CA2202510A1 - Controlled release container with core and outer shell - Google Patents

Controlled release container with core and outer shell

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Publication number
CA2202510A1
CA2202510A1 CA002202510A CA2202510A CA2202510A1 CA 2202510 A1 CA2202510 A1 CA 2202510A1 CA 002202510 A CA002202510 A CA 002202510A CA 2202510 A CA2202510 A CA 2202510A CA 2202510 A1 CA2202510 A1 CA 2202510A1
Authority
CA
Canada
Prior art keywords
outer shell
container
container according
polymeric material
release
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
Application number
CA002202510A
Other languages
French (fr)
Inventor
Michael Francis O'donoghue
James Allan Morris
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Agriculture Victoria Services Pty Ltd
Original Assignee
Individual
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of CA2202510A1 publication Critical patent/CA2202510A1/en
Abandoned legal-status Critical Current

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816Wall or shell material

Abstract

A controlled release container comprises: an outer shell, at least a portion of which comprises a biodegradable polymeric material having a predetermined rate of degradation; and a core enclosed by the outer shell, the core comprising at least one bioactive molecule as an active ingredient optionally admixed with one or more pharmaceutically or veterinarily acceptable carriers and/or excipients; wherein the portion of said outer shell preferably is nonporous, and provides a predetermined delay in the time period of release of the active ingredient.

Description

CA 02202~10 1997-04-11 WO 96/12466 PCT/AU91!i/00707 CONTROLLED RELEASE CONTAINER WITH CORE AND OUTER SHELL

This invention relates to controlled release cc., ~ldil lel b Cul ,t~.;"i"g bioactive molecules as active illylediellts, especially drugs or veterinary products suitable for ad",i"i:.l, " ~ to humans and other animals, in which the active ingredient is required to be a~"i"i~le,ed after a ,u,ed~.,,,i,,ed time interval (delay time prior 10 to release of the bioactiYe molecule) and with a release profile de~el~elll upon the bioactive molecule being adlllilli~le,ed.
BACKGROUND OF THE INVENTION
Different active i"yl ~:diel ,t~ used in treatment of humans and other animals 15 require different release profiles. For example, vaccine materials may require a pulsatile release profile s~ ~hseq-lent to an initial delay of release, while antibiotics may require a continuous release profile c~ ~hseq~ nt to the initial delay of release.
The ~,,ed~.",i"ed time interval (delay time prior to release of the bioactive molecule) referred to above is de,uelldél,l upon the rate of déyl; ' ' ~ of the 20 materials and s~hseq~ nt dissolution of the deyl ' ' 1 products used for the construction of the controlled release container.
To obtain a "pulsatile" time delayed delivery system for active i, Iylediellts, it is desired that the controlled release container provide a "burst" release rather 25 than a "continuous dribble" after the required initial time delay. Thus, cu,,' Illlell~ of a bioactive molecule requires a coat or shell which remains - impervious while the structure is intact but u"d~,yui"g deyldddtiu~.
Typical prior art methods of providing controlled release devices involve 30 coating an active ingredient with a deyldddLle polymer using l,ullJ~ iulldl tablet coating methods. These generally involve cu,"~ i"9 the active ingredient with an excipient and other additives into a tablet of the desired size and shape. The CA 02202~10 1997-04-11 cu~ ul t:ased tablet may then be coated in a pan coater by spraying with a solution or dispersion of the coating material in a solvent in an amount sufficient to give the device the required coating thickness. In an " ~ h~ coating method known as the Wurster method, the tablet is coated in a fluidised bed system.

It has been found that devices formed by these conventional techniques are most suikd to short delays in release of the active ingredient. They are generally unsuitable for devices for which release of the active ingredient is desired after a longer period of, for example, about 4 to 6 weeks from 0 adl l l;l l;:>ll dliUIl. In addition, devices formed by conventional methods such as pan or Wurster coating, or I l li..l u~,uh~ ul ,l lology, often do not provide a sumciently well defined "burst" for ddlllilli::lldLiUII of active il,u,~d;~:rl.s such as vaccine materials.
PCT Publication No. WO 92/17165 describes a plld,lllaceutical or veterinary implant which is stated to release a pulse of at least one L~
active material at a culltlulldule time interval after ;Ill,uldl ' " 1. The implant comprises the uiuluu;~,al:~ active makrial; an excipient culll~uli~illg at least one water soluble material and at least one water insoluble material; and a polymer 20 film coating adapted to rupture at a ~ d~'~,lll;ll~d period of time after ;llI,Uldll' " ~, and wherein the excipients and polymers are L~;o~,ulll,udLiLJlt:. The implants of this cltation are prepared by conventional techniques from the tableffing art. Plt:pdldLiul) methods described comprise Culll,ul~aS;Ilg the excipients with the active ingredient into tablet-shaped solid cores using known25 techniques and coating with a polymer by spraying in a pan coater or a fluidised bed coater. Disadvantages with these implants is that a water insoluble non-L~iud~ldddLlle cage remains in the body. The implants are c~ll, ' ' ' involving complex production plu~esses and delay times longer than about 4 weeks are difficult to achieve. The implants of this disclosure are most suited to short 30 delays.

CA 02202~10 1997-04-11 WO 96112466 ' - PCT/AU95/00707 It is an object of the present invention to overcome or alleviate one or more of the above limitations ,.,~ 1 with conventional controlled release devices.
SUMMARY OF THE INVENTION
According to the present invention there is provided a controlled release container . ~." ,,u, iail ,y.
an outer shell, at least a portion of which CCrlll~rliaeS a Lriur~éyldr~dLrle polymeric material having a Frler~elellllilled rate of deyl ' ~, and a core enclosed by said outer shell, said core r_ulll,uliaillg at least one 1û bioactive molecule as an active ingredient optionally admixed with one or more phdllllar-eutically or veterinarily ~ t '~ carriers and/or ê~ riellt~, said portion of said outer shell preferably being non-porous, and providing a ~.,ede~e""i"ed delay in the time period of release of said active ingredient.
Preferably, the polymeric material degrades when in contact with bodily fluids, this r léyl dr~ld~iùl, cu, ",u, iail ,g reduction in molecular weight of the polymeric materialtoaFrler~et~lllillèdvalueduringthe~rledetellllilleddelayperiod~wherein this deyldr~dliùl~ is sufficient to allow release the active ingredient after the Frl er~elel I l lil ~ed delay period.

Preferably also, the polymeric material has an initial molecular weight of less than 2ûû,û0û and a molecular weight of 10,û00 or less at the end of the ,rled~,t~rlllilled delay period.
In another aspect, the present invention also extends to an outer shell for a controlled release container, at least a portion of said outer shell ._ulll~rliailly a UiUdeyldr dLrle polymeric material having a pledeiellllilled rate of deyli ' " "said portion of said outer shell preferably being non-porous and providing a ~rled~t~,lll ,ed delay in the time period of release of the contents of a core 3û enclosed by said outer shell.

CA 02202~10 1997-04-11 WO 96/12466 ~ PCT/AU95/00707 It will of course be a~ uidl~d that this outer shell provides a void into which a core containing the active ingredient can be inserted.
The term "non-porous" as used herein means that the biu~eyldddlJlt:
5 portion of the outer shell is esse~ free of any pores or ~U.~u,uult::~ which might allow release of the contents of a core enclosed by the outer shell prior to d~ylddd~iulloftheLiu~eyldddblepolymericmaterialprovidingthep~e:d~t~lll;lled delay in the time period of release of the contents of the outer shell.
The present invention also provides methods for the production of a controlled release container in ac..c.rdd"ue with this invention. Preferably, the outer shell of the container is formed by melt p, u~ .s;"y.
Throughout this cl~æ~ r;~ -l1 and the claims which follow, unless the 15 context requires otherwise, the word "I,ulll~Jliat:", or variations such as ''~,~Ill~Jliae~'' or "uulll,uliailly", will be ulld~ uod to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

The Illul~Jllol~y,l of the Liud~ylddd~le portion of the outer shell of the container of this invention is ,~ ' with the ,.,t:d~.",i"~d d~yldddliùl~
profile and the 1' - ' dissolution of the dæy, ' ~ products which results in a ~ t~.", I~:d delay in the time period of release of the active ingredient.
The ~ uluyy of an outer shell formed by melt p~u~esc~ g techniques is of greater integrity wlth respect to lack of porosity and general uniformity than c~ .ltiulldl coatings formed using solvent based systems such as with the pan or Wurster coaters. Such conventional coatings have difficulties ~o~ d with 30 micro-porosity, an inherent effect which results during drying of "solvent" coating techniques. In general, the presence of Illi~,lupûlt~a in the shell or coating will resuU in an inltial dribbling of the active ingredient rather than a desired burst CA 02202~10 1997-04-11 effect. A desirable feature of the controlled release C~ a;ll~la of the present invention is that the need to use organic soivents ~cco..; ' -~ with solvent coating techniques is avoided, and in addition the potentially adverse effects of residual solvent are removed.

Commonly used polymers may be modified to have a broad range of rates of dey, ' " ~, and cllhsequ~nt dissolution of the deyldddliui~ products. It has also been found that by adjusting the IllulfJllOlûyy of the polymer, which is possible when using melt plu~esailly techniques, the d~yl ' " ~ rate and 1û 5~hseq~Pnt "icc,~l, ' , of the deyldddliull products of a known polymer may be accurately adjusted. The ~ ,ullol~y~ of the outer shell may also be modified using additives such as pld~ .el~, nucleating agents, lubricants, p~ucess;~g aids, fillers, ' ' ' " ~ :" and related additives, to provide control over the range of desired rates of dt:ylddd~ , and cllhC.~qll~nt dissolution of the de:yl~
5 products. Accordingly, the present invention extends to the use of polymeric materials which do not form crystalline regions but remain in an amorphous form.
Devices formed by conventional solvent coating methods 1, ,~, ,Liù,~ed above have a generally amorphous coating. It has been found that when the outer 20 shell of the container of the present invention is formed by melt pru~,ess;"y rather than cu"~. " Idl solvent coating techniques, it is possible to obtain the polymeric material in at least a partially crystalline form and having a deflned ",u"ul~oloyy with respect to crystaliine and amorphous regions. It is also possible to control the u~' " ,;;y of the polymeric material and acco,di,,yl~ adjust the rate of 25 deyld~d~iUil of the outer shell and s~hseq~lPnt ~ics~ of the dey, ' products.
Although melt p~u~essi~g has been used in the past to form gelatine capsules, such capsules have not been used for delayed release systems.
30 Gelatine has limited:,, ' S."ly as a material for a delayed release system asa result of the amorphous nature of the polymer (it has little or no ability to form a crystalline phase) and the ability to modify the gelatin, whether through CA 02202~10 1997-04-11 Wo 96112466 PCT/~119~100707 blending, illCOl~Juld~iul- of additives or physico-chemical derivatization, is limited.
Accordingly, the advantages of the present invention could not have been suspected from lt:ullllolc,yy ~c~O~ cl with the formation of gelatine capsules.
The outer shell of the container of this invention may be in any shape including elongate, oval, round, ball, h~ .,ul,eriGal, capsule, rod, needle or cylinder shape. Conveniently, the shape is an elongate, cylindrical, rod or needle shape. In a most preferred ,:",~o~i",t:"~, the outer shell is elongate or generally cylindrical.

In one preferred t:lllbO.lillle:lll, the container of this invention is formed as an implant device. Such an implant device may comprise a single controlled release container in acc,c,dd"-,e with this invention, or it may comprise an assembly of two or more such UUllLdil Ic:la, each of which may, if desired, provide 15 a dlflerent ~ d~L~""i"ed delay in the time period of release of the active ingredient, or contain a dlfferent active ingredient.
Only a portion of the outer shell of the container of this invention may comprise the LJiOdey,d~dL,I~ polymeric material, and in this case the ,t:, ,d~r 2û of the outer shell may be non-deyldddLI~. Thus, the container may be in the form of a two-part capsule with one part being deyldddL~ and the other part either deyladdLJle: at a different rate or non-dey,dddL,le. In another e",L,odi",t:"L, the container may be in the form of a capped cylinder or rod, with either the cap or the cylinder or rod being dey,dddLI~ and the other dc:yldddL~le at a different 25 rate or non-dey, ddd~
Preferably, however, the container of this invention is completely biudeyld~dLJII:, that is the outer shell entirely consists of the biùdeylddaiJlepolymeric material.

Preferably, the wall thickness of the outer shell of the container of this invention is about û.25 to 1.5 mm, more preferably about û.5 mm.

CA 02202~10 1997-04-11 WO 96/12466 PCT/~l~ 5 /u In particularly preferred ~Illbo.li,~ ts of this invention, the controlled release container is provided in a generally cylindrical or capsule shape, of external dilll~ iulla of about 15-2û mm x 34 mm for use as an implant device alone (or about 3-1 0 mm x 3 mm for use as one part of an assembly of parts) for5 subcutaneous or similar delivery, or of external di,ll~l~sions of about 40 mm x 10 mm for use as an device for oral delivery.
Adlllillialld~iùl~ of the controlled release container of this invention may be by any convenient means but generally by oral ingestion or injection via the 10 illlldp~lilui-edl, intramuscular, sub-cutaneous or illLldder-lldl route. The device may also be surgically implanted or implanted by sub-surgical procedures such as during biopsy procedures. Subcutaneous delivery of the container in the form of an implant device is particularly preferred. Where the container is to be a.lll.i"ial~ d by oral ingestion, particularly to ruminants, it may be i"cul~u,; ' -' 15 into a weighed capsule or bolus or other intraruminal device, for example a device as described in ll ' "dLiu,~al Patent Publication No. WO 93/19698 (Australian Patent Application No. 37399/93).
The bioactive molecule in the active ingredient in the core of the container 20 may comprise any native, synthetic or ~ ,UI l IL~il Idl ll pl ldl l "aceutical or veterinary agent, or food additive or supplement, including antigens, antibodies, antitoxins, nucleic acids, vaccines, cytokines, growth ,UlUlllULdl~ts, hommones, cancer cellinhibitory molecules or agents, immune stimulants or Su~J~ult:asdllts~ anti-i"lld""" ' i~s, anti-microbial agents including dl "L' " , anti-viral agents, anti-25 parasitic agent, vitamins, tonics or stimulants, minerals or inorganic or organicnutrients. The active ingredient may comprise one type of bioactive molecule or may be a mixture of different bioactive molecules.
The pl,d""aceutical or veterinary carriers and/or excipients may include 30 any and all di~,u~laiùl~ media, coatings, d"LiL,aul~lial, anti-fungal and/or antiviral agents and the like as well as salts such as dicalcium pllua~lldl~. Additional OU~,uul~ t~ which may be included are binders (e.g. gum l~dyd~;d~L I, acacia, CA 02202~10 1997-04-11 corn starch or gelatin), ~ia;~ l dLil Iy agent (e.g. corn starch, potato starch, alginic acid and the like) and/or a lubricant (e.g. magnesium stearate). All such ~u~,uoliellt~ carriers and excipients must be subatdll 'I~ lldllll~l`rllt~ ly orveterinarily pure and non-toxic in the amounts employed and must be 5 Lioco,,,,udtiL,le with the bioactive molecules.
Biudey,dddL,lr polymeric materials with a wide variety of ,ulll,uuailiul~s, properties and forms are available for use in acc~,dd"ue with the present invention. They are readily amenable to ~, u~,~Sail ,y using standard melt 1û pr~esaillg Irulll~OlOyirs to give complex shapes and structures. Examples of suitable materials include the polyester family of polymers, such as the polylactide, polyld~,lide-polyglycolide and the polyl,yd,uxyLutyrate-polyhy~ /dlrl ' polyesters. Other suitable polymers include polyamides such as nylon and polysac~,l,a~ides, for example starch, hydrogel, cellulose acetate,15 hydroxypropyl~ "~;hJlc~llulose, hydl UAy~i U,.Jyl~ tl ,ylcellulose phthalate, cellulose acetate phthalate and ethyl cellulose. Polylactide-polJyl~.~ ' ' copolymers are particularly preferred for use in the container of this invention.
A "burst" release of the active ingredient from the controlled release 2û container of this invention is achieved as a consequence of a bulk deyldddtiull of the Liud~ylddd~le polymeric material in the outer shell. In general, the polymeric material l ,~ ly3~.~ in vfvo so that the average molecular weight of the polymer drops over a particular period of time. Preferably, the polymeric material will have an initial molecular weight not greater than about 2ûû,ûûû, more 25 preferably about 1ûû,ûûû, and this will then hydrolyse to an average final molecular weight of 10,0û0 or less, at which point the Liudey,d;Jal,le portion of the outer shell will break up releasing s~lald"" 'l~ all the active ingredient contained in the core of the container in a pulsatile manner.
3û Preferably, the biudeyld~alJle polymeric material is selected so as to provide for a ,clr~tu~lll;lled time delay of release of at least two days, more CA 02202~10 1997-04-11 _ 9 _ preferably at least four days, most preferably at least two weeks after a~" ,;"i~l, dliu11.
Structural and other attributes of the polymeric material which may be 5 adjusted to affect the rate of deUldddliUII in vitro and in vivo include copolymer c~",~,ûSiliull~ isomer content and molecular weight. The effect of each of thesehas not in the past been cu""u,~l1e,~ ly studied with respect to melt y, in cu",i i" " ) with additive fu,,-,liur "ty, the summation of the bulk properties of the polymeric material and the c~ Ihseql l~nt d~yl d~dliUI, profiles.
10 For example, _,~, ' " )s reported in the literature for the pLa/pGa polyesters involve their use in solvent based ,,' " ,~ eg. micro- and nano-sphere ~ ,llllulug~r. For these :1"~' " )s, solubility of the polymer in the solvent for production is a primary factor d~t~.ll,;.,i,l~ utility.
The rate of .I~ul_ ' " ) of the polymeric material may be adjusted by adjusting co-polymer cu,,,,uu~iliun, isomeric culll~uo~;~iul) and starting molecular weight. For example, the rate of d~,d~dliun of the pLa/pGa polyesters dec,tases with increases in the lactate, isomeric purity and molecular weight.
These variables will now be discussed in more detail. The c~,ltdi"e,:, discussed20 beiow were formed as described in the i-xamples.
Co~ , C, . 1-ln the fûllowing tables, the "mean ~,u,, ' " ," is the average time of 25 release of core (.Iy~/;a_lu~e mixture) from a standard size implant device (19 mm x 3 mm o.d.). ~n vitro tests were conducted at 37C in pl1~,ul ,dl~-buffered saline (PBS). In vivo tests were conducted in mice or sheep with the device implanted subcutaneously ~in mice, under skin on back; in sheep, under skin on inside of hind leg).

For the pLalpGa polyesters, which are illustrative of polymers which may be used in the present invention, it has been found that ill~ a~illg the glycolide CA 02202~10 1997-04-11 content of the copolymer results in a decrease in the time required for de~,dddLiùl~ both in vi~ro and in vivo. In Table 1 is provided data for polymer samples with or without additives. C~ ,udldbl~: trends are observed when Gulll~udldble amounts and t,vpes of additives are present in the various base 5 polymers.
Table 1: COPGI~ I c~ o~;~;on Release time Molecular Weight (mean days + standard (Mn = after degradation) deviation) (Mw = before degradation) in vitro mice sheep Mn Mw Disp-(37C) (dye) (dye) ersity d,l-polylactic acid (iv=1.0; 57+5 69+4 61+3 45698 69699 1.53 Mw=137,000) 15% ethyl citrate 75:25 d,l-polylactide-co- 28~0 39~3 77+17 48218 74278 1.54 glycolide (iv=0.8;
Mw=98,000) +5% ethyl citrate 65:35 d,l-polylactide-co- 11~1 9+3 28~6 11399 17689 1.55 glycolide (iv=0.6;
Mw=63,000) ~5% ethyl citnate 75:25 d,l-polylactide~ 32+3 32~5 ND 9342 31460 3.37 glycolide (iv=0.8;
Mw=98,000) 10.5% Mg stearate 65:35 d,l-polylactide-co- 20~2 17~2 ND 13761 26038 1.89 glycolide (iv=0.6;
Mw=63,000) 10.5% Mg stearate 1-polylactic acid (iv=1.0; ND 136+22 ND 73237 101072 1.38 Mw=1 02,000) d,l-polylactic acid (iv=1.0; 87~10 121+14 116+4 49301 72776 1.48 Mw=137,000) 85:15 d,l-polylactide-co- 41~5 64+5 88+21 41808 90463 2.16 glycolide (iv=1.4;
Mw=232,000) 75:25 d,l-polylactide-co- 30+8 41i2 54:~9 34451 53140 1.54 glycolide (iv=0.8 Mw=98,000) CA 02202~10 1997-04-11 Polymer Type Release time Molecular Weight (mean days + standard (Mn = after d~
deviation) (Mw = before degradation) in vitro mice sheep Mn Mw Disp-(37C) (dye) (dye) erslty 75:25 d,l-polylactide-co- 42_2 58_2 ND 34227 57071 1.67 glycoiide (iv=0.6;
Mw-63,000) 65:35 d,l-polylactide-co- 17+1 26+0 27+10 17664 30896 1.75 glycolide (iv=0.6;
Mw=63,000) 50:50 d,l-polylactide-co- 17+0 15+4 ND 34802 55656 1.63 glycolide (iv=0.8;
Mw=98,000) 1-polylactic acid (iv=1.0; 118+42 112_14 117_3 15039 28046 1.87 Mw=102,000) +0.5% boron nitride 75:25 d,l-polylactide-co- 38+3 46_0 70+6 ND ND ND
glycolide (iv=0.8;
Mw=98,000) +0.5% boron nitride 75:25 d,l-polylactide-co- . 52+3 60+6 53+0 45022 64109 1.42 glycolide (iv=0.6;
Mw=63,000) +0.5% boron nitride 50:50 d,l-polylactide co- 12_6 16+2 = 32+9 10744 17887 1.67 glycolide (iv=0.8;
Mv~98,000) +0.5% boron nitride 85:15 d,l-polylactide-co- 17i5 20+3 24+8 23205 41503 1.79 glycolide (iv=1.4;
Mw=232,000) +10% ethyl citrate 75:25 d,l-polylactide~ 20+3 18+4 ND 19838 45192 2.28 glycolide (iv=0.8 Mw=98,000) +10% ethyl citrate - 65:35 d,l-polylactide-co- 11_1 9+3 27+10 14789 24047 1.63 glycolide (iv=0.6;
Mw63,000) +10% ethyl dtnate CA 02202~10 1997-04-11 Isomeric C~ 0115 The proportion of diflerent isomers present in a polymer will affect the ~,ly~ lity of the resulting polymer. Accordingly, by adjusting the proportion of5 isomers present in a polymer, the rate of dey,dddliun can be adjusted.
By way of ex~,",'~ ~ the pLa/pGa polyesters will be fliQc~ssf~rl Naturally occurring lactic acid is an optically pure molecule. It is also possible to obtain a racemic mixture of lactide monomer via chemical synthesis. As a result 0 the polylactides are available as either e,,d,,liu,,,~l~c~ll) pure or racemic polymer.
The racemic d,l-pLa is amorphous whereas the optically pure l-pLa is a highly crystalline material. I-pLa degrades slowly both ~n vitro and in vivû.
In Table 2 is illustrated a cul, I~Udl iaul I of the ~y, dddliul~ rate of d,l-pLa and 15 I-pLa as the neat polymer and with additives.
The nle-,l Idl l;al 1 l for the difference in the rate of dey, ' ~ of the d,l- and l-lactide polymers is thought to be ~ dolll;lldlllly physical rather than chemical in nature. For crystalline materials (I-pLa), water entry is retarded as a result of 20 the packing of the matrix. Amorphous materials (d,l-pLa), on the other hand, have a relatively open matrix allowing relatively free passage of water into thebulk of the polymer.
This ~ y is a useful pdldlll~t~l for control of the deyldddliol- rate.
25 The use of additives, for example, pldali~,;a~l~ such as ethyl citrate or diisooctyl phthalate plus nucleating agents such as boron nitride, and internal lubricants such as magnesium and zinc stearate, aflects the degree and distribution of crystallinity and in conjunction with control of molecular weight, allows control of the .l~yl ' ~ profile.

CA 02202~10 1997-04-11 .

Table 2: Isomer c., .~I vs~ n effects Polymer C , " Release time (Mean days _ Molecular Weight star dard devia-ion) in vitro mice sheep Mn Mw Dispersily (37C) (dye) (dye) d,l-polylacUc acid 87+10 121_14 116+4 49301 72776 1.48 (iv=1.0; Mw=137,000) 1-polylactic acid ND 136+22 ND 73237 101072 1.38 (iv=1.0; Mw=102,000) d,1-polylactic acid 74_4 76_5 97_7 71077 104247 1.47 (iv=1.0; Mw=137,000) +10% ethyl citrate +0.5% t10ron nitride 1-polylactic acid 66+29 99+15 ND 29922 46982 1.57 (iv=1.0, Mw=102,000) +0.5% boron nitride +10% ethyl citrate Starting r-~l? Weight Data indicating the effect of starting molecular weight on the deulddd~;v"
5 profile are provided in Table 2. In general, the higher the starting molecularweight for a given material the longer the period for de~lddd~iull.
Moulding Conditions 1û Examples of suitable techniques for melt extrusion to produce continuous tubing and injection moulding for the production of capsules follow. The resultsin Table 3 are illustrative of the ,"'' el~ces in deyldddliul) outcomes obtained- from the ~luceaaes of melt extrusion to produce continuous tubing and injection moulding for the production of capsules. It can be seen in the examples that the15 difference in delay of release between 50:50 pLa/pGa extruded tubing and injection moulded capsules was 30 compared to 15 days.

CA 02202~10 1997-04-11 The difference in delay of release between extruded tubing and injection moulded capsules is due to dey,dddLiu,l which occurs during production of the injection moulded samples which results in the molecular weight of the injectionmoulded samples falling. Little or no d~yldddLiull of molecular weight results 5 during extnusion plu~,~s~illy~
It has been found that a consistent degree of dey,d~dLiull is obtained upon repeated p, uC~aSil ,g of the same materials under the same conditions during the injection moulding process and acG~,-li"~l~ selection of the process is an 10 additional ~dldll,eLe:r by which the IllullJh~luy) of the outer shell may be adjusted to adjust the rate of dey, dddLiU~ of the outer shell.
The equipment used for ,~ucessillg the polymers also has an effect on the ;JCI~Illi.,dl properties of the container and affects the rate of dey, ' ~.
15 As noted aboYe, melt extrusion has little effect on the polymers with respect to molecular weight whereas injection moulding has a significant effect with d~yldddliu~ levels of the order of 30 to 50% being observed in some instances.
The design of the moulding equipment also has an effect. For example, 20 injection moulded capsules have been produced by a "Ram" based injection moulder, the Butler 10/60 and by a screw based injection moulder, a Boy. Both induce signlficant dey, ' ~ during ~,uce~si"g although to.different levels, about 75% for a Ram based injection moulder compared with 50% for a screw based injection moulder. The reason for this is that the screw injection moulder25 is able to force feed the polymer into the moulding tool using the power of the screw enabling ~u~ uuessi"g of materials at lower Lt:""~ Ires, thus inducing less thermal dey, ' ~. Accordingly, selection of the moulding equipment enables the rate of d~yld~c~Liùl~ of the outer shell to be adjusted.

CA 02202~10 1997-04-11 WO 96/12466 = - PC'r/AU95/00707 Table 3: Extruded tubing vs injeFLon moulding Polymer Type Mean Degradation Time (Days) in vitro in vivo samples samples (37~C) mice (Dye) Extruded Tubing Samples 50:50 d,1-polylactide-co-glycolide 29 31 (i.v. = 0.8; MW = 98,000) 50:50 d,l-polylactide-co-glycolide 31 31 (i.v. = 0.8; MW = 98,000) 1 0.5% boron nitride d,l-polylactic acid 150 (i.v. = 1.0; MW = 137,000) + 0.5% boron nitride 1 0.5% ethyl citrate Injection Moulded Samples 50:50 d,l-polylactide-co-glycolide 17 15 (i.v. = 0.8; MW = 98,000) 50:50 d,l-polylactide-co-glycolide 19 16 (i.v. = 0.8, MW = 98,000) 0.5% boron nitride d,l-polylactic acid 94 95 (i.v = 1.0; MW = 137,000) + 0.5% boron nitride + 0.5% ethyl citrate rl~ li..lion rirradiation increases the rate of d~gldddliùll of the polymeric material, 5 and may decrease the deulddd~ time by about 25Yo.
The presence of additives in the polymer matrix may reduce the time required for deuldddti~/l l and may be, for example, about 20% compared to 25%
for polymers not ~u,,'..;.,i,,g additives. The presence of more than one addltive 10 may have a ~r"t~ t~, effect, for example, the presence of ethyl citrate and boron nitride may reduce the dt:yld~d~iuil time more than would be expected on the basis of summation of the additive effect.
Results of the effect of y-irradiation on the dt:yldlldliui~ profile of dlfferent 5 polymer colllpo5iLiui~s are provided in Table 4.
Table 4: I" .,.I;~Liol) effects Polymer Type Mean Degradation Time (Days) in vitro in vivo irradiation samples samples (37C) mice kGy (Dye) Extnuded Tubing Samples 75:15 d,l-polylactide-coglycolide 93 - 0 (i.v. = 0.6; MW = 63,000) 56 25 75:25 d,l-polylactide-co-31ycolide 69 84 0 (i.v. = 0.6; MW = 63,000) + 0.5% ethyl citrate 56 64 25 75:25 d,l-polylactide-coglycolide 114 o (i.v. = 0.8; MW = 98,000) 45 25 85:15 d,l-polylactide-coglycolide 62 0 (i.v. = 1.4; MW = 232,000) 50 25 d,l-polylactic acid 138 0 (i.v. = 1.0; MW = 137,000) 122 . 25 d,l-polylactic acid 149 164 0 (i.v. = 1.0, MW= 137,000) + 0.5% ethyl citrate 116 104 25 d,l-polylactic acid 153 123 0 (i.v. = 1.0; MW = 137,000) + 0.5% boron nitride 113 >266 25 d,l-polylactic acid 150 ~266 0 (i.v.= 1.0; MW = 137,000) + 0.5% boron nitride 104 >266 25 + 0.5% ethyl citrate CA 02202~10 1997-04-11 WO 96/12466 ~ PCTIAU95/00707 Fl~ ,Li~ er Effects The addition of pldbli~iibel to the polymer material cle.;,~dbes the time of delay in the period of release of the active ingredient. The effect of plasticiser on 5 the dt:yl ' " , profiles of polymers is illustrated in Table 5. It is post~ t~d that the effect of the plasticiser is as a result of the de~,,c:ased amorphous polymer material density. It is preferred that the level of added plasticiser is above about 0.5%. If the level of added plasticiser is less than 0.5%, there may be insuffficient IJIdbli~,ib~l necessary to induce an effect on the d~yl ' ~ profile.

CA 02202~10 1997-04-11 Wo 96/12466 PCTIAU95100707 Table 5: F; l effects Polymer Type Release Time (mean days + Molecular wei9ht standard deviation) in vi~ro mioe sheep Mn Mw Disper-(37C) (dye) (dye) sity d,l-polylactic acid (iv=1.0; 87+10 121+14 116+4 49301 72776 1.48 Mw=137,000) + 0.5% ethyl citrate 92+11 88~11 96+7 43382 94615 2.18 + 2.5% ethyl citrate 55+9 75+2 ND 28306 62045 2.19 + 5% ethyl citrate 57+5 69+4 61::3 45698 69699 1.53 + 10% ethyl citrate 74+4 76+5 97+7 71077 104247 1.47 85:15 d,l-polylactide-co- 41+5 64+5 88+21 41808 90463 2.16 glycolide (iv=1.4 Mw=232,000) + 5JO ethyl cltrate 22+4 29+3 14+0 17237 341444 1.98 + 10% ethyl cltrate 17+5 20+3 24+8 23205 41503 1.79 75:25 d,l-polylactide~ 30+8 41+2 54_9 34451 53140 1.54 glycolide (iv=0.8;
Mw=98,000) + 5% ethyl citrate 28+0 39+3 77_17 48218 74278 1.54 + 10% ethyl citrate 20+3 18+4 ND 19838 45192 2.28 + 15% ethyl c-ltrate ND ND ND 17140 46453 2.71 65:35 d,l-polylactide-co- 17+1 26~0 27+10 17664 30896 1.75 glycolide (iv=0.6, Mw=63,000) + 5% ethyl citrate 11+1 9+3 28+6 11399 17689 1.55 + 10% ethyl citrate 11+1 9+3 27~10 14789 24013 1.68 As discussed above, the present invention provides a controlled release container having a predicted rate of dey, ' " ~ and subsequent dissolution of the dey~dddlioll products providing a defined delay in the time period of release 5 of the active illyl~di~
The following Table 6 illustrates specific delay times which may be achieved by adjusting the Illo,f h~ y of the outer shell.

CA 02202~10 1997-04-11 Table 6 Delay Time (days) C~ ,uu~itiu~ of Outer Coating 50:50 d,l-pLa/pGa 65:35 d,l-pLa/pGa 75:25 d,l-pLa/pGa 85:15 d,L-pLa/pGa 100 d,l-pLa The deyladdliul~ time may be further reflned by adjusting the starting molecular weight and level and type of additive.
In a preferred method of forming the ~ullldillel~ of the present invention, heat and/or pressure is applied to polymeric materials to convert the polymer toa fluid state. Once in a fluid state the polymer may be shaped to fomm the outershell by moulding and the shape ",di,ltcli"ed by cooling to below the flow l~l"~,e, Ire of the polymer. This has the added adv_"ldye that the size and 10 shape of the outer shell of the container may be co"~r~ "~~' No additives such as solvent are present which will require removal, avoiding porosity of the outer shell. Where solvent removal from a coating material is required, a porous coating generally resuUs.
Some of the additional advdllldy~s of controlled release Cullldill~la which have been formed by melt ~J~u~e~ y include:
- unifommity of shape (the mould design d~ s the size and shape of the product);
- ease of quality control through (a) control of addition of various agents, (b) control over the product shape, (c) control over the ~u~es~ y conditions, etc.;
- no requirement for removal of materials used in the production process (such as solvents in the solvent coating ~u~æss~s indicated above);

CA 02202~10 1997-04-11 WO 96/12466 PCI~/AU95/00707 - , ,: 'i ' "ty to a wide range of polymeric materials and blends of various materials, - simplicity of p~u~eaai~y, and - flexibility in design and manufacture, e.g. use of multiple cu,l".u"e"ts 5 using the same or different materials for construction of each part.
In a preferred form, the entire outer coating is cu,,,,uu:,ed of a L;udey, dddble polymeric material. A container may be formed in two (or three ormore) parts by injection moulding such that the parts may be joined to form a 10 sealed container. During assembly of the parts of the container a core is placed inside before assembly of the cu,, ,,uu, ,~, Its and may be sealed using any suitable means such as glue, friction or a self locking screw design or by welding with ultrasonic It:~llllOluyy~
The entire outer shell or part only of the outer shell of the controlled release container may be made of the L;u~yldddLlle polymeric material with defined d~yl dddl;ù~l and dissolution rates. The I t:" ,~:. ,der of the outer shell of the container may be prepared from a tough non-L;ode:yldddLle or very slowly degrading or even photo-d~yldddL.la polymeric material. Such devices may be 20 useful for ,, " " ~ to the sub-cutaneous, i"l, dde" "dl, intramuscular, illlld,U~ edl and ruminal deliver,v of bioactive molecules where the size of thecontainer and ac~ ly the cost of containing the active ingredient within a l.iudey,dddLle material may be relatively significant. For example, the container may comprise a sleeve which is cullly~s~d of ~iudeyld~dbl~ materials and the 25 ,~",~;.,.ler of the body of the container cu",~,osed of an alternate material.
The core fommulation may also be adjusted to assist in dlldilllllt:lll of the burst effect required for pulsatile delivery. For example, the use of osmotic modifiers to swell the active ingredient and thus cause a burst as soon as the 30 Liud~y~ddaLl~ portion of the outer shell of the container reaches a critical stage of weakness. All~llldli~_ly, for continuous or sustained release of the active ingredient from the container s~ ~hse~ent to b;ud~yl dddliùl~ of the outer shell, i.e.

CA 02202~10 1997-04-11 WO 96/12466 PCT/~IJ95/00707 51 Ihs~ t to the time interval of delay of release, excipients in the core may be used which inhibit the rapid release and result in a "dribble" effect and thus asustained release profile is obtained after the initial delay.
In another aspect, the present invention provides a method of ad",i"i~ ,i"g an active ingredient to a human or animal in a controlled release regime by a~ "i"i~ l il lg to the human or animal a container as described above.
The recipient of the container may be a human, livestock animal, eg. a sheep, cow, horse, pig, goat or donkey, poultry, eg. chicken, turkey, goose or game bird, a laboratory test animal, eg. a rabbit, guinea pig, rat or mouse, CUlll,~dlliUIl animal, eg. dog or cat or a wild animal in the captive or free state.
As previously described, ad",;"ial, ", of the container may be by any co" /~ "l means such as by oral ingestion or by injection via the il ,~, d,Jel i' ~edl, intramuscular, sub-cutaneous or i"' dd~lllldl route.
The amount of active ingredient used in a container will vary depel ,~i. ,g on the type of active ingredient, condition in the animal being treated and the 20 presence or absence of agonists to the active ingredient or dlltdyUlli~LC~ to the condition being treated. In general, an effective amount of an active ingredientis employed meaning an amount effective to induce, stimulate, promote or otherwise initiate the i"""e.lial~ly intended result. For example, if the activeingredient is an antigen, the effective amount is that required to stimulate an immune response to the antigen. Commonly, the active ingredient will be present in amounts ranging from a few IlliWU~ldlll::. to gram quantities per container.
The invention will be further described by reference to the following non-limiting Figures and Examples. In the Figures:
Figure 1 is a s.,l,~",dliu cross section of a container of the present invention; and CA 02202~10 1997-04-11 Figure 2 is a s~ e~ldLi~, cross section of a further ~Illbodilllclll of a container of the invention.
Container 10 shown in Figure 1 has a two-part outer shell for a capsule or 5 implant, for example having outer .li",~"~iv,~s 15.5 mm x 3.5 mm and wall thickness of 0.5 mm. The outer shell consists of parts 11 and 12, either or bothof which may be formed from biodey, d~dLI~ polymeric material, which are shaped to sealingly fit together after a core containing active ingredient has been inserted into the outer shell. Container 20 shown in Figure 2 similarly has a two-part outer 10 shell forming an implant device, for example having outer dilllt:l~siulla of about 19 mm x 3.5 mm and a wall thickness of 0.5 mm. Container 20 consists of tubular implant body 21 to house a core containing active ingredient and a cap 22 which seals the implant body 21. Once again, either or both of the implant body 21 or the cap 22 may be formed from biùdeyldddl)l~ polymeric material.

EXAMPLES
EXAMPLE 1 Melt ~ of Materials The ~,ul~es~ ,9 of the polymers involved in this investigation involved two separate stages. These consisted of compounding and extrusion (treated as a single process), and secondly injection moulding. Each of these ~ul~esses can have a ~e:Llillle~ dl effect on the polymer due to thermal and shear d~yld~dLiui~.
A large part of this work was directed towards u~de~ld~ g how the polymers 25 of interest were affected by these factors and the most effective ways to minimise these effects. In addition, the effect of various additives, e.g. pld~ and intemal lubricants on the molecular weight of the final capsules was studied in dll~ ldtiUI~ that the deyldddliUI~ of the polymer may be modified by the inclusion of these compounds.

CA 02202~10 1997-04-11 1. C~- . . Q and E..L,.I~;ol~.
The compounding of additives and ~la~ into the po~ymers was p~rulllled on a Brabender r-xtruder fitted with either a single or twin screw extruder. Initial work to produce tubing was pe:lrullll~d using a cross head 5 attached to the single screw extruder. The single screw was also used to compound some of the earlier blends but later work used the twin screw which was quicker and the materials generally fed more easily. The process was basically the same for both extruders, with the only ~;rre:rt:llc~ s being:
- torque settings 1û - the single screw requires harder stuffing (into the feed throat) of some materials - the twin screw requires juggling of two polymer strands into the pelletiser - more loss a~ol ' with the twin screw extruder.
Extrvsion Cûndifions.
r-xtruder temperatures were very de:pe:l~d~l IL on the polymer in use and on addltives present. Table 7 SUI l ll l Idl i:,es some of the conditions used for the poly-l lactide (pLa) and pol~,lduli~ ,oly~!~colide (pLa/Ga) polymers, with zone 2û temperatures of 9û-13ûC and die temperatures of generally 12û-140C (high MW or crystalline materials, e.g. L210, L214, which had melting points of ~1 85C, required zone temperatures of 21 0-250C, and die L~ l ' Ires of 235-275C) ~ .

CA 02202~10 1997-04-11 TABLE 7. Br.~l~el~de~ extruder co~ r~
Polymer MW ID Melt Zon Zone Zon Die rp screw C e 2C e C m l-pLa 2000 L104 132 85 95 115 120 15 single l-pLa 102k L206 183 190 185 185 185 20 single l-pLa 629k L210 235 195 210 225 235 20 single l-pLa L214 ~255 210 235 250 275 20 single dl-pLa 137k R206 140 90 110 125 135 20 single 10.5%MgSt 90 110 125 130 25 twin +1%MgSt 90 110 125 130 25 twin ~0.5%ZnSt 90 110 125 135 25 twin ~1%ZnSt 90 110 125 135 25 twin p-Ga G205 192 pLa/Ga(65:35) 100 120 120 140 20 twin pLalGa(75:25) 63k RG755 127 130 130 140 130 20 twin pLa/Ga(75:25) 98k RG756 135 130 130 140 130 16 twin 15% EC 90 110 125 130 20 twin pLa/Ga(85:15) 232k RG858 150 135 155 160 180 20 single pLa/Ga(50:50) 98k R506 D~yld~ldtiVI~ of polymer dunng extrusion.
A series of repeated Brabender extrusions in which polymer samples were subjected to 2, 4, 6 and 8 extrusion cycles was completed on DL-pLa (R206) and 5 DL-pLa/Ga 75:25 (RG756) to determine the extent of de~l ' ) that is caused by excessive ~, u~ Sail Iy.
In the case of polymer DL-pLa (R206), as shown in the following Table 8, multiple passes through the Brabender have very little effect on the molecular 10 weight of the polymer extrusion, dropping from 99084 (nom. 137000) to 96163 after 8 passes. Sllhse~l''Pnt ~UIU~:SS;ll~ through the Butler injection moulder has a much greater effect; two passes through the Brabender, followed by injection moulding to form capsules resulted in a 30% drop in polymer MW from 99084 CA 02202~10 1997-04-11 (MW) to 69699 (MW). A further two cycles reduced it to 49186"t,u,t:ber,li"g a 50% reduction from the inltial figure.
Addltional 2 or 4 cycles did not appear to reduce the MW any further although the figures are i, ICollSib~ Il. For the polymer DL-pLa/Ga 75:25 (RG756), 5 again multiple cycles through the Brabender reduced the molecular weight from 93323 to 82701 after 2 passes, a drop of 12%, and down to 73782 after 8 passes, a drop of d,U,UI UAil I Id~t:ly 25%. When capsules were moulded from these eAtruded polymers much more significant reductions were recorded. Moulding after 4, 6 and 8 Brabender passes dew ~dbed the polymer to 48%, 51% and 37%
10 of its original MW.
Table 8 Effect of Br.lLel~der cycles and injection moulding on polymer MW.
Polymer Bra~ender Initial MW MW MW
passes (pellets) (capsules) DL-pLa (R206) 2 (137000) 99084 69699 DL-pLa/Ga75:25 2 (93323) 87201 n.a.
(RG756) .
2. Injection~~ J~- ~
The technique for in3ection moulding the polymers and polymer blends using a Butler 10/60 Injection Moulding machine follows the same principles as 5 moulding cu~ . ,' Idl polymers. The polymers degrade readily when thermally u,uc~ssed and not having a stable e..~;,u,...,e:"l (temperature, humidity, etc.), the ûperation has required in-process u~Jtilll " I for each polymer blend. The automatic moulding cycle, including the operation of the four cavity capsule andlid moulding tool is as follows:

CA 02202~10 1997-04-11 1. Insert moulding pins into capsule cavitv in tool.
2. Close mould.
3. Position sprue puller pin on tool.
4. Inject polymer into mould.
5 5. Allow polymer to cool.
6. Retract moulding pins from capsule cavity in tool.
7. Open tool retract sprue puller pin after tool opens but before ejector plate is actuated.
8. Blow ejected moulding clear of tool.
Cycle times and moulding conditions.
The total cycle time of 10-20 seconds for the injection moulding process is dep~,d~"~ on the above cpe,d~iu''~ The main contributors to the cycle time being:
close mould 1 sec.
inject polymer 3-1û sec.
COOI 5-10 sec.
open mould 1-2 sec.
20 The cycle time for this process varies u~side~dbl~ de~e~ g on the individual polymer or polymer blend . l Idl d~.Lel i~lius. Polymer injection time as " ,~"liu"ed above can vary between 3-10 seconds and is largely det~:""i"ed by the melt viscositv of the polymer. This is further dependel ,l on polymer melt temperature and MW of the polymer. The following Table 9 gives an indication of the 25 conditions used in the injection moulding of the polymers.
Table 9 Typical ~ t settings forinjection moulding.
Feed zone Main heat zone Die temp.
amorphous polymer, 100-110C 145C 40-45C
eg R206, RG756, RG705 crystalline polymer, 170 185 55-60 eg L206, L210, L214 CA 02202~10 1997-04-11 WO 96/12466 = PCTIAU95/00707 EXAMPLE 2 F;le~- ' ty and R~p,. ' ' ~ Studies.
The initial tA,ud, i" ,~"l, involving 500 mice and 100 sheep and implants was co,,,,uùsed of the d,l-pLa R206, (samples LC, LD, LE, LF and LG). In this ~A,U~ lll, 5 batches of the same polymer (dl,-pLa, i.v. =1.0) plus additives 5 (0.5% ethyl citrate and 0.5% boron nitride) were prepared (B,dL~ d~r eAtrusion) and then injection moulded as individual batches. Samples for evaluation, both in vitro and in vivo, were collected s~hseq~Pnt to the run having "settled" to aconstant state of cl~yld~ldliuil.
The data from the t~ ,i",~"l indicak:
- intra-group variability (r~ y);
- inter-group variation (reprsr~ ); and - a lack of species speclficity for in vivo deyldddliun.
Overall, the data collected indicate good l-r ' ~ f and reproducabillty with minimal species-to-species variation. The physico-chemical datas (thermal and molecular weight analysis) collected from samples of implants from differentpositions, wlthin the same run and from the 5 dfflerent production batches indicated that the samples were, nominally, identical in fomm and structure.
Intra-run l-r ? ' ' "'y.
Capsules from batches of the run were separated into groups of 10 as they were moulded. Cu,,,,..d,iau,, of the available data from these batches indicatesa random distribution of release of dye wlth respect to time and position within the 25 run for each set of data.
- The conclusion from these data is that the intra-run distribution of release is random and that the I r ~ ' ~ / of the samples from this eA,ual i" ,~"l has been sufficient to prove the adequacy of the k~ 1uyy.

CA 02202~10 1997-04-11 Inter-run reproducability.
The second objective of this t~ ,i",~"l was to ascertain the ability to prepare implants with cu,, I,Udl dLIt: properties, physico-chemical and physiological, on a batch to batch basis. To eYaluate the variability 5 separate batches of 5 implants were prepared. The data was collected as a cumulative number of releases for each implant group against time for each of the runs in vitrû and in both mice and sheep.
The collected data indicated the following:
1û - the trend of releases is COlll,UdldlJIt: for the groups;
- there have been no failures (releases within 14 days of illllUldll~d~iull); and - there have been very few early releases (1% released prior to 70 days).
The data also indicate the following with respect to inter-run l-r Y;
15 - the trend within groups is culll~udldLle between groups (for both species);- the variability within groups, as measured by the standard deviation, is Cul~l,Udld~ between groups (for both species);
- with the mice, 4 of the 5 batches have exhibited cc,,,,,uc,,dl,le mean and standard deviation; and 20 - the 5 batches in sheep have shown good repr~dll ' "~y EXAMPLE 3 Delayed Pulsed Release of a Vaccine.
The subcutaneous implant delayed release delivery system of this invention was used to deliver Pasteurella multocida antigen to mice. Four groupsof 50 animals were used. The four groups consisted of:
Group 1 Non-vc~ ,i" ' -' controls no antigen;
Group 2 Vaccinated controls liquid priming dose only;
Group 3 Vaccinated controls liquid priming dose only delivered by the delayed release system;

CA 02202~10 1997-04-11 WO 96/12466 PCTlAU9~i/00707 Group4 Vac~i" ~ kstgroup liquid priming dose plus booster dose delivered by the delayed release system.
Mice in Group 1 were ad,, ,i, ,i~L~ d with a subcutaneous implant containing only an inert marker (Il.. I~,ylc.~ blue) at day zero. This group served the purpose of being both the negative control group and the indicator group for d~L~Illlilldliull of the time of release of the antigen.
1û Mice in Group 2 were a~lll;llia~ d~ by subcutaneous injection, a liquid priming dose of the antigen formulation on day zero. No booster dose was given to animals in this group.
Mice in Group 3 were dd~ ,L~ d, at day zero, with a priming dose of the15 antigen formulation within the delayed release implant delivery system. No booster dose was given to animals in this group.
Mice in Group 4 were ddlllilliaLt~ d, by subcutaneous injection a liquid priming dose of the antigen formulation at day zero followed by a booster dose 20 of the antigen formulation within the delayed release delivery system, also adlllilliaL~l~d at day zero.
The antibody levels of all mice were monitored by Enzyme Linked Immu"ùsu, Jel 11 Assay (ELISA) for 47 days. At day 52, the mice were ul l ~ged 25 with live Pasteurella multocida (d,~J,JlUAil 'y 5x105 ~lydllialll:~lmouse)~ Mice were monitored for survival and blood antibody levels (by ELISA) for a further 3û
days (not all data presented). The results are presen~d in Table 10.

=
CA 02202~10 1997-04-11 Table 10 Reaponse to P~.~ft..,~ " antigen Group # Time for ~ ' ' " (days`

% S~u~ iu~ % Survival The mean delay time for the materials used in production of this speclfic delayed release delivery system was 18 days with a standard deviation of three days (based on release of an inert marker in the Group 1). Less than 10% of 5 mice in Group 1 gave a positive ELISA result over the time of the c~e,i",c"l.
None of the mice in this control group survived the challenge with the live organisms.
In Group 2, sc~u~ iui~ was observed in 22% of the mice at 33 days 10 after immunisation. 18% of the animals in this control group survived the challenge with the live ~Iydlli~
Mice in Group 3 showed sclu~,ull~ ;ûll in 24% of the animals 33 days after immunisation. This compares with the results obtained for Group 2. 18%
15 of the animals in Group 3 survived challenge.
70% of mice in Group 4 had se~uw"-crted at 33 days. 58% of the animals in this control group survived the challenge.
20 EXAMPLE 4 Delayed Pulsed Release of Allll, ' from an l"l,~ ' Bolus.
Abamectins and ivermectins are macrolide antibiotics well known for their use in livestock as dl~t;udldalti. or dlllilCIlll;lll;. agents. In particular, use against nematode worms and el-d~"~aldai~cs and e- lU~Jdld` :~ has been a specific area CA 02202~10 1997-04-11 of,, ' ~ ~. Prolonged exposure of the parasites to dlllll~llllillLi~,~, often atsublethal doses, has resulted in selection of resistant parasites. Adverse er.,~;.ulllllelltdl consequences have also arisen. The effectiveness of, ~' ' of these d~ I,i, ' could be extended by delayed release, the most preferred 5 de~ivery system being one that can produce a pulsed release at periodic intervals 51 Ih5~rjl IPrlt to a~ libll dliul 1.
The delayed release delivery system of this invention was used to deliver an dlllll~ ll;l " orally to cattle. Five Hereford heifers, d~J,UlU,~ 2 years of age, were adll,;"i~ d a bolus by a ~llllll~luidl balling gun. The bolus contained a test formulation of the dl Itl ,~I~ "i"t;~, in a device that fitted tightly within the cage portion of the bolus device. The five animals selected had moderak ga~Llui,d~:~Li~dl nematode egg counts of 18û to 3ûû eggs per gram (epg) of faeces. Faecal samples were collected before treatment (day zero) and 15 p~liud;u.~l ~ after treatment to monitor changes in faecal egg counts.
A modified McMaster technique was used to estimate faecal egg counts.
Faeces (4 gm) were mixed with 6û ml saturakd NaCI (SG 1.16). vVhen 1 chamber (û.5 ml) of the McMaster slide was counted, sensitivity was 3û epg; if 20 2 chambers were counted, it increased to 15 epg. Observed Faecal Egg Counts (FEC) are presented in Table 11.

CA 02202~10 1997-04-11 Wo 96/12466 PCT/AUs~/00707 Table 11 I~ Faecal Egg Counts recorded in calves following ~ ' t,lionof;.-t.a,. ` 'boluscor,L;.,- 3an,:~.~' Calf # Days after bolus devir,e was ~

Mean= 290 250 730 265 165 225 280 42 105 0 Between days zero and 12, all five calves Illa;lltd;lled low to moderate FECs. Sllhseq~l~nt to day 12, the following observations were made:
5 (a) the FEC had dt~ ased to 0 in one animal by day 17;
(b) the FEC had de~ as~d to 0 by day 25 in a further two animals;
(c) the FEC had de~ dsed to 0 in a further animal by day 28;
(d) the FEC had d~ d~,e~ to 0 in a fifth animal by day 35.
A zero FEC was observed at the mean time of 26 days with a standard deviation of 6 days. The observed time for a drop in the FEC from 180 to 300 epg to ~ero epg, in such animals, is a~ y 4 days (data not presented).
This data indicates that the mean time of a release of the d"ll,el~";"t;~. test formulation from the device was 22 days with a standard deviation of 6 days.

Claims (27)

CLAIMS:
1. A controlled release container comprising:
an outer shell, at least a portion of which comprises a biodegradable polymeric material having a predetermined rate of degradation; and a core enclosed by said outer shell, said core comprising at least one bioactive molecule as an active ingredient optionally admixed with one or more pharmaceutically or veterinarily acceptable carriers and/or excipients;
said portion of said outer shell providing a predetermined delay in the time period of release of said active ingredient.
2. A container according to claim 1, wherein said polymeric material degrades when in contact with bodily fluids, said degradation comprising reduction in molecular weight of the polymeric material to a predetermined value during said predetermined delay, wherein said degradation is sufficient to release said active ingredient after said predetermined delay.
3. A container according to claim 1, wherein said predetermined delay is at least two days after administration.
4. A container according to claim 3, wherein said predetermined delay is at least four days after administration.
5. A container according to claim 4, wherein said predetermined delay is at least two weeks after administration.
6. A container according to claim 1, wherein said biodegradable polymeric material is a polyester, a polyamide or a polysaccharide.
7. A container according to claim 6, wherein said biodegradable polymeric material is a polyester selected from the group consisting of polylactide, polylactide-polyglycolide and polyhydroxybutyrate-polyhydroxyvalerate polyesters.
8. A container according to claim 7, wherein the biodegradable polymeric material is a polylactide-polyglycolide copolymer.
9. A container according to claim 1, wherein the outer shell is formed by melt processing.
10. A container according to claim 9, wherein the outer shell is formed by injection moulding.
11. A container according to claim 1, wherein said portion of said outer shell is non-porous.
12. A container according to claim 1, wherein said polymeric material has an initial molecular weight of less than 200,000 and a molecular weight of 10,000 or less at the end of said predetermined delay.
13. A container according to claim 1, which has an elongate or generally cylindrical shape.
14. A container according to claim 13, which is formed as an implant device, or as part of an implant device.
15. A container according to claim 1, which is in the form of a two-part capsule, wherein one part is biodegradable and the other part is non-biodegradable or biodegradable at a different rate.
16. A container according to claim 1, which is in the form of a capped tube, cylinder or rod, wherein either the cap or the tube, cylinder or rod is biodegradable and the other is non-biodegradable or biodegradable at a different rate.
17. A container according to claim 1, wherein the entire outer shell comprises said biodegradable polymeric material.
18. A container according to claim 1, wherein the active ingredient in the core enclosed by the outer shell comprises one or more bioactive molecules selected from the group consisting of antigens, antibodies, antitoxins, nucleic acids, vaccines, cytokines, growth promotants, hormones, cancer cell inhibitory molecules or agents, immune stimulants or suppressants, anti-inflammatories, anti-microbial agents including antibiotics, anti-viral agents, anti-parasitic agent, vitamins, tonics or stimulants, minerals and inorganic or organic nutrients.
19. An outer shell for a controlled release container, at least a portion of said outer shell comprising a biodegradable polymeric material having a predetermined rate of degradation, said portion of said outer shell providing a predetermined delay in the time period of release of the contents of a core enclosed by said outer shell.
20. An outer shell according to claim 19, wherein said portion of said outer shell is non-porous.
21. A method of administering an active ingredient to a human or other animal in a controlled release regime, which comprises administering to said human or other animal a controlled release container according to any of claims 1 to 18, wherein said core of said container comprises said active ingredient.
22. A method according to claim 21, wherein said container is administered by oral ingestion or by injection via the intraperitoneal, intramuscular, subcutaneous or intradermal route.
23. A method according to claim 22, wherein said container is in the form of an implant device, and is administered subcutaneously.
24. A method according to claim 22, wherein said container is incorporated into a weighted capsule or bolus and is administered orally.
25. A method for the production of a controlled release container, comprising the steps of:
(i) producing a hollow outer shell by melt processing, at least a portion of said outer shell comprising a biodegradable polymeric material having a predetermined rate of degradation and providing a predetermined delay in the time period of release of the contents of a core enclosed by said outer shell;
(ii) inserting a core into said outer shell, said core comprising at least one bioactive molecule as an active ingredient optionally admixed with one or more pharmaceutically or veterinarily acceptable carriers and/or excipients; and (iii) sealing said core within said hollow outer shell.
26. A method according to claim 25, wherein said biodegradable polymeric material is a polyester, a polyamide or a polysaccharide.
27. A method according to claim 26, wherein said biodegradable polymeric material is a polyester selected from the group consisting of polylactide, polylactide-polyglycolide and polyhydroxybutyrate-polyhydroxyvalerate polyesters.
CA002202510A 1994-10-25 1995-10-25 Controlled release container with core and outer shell Abandoned CA2202510A1 (en)

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WO1996012466A1 (en) 1996-05-02
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US5916584A (en) 1999-06-29
NZ294546A (en) 1999-04-29

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