Polyu~ e used was Pellethane 80~ S~mpl-~ 5 and 6 were loaded with 10% fentanyl powder and 25~,/o fentanyl powder, lc;s~e-;Lively by weight and prepared in a film 15 c~."l~ Lion a~plux;~ ly one quarter inch wide by one quarter inch long by 0.01 inches thick. S~mpl-s 5 and 6 were placed in ~L~d~d phosphate bu~fered solution (PBS) and allowed to elulte drug for 60 days at 37C.
Figure 8 shows the l,l l . .~ ;v~ amount of fentanyl delivered as a percent of the total amount of fentanyl loaded into the s~ The graph shows that the higher the 20 C~ lion offentanyl loaded into the sample, the greater the release rate ofthe ~n~lgPoi~
The 25% fentanyl loaded sample 6 e~ibits nearly zero order release kinetics over the first 30 days, with dnlg elution rates tailing offfrom day 30 to day 60.
This ~Y~ plc cO--l~aleS release kinetics of a nurnber of fentanyl loading concentrations from a l~,ldLiv~ly porous polyul~ e pellet.
Polyu.~ e samples 7, 8 and 9 in Figure 9 were p~ d by the dispersion ~echn:qlle ~ ecl earlier. Polyu~ e used was PP.IIP.t~l~nP 80A as in the previousPY~mplec, bul: the polymer samples were allowed to cure in a high humidity en~ e,lL
30 rather than in a vacuum. Casting the polyul~ll~e film in a high humidity e~ ol~c~
created a phase inversion allowing the polyurethane to pler.;p;l;.le and cure in a ~ liv~ly porous fashio:n. Samples 7, 8 and 9 ~,vere loaded with 10% fentanyl powder, 25% fentanyl powder, and 40% fentanyl powder, le~e~;LIv~ly by weight, and were pl~al~d as pellets aE~ x;~ y one halfinch long by 0.05 inches wide by 0.03 inches thick. The samples were placed in standard phosphate buffered sollltion and allowed to elute drug for 60 days at 37C.
Figure 9 shows the amount of fentanyl delivered as a percent of the t.otal amount of 5 fentanyl loaded into the s~mplee The graph shows that the higher the CO~ Lion of drug loaded into the sample, the greater the release rate. All samples suggest a large ~n~lge.~ic bolus is delivered on day one, followed by de~a~ g ~n~l~P.eic elution t~l~r~[lel.
This ~ .le cc~ s effects of gec,.. ~l~y of a sample on release kinrtire Polymer matrix m~tP.ri~l and fentanyl loading cr,nr.~.ntration are held c~ n~li ..1 polyulc~LLalle samples 10 and 11 in Figure 10 were pl~ d by the dispersion J~ ue .~ sed earlier. Polyul~LI~e used was p~ th~n~ 80A. S~nnrles 10 and 11 wereloaded with 10% fentanyl powder and were prep~ed as a film and a tube, le;*Je~;Li~ ly.
15 Tubing sample 11 was p~e~d applu~aL~ly one eighth inches in outer ,l;~ with awall th:-.kn~e.e of 0.005 inches and one quarter inch in length. Film sample 10 was ~l~a.~d ap~l.J,~;",s.l~.ly one quarter inch wide by one quarter inch long by 0.01 inches thick. S~mpl~e 10 and 11 were placed in standard phnsrh~te bu~l~d sC~1-lti~n and allowed to elute drug for 60 days at 37C.
Figure 10 shows the amount offentanyl deliv~l~d as a percent ofthe total amount of fentanyl loaded into the s~mrlle The samples provide coll~ .ll drug release over 60 days, with the tube geo ~ y r~lea~ll.g a greater amount offentanyl and at a greater rate.
The above FY~"~ and r1i~rlosllre are int~n-led to be illu~L.~Liv~ and not e~rh~llstive.
These 1~! rt~s and description will suggest rnany viqri~tion~ and ~ l;v~s to one of 25 oldi~y skill in this art. All these ~ "~l;v~s and v~ri~tion~ are int~nrled to be inrJlltled within the scope of the ~tt~rh~d claims. Those familiar with the art may recognize other equivalents to the specific embodirnents cl~er.rihçd herein which equivalents are also int~.ntled to be enct mp -~ed by the claims ~ rh~d hereto. The ~ Jlcs cl~o.m~-n~rate that an o~Lil..u", geometry and ~n~lg~ic loading rnay be prepared to allow for nearly zero order 30 release kinetics (straight line) oftherapeutic ~lluullL~ of an ~n~lg~ic over a period oftirne, for ,lc one month to one year.
=
Claims (37)
-
- What is claimed is as follows:
- 3. A method for making a device to be implanted in the region of the neuraxis of an animal, the device to diffuse analgesic into the region of the neuraxis of the animal at a substantially constant rate over the life of the device, the method comprising the steps of:
a. forming a polymeric substance of a biocompatible material into a desired configuration;
b. forming a mixture of a solvent and an analgesic;
c. introducing the polymeric substance formed in step a. into the mixture formed in step b.;
d. allowing the polymeric substance formed in step a. to absorb the mixture formed in step b. during the performance of step c.;
e. removing the polymeric substance and absorbed mixture of solvent and analgesic from the mixture of solvent and analgesic after step d. has been performed;
f. drying the polymeric substance and solvent and analgesic mixture removed in step e.
so that the solvent evaporates from the polymeric substance and solvent and analgesic mixture thereby leaving only the analgesic absorbed in the polymeric substance. - 4. A method for making a device to be implanted in the region of the neuraxis of an animal, the device to diffuse analgesic into the region of the neuraxis of the animal at a substantially constant rate over the life of the device, the method comprising the steps of:
a. forming a polymeric substance of a biocompatible material into a hollow tube, the polymeric material capable of allowing a selected analgesic to diffuse therethrough;
b. loading the selected analgesic into the hollow tube formed in step a.; and, c. sealing the ends of the tube formed in step a. with the selected analgesic inside. - 5. - A device for administering an analgesic to an animal at a gradual rate over a period of time, the device being shaped, sized and adapted for administering the analgesic into the region of the neuraxis of the animal, the device comprising:
a biocompatible polymeric matrix body; and, an analgesic, loaded into the matrix body, the analgesic available for diffusion therefrom into the region of the neuraxis of the animal. - 6. The device of claim 5 wherein the analgesic is loaded into the matrix body by means of dispersion loading.
- 7. The device of claim 5 wherein the analgesic is loaded into the matrix body by means of solvent swelling.
- 8. The device of claim 5 wherein the analgesic is loaded into the matrix body by means of solution loading.
- 9. The device of claim 5 wherein the analgesic is loaded into the matrix body by means of reservoir loading.
- 10. The device of claim 5 wherein the matrix body is configured as a rod.
- 11. The device of claim 5 wherein the matrix body has a diameter of less than about 0.10 inches in diameter.
- 12. The device of claim 5 wherein the matrix body has a width of less than about 0.10 inches in diameter.
- 13. -The device of claim 5 wherein the matrix body is configured as a rolled up sheet.
- 14. The device of claim 5 wherein the matrix body is configured as a button.
- 15. The device of claim 5 wherein the matrix body is configured as a disc.
- 16. The device of claim 5 wherein the matrix body is configured as a tube.
- 17. The device of claim 5 wherein the matrix body is configured of a combination of microspheres and fibers.
- 18. The device of claim 5 wherein the polymeric matrix body is made of a material that is biodegradable.
- 19. The device of claim 18 wherein the polymeric matrix body is made of a biodegradable material selected from the group consisting of polyanhydrides, cyclodestrans, poly lactic-glycolic acid, polyorthoesters, n-vinyl alcohol, polyethylene oxide/polyethylene terephthalate, polyglycolic acid and polylactic acid.
- 20. The device of claim 5 wherein the polymeric matrix body is made of a material that is biostable.
- 21. The device of claim 20 wherein the polymeric matrix body is made of a biostable material selected from the group consisting of silicone, polyurethane, polyether urethane, polyether urethane urea, polyamide, polyacetal, polyester, poly (ethylene-chlorotrifluoroethylene), poly tetrafluoroethylene (Teflon), styrene butadiene rubber, polyethylene, polypropylene, polyphenylene oxide-polystyrene, poly-a-chloro-p-xylene, polymethylpentene and polysulfone.
- 22. The device of claim 5 further comprising a recovery tether attached to the matrix body
- 23. The device of claim 5 wherein the analgesic is an analgesic that acts on opioid pain receptors.
- 24. The device of claim 23 wherein the analgesic that acts on opioid pain receptors is selected from the group consisting of morphine, fentanyl, sulfentanil, alfentanil, hydromorphone, meperidine, methadone, buprenorphine, DADL and butorphanol.
- 25. The device of claim 5 wherein the analgesic is an analgesic that acts on non-opioid pain receptors.
- 26. The device of claim 25 wherein the analgesic that acts on non-opioid pain receptors is selected from the group consisting of ketorolac, super oxide dismutase, baclofen, calcitonin, serotonin, vasoactive intestinal polypeptide, bombesin and omega-conopeptide.
- 27. The device of claim 25 wherein the analgesic that acts on non-opioid pain receptors is an alpha-2 adrenergic agonist.
- 28. The device of claim 27 wherein the alpha-2 adrenergic agonist is selected from the group consisting of clonidine, tizanidine, ST-91, medetomidine and dexmedetomidine.
- 29. - The device of claim 25 wherein the analgesic that acts on non-opioid pain receptors is an NMDA receptor antagonist.
- 30. The device of claim 29 wherein the NMDA receptor antagonist is selected fromthe group consisting of dexmethorphan, Ifenprodil and MK-801.
- 31. The device of claim 25 wherein the analgesic that acts on non-opioid pain receptors is a somatostatin analog.
- 32. The device of claim 31 wherein the somatostatin analog is selected from the group consisting of Octreotide, Sandostatin, Vapreotide and Lanreotide.
- 33. The device of claim 5 wherein the body is configured for ease of introduction to and removal from the neuraxis of a body.
- 34. The device of claim 5 wherein the analgesic is present in the matrix in an amount of about 10% to 80% by weight.
- 35. The device of claim 5 configured such that the analgesic is eluted at a nearly constant rate over the useful life of the device.
- 36. A device for administering an analgesic at a gradual rate over a period of time, the device being shaped, sized and adapted for administering the analgesic into the region of the neuraxis of an animal environment, the device comprising: a biocompatible polymeric matrix body containing an analgesic available for diffusion therefrom in the animal environment into the neuraxis, the analgesic selected from the group consisting of alpha-2 adrenergic receptor agonists, ketorolac, super oxide dismutase and serotonin.
- 37. A device for administering an analgesic at a gradual rate over a period of time, the device being shaped, sized and adapted for administering the analgesic into the region of the neuraxis of an animal environment, the device comprising:
a biocompatible polymeric matrix body containing an analgesic available for diffusion therefrom in the animal environment into the neuraxis, the analgesic selected from the group consisting of opioids, alpha-2 adrenergic receptor agonists, NMDA receptor antagonists, somatostatin analogs, ketorolac, super oxide dismutase, baclofen, calcitonin, serotonin, vasoactive intestinal polypeptide, bombesin and omega-conopeptides; and, a recovery tether attached to the body.
Applications Claiming Priority (2)
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|---|---|---|---|
| US38685395A | 1995-02-10 | 1995-02-10 | |
| US08/386,853 | 1995-02-10 |
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| CA2212165A1 true CA2212165A1 (en) | 1996-08-15 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002212165A Abandoned CA2212165A1 (en) | 1995-02-10 | 1996-02-08 | Method and device for administering analgesics |
Country Status (7)
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| US (2) | US5980927A (en) |
| EP (1) | EP0808153B1 (en) |
| JP (1) | JPH10513471A (en) |
| AU (1) | AU4975996A (en) |
| CA (1) | CA2212165A1 (en) |
| DE (1) | DE69603577T2 (en) |
| WO (1) | WO1996024330A1 (en) |
Families Citing this family (109)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU735588B2 (en) | 1997-09-18 | 2001-07-12 | Pacira Pharmaceuticals, Inc. | Sustained-release liposomal anesthetic compositions |
| ES2384094T3 (en) | 1997-11-14 | 2012-06-29 | Pacira Pharmaceuticals, Inc. | Production of multivesicular liposomes |
| KR100289471B1 (en) * | 1998-01-19 | 2001-09-17 | 김충섭 | A controlled/sustained implant delivery containing fentanyls |
| JP2002504505A (en) | 1998-02-25 | 2002-02-12 | アボット・ラボラトリーズ | Butorphanol sustained release formulation |
| WO2000003716A1 (en) * | 1998-07-16 | 2000-01-27 | Memorial Sloan-Kettering Cancer Center | Topical compositions comprising an opioid analgesic and an nmda antagonist |
| AU752225B2 (en) | 1998-07-17 | 2002-09-12 | Pacira Pharmaceuticals, Inc. | Biodegradable compositions for the controlled release of encapsulated substances |
| US6168801B1 (en) * | 1998-09-09 | 2001-01-02 | Cardiac Pacemakers, Inc. | Controlled release drug delivery |
| US6835194B2 (en) | 1999-03-18 | 2004-12-28 | Durect Corporation | Implantable devices and methods for treatment of pain by delivery of fentanyl and fentanyl congeners |
| US6541021B1 (en) | 1999-03-18 | 2003-04-01 | Durect Corporation | Devices and methods for pain management |
| US6436091B1 (en) * | 1999-11-16 | 2002-08-20 | Microsolutions, Inc. | Methods and implantable devices and systems for long term delivery of a pharmaceutical agent |
| US7074803B2 (en) * | 2001-03-02 | 2006-07-11 | Durect Corporation | Opioid formulations |
| AU7576501A (en) * | 2000-03-28 | 2001-12-03 | John W. Olney | Combination of adrenergic agonist and nmda antagonist for relieving chronic painwithout adverse side effects |
| US6632005B1 (en) * | 2000-06-22 | 2003-10-14 | Quorum International, Lp | Alabaster framing device |
| US6767550B1 (en) * | 2000-06-30 | 2004-07-27 | Berkeley Advanced Biomaterials, Inc. | Hydroxyapatite based drug delivery implant for cancer treatment |
| US6890343B2 (en) | 2000-12-14 | 2005-05-10 | Ensure Medical, Inc. | Plug with detachable guidewire element and methods for use |
| US8083768B2 (en) * | 2000-12-14 | 2011-12-27 | Ensure Medical, Inc. | Vascular plug having composite construction |
| EP1395243A2 (en) * | 2001-05-31 | 2004-03-10 | SkyePharma Inc. | Encapsulation of nanosuspensions in liposomes and microspheres |
| DE10141650C1 (en) | 2001-08-24 | 2002-11-28 | Lohmann Therapie Syst Lts | Safe transdermal therapeutic system for administration of fentanyl or analogous analgesics, having matrix layer of carboxy group-free polyacrylate adhesive providing high permeation rate |
| US6455557B1 (en) | 2001-11-28 | 2002-09-24 | Elan Pharmaceuticals, Inc. | Method of reducing somnolence in patients treated with tizanidine |
| US20040220240A1 (en) * | 2001-11-28 | 2004-11-04 | Pellegrini Cara A. | Method of increasing the extent of absorption of tizanidine |
| US20030181426A1 (en) * | 2002-02-11 | 2003-09-25 | Eisenach James C. | Compositions and methods for treating pain using cyclooxygenase-1 inhibitors |
| DK2561860T3 (en) * | 2002-05-31 | 2018-04-30 | Titan Pharmaceuticals Inc | Implantable polymer device for prolonged release of buprenorphine |
| US7097850B2 (en) * | 2002-06-18 | 2006-08-29 | Surmodics, Inc. | Bioactive agent release coating and controlled humidity method |
| US20040102476A1 (en) * | 2002-11-25 | 2004-05-27 | Chan Tai Wah | High concentration formulations of opioids and opioid derivatives |
| JP2006517850A (en) * | 2003-02-18 | 2006-08-03 | メドトロニック・インコーポレーテッド | Occlusion resistant hydrocephalus shunt |
| US20050079199A1 (en) * | 2003-02-18 | 2005-04-14 | Medtronic, Inc. | Porous coatings for drug release from medical devices |
| US8673339B2 (en) * | 2003-03-11 | 2014-03-18 | Medtronic, Inc. | Demand-release bioactive composition for implantable medical devices |
| US9445901B2 (en) * | 2003-03-12 | 2016-09-20 | Deger C. Tunc | Prosthesis with sustained release analgesic |
| NZ542548A (en) | 2003-03-31 | 2009-04-30 | Titan Pharmaceuticals Inc | Implantable polymeric device for sustained release of dopamine agonist |
| US20040202717A1 (en) | 2003-04-08 | 2004-10-14 | Mehta Atul M. | Abuse-resistant oral dosage forms and method of use thereof |
| CA2526101A1 (en) * | 2003-05-30 | 2004-12-23 | Titan Pharmaceuticals, Inc. | Implantable polymeric device for sustained release of nalmefene |
| US20090208540A1 (en) * | 2003-08-11 | 2009-08-20 | Indevus Pharmaceuticals, Inc. | Implantable device for the delivery of naltrexone and methods of use thereof |
| CA2437639C (en) | 2003-08-11 | 2016-07-05 | Valera Pharmaceuticals, Inc. | Long term drug delivery devices with polyurethane based polymers and their manufacture |
| US7858110B2 (en) | 2003-08-11 | 2010-12-28 | Endo Pharmaceuticals Solutions, Inc. | Long term drug delivery devices with polyurethane based polymers and their manufacture |
| WO2005032556A1 (en) | 2003-10-02 | 2005-04-14 | Elan Pharmaceuticals, Inc. | Method for reducing pain |
| US8708993B1 (en) * | 2003-10-15 | 2014-04-29 | Physician Technologies, Inc. | Infusion catheter procedure and system |
| US20060111382A1 (en) * | 2004-05-17 | 2006-05-25 | Pharmacofore, Inc. | Compositions and methods for treating or preventing pain |
| US7824697B2 (en) | 2004-07-12 | 2010-11-02 | Board Of Regents, The University Of Texas System | High concentration baclofen preparations |
| WO2006078320A2 (en) | 2004-08-04 | 2006-07-27 | Brookwood Pharmaceuticals, Inc. | Methods for manufacturing delivery devices and devices thereof |
| US20060051392A1 (en) * | 2004-09-03 | 2006-03-09 | Medtronic, Inc. | Porous coatings for drug release from medical devices |
| US20060051393A1 (en) * | 2004-09-08 | 2006-03-09 | Medtronic, Inc. | Method of manufacturing drug-eluting medical device |
| US20060069086A1 (en) * | 2004-09-23 | 2006-03-30 | Alexander Michalow | Methods for regulating neurotransmitter systems by inducing counteradaptations |
| US20060253100A1 (en) * | 2004-10-22 | 2006-11-09 | Medtronic, Inc. | Systems and Methods to Treat Pain Locally |
| DE102006012671A1 (en) * | 2006-03-20 | 2007-09-27 | Bastian-Werk Gmbh | Means for influencing the nociception and its consequences |
| US20070253994A1 (en) * | 2006-04-28 | 2007-11-01 | Medtronic, Inc. | Intraspinal Drug Delivery Methods and Devices To Alleviate Chronic Pelvic Pain |
| US8536445B2 (en) * | 2006-06-02 | 2013-09-17 | Emcore Solar Power, Inc. | Inverted metamorphic multijunction solar cells |
| US20080031872A1 (en) * | 2006-08-02 | 2008-02-07 | Karp Nelson M | HIV immunogenic composition and method of administration |
| JP5161452B2 (en) * | 2006-10-03 | 2013-03-13 | 日本コヴィディエン株式会社 | Method for manufacturing medical device, method for applying antibiotic to surface of medical device, and medical device |
| US20080220062A1 (en) * | 2006-10-23 | 2008-09-11 | Psivida, Inc. | Sustained release of agents for localized pain management |
| US20080102097A1 (en) * | 2006-10-31 | 2008-05-01 | Zanella John M | Device and method for treating osteolysis using a drug depot to deliver an anti-inflammatory agent |
| US8470360B2 (en) * | 2008-04-18 | 2013-06-25 | Warsaw Orthopedic, Inc. | Drug depots having different release profiles for reducing, preventing or treating pain and inflammation |
| WO2009046299A2 (en) * | 2007-10-04 | 2009-04-09 | Boston Scientific Scimed, Inc | Implantable drug depot for intrathecal drug delivery system for pain management |
| US8790684B2 (en) * | 2007-10-31 | 2014-07-29 | Cordis Corporation | Vascular closure device |
| WO2009085952A1 (en) | 2007-12-20 | 2009-07-09 | Brookwood Pharmaceuticals, Inc. | Process for preparing microparticles having a low residual solvent volume |
| US20150258279A1 (en) | 2008-03-18 | 2015-09-17 | Mallinckrodt Llc | Intrathecal baclofen pharmaceutical dosage forms and related delivery system |
| US8969414B2 (en) * | 2009-02-06 | 2015-03-03 | Mallinckrodt Llc | Intrathecal baclofen pharmaceutical dosage forms with fewer degradation products |
| EP2265260A4 (en) * | 2008-03-21 | 2013-07-03 | Paindure Ltd | Solid dosage form for treating headaches |
| US9610243B2 (en) * | 2008-04-18 | 2017-04-04 | Warsaw Orthopedic, Inc. | Clonidine compounds in a biodegradable polymer |
| US20090264477A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc., An Indiana Corporation | Beta adrenergic receptor agonists for treatment of pain and/or inflammation |
| US8956641B2 (en) * | 2008-04-18 | 2015-02-17 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for treatment of inflammatory diseases |
| US20090263489A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Analgesic and anti-inflammatory compositions and methods for reducing, preventing or treating pain and inflammation |
| US8889173B2 (en) * | 2008-04-18 | 2014-11-18 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for treatment of pain and/or inflammation |
| US9072727B2 (en) * | 2008-04-18 | 2015-07-07 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for treatment of degenerative disc disease |
| US9289409B2 (en) * | 2008-04-18 | 2016-03-22 | Warsaw Orthopedic, Inc. | Sulindac formulations in a biodegradable material |
| US9132119B2 (en) * | 2008-04-18 | 2015-09-15 | Medtronic, Inc. | Clonidine formulation in a polyorthoester carrier |
| US8946277B2 (en) * | 2008-04-18 | 2015-02-03 | Warsaw Orthopedic, Inc. | Clonidine formulations in a biodegradable polymer carrier |
| US8557273B2 (en) | 2008-04-18 | 2013-10-15 | Medtronic, Inc. | Medical devices and methods including polymers having biologically active agents therein |
| US8420114B2 (en) * | 2008-04-18 | 2013-04-16 | Warsaw Orthopedic, Inc. | Alpha and beta adrenergic receptor agonists for treatment of pain and / or inflammation |
| US9132085B2 (en) | 2008-04-18 | 2015-09-15 | Warsaw Orthopedic, Inc. | Compositions and methods for treating post-operative pain using clonidine and bupivacaine |
| US8475823B2 (en) * | 2008-04-18 | 2013-07-02 | Medtronic, Inc. | Baclofen formulation in a polyorthoester carrier |
| US8956642B2 (en) * | 2008-04-18 | 2015-02-17 | Medtronic, Inc. | Bupivacaine formulation in a polyorthoester carrier |
| US8722079B2 (en) * | 2008-04-18 | 2014-05-13 | Warsaw Orthopedic, Inc. | Methods for treating conditions such as dystonia and post-stroke spasticity with clonidine |
| US8629172B2 (en) | 2008-04-18 | 2014-01-14 | Warsaw Orthopedic, Inc. | Methods and compositions for treating post-operative pain comprising clonidine |
| USRE48948E1 (en) * | 2008-04-18 | 2022-03-01 | Warsaw Orthopedic, Inc. | Clonidine compounds in a biodegradable polymer |
| US9125917B2 (en) * | 2008-04-18 | 2015-09-08 | Warsaw Orthopedic, Inc. | Fluocinolone formulations in a biodegradable polymer carrier |
| US8883768B2 (en) * | 2008-04-18 | 2014-11-11 | Warsaw Orthopedic, Inc. | Fluocinolone implants to protect against undesirable bone and cartilage destruction |
| US20090264489A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Method for Treating Acute Pain with a Formulated Drug Depot in Combination with a Liquid Formulation |
| US20100022574A1 (en) * | 2008-07-28 | 2010-01-28 | EndogenX, Inc. | Methods to Treat Pain Using an Alpha-2 Adrenergic Agonist and an Endothelin Antagonist |
| MX2011003301A (en) * | 2008-09-30 | 2011-06-09 | Endo Pharmaceuticals Solutions | Implantable device for the delivery of risperidone and methods of use thereof. |
| WO2010039643A1 (en) * | 2008-09-30 | 2010-04-08 | Endo Pharmaceuticals Solutions Inc. | Implantable device for the delivery of histrelin and methods of use thereof |
| US20100098746A1 (en) * | 2008-10-20 | 2010-04-22 | Warsaw Orthopedic, Inc. | Compositions and methods for treating periodontal disease comprising clonidine, sulindac and/or fluocinolone |
| US8822546B2 (en) * | 2008-12-01 | 2014-09-02 | Medtronic, Inc. | Flowable pharmaceutical depot |
| US20100291182A1 (en) * | 2009-01-21 | 2010-11-18 | Arsenal Medical, Inc. | Drug-Loaded Fibers |
| US20100228097A1 (en) * | 2009-03-04 | 2010-09-09 | Warsaw Orthopedic, Inc. | Methods and compositions to diagnose pain |
| US20100239632A1 (en) * | 2009-03-23 | 2010-09-23 | Warsaw Orthopedic, Inc. | Drug depots for treatment of pain and inflammation in sinus and nasal cavities or cardiac tissue |
| US8617583B2 (en) * | 2009-07-17 | 2013-12-31 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for prevention or treatment of a hematoma, edema, and/or deep vein thrombosis |
| US8231891B2 (en) * | 2009-07-31 | 2012-07-31 | Warsaw Orthopedic, Inc. | Implantable drug depot for weight control |
| US9173817B2 (en) | 2009-08-24 | 2015-11-03 | Arsenal Medical, Inc. | In situ forming hemostatic foam implants |
| US20110202016A1 (en) * | 2009-08-24 | 2011-08-18 | Arsenal Medical, Inc. | Systems and methods relating to polymer foams |
| US9044580B2 (en) | 2009-08-24 | 2015-06-02 | Arsenal Medical, Inc. | In-situ forming foams with outer layer |
| US10420862B2 (en) | 2009-08-24 | 2019-09-24 | Aresenal AAA, LLC. | In-situ forming foams for treatment of aneurysms |
| US20110097375A1 (en) | 2009-10-26 | 2011-04-28 | Warsaw Orthopedic, Inc. | Formulation for preventing or reducing bleeding at a surgical site |
| US20110097380A1 (en) * | 2009-10-28 | 2011-04-28 | Warsaw Orthopedic, Inc. | Clonidine formulations having antimicrobial properties |
| WO2012075447A2 (en) | 2010-12-03 | 2012-06-07 | Warsaw Orthopedic, Inc. | Compositions and methods for delivering clonidine and bupivacaine to a target tissue site |
| WO2012075451A2 (en) | 2010-12-03 | 2012-06-07 | Warsaw Orthopedic, Inc. | Clonidine and gaba compounds in a biodegradable polymer carrier |
| US8968626B2 (en) | 2011-01-31 | 2015-03-03 | Arsenal Medical, Inc. | Electrospinning process for manufacture of multi-layered structures |
| US9194058B2 (en) | 2011-01-31 | 2015-11-24 | Arsenal Medical, Inc. | Electrospinning process for manufacture of multi-layered structures |
| US9034240B2 (en) | 2011-01-31 | 2015-05-19 | Arsenal Medical, Inc. | Electrospinning process for fiber manufacture |
| US8993831B2 (en) | 2011-11-01 | 2015-03-31 | Arsenal Medical, Inc. | Foam and delivery system for treatment of postpartum hemorrhage |
| US9511018B2 (en) | 2012-04-05 | 2016-12-06 | Warsaw Orthopedic, Inc. | Clonidine compounds in a biodegradable matrix |
| US9066853B2 (en) | 2013-01-15 | 2015-06-30 | Warsaw Orthopedic, Inc. | Clonidine compounds in a biodegradable fiber |
| US9775978B2 (en) | 2014-07-25 | 2017-10-03 | Warsaw Orthopedic, Inc. | Drug delivery device and methods having a retaining member |
| US10080877B2 (en) | 2014-07-25 | 2018-09-25 | Warsaw Orthopedic, Inc. | Drug delivery device and methods having a drug cartridge |
| US10076650B2 (en) | 2015-11-23 | 2018-09-18 | Warsaw Orthopedic, Inc. | Enhanced stylet for drug depot injector |
| USD802755S1 (en) | 2016-06-23 | 2017-11-14 | Warsaw Orthopedic, Inc. | Drug pellet cartridge |
| US10434261B2 (en) | 2016-11-08 | 2019-10-08 | Warsaw Orthopedic, Inc. | Drug pellet delivery system and method |
| US11278494B1 (en) | 2021-01-22 | 2022-03-22 | Pacira Pharmaceuticals, Inc. | Manufacturing of bupivacaine multivesicular liposomes |
| US11033495B1 (en) | 2021-01-22 | 2021-06-15 | Pacira Pharmaceuticals, Inc. | Manufacturing of bupivacaine multivesicular liposomes |
| US11357727B1 (en) | 2021-01-22 | 2022-06-14 | Pacira Pharmaceuticals, Inc. | Manufacturing of bupivacaine multivesicular liposomes |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4344431A (en) | 1969-03-24 | 1982-08-17 | University Of Delaware | Polymeric article for dispensing drugs |
| US4164560A (en) | 1977-01-05 | 1979-08-14 | Folkman Moses J | Systems for the controlled release of macromolecules |
| US4346709A (en) * | 1980-11-10 | 1982-08-31 | Alza Corporation | Drug delivery devices comprising erodible polymer and erosion rate modifier |
| US4774091A (en) * | 1983-10-14 | 1988-09-27 | Sumitomo Pharmaceuticals Company, Ltd. | Long-term sustained-release preparation |
| US4624848A (en) | 1984-05-10 | 1986-11-25 | Ciba-Geigy Corporation | Active agent containing hydrogel devices wherein the active agent concentration profile contains a sigmoidal concentration gradient for improved constant release, their manufacture and use |
| US4559054A (en) | 1984-08-09 | 1985-12-17 | Research Corporation | Rate-controlled drug release system |
| US5871472A (en) * | 1987-11-17 | 1999-02-16 | Brown University Research Foundation | Planting devices for the focal release of neuroinhibitory compounds |
| US4892538A (en) * | 1987-11-17 | 1990-01-09 | Brown University Research Foundation | In vivo delivery of neurotransmitters by implanted, encapsulated cells |
| US5487739A (en) * | 1987-11-17 | 1996-01-30 | Brown University Research Foundation | Implantable therapy systems and methods |
| US5180716A (en) * | 1990-08-01 | 1993-01-19 | The Regents Of The University Of California | Cyclodextrin complexes for neuraxial administration of drugs |
| US5330768A (en) * | 1991-07-05 | 1994-07-19 | Massachusetts Institute Of Technology | Controlled drug delivery using polymer/pluronic blends |
-
1996
- 1996-02-08 CA CA002212165A patent/CA2212165A1/en not_active Abandoned
- 1996-02-08 DE DE69603577T patent/DE69603577T2/en not_active Expired - Lifetime
- 1996-02-08 AU AU49759/96A patent/AU4975996A/en not_active Abandoned
- 1996-02-08 JP JP8524439A patent/JPH10513471A/en active Pending
- 1996-02-08 WO PCT/US1996/001753 patent/WO1996024330A1/en active IP Right Grant
- 1996-02-08 EP EP96906348A patent/EP0808153B1/en not_active Expired - Lifetime
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1997
- 1997-01-02 US US08/775,528 patent/US5980927A/en not_active Expired - Lifetime
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1999
- 1999-04-09 US US09/291,571 patent/US6214370B1/en not_active Expired - Lifetime
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| JPH10513471A (en) | 1998-12-22 |
| US6214370B1 (en) | 2001-04-10 |
| DE69603577D1 (en) | 1999-09-09 |
| EP0808153A1 (en) | 1997-11-26 |
| AU4975996A (en) | 1996-08-27 |
| DE69603577T2 (en) | 1999-11-25 |
| US5980927A (en) | 1999-11-09 |
| WO1996024330A1 (en) | 1996-08-15 |
| EP0808153B1 (en) | 1999-08-04 |
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| FZDE | Discontinued |