CA1045977A - Biodegradable, implantable drug delivery device, and process for preparing and using the same - Google Patents
Biodegradable, implantable drug delivery device, and process for preparing and using the sameInfo
- Publication number
- CA1045977A CA1045977A CA199,552A CA199552A CA1045977A CA 1045977 A CA1045977 A CA 1045977A CA 199552 A CA199552 A CA 199552A CA 1045977 A CA1045977 A CA 1045977A
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- Prior art keywords
- poly
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- implant device
- amino acid
- substance
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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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61D—VETERINARY INSTRUMENTS, IMPLEMENTS, TOOLS, OR METHODS
- A61D7/00—Devices or methods for introducing solid, liquid, or gaseous remedies or other materials into or onto the bodies of animals
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
- A61K9/2045—Polyamides; Polyaminoacids, e.g. polylysine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
- A61M31/002—Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time
-
- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0092—Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Anesthesiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Neurosurgery (AREA)
- Dermatology (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Medicinal Preparation (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
An implantable drug delivery device comprising a matrix formed of a poly-.alpha.-amino acid having one or more drugs and/
or diagnostic agents physically admixed therein. The drug or diagnostic agent is released by action of enzymes, present in the host in which the implant is placed, on the polymeric matrix material. The implant device may be designed to release the drug or drugs at predetermined rates and in predetermined sequences.
An implantable drug delivery device comprising a matrix formed of a poly-.alpha.-amino acid having one or more drugs and/
or diagnostic agents physically admixed therein. The drug or diagnostic agent is released by action of enzymes, present in the host in which the implant is placed, on the polymeric matrix material. The implant device may be designed to release the drug or drugs at predetermined rates and in predetermined sequences.
Description
;977 This invention relates to a new form of pharmaceutical preparation and more particularly to a biodegradable implant adapt-ed to be located within a specified region or organ of the body of a livin~ organism for ~eleasing one or more substances ~e.g., drugs or diagnostic agents~ at a controlled rate'for localized or systemic utilization.
Background of the In~ention In the administration of drugs and in the diagnosis of certain pathological conditions it is highly desirable, if not necessary, to effect a controlled release of one or more sub-stances within the livin~ organism, in particular w;thin a mam-malian host. For example, the controlled release of drugs (a term used hereinafter to include all substanees which efect some biological response~ over a period of time within a speeified region or organ of the body can be used as a continuous dose, long-term delivery system for sueh agents as antibiotics, eardio-aetive medicaments and fertility control agents. Likewise, the implantation of a dia~nostic substanee sueh as a dye can be used to monitor the presenee or absenee of a pathological condition. ' Field of the Invention ~ ' Continuous, long term drug delivery systems have dis-tinet advanta~es over oral or direct injeetion introduetion sinee neither of these earlier developed modes ean aehieve a desired blood level of a drug in eireulation for an extended period of time. Oral administration or direet injeetion bring about a ' pulse entry of the drug whieh may ereate drug eoneentrations be-yond the capaeity of the active centers to aeeept it, and may also exeeed the eapaeity of the metabolie and exeretory meehanism ~
of the living organism. Thus~ if the level of the drug remains '`
:'~
-3- ~ ~
5~77 elevated, tissues and~or organs may sustain dekrîmental effects.
One technique for reducing excessive concentrations has been to modify the drug structure to pro~ide a longer metabolic half-life; but this in turn has frequently demonstrated lowered thera-peutic e~fectiveness. -To avoid the disadvantages of oral or direct injection administration of dru~s, a number of modes of administration of continuous dose, long-term delivery systems have been used or proposed. These include systems ~ased upon ingestion, injection, vaginal and uterine insertion, percutaneous application (see for e~ample U.S. Patents, 3,598,122 and 3,598,123~ and subcutaneous implantation. While all of these routes of administration may be found useful under one set o~ circumstances or the other, the use of subcutaneous implants offexs a particularly desirable combination of properties to permit the administration of sub-stances on a localized or systemic basis. To this end, sub-cutaneous implants serving as depots capable of slow release of a drug have been proposed. These implants suggest the possibility of attaining continuous administration over a prolonged period of time to achieve a relatively uniform delivery rate and, if de-sired, a static blood level. Since an excessive concentration of drug never enters the body ~luids, problems of pulse entry are `~
o~ercome and met~bolic half-life is not a ~actor of controlling importance.
Despite the advantages of administering drugs from implants, prior art devices designed for this purpose, in which diffusion processes control the rate of release, have been unable to pxovide continuous administration and constant delivery rate and have introduced ancillary problems. If the implant, after ~0~97~
discharging its dru~ conten-t, remains as a matrix structure, then it may have to be remo~ed ~y a surgical procedure to prevent its possible migration to sensitive areas or organs of the body. On the other hand, if the implant is of such a nature that the drug- ;
carrying substrate is absorbable by the host into which it is placed, then there occurs the likelihood that the substrate will introduce undesirable, and even harmful, su~stances into the ~ody.
Description of the Prior rt In the prior art, a number of nonabsorbable materials of construction and several dif~erent structural designs have been proposed for subcutaneous implants. Such materials as hydro-gels, gelatin, carboxymethyl cellulose, polyurethanesj waxes, pol~vinyl alcohol, polyglycolic acid, and polylactic acid have been suggested for this purpose. However, organopolysiloxane rubbers as carriers for the controlled release of drugs, have probably received the most ~idespread use. The use of these so-called "silicone rubbers'l is described ;n U.S. Patent 3,279,996.
Implants which use any of these materials as substrates or carriers which are not absorbable by the living organism into which they axe introduced normally re~uire removal ~y surgery. The silicone ~
rubbers are among the nonabsorbable materials and therefore they `
suffer from this drawback. Typically, implants ~ormed of silicone rubber, or of any of the other above-named materials have been fabricaked either in the form of closed hollow tubes or capsules (with or without a sponge sleeve~ in whîch the drug is contained fox dif~usion through the tube walls; or they have ~een made up into structures of homogeneous polymer-drug ~lends.
Some work has been reported (see for example ~ablon, PoA~M~ ~ Ph.D. Thesis, Purdue University, 1969~ on implants formed ~O~S~7~
by chemically bonding drugs to polypeptides. This approach neces-sitates providiny a dru~ having a reactive site amenable to chem-ical boncling to the polypeptide; and it also ;ntroduces the danger that in the breaking o~ the chemical bond to release the drug the effectiveness and acceptability of the drug to the system may be materially altered. Moreover, the drug-polypeptide complex will, in fact, represent a new dru~ of unknown properties. Finally, an implant in which the drug is chemically bonded to the matrix material can not release the drug from the matrix by the process of diffusion, since release is predicated on the actual breaking of chemical bonds.
U.S. Patent 3,493,652 teaches the incorporation of medicaments such as cardioactive, adrenerg~c, choliner~ic, anti-spasmodic and curariform agents, tranquilizers, antihistamines, antibiotics and the like into a matrix which contains one or more enzymes or enzyme precursors capable of digesting the matrix material which, in turn, may be formed of such diverse materials as casein, fibrinogen, proteins, polypeptides with free amino groups, urea and amino acids. The dosage formulation may take many different forms including suspensions, emulsions, tablets (sublingical, buccal, oral or vaginal), capsules, ointments, suppositories and implants. When such a controlled release medicament is introduced into a living organism it must, of nec-essity, introduce both the substrate material and enzyme into the system and one or both of these may be antagonistic to the system.
In particular, to introduce those enzymes which are not normally present in the living organism may result in harmful side effects.
Moreover, enzymes are known to degrade or denature and this pro-cess may take place prior or subsequent to the administration of 7~
the dosage. In the fi~s-t c~se, the effectiveness o the dosage-contained enzyme is lessened or even cancelled; and in the second case, premature enzyme degradation could materially alter or even destroy any control over the dru~ release rate.
An implantable drug delivery system which overcomes at least a number of the disadvantages associated with the prior art has been proposed. (See Contract DADA-17-72-C-2079 to Dyna-tech Rese~rch and Development Co., by U.S. Army Medical Research and Development Command, Washington, D.C. (1972~. This delivery system consists of a polymer matrix in which the drug is physic-ally entrapped. The drug is released, not by diffusing through a polymeric membrane, but by hydrolytic breakdown of the polymer matrix itself. As the polymeric matrix disintegrates, the enclosed drug is released into the surrounding body fluids. By the time ` all of the drug has been released from the matrix, the polymer fxagments have been almost completely absorbed.
The polymeric materials proposed for this device are polyesters (e.g., polylactic acid and polyglycolic acid~ having low toxicity, lo~ drug permeability and slow rates of hydrolysis to form metabolizable fragments (e.g., lactic acid and glycolic acid~. EIowever, these polymers hydrolyze at a rate that is highly dependent upon both pH and degree of crystallinity. Since the products o~ hydrolysis reactions are acids, there is a tendency ;~
for the products that do not immediately diffuse away from the ~ -implant site to inhibit further hydrolysis. In addition, the crystalline re~ions degrade at a much slower rate than the amor-phorus regions, thus gi~ing rise to a nonuniform degradation pattern and a porous structure from which the drugs may be released at an uncontrollable rate.
5~ 7 It will thus be apparent from this di~cussion of the prior art that implants for controlled drug release have distinct theoretical advantages; but that there is a need for an improved implant device to achieve a continuous dose, controlled release of drugs or other substances which overcomes the major disadvantages (i.e~, dif~iculty in continuously controlling the release of the drugs, production of unwanted degradation products and/or the need for surgically removing the implanted matrix~ associated with the presently available implant devices.
Ob~jects_of the Invention It is therefore a primary object of this invention to provide an improved implant device for achieving continuous dose, controlled-release of drugs or other substances such as diagnostic agents. It is a further object of this invention to provide an implant device of the character described which may be biocompat-ible and biodegradable to form amino acids and/or amino acid com-plexes already present in the organism into which the implant is placed, thus eliminating the introduction of foreign or antagonistic substances and at the same time eliminating the need of surgical procedures to remove a matrix structure. An additional object of this invention is to provide an improved implant device which exhi-bits improved re.lease rate control, the rate of release being op-tionally constant or at some predetermined changing rate. Another object is to provide an implant device which relies upon one or more enzymes normally present in the living organism to release one or more drugs continuously, or upon one or more enzymes which are only present under certain pathological conditions to release one or more drugs and/or diagnostic indicators when such patholog-ical conditions are present. It is yet a further object of this invention to provide an impro~ed implant device which may ~e used -~
.: . , ~0~5~77 to deliver a wide range of drugs or other a~ents, including twoor more drugs simultaneously or serially.
It is another prlmary object of ~his invention to pro-vide a process for forming a biodegradable implant device in various configurations to attain controlled drug release at a constant or varying release rate and to attain the release of two or more drugs either simultaneously or serially. Another object of this invention is to provide a process of the character described which is amenable to the formation of an implant device to deliver a wide range of drugs and other substances such as diagnostic agents.
Still another primary object of this invention is to provide an improved process for the continuous, rate-controlled delivery of drugs and/or other substances into selected areas or organs of living organisms in a manner to minimize or elimi-nate the introduction of any substance, other than the drug or other agent, not normally present in the organism.
Other objects of the invention will in part be obvious and will in part be apparent hereinafter.
Sùmmary of the Invention According to this invention there is provided an im- ' plant device for the controllable release o at least one sub-stance into a living host into which it is implanted, comprising a matrix structure having the substance to be released physically admixed therethrough, at least a major portion of the matrix structure being formed of poly-~-amino acid whereby the substance is released by diffusion, by the hydrolysis of the poly-~-amino acid by one or more enzymes present in the host or by a combina-tion of diffusion and hydrolysis. The degradation products, 30 i.e., amino acids, are metabolized or excreted by the organism '`
.,.~'~' . .~ .... . ...... ' ,.
45~7~
during and/or a~ter rel~ase of the sub~tance. The implant may be in the form of a ~ilm, rod, fibex, hollow cylindex and the like; and it may have the drug 80 distributed as to provide a constant or a changing rate of release. The poly-a-amino acid may be a homopolymer or copolymer of two or more amino acids;
and it may be chosen as to be biodegradable through action of one or more enzymes which are normally present in the living organism or through action of one or more enzymes developed by a pathological condition thus effecting the triggering of the release only upon certain predetermined conditions.
The biodegradable implant of this invention is formed by blending the substance to be controllably released with the poly-~-amino acid thereby to form a physical mixture; and fabri-cating the physical mixture into a structural configuration suit-able as an implant device. The implant is then placed within the living organism by any suitable known technique.
The invention accordingly comprises the several steps and the relation of one or more of such steps with respect to each of the others, and the article possessing the features, properties and the relation of elements, which are exempli~ied in the following detailed disclosure, and the scope of the in-vention will be indicated in the claims.
Brief Description o~ the Drawin~s For a fuller understanding of the nature and objects of the invention, reference should be had to the following de-tailed de~cription taken in connection with the accompanying drawings in which Fig. 1 illustrates an essentially "two-dimensional"
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implant device designed to achieve a constant rate of drug release;
Fig. 2 illustrates an implant devic~ in the form of a rod or fiber designed to achieve a decreasing rate of drug release;
Fig. 3 illustrates an implant device in the ~orm of a hollow cylinder designed to achieve a near constant rate of drug ' release;
Fig. 4 illustrates an implant devîce in the form of a layered rod in which the drug concentration is different from its adjacent layer or layers to achieve a predetermined rate of drug release; and Fig. 5 illustrates an implant device in the form of a rod with a core containing a drug different from the surrounding layer.
Detailed Description o~ the Invention The biocompatible, biodegradable implant device of this invention is formed as a structure in which the drug or other releasable substance to be delivered is physically distri-buted through a matrix. In the following description and claims the term "drug" is used in its broadest sense and it includes any substance which has any biological activity r whether such activity is medicinal or otherwise. For convenience in present-ing this detailed description, the implant will be descri~ed in terms o~ containing a dr~g, although it is to be understood that it may also contain a diagnostic agent such as a releasable dye ' which has no biological activity per se. Thus, in its broadest sense, the implant may be defined as containing a releasable sub- ' stance, which may or may not exhi~it biological activity.
The matrix, throughout which the drug is distributed for release, is one or more poly-~-amino acids having low toxicity -11- .
~04~9~77 and being biodeyradable Ln VLVO through enzymatic hydrol~sis to form amino acids. The poly-a-amino acids may be further generally characterized as thermoplastic re~ins inert to the drugs contained, and soluble in selected solvents.
Poly-~-amino acids are synthetic polymers composed of a-amino acid residues linked by peptide bonds. They have been extensively studied r particularly with relation to the structure of the polypetide chain and its susceptibility to hydrolysis by proteolytic enzymes (see for example C. H. Bam~ord, ~. Elliott and W. E. Hanby, "Synthetic Polypeptides," Academic Press Inc., New ~ork, 1956, pp. 113-425~. The ~iological properties of poly-petides have also been extensively investigated ~see for example M. A. Stahman, Ed., "Polyamino Acids, Polypeptides, and Proteins,"
The University of Wisconsin, 1962, Part ~, pp 283-385~.
Synthetic techniques have been developed -Eor forming ` homopolymers, random copolymers, ~lock copolymers, multi-chain polymers and polymers containing a predetermined sequence of amino acid residues from a-amino acids.
Homopolymeric poly-~-amino acids may be represented as ~ HN-CHCO~
Rl n wherein Rl is a side chain characteristic of the common, well-known amino acids, including, but not limited to -~I, -CH3, -CH2COOH, -CH2-SH, -CH2- ~ , -CH2-OH, -CH2-C ~ , and the like. ;
~N
The poly-~-amino acid copolymers are composed of two or more ~-amino acids distributed at random along the polymer chain; and they can be represented, as for example, as .. ,.. ,, , , ......... . :
, , . . . - ~ , . , Si977 -HN-CH-CO-~CH-CO-HN-CH-CO-EIN-CH-Rl R2 R2 R2 ' where Rl and R2 are di~ferent and are chosen from the groupings given above for R~
Block copolymers are also known and can ~2 represented generally as ~HN-CHCO ~ HN-fH-Co3 Rl m R2 n where Rl and R2 are different and are chbsen from the grouping given for Rl and m and n range generally between one and one hund-red. The poly-a-amino acids may be synthesized to have a wide range of average molecular weight, e.g., from 103 to 106, and the matrix material may be formed of a mixture of polymers have dif-ferent molecular weights.
Although a number of derivatives of a-amino acids and peptides have been used as monomers for the preparation of the poly-a-amino acids, the most commonly used monomers are the N-carboxy-~-amino acid anhydrides represented as R
/ CH \
HN C=O
O=C--O
where R is chosen from the same groupings as given for Rl above.
The polymerization technique may be either the well-known bulk or solution polymerization process. Bulk polymerization is usually carried out at elevated temperatures and yields polymers with reIatively low avera~e molecular welghts. Solution poly-~04~977 :~
merization, on the other hand, may be perormed at low temperatures, it .is easily controlled and can result in relatively high mole- ~
cular weight polymers. Inert solvents such as dioxane, dimethyl- ; .:
formamide and nitrobenzene may be used with such polymerization : -~
catalysts as primary, secondary or tertiary amines, or strong ~ases :~ -such as sodium methoxide or sodium hydroxide. The use of ter-tiary amines or sodium methoxide as initîators are preferred for the preparation of poly-a-amino acids with average molecular ~eights of 20,000 to 1,000,000. The primary and secondary amines have been found useful in.preparing intermediate molecular weight .
polymers, e.g., 103 to 104.
Almost all of the amino acids occuring in proteins have been prepared in homopolymeric form. The follow;ng are repre- .
sentative amino acid which have been polymerized and solvents for the polymers amino acid solvents ~
L-Alanine dichIoroacetic acid, trifluoroacetic : `
acid Glycine dichIoroacetic acid, trifluoroacetic acid, concentrated aqueous LiBr L-Leucine trifluoroacetic ac;d L-Lysine ~ater L-Methionine chloro~orm, dichloroacetic acid L-Phenylalanine 33~ HBr in glacial acetic acid L-Proline water, acetic acid L-Valine tri~luoroacetic acid.
In yeneral, the copolymers exhibit solu~ility ;n common or~anic solvents such:as chloroform, ~enzene and diozane, and they ~enerally possess improved phy ical characteristics, such as impr.o~ed malleability and greater elongation to break, than . ' .... :
597~
the homopolymers, thus making them preferable in the practice of this invention. Exemplary oE such copolymers are those ~ormed y-benzyl-L-glutamate and leucine following the procedure of Blout and Karlson (see J. Amer. Chem. Soc. 78, 941 (1956~. These co-polymers have molecular wei~hts in excess of 50,000 and have the desirable film forming and mechanical properties. It may also be desirable to add a minor quantity of a monomer other than an a-p~/s/~a ~
w~ amino acid to contribute desired plupiaal properties.
The poly-a-amino acids used as the matrix material in ~ 10 the implant devices of this invention must have sufficient ;~ mechanical strength to be formed into such structuxes as films, .~ -, .
-~; rods, fibers, and hollow cylinders. As examples, the dimensions ~or a film implant may be about 2 cm by 2 cm and 0.05cm thick, and the diameter of a fiber or rod may be about 0.5cm. The poly- `
a~amino acids must also be of a type which lend themselves to formation into such structures by known synthtic resin fabrica-tion techniques as described below.
A wide range of drugs may be incorporated into these ~; l synthetic polymer matrices to form the implant devices of this invention. Such drugs include, but are not limited to, fertility control agents such as estradiol valerate, medroxyprogesterone acetate, and hydroxyprogesterone caproate, anticoa~ulants such as heparin or ethylenediaminetetraacetic acid, antibacterials, antibiotics, antineoplastic agents, cardiovascular agents such as digitalis, quinidine and nitroglycerine, immunolog;cal agents, central nervous system stimulants and depressants, antidiabetic agents, and the like. Diagnostic agents such as dyes ~e.g., ; bromsulphalein~ may be incorporated for implantation at a site where enzymes, formed as a xesult of a pathological condition to :` ` , , ; ::
- :: .
l~S~77 , ..
be detected, are available for the hydrolysis o~ the matrix mater-ial. The release of such diagnostic agen~s brought about by the presence of the patholo~ically-induced enzyme may be detected in the body fluids, e.g., the urine to indicate the presence of the pathological condition being monitored.
The quantity of the drug or drugs or of diagnostic agent incorporated into the poly-a-amino acid matrix will depend upon the rate it is to be released, which in turn will depend upon the diffusion rate of the drug and upon the rate at which the poly-mexic matrix is hydrolyzed by one or more enzymes. Actual con-tinuous dosage rates may be determined in vitro using the enzymes to be encounted in vi~o in the biodegradation of the matrix poly-mer and release of the drug or diagnotic agent contained.
In the process of forming the implant device according to this invention, the drug (or diagnostic agent~ is blended with the polymeric matrix material and then the resulting physical mixture is fabricated into the desired structural shape.
Blendin~ may be done by one of several tecniques. The first of these comprises forming a solution of the polymeric matrix material and adding the drug to the solution. If the solvent or solvent mixture used to form the solut;on of the matrix is also a solvent for the drug, then a homogeneous solu-tion may be formed. If the solvent system is not a solvent for the dru~, then the drug may be dispersed as fine particulate mater-ial r as a liquid, or in other suitable form, throughout the poly-mer solution using, if necessary, a high-shear m;xer to obtain a homogeneous suspension. The solution or suspension thus formed may be cast into films or ribbons such as ;llustrated in Fig. l which illustrates an implant lO hav;ng essentially but two dimen-~ ,:
~:
,, ~04~'37~
sions, width and leng-th. SolYent and casting conditions are chosen to prevent any appreciable segregation of the drug and polymer when the solvent is removed. The flat, essentially two~
dimensional implant 10 of Fig. 1 exhibits a relatively constant surface area over its useful life within a living organism and hence it may be used to administer a relatively constant dose rate. The film or ribbon form of implant is not, however, par- ;
ticularly amenable to administration by trocar, a fact which means that surgical implantation procedures may be required.
Another blending technique may comprise mixing the drug with the dry polymeric matrix material in powdered form and then forming the desired structural shape with heat and pressure, the fabrication conditions being such as not to destro~ the efficacy o~ the drug or to degrade the matrix material. The blend of drug and dry polymeric matrix material may be injection molded, compression molded or extruded into three-dimensional shapes of a required design.
Extrusion of such a blend may be used to form fibers or rods such as shown in Fîg. 2 which illustrates a solid rod-shaped implant 11. Such a rod-shaped implant, as the poly-~-amino acid matrix is degraded through action of the enz~mes pre-sent in the host into which it is implanted, will expose a con-stantly decreasing surface area and hence will release the drug at a decreasing rate. Under those circumstances where this is ;
desirable, the rod- or ~iber-shaped implant of Fig. 2 may be used without further modification.
Since a rod- or fiber-shaped implant is desirable for administration by means of a trocar, it may ~e desirable to modif~ this implant configuration to obtain a constant drug ~ S977 release rate, or a release rate which does not decrease as rapidly as the implant 11 of Fig. 2. Figs. 3 and 4 illustrate two exemplary modifications of a rod-shaped implant. In Fig. 3 the implant 12 is constructed as an open cylinder having an ex-ternal surface 13 and axial opening defining an internal sur-face 14. Since the surface axea of external surface 13 will decrease and that of internal surface 14 will increase as the ~mplant is degraded, the rate of drug release may be held con-stant, or it may be increasing or decreasing depending upon the relative rate at which the surface areas of surfaces 13 and 14 de-crease and increase.
In the modification of F1g. 4, the implant device 15 is formed of multiple la~ers as exemplified by layers 16, 17 r 18 and l9, the last se~ving as a core. In this implant, each layer has a drug concentration different from that of an adja-cent layer or layers. If these drug concentrations are arranged to provide a concentration gradient which increases from the outermost layer 16 to core l9, a constant drug release device ;
may be formed in rod form. In forming the rod implant 15 of Fig. 4, the multiple la~ers may be coextruded using well deve-loped techniques. If desired, the concentration gradient profile from the rod center to its external surface may be smoothed by annealing the extrudate at a temperature slightly below the melt temperature of the polymeric matrix material so that thermal diffusion of the drug is effected. An alternative procedure for forming the multilayered implant with a drug concentration gradient is to ~orm a core and coat it with successive layers of a polymeric matrix solution containing the drug dissolved or dispersed therein. It is, of course, also within the scope of S~7~
this invention to ~orm a multila~ered implant such as 15 of Fig. 4 by ~ combination o~ techniques, e.g., extrusion and coat-ing; and -to make multilayered implants wherein the drug concen-tration as well as the poly-~-amino acid matrix differs from layer to layer.
Under some circumstances, it may be desirable to release two different substances în series. For example, in the implant 20 of Fig. 5, the outer layer 21 may contain a diagnostic agent which, when released throu~h action of a patholo~ically- -developed enzyme, will indicate an abnormal situation and then after giving such warning ~ill release one or more drugs from ~`~ ?
core 22. The implant embodiments of Figs. 4 and 5 may also be used to release more toxic drugs or more toxic dosages if the system does not respond to the first drug or dosage released. It will thus be apparent that a large number of embodiments of the multilayered implant are possible to meet different needs.
The implant devices of this invention may be located in or near an organ of the body, or they may be implanted sub-dermally, e.g., in the forearm or sublingually. They may also be administered as uterine or vaginal inserts. The location of the implant will determlne the enzymes which will be present to ef-fect the biode~radation of the poly-~-amino acid matrix and hence will determine the composition of the matrix material. The pro-teolytic enzymes ~ithin the mammalian system include, among others, prolidase, prolinase, thrombin, renin, carboxypeptidase A, pro~ ;;~
line, iminopeptidase, pepsin, trypsin, chymotrypsin, leucineamino-peptidase, carboxypeptidase B, and cathepsin C.
The poly-~-amino acid drug delivery system of this in-vention, ~hen implanted in the body, ~ill be exposed to a multi-.~ . . ~ . . . - . .
~34~5i9~
plicity of pro-teolytic enzymes, all of ~hich are capable of forming enzyme-substrate complexes~ As noted above, the poly~
amino acid substrate (matri~ is chosen according to the location ~ ~' of implant and the reactive enzymes present at that location. ~;
The effect o~ selected enzymes on selected poly-a-amino :~
acids is shown below: :
Enzyme Poly-~-amino acid Eff ct Trypin poly-L-ornithine resistant poly-D-lysine resistant poly-L-lysine hydrolyzed copol-(L-lysine: L-glutamic acid, 1:4) resistant copol-(L-lysine: L-glutamic acid, 1:1) sl. hydrolyzed copol-(L-lysine: L-tyrosine, 3:1) sl. hydrolyzed Chymotrypsin poly-L-glutamic acid resistant poly-L-tyrosine resistant poly-L-phenylalanine resistant poly-L-tryptophan resistant copol-(L-lysine: L-leucine: L-tyrosine,
Background of the In~ention In the administration of drugs and in the diagnosis of certain pathological conditions it is highly desirable, if not necessary, to effect a controlled release of one or more sub-stances within the livin~ organism, in particular w;thin a mam-malian host. For example, the controlled release of drugs (a term used hereinafter to include all substanees which efect some biological response~ over a period of time within a speeified region or organ of the body can be used as a continuous dose, long-term delivery system for sueh agents as antibiotics, eardio-aetive medicaments and fertility control agents. Likewise, the implantation of a dia~nostic substanee sueh as a dye can be used to monitor the presenee or absenee of a pathological condition. ' Field of the Invention ~ ' Continuous, long term drug delivery systems have dis-tinet advanta~es over oral or direct injeetion introduetion sinee neither of these earlier developed modes ean aehieve a desired blood level of a drug in eireulation for an extended period of time. Oral administration or direet injeetion bring about a ' pulse entry of the drug whieh may ereate drug eoneentrations be-yond the capaeity of the active centers to aeeept it, and may also exeeed the eapaeity of the metabolie and exeretory meehanism ~
of the living organism. Thus~ if the level of the drug remains '`
:'~
-3- ~ ~
5~77 elevated, tissues and~or organs may sustain dekrîmental effects.
One technique for reducing excessive concentrations has been to modify the drug structure to pro~ide a longer metabolic half-life; but this in turn has frequently demonstrated lowered thera-peutic e~fectiveness. -To avoid the disadvantages of oral or direct injection administration of dru~s, a number of modes of administration of continuous dose, long-term delivery systems have been used or proposed. These include systems ~ased upon ingestion, injection, vaginal and uterine insertion, percutaneous application (see for e~ample U.S. Patents, 3,598,122 and 3,598,123~ and subcutaneous implantation. While all of these routes of administration may be found useful under one set o~ circumstances or the other, the use of subcutaneous implants offexs a particularly desirable combination of properties to permit the administration of sub-stances on a localized or systemic basis. To this end, sub-cutaneous implants serving as depots capable of slow release of a drug have been proposed. These implants suggest the possibility of attaining continuous administration over a prolonged period of time to achieve a relatively uniform delivery rate and, if de-sired, a static blood level. Since an excessive concentration of drug never enters the body ~luids, problems of pulse entry are `~
o~ercome and met~bolic half-life is not a ~actor of controlling importance.
Despite the advantages of administering drugs from implants, prior art devices designed for this purpose, in which diffusion processes control the rate of release, have been unable to pxovide continuous administration and constant delivery rate and have introduced ancillary problems. If the implant, after ~0~97~
discharging its dru~ conten-t, remains as a matrix structure, then it may have to be remo~ed ~y a surgical procedure to prevent its possible migration to sensitive areas or organs of the body. On the other hand, if the implant is of such a nature that the drug- ;
carrying substrate is absorbable by the host into which it is placed, then there occurs the likelihood that the substrate will introduce undesirable, and even harmful, su~stances into the ~ody.
Description of the Prior rt In the prior art, a number of nonabsorbable materials of construction and several dif~erent structural designs have been proposed for subcutaneous implants. Such materials as hydro-gels, gelatin, carboxymethyl cellulose, polyurethanesj waxes, pol~vinyl alcohol, polyglycolic acid, and polylactic acid have been suggested for this purpose. However, organopolysiloxane rubbers as carriers for the controlled release of drugs, have probably received the most ~idespread use. The use of these so-called "silicone rubbers'l is described ;n U.S. Patent 3,279,996.
Implants which use any of these materials as substrates or carriers which are not absorbable by the living organism into which they axe introduced normally re~uire removal ~y surgery. The silicone ~
rubbers are among the nonabsorbable materials and therefore they `
suffer from this drawback. Typically, implants ~ormed of silicone rubber, or of any of the other above-named materials have been fabricaked either in the form of closed hollow tubes or capsules (with or without a sponge sleeve~ in whîch the drug is contained fox dif~usion through the tube walls; or they have ~een made up into structures of homogeneous polymer-drug ~lends.
Some work has been reported (see for example ~ablon, PoA~M~ ~ Ph.D. Thesis, Purdue University, 1969~ on implants formed ~O~S~7~
by chemically bonding drugs to polypeptides. This approach neces-sitates providiny a dru~ having a reactive site amenable to chem-ical boncling to the polypeptide; and it also ;ntroduces the danger that in the breaking o~ the chemical bond to release the drug the effectiveness and acceptability of the drug to the system may be materially altered. Moreover, the drug-polypeptide complex will, in fact, represent a new dru~ of unknown properties. Finally, an implant in which the drug is chemically bonded to the matrix material can not release the drug from the matrix by the process of diffusion, since release is predicated on the actual breaking of chemical bonds.
U.S. Patent 3,493,652 teaches the incorporation of medicaments such as cardioactive, adrenerg~c, choliner~ic, anti-spasmodic and curariform agents, tranquilizers, antihistamines, antibiotics and the like into a matrix which contains one or more enzymes or enzyme precursors capable of digesting the matrix material which, in turn, may be formed of such diverse materials as casein, fibrinogen, proteins, polypeptides with free amino groups, urea and amino acids. The dosage formulation may take many different forms including suspensions, emulsions, tablets (sublingical, buccal, oral or vaginal), capsules, ointments, suppositories and implants. When such a controlled release medicament is introduced into a living organism it must, of nec-essity, introduce both the substrate material and enzyme into the system and one or both of these may be antagonistic to the system.
In particular, to introduce those enzymes which are not normally present in the living organism may result in harmful side effects.
Moreover, enzymes are known to degrade or denature and this pro-cess may take place prior or subsequent to the administration of 7~
the dosage. In the fi~s-t c~se, the effectiveness o the dosage-contained enzyme is lessened or even cancelled; and in the second case, premature enzyme degradation could materially alter or even destroy any control over the dru~ release rate.
An implantable drug delivery system which overcomes at least a number of the disadvantages associated with the prior art has been proposed. (See Contract DADA-17-72-C-2079 to Dyna-tech Rese~rch and Development Co., by U.S. Army Medical Research and Development Command, Washington, D.C. (1972~. This delivery system consists of a polymer matrix in which the drug is physic-ally entrapped. The drug is released, not by diffusing through a polymeric membrane, but by hydrolytic breakdown of the polymer matrix itself. As the polymeric matrix disintegrates, the enclosed drug is released into the surrounding body fluids. By the time ` all of the drug has been released from the matrix, the polymer fxagments have been almost completely absorbed.
The polymeric materials proposed for this device are polyesters (e.g., polylactic acid and polyglycolic acid~ having low toxicity, lo~ drug permeability and slow rates of hydrolysis to form metabolizable fragments (e.g., lactic acid and glycolic acid~. EIowever, these polymers hydrolyze at a rate that is highly dependent upon both pH and degree of crystallinity. Since the products o~ hydrolysis reactions are acids, there is a tendency ;~
for the products that do not immediately diffuse away from the ~ -implant site to inhibit further hydrolysis. In addition, the crystalline re~ions degrade at a much slower rate than the amor-phorus regions, thus gi~ing rise to a nonuniform degradation pattern and a porous structure from which the drugs may be released at an uncontrollable rate.
5~ 7 It will thus be apparent from this di~cussion of the prior art that implants for controlled drug release have distinct theoretical advantages; but that there is a need for an improved implant device to achieve a continuous dose, controlled release of drugs or other substances which overcomes the major disadvantages (i.e~, dif~iculty in continuously controlling the release of the drugs, production of unwanted degradation products and/or the need for surgically removing the implanted matrix~ associated with the presently available implant devices.
Ob~jects_of the Invention It is therefore a primary object of this invention to provide an improved implant device for achieving continuous dose, controlled-release of drugs or other substances such as diagnostic agents. It is a further object of this invention to provide an implant device of the character described which may be biocompat-ible and biodegradable to form amino acids and/or amino acid com-plexes already present in the organism into which the implant is placed, thus eliminating the introduction of foreign or antagonistic substances and at the same time eliminating the need of surgical procedures to remove a matrix structure. An additional object of this invention is to provide an improved implant device which exhi-bits improved re.lease rate control, the rate of release being op-tionally constant or at some predetermined changing rate. Another object is to provide an implant device which relies upon one or more enzymes normally present in the living organism to release one or more drugs continuously, or upon one or more enzymes which are only present under certain pathological conditions to release one or more drugs and/or diagnostic indicators when such patholog-ical conditions are present. It is yet a further object of this invention to provide an impro~ed implant device which may ~e used -~
.: . , ~0~5~77 to deliver a wide range of drugs or other a~ents, including twoor more drugs simultaneously or serially.
It is another prlmary object of ~his invention to pro-vide a process for forming a biodegradable implant device in various configurations to attain controlled drug release at a constant or varying release rate and to attain the release of two or more drugs either simultaneously or serially. Another object of this invention is to provide a process of the character described which is amenable to the formation of an implant device to deliver a wide range of drugs and other substances such as diagnostic agents.
Still another primary object of this invention is to provide an improved process for the continuous, rate-controlled delivery of drugs and/or other substances into selected areas or organs of living organisms in a manner to minimize or elimi-nate the introduction of any substance, other than the drug or other agent, not normally present in the organism.
Other objects of the invention will in part be obvious and will in part be apparent hereinafter.
Sùmmary of the Invention According to this invention there is provided an im- ' plant device for the controllable release o at least one sub-stance into a living host into which it is implanted, comprising a matrix structure having the substance to be released physically admixed therethrough, at least a major portion of the matrix structure being formed of poly-~-amino acid whereby the substance is released by diffusion, by the hydrolysis of the poly-~-amino acid by one or more enzymes present in the host or by a combina-tion of diffusion and hydrolysis. The degradation products, 30 i.e., amino acids, are metabolized or excreted by the organism '`
.,.~'~' . .~ .... . ...... ' ,.
45~7~
during and/or a~ter rel~ase of the sub~tance. The implant may be in the form of a ~ilm, rod, fibex, hollow cylindex and the like; and it may have the drug 80 distributed as to provide a constant or a changing rate of release. The poly-a-amino acid may be a homopolymer or copolymer of two or more amino acids;
and it may be chosen as to be biodegradable through action of one or more enzymes which are normally present in the living organism or through action of one or more enzymes developed by a pathological condition thus effecting the triggering of the release only upon certain predetermined conditions.
The biodegradable implant of this invention is formed by blending the substance to be controllably released with the poly-~-amino acid thereby to form a physical mixture; and fabri-cating the physical mixture into a structural configuration suit-able as an implant device. The implant is then placed within the living organism by any suitable known technique.
The invention accordingly comprises the several steps and the relation of one or more of such steps with respect to each of the others, and the article possessing the features, properties and the relation of elements, which are exempli~ied in the following detailed disclosure, and the scope of the in-vention will be indicated in the claims.
Brief Description o~ the Drawin~s For a fuller understanding of the nature and objects of the invention, reference should be had to the following de-tailed de~cription taken in connection with the accompanying drawings in which Fig. 1 illustrates an essentially "two-dimensional"
--10-- ,.
~ ,.
: ~' , '' :', , ... . . . . .. . .
97~
implant device designed to achieve a constant rate of drug release;
Fig. 2 illustrates an implant devic~ in the form of a rod or fiber designed to achieve a decreasing rate of drug release;
Fig. 3 illustrates an implant device in the ~orm of a hollow cylinder designed to achieve a near constant rate of drug ' release;
Fig. 4 illustrates an implant devîce in the form of a layered rod in which the drug concentration is different from its adjacent layer or layers to achieve a predetermined rate of drug release; and Fig. 5 illustrates an implant device in the form of a rod with a core containing a drug different from the surrounding layer.
Detailed Description o~ the Invention The biocompatible, biodegradable implant device of this invention is formed as a structure in which the drug or other releasable substance to be delivered is physically distri-buted through a matrix. In the following description and claims the term "drug" is used in its broadest sense and it includes any substance which has any biological activity r whether such activity is medicinal or otherwise. For convenience in present-ing this detailed description, the implant will be descri~ed in terms o~ containing a dr~g, although it is to be understood that it may also contain a diagnostic agent such as a releasable dye ' which has no biological activity per se. Thus, in its broadest sense, the implant may be defined as containing a releasable sub- ' stance, which may or may not exhi~it biological activity.
The matrix, throughout which the drug is distributed for release, is one or more poly-~-amino acids having low toxicity -11- .
~04~9~77 and being biodeyradable Ln VLVO through enzymatic hydrol~sis to form amino acids. The poly-a-amino acids may be further generally characterized as thermoplastic re~ins inert to the drugs contained, and soluble in selected solvents.
Poly-~-amino acids are synthetic polymers composed of a-amino acid residues linked by peptide bonds. They have been extensively studied r particularly with relation to the structure of the polypetide chain and its susceptibility to hydrolysis by proteolytic enzymes (see for example C. H. Bam~ord, ~. Elliott and W. E. Hanby, "Synthetic Polypeptides," Academic Press Inc., New ~ork, 1956, pp. 113-425~. The ~iological properties of poly-petides have also been extensively investigated ~see for example M. A. Stahman, Ed., "Polyamino Acids, Polypeptides, and Proteins,"
The University of Wisconsin, 1962, Part ~, pp 283-385~.
Synthetic techniques have been developed -Eor forming ` homopolymers, random copolymers, ~lock copolymers, multi-chain polymers and polymers containing a predetermined sequence of amino acid residues from a-amino acids.
Homopolymeric poly-~-amino acids may be represented as ~ HN-CHCO~
Rl n wherein Rl is a side chain characteristic of the common, well-known amino acids, including, but not limited to -~I, -CH3, -CH2COOH, -CH2-SH, -CH2- ~ , -CH2-OH, -CH2-C ~ , and the like. ;
~N
The poly-~-amino acid copolymers are composed of two or more ~-amino acids distributed at random along the polymer chain; and they can be represented, as for example, as .. ,.. ,, , , ......... . :
, , . . . - ~ , . , Si977 -HN-CH-CO-~CH-CO-HN-CH-CO-EIN-CH-Rl R2 R2 R2 ' where Rl and R2 are di~ferent and are chosen from the groupings given above for R~
Block copolymers are also known and can ~2 represented generally as ~HN-CHCO ~ HN-fH-Co3 Rl m R2 n where Rl and R2 are different and are chbsen from the grouping given for Rl and m and n range generally between one and one hund-red. The poly-a-amino acids may be synthesized to have a wide range of average molecular weight, e.g., from 103 to 106, and the matrix material may be formed of a mixture of polymers have dif-ferent molecular weights.
Although a number of derivatives of a-amino acids and peptides have been used as monomers for the preparation of the poly-a-amino acids, the most commonly used monomers are the N-carboxy-~-amino acid anhydrides represented as R
/ CH \
HN C=O
O=C--O
where R is chosen from the same groupings as given for Rl above.
The polymerization technique may be either the well-known bulk or solution polymerization process. Bulk polymerization is usually carried out at elevated temperatures and yields polymers with reIatively low avera~e molecular welghts. Solution poly-~04~977 :~
merization, on the other hand, may be perormed at low temperatures, it .is easily controlled and can result in relatively high mole- ~
cular weight polymers. Inert solvents such as dioxane, dimethyl- ; .:
formamide and nitrobenzene may be used with such polymerization : -~
catalysts as primary, secondary or tertiary amines, or strong ~ases :~ -such as sodium methoxide or sodium hydroxide. The use of ter-tiary amines or sodium methoxide as initîators are preferred for the preparation of poly-a-amino acids with average molecular ~eights of 20,000 to 1,000,000. The primary and secondary amines have been found useful in.preparing intermediate molecular weight .
polymers, e.g., 103 to 104.
Almost all of the amino acids occuring in proteins have been prepared in homopolymeric form. The follow;ng are repre- .
sentative amino acid which have been polymerized and solvents for the polymers amino acid solvents ~
L-Alanine dichIoroacetic acid, trifluoroacetic : `
acid Glycine dichIoroacetic acid, trifluoroacetic acid, concentrated aqueous LiBr L-Leucine trifluoroacetic ac;d L-Lysine ~ater L-Methionine chloro~orm, dichloroacetic acid L-Phenylalanine 33~ HBr in glacial acetic acid L-Proline water, acetic acid L-Valine tri~luoroacetic acid.
In yeneral, the copolymers exhibit solu~ility ;n common or~anic solvents such:as chloroform, ~enzene and diozane, and they ~enerally possess improved phy ical characteristics, such as impr.o~ed malleability and greater elongation to break, than . ' .... :
597~
the homopolymers, thus making them preferable in the practice of this invention. Exemplary oE such copolymers are those ~ormed y-benzyl-L-glutamate and leucine following the procedure of Blout and Karlson (see J. Amer. Chem. Soc. 78, 941 (1956~. These co-polymers have molecular wei~hts in excess of 50,000 and have the desirable film forming and mechanical properties. It may also be desirable to add a minor quantity of a monomer other than an a-p~/s/~a ~
w~ amino acid to contribute desired plupiaal properties.
The poly-a-amino acids used as the matrix material in ~ 10 the implant devices of this invention must have sufficient ;~ mechanical strength to be formed into such structuxes as films, .~ -, .
-~; rods, fibers, and hollow cylinders. As examples, the dimensions ~or a film implant may be about 2 cm by 2 cm and 0.05cm thick, and the diameter of a fiber or rod may be about 0.5cm. The poly- `
a~amino acids must also be of a type which lend themselves to formation into such structures by known synthtic resin fabrica-tion techniques as described below.
A wide range of drugs may be incorporated into these ~; l synthetic polymer matrices to form the implant devices of this invention. Such drugs include, but are not limited to, fertility control agents such as estradiol valerate, medroxyprogesterone acetate, and hydroxyprogesterone caproate, anticoa~ulants such as heparin or ethylenediaminetetraacetic acid, antibacterials, antibiotics, antineoplastic agents, cardiovascular agents such as digitalis, quinidine and nitroglycerine, immunolog;cal agents, central nervous system stimulants and depressants, antidiabetic agents, and the like. Diagnostic agents such as dyes ~e.g., ; bromsulphalein~ may be incorporated for implantation at a site where enzymes, formed as a xesult of a pathological condition to :` ` , , ; ::
- :: .
l~S~77 , ..
be detected, are available for the hydrolysis o~ the matrix mater-ial. The release of such diagnostic agen~s brought about by the presence of the patholo~ically-induced enzyme may be detected in the body fluids, e.g., the urine to indicate the presence of the pathological condition being monitored.
The quantity of the drug or drugs or of diagnostic agent incorporated into the poly-a-amino acid matrix will depend upon the rate it is to be released, which in turn will depend upon the diffusion rate of the drug and upon the rate at which the poly-mexic matrix is hydrolyzed by one or more enzymes. Actual con-tinuous dosage rates may be determined in vitro using the enzymes to be encounted in vi~o in the biodegradation of the matrix poly-mer and release of the drug or diagnotic agent contained.
In the process of forming the implant device according to this invention, the drug (or diagnostic agent~ is blended with the polymeric matrix material and then the resulting physical mixture is fabricated into the desired structural shape.
Blendin~ may be done by one of several tecniques. The first of these comprises forming a solution of the polymeric matrix material and adding the drug to the solution. If the solvent or solvent mixture used to form the solut;on of the matrix is also a solvent for the drug, then a homogeneous solu-tion may be formed. If the solvent system is not a solvent for the dru~, then the drug may be dispersed as fine particulate mater-ial r as a liquid, or in other suitable form, throughout the poly-mer solution using, if necessary, a high-shear m;xer to obtain a homogeneous suspension. The solution or suspension thus formed may be cast into films or ribbons such as ;llustrated in Fig. l which illustrates an implant lO hav;ng essentially but two dimen-~ ,:
~:
,, ~04~'37~
sions, width and leng-th. SolYent and casting conditions are chosen to prevent any appreciable segregation of the drug and polymer when the solvent is removed. The flat, essentially two~
dimensional implant 10 of Fig. 1 exhibits a relatively constant surface area over its useful life within a living organism and hence it may be used to administer a relatively constant dose rate. The film or ribbon form of implant is not, however, par- ;
ticularly amenable to administration by trocar, a fact which means that surgical implantation procedures may be required.
Another blending technique may comprise mixing the drug with the dry polymeric matrix material in powdered form and then forming the desired structural shape with heat and pressure, the fabrication conditions being such as not to destro~ the efficacy o~ the drug or to degrade the matrix material. The blend of drug and dry polymeric matrix material may be injection molded, compression molded or extruded into three-dimensional shapes of a required design.
Extrusion of such a blend may be used to form fibers or rods such as shown in Fîg. 2 which illustrates a solid rod-shaped implant 11. Such a rod-shaped implant, as the poly-~-amino acid matrix is degraded through action of the enz~mes pre-sent in the host into which it is implanted, will expose a con-stantly decreasing surface area and hence will release the drug at a decreasing rate. Under those circumstances where this is ;
desirable, the rod- or ~iber-shaped implant of Fig. 2 may be used without further modification.
Since a rod- or fiber-shaped implant is desirable for administration by means of a trocar, it may ~e desirable to modif~ this implant configuration to obtain a constant drug ~ S977 release rate, or a release rate which does not decrease as rapidly as the implant 11 of Fig. 2. Figs. 3 and 4 illustrate two exemplary modifications of a rod-shaped implant. In Fig. 3 the implant 12 is constructed as an open cylinder having an ex-ternal surface 13 and axial opening defining an internal sur-face 14. Since the surface axea of external surface 13 will decrease and that of internal surface 14 will increase as the ~mplant is degraded, the rate of drug release may be held con-stant, or it may be increasing or decreasing depending upon the relative rate at which the surface areas of surfaces 13 and 14 de-crease and increase.
In the modification of F1g. 4, the implant device 15 is formed of multiple la~ers as exemplified by layers 16, 17 r 18 and l9, the last se~ving as a core. In this implant, each layer has a drug concentration different from that of an adja-cent layer or layers. If these drug concentrations are arranged to provide a concentration gradient which increases from the outermost layer 16 to core l9, a constant drug release device ;
may be formed in rod form. In forming the rod implant 15 of Fig. 4, the multiple la~ers may be coextruded using well deve-loped techniques. If desired, the concentration gradient profile from the rod center to its external surface may be smoothed by annealing the extrudate at a temperature slightly below the melt temperature of the polymeric matrix material so that thermal diffusion of the drug is effected. An alternative procedure for forming the multilayered implant with a drug concentration gradient is to ~orm a core and coat it with successive layers of a polymeric matrix solution containing the drug dissolved or dispersed therein. It is, of course, also within the scope of S~7~
this invention to ~orm a multila~ered implant such as 15 of Fig. 4 by ~ combination o~ techniques, e.g., extrusion and coat-ing; and -to make multilayered implants wherein the drug concen-tration as well as the poly-~-amino acid matrix differs from layer to layer.
Under some circumstances, it may be desirable to release two different substances în series. For example, in the implant 20 of Fig. 5, the outer layer 21 may contain a diagnostic agent which, when released throu~h action of a patholo~ically- -developed enzyme, will indicate an abnormal situation and then after giving such warning ~ill release one or more drugs from ~`~ ?
core 22. The implant embodiments of Figs. 4 and 5 may also be used to release more toxic drugs or more toxic dosages if the system does not respond to the first drug or dosage released. It will thus be apparent that a large number of embodiments of the multilayered implant are possible to meet different needs.
The implant devices of this invention may be located in or near an organ of the body, or they may be implanted sub-dermally, e.g., in the forearm or sublingually. They may also be administered as uterine or vaginal inserts. The location of the implant will determlne the enzymes which will be present to ef-fect the biode~radation of the poly-~-amino acid matrix and hence will determine the composition of the matrix material. The pro-teolytic enzymes ~ithin the mammalian system include, among others, prolidase, prolinase, thrombin, renin, carboxypeptidase A, pro~ ;;~
line, iminopeptidase, pepsin, trypsin, chymotrypsin, leucineamino-peptidase, carboxypeptidase B, and cathepsin C.
The poly-~-amino acid drug delivery system of this in-vention, ~hen implanted in the body, ~ill be exposed to a multi-.~ . . ~ . . . - . .
~34~5i9~
plicity of pro-teolytic enzymes, all of ~hich are capable of forming enzyme-substrate complexes~ As noted above, the poly~
amino acid substrate (matri~ is chosen according to the location ~ ~' of implant and the reactive enzymes present at that location. ~;
The effect o~ selected enzymes on selected poly-a-amino :~
acids is shown below: :
Enzyme Poly-~-amino acid Eff ct Trypin poly-L-ornithine resistant poly-D-lysine resistant poly-L-lysine hydrolyzed copol-(L-lysine: L-glutamic acid, 1:4) resistant copol-(L-lysine: L-glutamic acid, 1:1) sl. hydrolyzed copol-(L-lysine: L-tyrosine, 3:1) sl. hydrolyzed Chymotrypsin poly-L-glutamic acid resistant poly-L-tyrosine resistant poly-L-phenylalanine resistant poly-L-tryptophan resistant copol-(L-lysine: L-leucine: L-tyrosine,
2:1:1) hydrolyzed copol-(L~glutamic acid: DL-alanine:
L-tyrosine,2~ hydrolyzed : ;
copol-(L-lysine: L-tyrosine, 2:5:1) copol-(L-lysine: L-phenylalanine, 2:1) hydrolyzed ~' copol ~DL-alanine: L-tyrosine, 9:1~ resistant copol-(L-proline: L-tyrosine, 23:1) resistant Pepsin poly-L-~lutamic acid hydrolyzed - :
copolymers of L-glutamic acid with L-lysine, L-aspartic acid -L-alanine; or L-phenylalanine hydrolyzed poly-h-lysine resistant poly-D-~lutamic acid resistant . '' poly-L-aspartic acid resistant Carbo~peptidase A poly-L-~lutamic acid hydrolyzed .. :
poly-L-lysine resistant ';
Proline .
Iminopeptidase poly-L-proline hydrolyzed Taka-Diastase poly-L-histidine hydrolyzed ' The implant device, the process for its preparation, and ~.
the process ~or its use to attain a continuous sustained drug release are further described in t.he ~ollo~ing example which is :
- .:
~V~5~77 meant to be illustrative and not limitiny. ,~
Implantable sustained release devices were prepared in accordance with this invention for the administration of pred-nisolone in laboratory rats. The polymeric matrix was a copolymer of two ~-amino acids, namely y-benzyl-L-glutamate and L-leucine (50/50 mole ratio~.
The copolymer used in forming the matrix was prepared from the N-carboxy anhydrides of the ~-amino acids. The procedure used in preparing the N-carboxy anhydrides was as follows. One ~
hundred grams of the finely powdered ~-amino acid was charged ~ ' into a reaction flask and suspended in 600 cc of a dryt inert solvent,,e.g., dioxane or tetrahydrofuran. A stream of phosgene was slowly introduced into the flask while the temperature was maintained between 40 and 60C. This was continued until the a-amino acid was dissolved,,usually about two to six hours. The straw-colored reaction mixture was concentrated in vacuo at a maximum temperature of 50C. The resulting oil was then diluted with chloroform and n-hexane was added slowly until crystalliza-tion began. Crystallization was complete in 12 hours at 3C.
The resulting precipitate was isolated ~y filtration,,was thor-oughly washed with n-hexane ko remove exces's phosgene and then recx~stallized ~Xom a chIoroform solution.
~ he meltin~ point of the N-carboxy anhydride of y-benzyl-L~glutamate thus prepared was 93-94C and that of the N-carboxy anhydride of L-leucine was 76-77C.
The copolymerization of the two N-carboxy anhydrides was carried out following the procedure of Blout and Karlson (J. Amer. Chem. Soc.- 78 941-46 ~19561~. Dioxane was used as the solvent and it ~as added at a level of 1-4 ml/millimole of ,........... . ,~ . ..
~l~4S~77 the N-carboxy anhydrides.
To prepare the 50~50 mole ratio copolymer e~ual moles o~ the two N-carboxy anhydrides were charged into a dry reaction flask. Suficient dioxane was added to produce a 5~ by weight solution of the N-carboxy anhydrides in the solvent. Dry triethylamine was used as the polymerization catalyst at a level ; ;
of one part by wei~ht catalyst to 200 parts o~ the N-car~oxy ~;
anhydrides.
The flask was stoppered and allowed to stand at room -temperature for 120 hours. The reaction solution was then poured with vigorous stirring into 95~ ethanol to precipitate the copoly-mer. It was recovered by filtering. The copolymer was recrystal-lized from dioxane using 95% ethanol as the nonsolvent until the resulting copolymer had a melting point range of 225 to 235C
(typically requiring about four recrystallizations~. ;
A drug delivery implant device in thin film form was prepared using this copolymer as the polymeric matrix and pred-nisolone as the drug.
To lOOcc of dioxane were added 1.5g of the copolymer and 0.15g of prednisolone ~ICI, Nutritional Biochemicals~ and 0.002 mg (specific activity, 45.5 cuxies/mM, in 0.5cc oE a benzene/
ethanol (9/1) solutioh) of tritium-labelled prednisolone (New England Nuclear, Boston, Mass.). This mixture was gently stirred for 16 hours to obtain a homogeneous solution.
The solution containing the copolymer and the drug was cast on a level glass plate that had ~een covered with a fluoro-polymer release film; and the-solution was spread with a draw down bar to giYe a uniform thickness of 30 mils.
The solvent in the coating was allowed to evaporate under the heat from a heat lamp until the film because nontacky.
~S~7~ :
This required ~bout two hours. ~t this point another layer of copolymer/drug solution was cast on the first film, drawn down to give a thickness of 30 mils and dried as before. A total of seven film layers were thus ~uilt up in this manner to give a film with a final thickness of 0.4 mil.
Scanning electron microscope pictures ~2000x~ of the ~
surfaces and of cross section of the film showed no evidence of ~; ;
separate drug and copolymer phases, thus ~ndicating that a very :
fine dispersion of the dru~ had ~een achleved.
Implants were prepared from the film by cutting it into rectangular pieces that exhibited various surface areas. ~ ;
These implants contained from 0.65 to 2.0 mg of radioactively-labelled prednisolone, depending on the size of the implant rectangle. The implants were sterilized by immersion in alcohol and then rinsed with sterile Earle's Balanced Salt Solution. The ... . .
devices were implanted subcutaneously into the backs of two groups each of eight female CD rats (Charles River Breeding Laboratories, Inc.~. To accomplish the implantations, the dorsal area was shaved, cleaned with alcohol and then a one-half inch incision was made in the skin. The skin was then separated from the muscle tissue and the implant inserted at this site. The incision was then sutured.
Each anim~l of a third group o~ four ~emale CD rats ~rom the same source was subcutaneously injected with 0.5cc of an 0.5~ h~drox~ propylcellulose solution containing an amount of the same radioactiviely la~eIled prednisolone approximately e~uiYalent to that contained in the implant devices (i.e., 1 mg pxednisolone/rat~. ;
All of the animals were housed in meta~olic cages. The .: . .. : . . - ~ , . .
radioactivities in the urines collected ~ere measured by the stan-dard procedure of scintill~tion counting, and ~ro~ these measure- ;~
ments values oE di.~integrations per minute ~PM~ were calculated.
Radioactivities were thus measured eYery 24 hours for the first four days and then for an additional 72 hour level to complete a week of testing.
The aYerage DPM values obtained for the two groups of implanted rats (average dosage of 1.5 mg~rat~ and the one group of control rats (average dosage o 1.0 mg/rat~ are given in Table 1. During the first day a number of rats escaped from their cages so that the average figures given are for fewer than the ::
total number of animals in each group.
Table 1 Tritium ~DPM~ in Urine of Rats ~`
Group : Time Span, Hours No.0-2~: 24-~ ~ 72:-:9:6: ;96-1:68 .. .~
l-Implanted. 11,006* 5,272+ 3,425 2,415 3,705 2-Implanted8,529~ 5,693~ 3,972 2,668 3,~68 .
L-tyrosine,2~ hydrolyzed : ;
copol-(L-lysine: L-tyrosine, 2:5:1) copol-(L-lysine: L-phenylalanine, 2:1) hydrolyzed ~' copol ~DL-alanine: L-tyrosine, 9:1~ resistant copol-(L-proline: L-tyrosine, 23:1) resistant Pepsin poly-L-~lutamic acid hydrolyzed - :
copolymers of L-glutamic acid with L-lysine, L-aspartic acid -L-alanine; or L-phenylalanine hydrolyzed poly-h-lysine resistant poly-D-~lutamic acid resistant . '' poly-L-aspartic acid resistant Carbo~peptidase A poly-L-~lutamic acid hydrolyzed .. :
poly-L-lysine resistant ';
Proline .
Iminopeptidase poly-L-proline hydrolyzed Taka-Diastase poly-L-histidine hydrolyzed ' The implant device, the process for its preparation, and ~.
the process ~or its use to attain a continuous sustained drug release are further described in t.he ~ollo~ing example which is :
- .:
~V~5~77 meant to be illustrative and not limitiny. ,~
Implantable sustained release devices were prepared in accordance with this invention for the administration of pred-nisolone in laboratory rats. The polymeric matrix was a copolymer of two ~-amino acids, namely y-benzyl-L-glutamate and L-leucine (50/50 mole ratio~.
The copolymer used in forming the matrix was prepared from the N-carboxy anhydrides of the ~-amino acids. The procedure used in preparing the N-carboxy anhydrides was as follows. One ~
hundred grams of the finely powdered ~-amino acid was charged ~ ' into a reaction flask and suspended in 600 cc of a dryt inert solvent,,e.g., dioxane or tetrahydrofuran. A stream of phosgene was slowly introduced into the flask while the temperature was maintained between 40 and 60C. This was continued until the a-amino acid was dissolved,,usually about two to six hours. The straw-colored reaction mixture was concentrated in vacuo at a maximum temperature of 50C. The resulting oil was then diluted with chloroform and n-hexane was added slowly until crystalliza-tion began. Crystallization was complete in 12 hours at 3C.
The resulting precipitate was isolated ~y filtration,,was thor-oughly washed with n-hexane ko remove exces's phosgene and then recx~stallized ~Xom a chIoroform solution.
~ he meltin~ point of the N-carboxy anhydride of y-benzyl-L~glutamate thus prepared was 93-94C and that of the N-carboxy anhydride of L-leucine was 76-77C.
The copolymerization of the two N-carboxy anhydrides was carried out following the procedure of Blout and Karlson (J. Amer. Chem. Soc.- 78 941-46 ~19561~. Dioxane was used as the solvent and it ~as added at a level of 1-4 ml/millimole of ,........... . ,~ . ..
~l~4S~77 the N-carboxy anhydrides.
To prepare the 50~50 mole ratio copolymer e~ual moles o~ the two N-carboxy anhydrides were charged into a dry reaction flask. Suficient dioxane was added to produce a 5~ by weight solution of the N-carboxy anhydrides in the solvent. Dry triethylamine was used as the polymerization catalyst at a level ; ;
of one part by wei~ht catalyst to 200 parts o~ the N-car~oxy ~;
anhydrides.
The flask was stoppered and allowed to stand at room -temperature for 120 hours. The reaction solution was then poured with vigorous stirring into 95~ ethanol to precipitate the copoly-mer. It was recovered by filtering. The copolymer was recrystal-lized from dioxane using 95% ethanol as the nonsolvent until the resulting copolymer had a melting point range of 225 to 235C
(typically requiring about four recrystallizations~. ;
A drug delivery implant device in thin film form was prepared using this copolymer as the polymeric matrix and pred-nisolone as the drug.
To lOOcc of dioxane were added 1.5g of the copolymer and 0.15g of prednisolone ~ICI, Nutritional Biochemicals~ and 0.002 mg (specific activity, 45.5 cuxies/mM, in 0.5cc oE a benzene/
ethanol (9/1) solutioh) of tritium-labelled prednisolone (New England Nuclear, Boston, Mass.). This mixture was gently stirred for 16 hours to obtain a homogeneous solution.
The solution containing the copolymer and the drug was cast on a level glass plate that had ~een covered with a fluoro-polymer release film; and the-solution was spread with a draw down bar to giYe a uniform thickness of 30 mils.
The solvent in the coating was allowed to evaporate under the heat from a heat lamp until the film because nontacky.
~S~7~ :
This required ~bout two hours. ~t this point another layer of copolymer/drug solution was cast on the first film, drawn down to give a thickness of 30 mils and dried as before. A total of seven film layers were thus ~uilt up in this manner to give a film with a final thickness of 0.4 mil.
Scanning electron microscope pictures ~2000x~ of the ~
surfaces and of cross section of the film showed no evidence of ~; ;
separate drug and copolymer phases, thus ~ndicating that a very :
fine dispersion of the dru~ had ~een achleved.
Implants were prepared from the film by cutting it into rectangular pieces that exhibited various surface areas. ~ ;
These implants contained from 0.65 to 2.0 mg of radioactively-labelled prednisolone, depending on the size of the implant rectangle. The implants were sterilized by immersion in alcohol and then rinsed with sterile Earle's Balanced Salt Solution. The ... . .
devices were implanted subcutaneously into the backs of two groups each of eight female CD rats (Charles River Breeding Laboratories, Inc.~. To accomplish the implantations, the dorsal area was shaved, cleaned with alcohol and then a one-half inch incision was made in the skin. The skin was then separated from the muscle tissue and the implant inserted at this site. The incision was then sutured.
Each anim~l of a third group o~ four ~emale CD rats ~rom the same source was subcutaneously injected with 0.5cc of an 0.5~ h~drox~ propylcellulose solution containing an amount of the same radioactiviely la~eIled prednisolone approximately e~uiYalent to that contained in the implant devices (i.e., 1 mg pxednisolone/rat~. ;
All of the animals were housed in meta~olic cages. The .: . .. : . . - ~ , . .
radioactivities in the urines collected ~ere measured by the stan-dard procedure of scintill~tion counting, and ~ro~ these measure- ;~
ments values oE di.~integrations per minute ~PM~ were calculated.
Radioactivities were thus measured eYery 24 hours for the first four days and then for an additional 72 hour level to complete a week of testing.
The aYerage DPM values obtained for the two groups of implanted rats (average dosage of 1.5 mg~rat~ and the one group of control rats (average dosage o 1.0 mg/rat~ are given in Table 1. During the first day a number of rats escaped from their cages so that the average figures given are for fewer than the ::
total number of animals in each group.
Table 1 Tritium ~DPM~ in Urine of Rats ~`
Group : Time Span, Hours No.0-2~: 24-~ ~ 72:-:9:6: ;96-1:68 .. .~
l-Implanted. 11,006* 5,272+ 3,425 2,415 3,705 2-Implanted8,529~ 5,693~ 3,972 2,668 3,~68 .
3-Control33,038~ 4,424~ 3,335 86 -248 *Average of twoj ~ average of 6; ~ average of 3; ~ average of 7 From Table 1 it will ~e seen that the control animals exhibited very hl~h excretion rates in the first 24 hours and that ~y the end of the ~ourth day there was practically no excretion of radioactive material. The presence of minus values in these readings indicates that there was some unidentified "noise" in the system. However, this does not detract from the conclusions which may be drawn from these data. It will be seen that the level of excretion of radioactive material released by ' :: : - : , .
the implant devices was considerably lower initially than when the drug was injected subcutaneously. However, the drug was released from -the implants at an essentially sustained rate and all of the animals were still showing significant levels of radioactivity (and hence drug release~ in their urine at the end of one week.
It will thus be seen that the objects set forth above, among those made apparent from the preceding description, are efficiently attained and, since certain changes may be made in carrying out the above process and in the article set foxth with-out departing from the scope of the invention, it is intended that all matter contained in the above description or shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense.
:: .. , : ".. ~
the implant devices was considerably lower initially than when the drug was injected subcutaneously. However, the drug was released from -the implants at an essentially sustained rate and all of the animals were still showing significant levels of radioactivity (and hence drug release~ in their urine at the end of one week.
It will thus be seen that the objects set forth above, among those made apparent from the preceding description, are efficiently attained and, since certain changes may be made in carrying out the above process and in the article set foxth with-out departing from the scope of the invention, it is intended that all matter contained in the above description or shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense.
:: .. , : ".. ~
Claims (30)
1. An implant device for the controllable release of at least one substance into a living host into which it is implanted, comprising a matrix structure having said substance to be released physically admixed therethrough, at least a major portion of said matrix structure being formed of poly-.alpha.-amino acid whereby said substance is released by diffusion, by the hydrolysis of said poly-.alpha.-amino acid by one or more enzymes pres-ent in said host or by a combination of diffusion and hydrolysis.
2. An implant device in accordance with claim 1 wherein said poly-.alpha.-amino acid is a homopolymer.
3. An implant device in accordance with claim 1 wherein said poly-.alpha.-amino acid is a copolymer of at least two .alpha.-amino acids.
4. An implant device in accordance with claim 1 wherein said substance is a drug.
5. An implant device in accordance with claim 1 wherein said substance is a diagnostic agent.
6. An implant device for the controllable release of at least one substance into a living host into which it is implanted, comprising a poly-.alpha.-amino acid matrix structure having said substance to be released physically admixed therethrough whereby said substance is released by diffusion, by hydrolysis of said poly-.alpha.-amino acid matrix by one or more enzymes present in said host or by a combination of diffusion and hydrolysis.
7. An implant device in accordance with claim 6 wherein said poly-.alpha.-amino acid matrix is a homopolymer.
8. An implant device in accordance with claim 6 wherein said poly-.alpha.-amino acid matrix is a copolymer of at least two .alpha.-amino acids.
9. An implant device in accordance with claim 8 wherein said poly-.alpha.-amino acid matrix is a copolymer of .gamma.-benzyl-L-glutamate and L-leucine.
10. An implant device in accordance with claim 6 wherein said poly-.alpha.-amino acid matrix is a mixture of at least two poly-.alpha.-amino acids of different molecular weights.
11. An implant device in accordance with claim 6 wherein said poly-.alpha.-amino acid matrix has a molecular weight between about one thousand and one million.
12. An implant device in accordance with claim 6 wherein the concentration of said substance is uniform throughout said matrix structure.
13. An implant device in accordance with claim 6 wherein the concentration of said substance varies throughout said matrix structure.
14. An implant device in accordance with claim 6 wherein said implant device contains a plurality of said substances for release in sequence.
15. An implant device in accordance with claim 6 wherein said matrix structure is configured as a thin self-supporting film.
16. An implant device in accordance with claim 6 wherein said matrix structure is configured as a rod.
17. An implant device in accordance with claim 16 wherein said rod is formed as a core with a plurality of layers built up thereon, each layer having a different concentration of said sub-stance than its adjacent layer.
18. An implant device in accordance with claim 16 where-in said rod is formed with an axial opening therethrough thereby defining an internal surface as well as an external surface.
19. An implant device in accordance with claim 6 where-in said substance is a drug.
20. An implant device in accordance with claim 19 where-in said drug is a fertility control agent.
21. An implant device in accordance with claim 6 where-in said substance is a diagnostic agent.
22. A process for preparing an implant device for the controllable release of at least one substance into a living host into which it is implanted, comprising the steps of (a) blending the substance to be controllably released with poly-?-amino acid thereby to form a physical mixture which is a matrix structure capable of releasing said poly-?-amino acid by diffusion, by hydrolysis of said poly-?-amino acid by one or more enzymes present in said host or by a combination of diffusion and hydrolysis, (b) fabricating said physical mixture into a structural configuration suitable as an implant device.
23. A process in accordance with claim 22 wherein said poly-?-amino acid is a homopolymer.
24. A process in accordance with claim 22 wherein said poly-?-amino acid is a copolymer of at least two ?-amino acids.
25. A process in accordance with claim 22 wherein said poly-?-amino acid is a mixture of at least two poly-?-amino acids of different molecular weights.
26. A process in accordance with claim 22 wherein said blending comprises forming a solution of said poly-?-amino acid in a solvent inert to said substance and adding said substance to said solution.
27. A process in accordance with claim 26 wherein said solvent is a solvent for said substance and said blending com-prises forming a homogeneous solution.
28. A process in accordance with claim 26 wherein said solvent is a nonsolvent for said substance and said blending comprises dispersing said substance in the form of fine particulate material or a liquid into said solution of said poly-?-amino acid.
29. A process in accordance with claim 26 wherein said fabricating comprises forming said solution containing said sub-stance into a film of at least one layer.
30. A process in accordance with claim 22 wherein said blending comprises mixing said substance and said poly-?-amino acid both in powdered form, and said fabricating comprising forming said structural configuration with heat and pressure, the condition of said forming being such as not to degrade the substance or the poly-?-amino acid matrix.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US36118273A | 1973-05-17 | 1973-05-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1045977A true CA1045977A (en) | 1979-01-09 |
Family
ID=23420985
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA199,552A Expired CA1045977A (en) | 1973-05-17 | 1974-05-10 | Biodegradable, implantable drug delivery device, and process for preparing and using the same |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JPS5040718A (en) |
| CA (1) | CA1045977A (en) |
| CH (1) | CH591255A5 (en) |
| DE (1) | DE2424169A1 (en) |
| FR (1) | FR2287242A1 (en) |
| GB (1) | GB1462958A (en) |
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| JPS5423050B2 (en) * | 1972-04-28 | 1979-08-10 | ||
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-
1974
- 1974-05-10 CA CA199,552A patent/CA1045977A/en not_active Expired
- 1974-05-14 GB GB2136174A patent/GB1462958A/en not_active Expired
- 1974-05-16 CH CH674474A patent/CH591255A5/xx not_active IP Right Cessation
- 1974-05-17 JP JP5459574A patent/JPS5040718A/ja active Pending
- 1974-05-17 DE DE19742424169 patent/DE2424169A1/en not_active Withdrawn
- 1974-10-11 FR FR7434307A patent/FR2287242A1/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| FR2287242B1 (en) | 1981-06-12 |
| GB1462958A (en) | 1977-01-26 |
| CH591255A5 (en) | 1977-09-15 |
| DE2424169A1 (en) | 1974-12-05 |
| FR2287242A1 (en) | 1976-05-07 |
| JPS5040718A (en) | 1975-04-14 |
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