CA1291064C - Ultrasonically modulated polymeric devices for delivering drug compositions - Google Patents
Ultrasonically modulated polymeric devices for delivering drug compositionsInfo
- Publication number
- CA1291064C CA1291064C CA000507996A CA507996A CA1291064C CA 1291064 C CA1291064 C CA 1291064C CA 000507996 A CA000507996 A CA 000507996A CA 507996 A CA507996 A CA 507996A CA 1291064 C CA1291064 C CA 1291064C
- Authority
- CA
- Canada
- Prior art keywords
- composition
- polymeric matrix
- release
- drug
- polymer
- 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.)
- Expired
Links
Classifications
-
- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0047—Sonopheresis, i.e. ultrasonically-enhanced transdermal delivery, electroporation of a pharmacologically active agent
-
- 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G67/00—Macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing oxygen or oxygen and carbon, not provided for in groups C08G2/00 - C08G65/00
- C08G67/04—Polyanhydrides
Abstract
ABSTRACT OF THE DISCLOSURE
A composition such as a biologically active substance is delivered upon demand from a polymeric matrix by exposing the polymeric matrix containing the composition to ultrasonic energy.
A composition such as a biologically active substance is delivered upon demand from a polymeric matrix by exposing the polymeric matrix containing the composition to ultrasonic energy.
Description
1 ', BACKGROUND OF THE INVENTION
Recently there have been many advances iD the develo~-¦ ment o~ polymeric systems for delivering drugs~ However, nearly I, all of these systems release drugs at decreasina or, at best, con-¦¦ stant rates. Prior to this invention there has been no satisfac-¦¦ tory means for increase in the release rates on demand nor has ¦I there been any way to control drug administration extexnally from the body once the release process has co~menced from the implanted¦
i polymer-drug composltion. It has been ~roposed to magnetically modr ulate drug delivery from implanted oolymer-drug compositions by utilizing a composition that includes small magnetic beads imbedde~
in the polymer together with the drugu Release rates can be en-hanced when desired by an oscillating external maqnetic field. I
However, the extent to which release rates of the drug can be in- ¦
cxeased by the magnetic field has been unduly limited so that it ~l i is difficult to apply such a system to a patient who requires a ¦ relatively large d~sage of drug within a short period of time.
¦ Constant rate delivery also may not be suficient to de-livex drugs in a way that will closely rese~ble a homeostatic pro-¦
cess. This situation is particularly acute in ~he case of insulin I
administration for the diabeticO In diabetes mellitus, augmented j insulin delivery is require~ fox short time periods after meal cons~mption~
¦ Accordingly, it would be highly desirable to provide a i means for rapidly delivering drugs in vivo from an implant. It ! would be desirable to provide such a drug delivery system which i5 ~capable of delivering the drug a much higher rates than is avail-able from present drug delivery systems~
~;
!l , SUMMARY OF T~E INVENTION
1 In accordance with this invention, there is provided a process for delivering a composition such as a drug from a polymeric matrix which includes the composition. In one particular aspect of this invention, the composition comprises a drug which is delivered from a polymeric matrix that is implanted in vivo. Delivery of the composition from the polymeric matrix is activated by an external source of ultrasonic energy capable of degrading the polymeric matrix thereby to effect release of the composition incorporated into the polymeric matrix. The polymeric matrix containing the composition to be released is surrounded by a liquid medium such as that available in vivo and then is subjected to an ultrasound shock wave which accelerates degradation of the polymer and thereby effects release of the composition incorporated in the polymer. The process of this invention is suitable for release of any composition which can be incorporated wikhin a polymeric matrix and subsequently can be released through the liquid medium surrounding the polymeric matrix.
DESCRIPTION OF THE DRA~INGS
The detailed description of the present invention may be more easily and completely understood when taken in conjunction with the accompanying drawing, in which:
FIG. 1 is a cross-sectional view of a thermostatically controlled ultrasonic bath useful for measuring the increased rate of release of drugs from bioerodible polyanhydride matrices;
Recently there have been many advances iD the develo~-¦ ment o~ polymeric systems for delivering drugs~ However, nearly I, all of these systems release drugs at decreasina or, at best, con-¦¦ stant rates. Prior to this invention there has been no satisfac-¦¦ tory means for increase in the release rates on demand nor has ¦I there been any way to control drug administration extexnally from the body once the release process has co~menced from the implanted¦
i polymer-drug composltion. It has been ~roposed to magnetically modr ulate drug delivery from implanted oolymer-drug compositions by utilizing a composition that includes small magnetic beads imbedde~
in the polymer together with the drugu Release rates can be en-hanced when desired by an oscillating external maqnetic field. I
However, the extent to which release rates of the drug can be in- ¦
cxeased by the magnetic field has been unduly limited so that it ~l i is difficult to apply such a system to a patient who requires a ¦ relatively large d~sage of drug within a short period of time.
¦ Constant rate delivery also may not be suficient to de-livex drugs in a way that will closely rese~ble a homeostatic pro-¦
cess. This situation is particularly acute in ~he case of insulin I
administration for the diabeticO In diabetes mellitus, augmented j insulin delivery is require~ fox short time periods after meal cons~mption~
¦ Accordingly, it would be highly desirable to provide a i means for rapidly delivering drugs in vivo from an implant. It ! would be desirable to provide such a drug delivery system which i5 ~capable of delivering the drug a much higher rates than is avail-able from present drug delivery systems~
~;
!l , SUMMARY OF T~E INVENTION
1 In accordance with this invention, there is provided a process for delivering a composition such as a drug from a polymeric matrix which includes the composition. In one particular aspect of this invention, the composition comprises a drug which is delivered from a polymeric matrix that is implanted in vivo. Delivery of the composition from the polymeric matrix is activated by an external source of ultrasonic energy capable of degrading the polymeric matrix thereby to effect release of the composition incorporated into the polymeric matrix. The polymeric matrix containing the composition to be released is surrounded by a liquid medium such as that available in vivo and then is subjected to an ultrasound shock wave which accelerates degradation of the polymer and thereby effects release of the composition incorporated in the polymer. The process of this invention is suitable for release of any composition which can be incorporated wikhin a polymeric matrix and subsequently can be released through the liquid medium surrounding the polymeric matrix.
DESCRIPTION OF THE DRA~INGS
The detailed description of the present invention may be more easily and completely understood when taken in conjunction with the accompanying drawing, in which:
FIG. 1 is a cross-sectional view of a thermostatically controlled ultrasonic bath useful for measuring the increased rate of release of drugs from bioerodible polyanhydride matrices;
~29~0~
1 FIGS. 2a and 2b respectively are graphs illustrating the rate of release for drugs and the individual modulation ratios over time from molded poly matrices with and without the use of 75 KHz ultrasonic energy; and FIGS. 3a and 3b respectively are graphs illustrating the degradation rates for molded poly matrices and individual modulation ratios over time with and without the use of 75 KHz ultrasonic energy.
DESCRIPTION OF SPECIFIC EMBODIMENTS
In accordance with this invention, a polymeric matrix containing the composition which is desired to be released in a controlled manner is first produced. In the case of the embodiment wherein it is desired to release drugs from the polymeric matrix in vivo, the polymeric matrix is biocompatible. The polymeric matrix is capable of being degraded by ultrasonic energy such that the incorporated composition is released at a rate within a desired release range, or, in the case of non-degradable polymers, release is enhanced presumably due to the effects of cavitation or other mechanical effects.
Representative suitable polymers include polyanhydrides having the formula:
~ ~ ~ ~
wherein R or R is a linking moity having a hydrophobicity such as alkyl group bearing from 1 to 20 carbon atoms~ a backbone having aromatic moities such as p-carboxyphenoxy methane, benzyl substituted or unsubstituted benzenes or 0~4 1 pyridine or other heterocyclic aromatic or the like. The homopolymer (R=Rl) and the copolymer (R=Rl) can have an average degree of polymerization ranging from about 10 ko 106. The monomers in the copolymer can be distributed regularly or at random. Since the anhydride linkage is highly reactive toward hydrolysis, it is preferable that the polymer backbone be hydrophobic in order to attain the heterogeneous erosion of the encapsu-ated composition.
Hydrophobicity can be regulated easily, for example, by regulating the concentration of aromatic moities in the linking backbone, or by monitoring the monomer ratio in the copolymer. A particularly suitable backbone comprises the acid such as l-phenylamine, tryptophan, tyrosine or glycine. Other suitable polymers include ethylene-vinyl acetate, polylactic acid, polyglutamic acid, polycaprolactone, lactic/glycolic acid copolymers, polyorthoesters, polyamides or the li~e. Non-degradable polymers include ethylene-vinyl acetate, silicone, hydrogels such as polyhydroxyethylmethacrylate, polyvinyl alcohol and the like.
Examples of suitable biologically active substances are interferon, anti-angiogenesis factors, antibodies, antigens, polysaccharides, growth factors, hormones including insulin, glucogen, parathyroid and pituitary hormones, calcitonin, vasopressin renin, prolactin, growth hormones, thyroid stimulating hormone, cortico-- 3a -.~: ` J
~.29~L0~
~, 1 !~trophin, follicle stimulating hormone, luteinizing hormone and ,~chorionic sonadotropins; enzymes inclu~in~ soybean, tyrpsin inhib-.
,~itor, lysozyme, catalase, tumor angioenesis factor, cartila~e ,~ factor, transferases, hydrolases, lysases, isomerases~ proteases, S !lligases and oxidoreductases such as esterases, phos2hatases, ~ly-tisidases, and pe~tidases; enzyme inhibitors such as leupeptin, ant-'jipain, chrymQstatin and ~epstatin; and drugs such as steroids, antl-¦cancer drugs or antibiotics. Other re resentative c~mpositions I¦which can be encapsulated within a polymeric matrix and subsequentt ¦~ly released with ultrasonic energy when the polymeric matrix is jsurrounded by a liquid or a solid medium include aromas such as perfu~es, pheromones, insecticides, pesticides or the like.
The relative proportions of the composition to be re-leased to form the two-phased system can be modified over a wide range depending upon the molecule to be administered or the de-sired effect. Generally, the ~olecule can be present in an a~.ount, which will be released over control~ed periods of time, accordin~ ¦
~to predetermined desired rates, which rates are dependent unon ¦
¦Ithe initial concentration of the active molecule in the pol~meric ¦
!¦matrix and the level of ultrasonic ener~y to which it is subjected;
This necessarily implies a quantity of molecule great~r than the standard single dosage. Proportions suitable for the pur~ose~ ¦
of this invention can ranoe from about 0.01 to 50 parts by wioht o~
the active composition to between about 99.99 and about 50 ~arts by i weish~ of the polymeric ma~rix, preferably between about 10 and about 30 parts by wei~ht in the case of ~he biolo~ically active molecule to be implanted to give 100 parts hy wei~ht of the final ,system.
~ I The polymeric ~atrix in the co~position to be released ` , 30 l¦can be admixed intimately in any convenient manner, preferably by ¦
Il . , '', It -4 Ii '.
`~J IJ
9~0~qL
.
1 mixin~ the components as powders and ~ubsequently forming the mi'x-'~ ture into a desired shape such as by thermal forming at a temper-'' ature less than that which the composition will become degraded 1 and at which the ~olymer has desired morphological prooerties.
S l; Generally, the final comp~sition is ~ormed as a slab which can be !I circular, rectangular or the like and having a thickness ~etween ~¦ about 0.1 mm and about 100 mm in a total surface area be-!~ tween about .01 cm and about 1,Q00 cm preferably'be~ween about ¦1 1 cm2 and about 100 cm2. The delivery systems o~ this invention 10 1 can be manufactured as devices that can t~ke a wide range of shape~, sizes and forms by delivering the active molecule to differen~ en-vironments of use. For example, the systems can be made as devic including buccal and oral devices; vaginal and intrauterine device~
of cylindrical, bullet, elliptical, circular, bulbous, loo, bow ¦¦or any other shape that lends itsel to placement in a particulax ! i l~environment such as an invivo implant. The devices'also include ¦¦ ocular devices of any geometric shape for comfortable pla~ement in the cul de sac such as ellipsoid, bean, banana, circular, rec-¦¦ tangular, doughnut, crescent and heart-ring shaped devices. In 2Q ¦cross section, the ocular devices can be doubly convex, concave, ¦ oconcavo-convex and the like. The dimensions of the ocular de~ l vices can vary acc:ording to the size of the eye, with satisfactoryj ye devices generally having a len~th of 4-20 mm or a width o 1-15 mm and a thickness of 0u 1-4 mm. Other'devices made accord-~ ing to this invention include implants, anal, pes~aries andprosthetic devices artificial ~lands for dispensina a pharmaceu ¦jtically active molecular agent having a physiological function essentially equivalent to a corresoonding meutral aland, cervical, nasal, ear and skin devices.
.. Ii I
,!
~9~
1 The polymeric matrix utilized in the pre~ent invention can be manufactured by standard techniques ~rovided as is import-ant to this invention that such manufacture includes process steps such as blendin~, mixina or the equivalent thereof for structu~
rally defining the ststem comprising the molecule to be released and the polymeric matrix. For example, one suitable ~ethod for making the systems comprises the polymer and an anpropriate sol-vent, thereby to form a casting solution, mixina a known amount of the composition to be released in the castin~ solution, char~-ing the solution into a mold and then drying the mold, usually under vacuum, causin~ the polymer to precipitate in forming the matrix with the molecule to be released therein. Alternatively, the polymer in the form of a powder can be admixecl with the mole-cule to be released in the form of a powder and then molded under adequate temperature and ~ressure to the desired shape, throu~h in~ection, compression, or extrusion.
After the polymeric matrix containing the com~ositio~
or molecule to be released is i~planted in the desired liquid environment, such as in vivo, it is subjected to ultrasonic en~rgy to partially degrade the Polymer thereby to release the compositio~
or molecule encapsulated by the polymer. It is believed that main polymer chain rupture in the case of biodegradable polymers is thou~ht to be induced by shock waves created throuqh the cavita-tion which are assumed to cause a rapid compression with subsequen~
expansion of the surroundins liquid or solid. Apart from the action of shock waves, the collapse of cavitation bubbles is thoug~t to create pronounced perturbation in the surrounding liquid which can possibly induce other chemioal effects as well. The aqitation may increase the accessibility of liqui~ molecules, eg water, to the polymer. In the case of nonde~radable polymers, cavitation enhance the diffusion process of molecules out of these polymers.
The acoustic energy and the extent of modulation can )fi~
readily be moditored over wide xange of frequencieR and irlten~ltie~.
This of course will depend upon the ~articular ~olymeric matrix utilized in the composition which is encapsulated by the polymeric matrix. In order to assure safety of the in vivo implant to the patient, a particular poly~eric matrix-composition system can be easily tested in a liquid medium which approaches that of an in~
v _ environment and observing the rate of release of the encap-sulated composition under the influence of ultrasonic energy.
Representative suitable ultrasonic fre~uencies are between about 20 KHz and about 1000 KHz, usually between about 50 KHz and about 200 KHz while the intensities can range between about 1 watt and about 30 wattsl generally bet~een about S w and about 20 w. The times at which the polymer matric-composition system are exposed to ultrasonic energy obviously can vary over a wide range depend-ing ~pon the environment of use. Generally suitable times are ~sually between about 1 minute an~ ~ about 2 hours.
It has been found that in acoordance with this invention the release rates of the molecules, eg biologically active sub-stances from a polymeric matrix can be repeatedly modulated at will from a position external to the environment of use by ultra-sonic energy. Upon subjecting a polymeric matrix to ultrasonic energy, increased release rates of more than about 200 fold can be routinely obtained as compared to the best that has been done with the above-described magnetic ststem of thirty ~old. In addi-tion, diagnostic ultrasound techniques are a routine technique which is safe, painless and riskless in many medical applications~
In neurology, for example, ultrasonic testing is used to detect brain tumors, clots, and identify subdural hematomas. The power levels employed in ultrasonic testing are very low and on ~he basi~
1 of extensive clinical and experimental data, these tests are con-sidered quite safe for the patient~ ~ccordingly, the process utilized in the present invention also is quite safe.
The following examples illustrate the present invention and are not intended to limit the same.
Bioerodible polyanhydrides were used as the drug carrier matrix. The Polyl bis(p-carboxy phenoxy) alkane anhydride~ having the strucural formula in equation 1 were utilized.
~ 1 ~ O ~ H~ n ~ C ---O
Equation 1 Drug incorporation matrices were formulated either by com~ression or injection molding a mixtUre of finely ground sieved ~90-150 m~
polymer and ~rug were pressed into circular discs in a Carver test cylinder outfit at 30 Kpfi at 5 C above Tg for ten minutes. In-jection'molding was performed in an SCI mini max injection molder.
A molding temperature of 10C above the Tm was used. The polymer drug matrix was extruded once for ~etter mixing before the final molding. The basing agent used for smal~ p-nitroaniline withload ing levels up ~o lO~~ercent.
The triggering device was a RAI Research Corporation Ultrasonic Cleaner model 250, which generated an ultrasonic fre-quency of 75 KH~ in a stainless steel tank of 3.5 inches by 3.5 inches by 2.5 inches filled with water. Drug incorporated poly-meric matrices were placed in a jacket vial filled with phosphate buffer, pH 7.4 at 37C and were exposed to alternating periods of triggering and non triggering in the ultrasonic ba~h. (~l~ure l)~
l after each period the sample was transferred to ~resh release media. The absorption of the release media was determined spectrophotometrically at 250 nm for monomer degradation products detection and 381 nm for the small p-nitroanilin.
The effects of the ultrasonic triggering of release rates of injection molded poly [bis(p-carboxy phenoxy)methane] PCPM samples on degradation are shown in figures 2b and 3b. As can be seen there is a good l~ correlation between the release rates and degradation, which suggests that the increase in release rates during the triggering is mainly due to enhanced erosion o~ the polymeric matrix. However, modulation has also been observed, although to a somewhat lesser extent, when molecules such as bovine serum albumin or insulin were incorporated into nondegradable polymers such as ethylene vinyl acetate (40 wt%~. When such molecules were cast within the polymer using published techniques, ((Langer R., Meth. Enzymol.) 73,57, 1981) and ultrasound was applied as above. The extent of modulation is more clearly expressed as the ratio of the rate of release in a given period of ultrasound exposure compared to the actual rates immediately preceding and following exposure (figures 2a and 3a). This study demonstrates that in vitro release of a drug from a polymeric system can be increased on demand by ultrasound.
_ g .~; ,i-" ~,,, ,~,.
1 FIGS. 2a and 2b respectively are graphs illustrating the rate of release for drugs and the individual modulation ratios over time from molded poly matrices with and without the use of 75 KHz ultrasonic energy; and FIGS. 3a and 3b respectively are graphs illustrating the degradation rates for molded poly matrices and individual modulation ratios over time with and without the use of 75 KHz ultrasonic energy.
DESCRIPTION OF SPECIFIC EMBODIMENTS
In accordance with this invention, a polymeric matrix containing the composition which is desired to be released in a controlled manner is first produced. In the case of the embodiment wherein it is desired to release drugs from the polymeric matrix in vivo, the polymeric matrix is biocompatible. The polymeric matrix is capable of being degraded by ultrasonic energy such that the incorporated composition is released at a rate within a desired release range, or, in the case of non-degradable polymers, release is enhanced presumably due to the effects of cavitation or other mechanical effects.
Representative suitable polymers include polyanhydrides having the formula:
~ ~ ~ ~
wherein R or R is a linking moity having a hydrophobicity such as alkyl group bearing from 1 to 20 carbon atoms~ a backbone having aromatic moities such as p-carboxyphenoxy methane, benzyl substituted or unsubstituted benzenes or 0~4 1 pyridine or other heterocyclic aromatic or the like. The homopolymer (R=Rl) and the copolymer (R=Rl) can have an average degree of polymerization ranging from about 10 ko 106. The monomers in the copolymer can be distributed regularly or at random. Since the anhydride linkage is highly reactive toward hydrolysis, it is preferable that the polymer backbone be hydrophobic in order to attain the heterogeneous erosion of the encapsu-ated composition.
Hydrophobicity can be regulated easily, for example, by regulating the concentration of aromatic moities in the linking backbone, or by monitoring the monomer ratio in the copolymer. A particularly suitable backbone comprises the acid such as l-phenylamine, tryptophan, tyrosine or glycine. Other suitable polymers include ethylene-vinyl acetate, polylactic acid, polyglutamic acid, polycaprolactone, lactic/glycolic acid copolymers, polyorthoesters, polyamides or the li~e. Non-degradable polymers include ethylene-vinyl acetate, silicone, hydrogels such as polyhydroxyethylmethacrylate, polyvinyl alcohol and the like.
Examples of suitable biologically active substances are interferon, anti-angiogenesis factors, antibodies, antigens, polysaccharides, growth factors, hormones including insulin, glucogen, parathyroid and pituitary hormones, calcitonin, vasopressin renin, prolactin, growth hormones, thyroid stimulating hormone, cortico-- 3a -.~: ` J
~.29~L0~
~, 1 !~trophin, follicle stimulating hormone, luteinizing hormone and ,~chorionic sonadotropins; enzymes inclu~in~ soybean, tyrpsin inhib-.
,~itor, lysozyme, catalase, tumor angioenesis factor, cartila~e ,~ factor, transferases, hydrolases, lysases, isomerases~ proteases, S !lligases and oxidoreductases such as esterases, phos2hatases, ~ly-tisidases, and pe~tidases; enzyme inhibitors such as leupeptin, ant-'jipain, chrymQstatin and ~epstatin; and drugs such as steroids, antl-¦cancer drugs or antibiotics. Other re resentative c~mpositions I¦which can be encapsulated within a polymeric matrix and subsequentt ¦~ly released with ultrasonic energy when the polymeric matrix is jsurrounded by a liquid or a solid medium include aromas such as perfu~es, pheromones, insecticides, pesticides or the like.
The relative proportions of the composition to be re-leased to form the two-phased system can be modified over a wide range depending upon the molecule to be administered or the de-sired effect. Generally, the ~olecule can be present in an a~.ount, which will be released over control~ed periods of time, accordin~ ¦
~to predetermined desired rates, which rates are dependent unon ¦
¦Ithe initial concentration of the active molecule in the pol~meric ¦
!¦matrix and the level of ultrasonic ener~y to which it is subjected;
This necessarily implies a quantity of molecule great~r than the standard single dosage. Proportions suitable for the pur~ose~ ¦
of this invention can ranoe from about 0.01 to 50 parts by wioht o~
the active composition to between about 99.99 and about 50 ~arts by i weish~ of the polymeric ma~rix, preferably between about 10 and about 30 parts by wei~ht in the case of ~he biolo~ically active molecule to be implanted to give 100 parts hy wei~ht of the final ,system.
~ I The polymeric ~atrix in the co~position to be released ` , 30 l¦can be admixed intimately in any convenient manner, preferably by ¦
Il . , '', It -4 Ii '.
`~J IJ
9~0~qL
.
1 mixin~ the components as powders and ~ubsequently forming the mi'x-'~ ture into a desired shape such as by thermal forming at a temper-'' ature less than that which the composition will become degraded 1 and at which the ~olymer has desired morphological prooerties.
S l; Generally, the final comp~sition is ~ormed as a slab which can be !I circular, rectangular or the like and having a thickness ~etween ~¦ about 0.1 mm and about 100 mm in a total surface area be-!~ tween about .01 cm and about 1,Q00 cm preferably'be~ween about ¦1 1 cm2 and about 100 cm2. The delivery systems o~ this invention 10 1 can be manufactured as devices that can t~ke a wide range of shape~, sizes and forms by delivering the active molecule to differen~ en-vironments of use. For example, the systems can be made as devic including buccal and oral devices; vaginal and intrauterine device~
of cylindrical, bullet, elliptical, circular, bulbous, loo, bow ¦¦or any other shape that lends itsel to placement in a particulax ! i l~environment such as an invivo implant. The devices'also include ¦¦ ocular devices of any geometric shape for comfortable pla~ement in the cul de sac such as ellipsoid, bean, banana, circular, rec-¦¦ tangular, doughnut, crescent and heart-ring shaped devices. In 2Q ¦cross section, the ocular devices can be doubly convex, concave, ¦ oconcavo-convex and the like. The dimensions of the ocular de~ l vices can vary acc:ording to the size of the eye, with satisfactoryj ye devices generally having a len~th of 4-20 mm or a width o 1-15 mm and a thickness of 0u 1-4 mm. Other'devices made accord-~ ing to this invention include implants, anal, pes~aries andprosthetic devices artificial ~lands for dispensina a pharmaceu ¦jtically active molecular agent having a physiological function essentially equivalent to a corresoonding meutral aland, cervical, nasal, ear and skin devices.
.. Ii I
,!
~9~
1 The polymeric matrix utilized in the pre~ent invention can be manufactured by standard techniques ~rovided as is import-ant to this invention that such manufacture includes process steps such as blendin~, mixina or the equivalent thereof for structu~
rally defining the ststem comprising the molecule to be released and the polymeric matrix. For example, one suitable ~ethod for making the systems comprises the polymer and an anpropriate sol-vent, thereby to form a casting solution, mixina a known amount of the composition to be released in the castin~ solution, char~-ing the solution into a mold and then drying the mold, usually under vacuum, causin~ the polymer to precipitate in forming the matrix with the molecule to be released therein. Alternatively, the polymer in the form of a powder can be admixecl with the mole-cule to be released in the form of a powder and then molded under adequate temperature and ~ressure to the desired shape, throu~h in~ection, compression, or extrusion.
After the polymeric matrix containing the com~ositio~
or molecule to be released is i~planted in the desired liquid environment, such as in vivo, it is subjected to ultrasonic en~rgy to partially degrade the Polymer thereby to release the compositio~
or molecule encapsulated by the polymer. It is believed that main polymer chain rupture in the case of biodegradable polymers is thou~ht to be induced by shock waves created throuqh the cavita-tion which are assumed to cause a rapid compression with subsequen~
expansion of the surroundins liquid or solid. Apart from the action of shock waves, the collapse of cavitation bubbles is thoug~t to create pronounced perturbation in the surrounding liquid which can possibly induce other chemioal effects as well. The aqitation may increase the accessibility of liqui~ molecules, eg water, to the polymer. In the case of nonde~radable polymers, cavitation enhance the diffusion process of molecules out of these polymers.
The acoustic energy and the extent of modulation can )fi~
readily be moditored over wide xange of frequencieR and irlten~ltie~.
This of course will depend upon the ~articular ~olymeric matrix utilized in the composition which is encapsulated by the polymeric matrix. In order to assure safety of the in vivo implant to the patient, a particular poly~eric matrix-composition system can be easily tested in a liquid medium which approaches that of an in~
v _ environment and observing the rate of release of the encap-sulated composition under the influence of ultrasonic energy.
Representative suitable ultrasonic fre~uencies are between about 20 KHz and about 1000 KHz, usually between about 50 KHz and about 200 KHz while the intensities can range between about 1 watt and about 30 wattsl generally bet~een about S w and about 20 w. The times at which the polymer matric-composition system are exposed to ultrasonic energy obviously can vary over a wide range depend-ing ~pon the environment of use. Generally suitable times are ~sually between about 1 minute an~ ~ about 2 hours.
It has been found that in acoordance with this invention the release rates of the molecules, eg biologically active sub-stances from a polymeric matrix can be repeatedly modulated at will from a position external to the environment of use by ultra-sonic energy. Upon subjecting a polymeric matrix to ultrasonic energy, increased release rates of more than about 200 fold can be routinely obtained as compared to the best that has been done with the above-described magnetic ststem of thirty ~old. In addi-tion, diagnostic ultrasound techniques are a routine technique which is safe, painless and riskless in many medical applications~
In neurology, for example, ultrasonic testing is used to detect brain tumors, clots, and identify subdural hematomas. The power levels employed in ultrasonic testing are very low and on ~he basi~
1 of extensive clinical and experimental data, these tests are con-sidered quite safe for the patient~ ~ccordingly, the process utilized in the present invention also is quite safe.
The following examples illustrate the present invention and are not intended to limit the same.
Bioerodible polyanhydrides were used as the drug carrier matrix. The Polyl bis(p-carboxy phenoxy) alkane anhydride~ having the strucural formula in equation 1 were utilized.
~ 1 ~ O ~ H~ n ~ C ---O
Equation 1 Drug incorporation matrices were formulated either by com~ression or injection molding a mixtUre of finely ground sieved ~90-150 m~
polymer and ~rug were pressed into circular discs in a Carver test cylinder outfit at 30 Kpfi at 5 C above Tg for ten minutes. In-jection'molding was performed in an SCI mini max injection molder.
A molding temperature of 10C above the Tm was used. The polymer drug matrix was extruded once for ~etter mixing before the final molding. The basing agent used for smal~ p-nitroaniline withload ing levels up ~o lO~~ercent.
The triggering device was a RAI Research Corporation Ultrasonic Cleaner model 250, which generated an ultrasonic fre-quency of 75 KH~ in a stainless steel tank of 3.5 inches by 3.5 inches by 2.5 inches filled with water. Drug incorporated poly-meric matrices were placed in a jacket vial filled with phosphate buffer, pH 7.4 at 37C and were exposed to alternating periods of triggering and non triggering in the ultrasonic ba~h. (~l~ure l)~
l after each period the sample was transferred to ~resh release media. The absorption of the release media was determined spectrophotometrically at 250 nm for monomer degradation products detection and 381 nm for the small p-nitroanilin.
The effects of the ultrasonic triggering of release rates of injection molded poly [bis(p-carboxy phenoxy)methane] PCPM samples on degradation are shown in figures 2b and 3b. As can be seen there is a good l~ correlation between the release rates and degradation, which suggests that the increase in release rates during the triggering is mainly due to enhanced erosion o~ the polymeric matrix. However, modulation has also been observed, although to a somewhat lesser extent, when molecules such as bovine serum albumin or insulin were incorporated into nondegradable polymers such as ethylene vinyl acetate (40 wt%~. When such molecules were cast within the polymer using published techniques, ((Langer R., Meth. Enzymol.) 73,57, 1981) and ultrasound was applied as above. The extent of modulation is more clearly expressed as the ratio of the rate of release in a given period of ultrasound exposure compared to the actual rates immediately preceding and following exposure (figures 2a and 3a). This study demonstrates that in vitro release of a drug from a polymeric system can be increased on demand by ultrasound.
_ g .~; ,i-" ~,,, ,~,.
Claims (8)
1. A process for delivering a composition on demand which comprises:
incorporating said composition within a polymeric matrix, surrounding said composition and polymeric matrix with an aqueous medium, and exposing said polymeric matrix to ultrasonic energy wherein said polymeric matrix is formed of a degradable polyanhydride which is hydrolysed by the aqueous medium when exposed to the ultransonic energy whereby said polymeric matrix is degraded and said composition released from said matrix.
incorporating said composition within a polymeric matrix, surrounding said composition and polymeric matrix with an aqueous medium, and exposing said polymeric matrix to ultrasonic energy wherein said polymeric matrix is formed of a degradable polyanhydride which is hydrolysed by the aqueous medium when exposed to the ultransonic energy whereby said polymeric matrix is degraded and said composition released from said matrix.
2. The process of claim 1 wherein said composition is a biologically active substance.
3. The process of claim 2 wherein said biologically active substance is a drug.
4. The process of claim 2 wherein said biologically active composition is insulin.
5. The process of claim 1 wherein the composition is a fragrance.
6. The process of claim 1 wherein said composition is a pheromone.
7. A composition within a polymeric matrix, capable of being degraded in an aqueous medium by ultrasonic energy whereon said polymeric matrix is a degradable polyanhydride.
8. A composition within a polymeric matrix according to claim 7, for implantation in vivo, wherein said composition is a biologically active substance.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/633,366 US4657543A (en) | 1984-07-23 | 1984-07-23 | Ultrasonically modulated polymeric devices for delivering compositions |
| CA000507996A CA1291064C (en) | 1984-07-23 | 1986-04-30 | Ultrasonically modulated polymeric devices for delivering drug compositions |
| DE198686106725T DE245535T1 (en) | 1984-07-23 | 1986-05-16 | ULTRASONICALLY CONTROLLED POLYMERS FOR DELIVERING ACTIVE SUBSTANCES. |
| EP86106725A EP0245535B1 (en) | 1984-07-23 | 1986-05-16 | Ultrasonically modulated polymeric devices for delivering compositions |
| DE8686106725T DE3685958T2 (en) | 1984-07-23 | 1986-05-16 | ULTRASONICALLY CONTROLLED POLYMERS FOR DELIVERING ACTIVE SUBSTANCES. |
| US06/936,000 US4779806A (en) | 1984-07-23 | 1986-11-28 | Ultrasonically modulated polymeric devices for delivering compositions |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/633,366 US4657543A (en) | 1984-07-23 | 1984-07-23 | Ultrasonically modulated polymeric devices for delivering compositions |
| CA000507996A CA1291064C (en) | 1984-07-23 | 1986-04-30 | Ultrasonically modulated polymeric devices for delivering drug compositions |
| EP86106725A EP0245535B1 (en) | 1984-07-23 | 1986-05-16 | Ultrasonically modulated polymeric devices for delivering compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1291064C true CA1291064C (en) | 1991-10-22 |
Family
ID=39628920
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000507996A Expired CA1291064C (en) | 1984-07-23 | 1986-04-30 | Ultrasonically modulated polymeric devices for delivering drug compositions |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US4657543A (en) |
| EP (1) | EP0245535B1 (en) |
| CA (1) | CA1291064C (en) |
| DE (2) | DE3685958T2 (en) |
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-
1984
- 1984-07-23 US US06/633,366 patent/US4657543A/en not_active Expired - Lifetime
-
1986
- 1986-04-30 CA CA000507996A patent/CA1291064C/en not_active Expired
- 1986-05-16 DE DE8686106725T patent/DE3685958T2/en not_active Expired - Lifetime
- 1986-05-16 DE DE198686106725T patent/DE245535T1/en active Pending
- 1986-05-16 EP EP86106725A patent/EP0245535B1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| DE3685958D1 (en) | 1992-08-13 |
| DE3685958T2 (en) | 1993-01-14 |
| EP0245535A1 (en) | 1987-11-19 |
| EP0245535B1 (en) | 1992-07-08 |
| US4657543A (en) | 1987-04-14 |
| DE245535T1 (en) | 1989-03-30 |
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