CA1053581A - Sustained release compositions - Google Patents
Sustained release compositionsInfo
- Publication number
- CA1053581A CA1053581A CA180,693A CA180693A CA1053581A CA 1053581 A CA1053581 A CA 1053581A CA 180693 A CA180693 A CA 180693A CA 1053581 A CA1053581 A CA 1053581A
- Authority
- CA
- Canada
- Prior art keywords
- active material
- methyl
- water
- composition
- betaine
- 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
Abstract
ABSTRACT OF THE DISCLOSURE
A sustained release dosage composition is disclosed. The composition comprises a complex of a therapeutically active material and a water-swellable betaine polymer selected from the group consisting of homopolymers of a betaine having the formula wherein R1 is hydrogen or methyl; A is oxygen or -NH-; R2 is ethylene, propylene, 2-hydroxypropylene or 2-acetoxypropylene;
R3 and R4 are alkyl having 1 to 4 carbon atoms; n is 1 to 4 and X- is SO3- or CO2-; and copolymers of monomers consisting essen-tially of about 5.0 to about 99.0 percent by weight of said betaine and about 1.0 to about 95.0 percent by weight of a monomer copolymerizable therewith to provide a water-swellable polymer.
A sustained release dosage composition is disclosed. The composition comprises a complex of a therapeutically active material and a water-swellable betaine polymer selected from the group consisting of homopolymers of a betaine having the formula wherein R1 is hydrogen or methyl; A is oxygen or -NH-; R2 is ethylene, propylene, 2-hydroxypropylene or 2-acetoxypropylene;
R3 and R4 are alkyl having 1 to 4 carbon atoms; n is 1 to 4 and X- is SO3- or CO2-; and copolymers of monomers consisting essen-tially of about 5.0 to about 99.0 percent by weight of said betaine and about 1.0 to about 95.0 percent by weight of a monomer copolymerizable therewith to provide a water-swellable polymer.
Description
lO~S81 ~EO-939 ~ his i.nvention r~lates to a sust~lre~ release do6age c~m ~osit~.on. ~ore ~articularlvr ~hi.s invention relat~s to ~ su~-tained release dosaye composition wherein a.~herapeutically acti~e materlal is ionically comp'exed to a water~sr~!ella~l~
polymeric ~arrier.
Va~lou~ sustained release compositions are well kno~rn in the art. For example, U.S. P~tent 3,577,512 discloses hydro-philic acrylate and methacrylate p~lymers whi.ch can be use~ ~
in s~stained release dosage forms. While functional for th~ -intended use, such gels serve sclely as physical carriers pro- :~
viding no interaction with the medication. U.S. Patent 3,551,556 teachss tllat it is known to have drugs ~ound ~y ionic or coordi-nation bonds to a soluble linear polymeric drug carrier, while IJ,S. Patent 3,~0,563 discloses the entrapment of ~ru~s in wat~r-soluhle hydro~;yal~yl acrylate or methacrylate polymers. Sustained release salts formed by reacting pharmacologically active ~eaX base amines with li~htly cross linked carboxylic acid or anhydride polymers are de~cribed in U.S. Patent 3,121,0~3. ..
Wow it has been ~ound in accordance ~lith this inv~ntion that therapeutically active materials ca~ be complexeG to a ~ ~ `
water-swellable carrier to provide stable, homogeneo~s dosag~ .
compositions having good sust.ai.ned release properties. . ~
More in detail, the sustained release dosage compositions of : -this invention comprise a cor.~plex of a. a therapeutically active material in an amount ~u~fi~ient to provide the desired ac~ivity upon release from sai~. composition, an~
~. a water-swellable betaine polymer selected from the gr~ consistil~ of h~mopolymers !
i~ S 3 5 8 ~ ~0-939 o ~ betaina ha~.ing the foxmu~.a ~ 3 ~2C C CA-R~-N - (CH2) -X
wherein ~1 is l~ydroge~ or methyl; A is oxygen or -NH-; ~2 is ethylene, propylene, 2-hydroxy- ;
propylene or 2-acetoxypxopylene; P~3 and R4 are alkyl having 1 to 4 car~on atoms; n is 1 to 4 and X is SO3 or CO2 ; and copolymers of mono mers consisting essentially of about 5.0 to about 99.0 percent by weight of said betaine and about 1.0 to about 95.0 percent ~y weight `~
of a monomer copolym~rizable therewith to pro~
vid~ a water-swellable polymer. :. .
The therapeutically acti~e material can be an organic or inorga~ic acid, base or salt. Exemplary active materials include antibiotics such as penicillin G, penicillin G potassium, te~ra~
cycline, tetracycline llydrochloride, erythromycin and erythro~ycin ~ .
stearate; sedativ~s such as phenoharbital, phenobarbital sodium, : -mepho~rbi~al ~nd me~hobarbital sodium; hypertensive agents such as ephedrine, ephearine hydrochloride, ~or epinephrine ~nd ~or-epinephrine hydrochloride; vasodilators such as papaverine, papaverine hydrochloride, dioxyli~e phospha~e and nicotinyl tartrate; tranquilizers such as chlorodiazepoxide, chloro- ;~
diazepoxide hydrochlorlde and di~ze~am hydrochloride; drug~ :
for the treatment of glaucomo such as pilocarpine and pilocarpine hydroc~loride; an~iconvulsants ~uch as diphenylhyaantoin and ~ :
diphenylhydantoin sodium; analges.ics such as ca~cium ~
~ lO~S~ KEO-939 ac~tyls~lic~lat~, ac~ty?.~alicylic acid, sodium salicylate, .or~hine ~nd ~orp~.ir.~ sulfate; anticholir.er~Jic compounds suc~
as atropine and atropille sulfatc; antimalarial compounds s~ch as cl~loroquine and cihlol-vquir.e hydrochloride; lccal anest~ietics such as procaine anrl procaine hydrochloride; antitussive co~-pounds ~uch as codeine and co~eine phosphate; antihistamin~s such as diphenylllydramir.e, diphenylhydramine hydrochloride, pyrilamine an~ pyrilaminc maleate; etc. Salts are preferred for complexiny to pro~ide the compositions of this invention~
'~he carboxyDetaine and sulfobetaine hvmopolymer~ are known materials. Tllus, the sulfobetaine ho~.opolymers are described in U.S. ~atent 3,497,482, while U.S. Patent 2,777,872 descrioes ::
carboxybetaine homopolymer5. Certain betaine copolymers are disclosed in U.S. Patent ~,671,502, while other co~olymers can be prepared as described hereinafter. :
rrhus, the copolymers suitable for use in this inYention are provided by polymexizing the betaine monomer with any comono~.er p~lymerizable therewith; The comonomer may alter or moai~y th~
hydrophilicity of the betaine homopolymer, provided that the re~
sultant copolymer retains hydrophilic and water-swellable prop-erties. Suitable comonorners include water-insoluble and partially water-soluble monomers, for example, acrylic and me~hacrylic esters such as methyl methacrylate, ethyl methacrylate, methyl acrylate, ethyl acrylate, 2-ethylhexyl acrylate, chloroethyl acrylate, hydroxypropyl methacrylate, etc.; vinyl esters SUC21 as vinyl acetate, vinyl propiona~e, vinyl ~utyrate, vinyl laurate, vinyl stearate, etc.; acrylonitri7e; styrene~ etc.
Ex~mpli~icati~e water-soluble monomers i~clude acrylic acid and methacry~.ic acid; hydroxyal]cyl acrylates and methacrylates such as hydro~:yethyl acrylate, hydro~yethy]. ~ethac~ylate, .
,, . . , .. . . , . , - .- , . . . .
JIUV ~ J_~
ll~S~581 hydroxyp~opyl acrylat~, etc.; ~inyl ethers such as vinyl rlethyl eth~r, v~n~ ethyl ether, etc.: v.inyl pyrollidone: acrylamide and methacrylamide.
The copolymers c~n be readily prep~ed by polym~rizing the carbo~ybetaine or ~ulfo~etaine or m~xture~ thereof wit~. at least one appro~7ri~te ~cmonomer, the proportion of mon~mers being with-in the aforement~oned range . The polymer~ zation can be initiated by ultraviole~ irradiatio~, heat, redox systems, pexoxides, 2,~ -azobis-isobutyronitrile or other sui~a~le ~eans. Prefera~ly, the 10 pol~merization is carried out in aqueous or organic solv~nt solu-tions at a temperature of ~rom about room temperaiure to 100C.
The homopolymers and copolymers can ~e partially cross-lin~ed if desired. For example, up to 10.0 per cent by weight of the total monomer charge of an appropriate crosslinking agent can be utilized. Thus, ethylene glycol dil"ethacrylate, polyethylene oxide dimethacrylate, N-methylol ~crylamide, glycidyl methacrylate, etc. can be suita~ly emPloyed as cross-linking agents.
The ~etaine homopolymers and copolymers are water-swellable, that is they are capable of a~sorbing water to become gels, the resultarl~ gel ~eing water-insoluble.
Wllile ~ny o the previously disclosed polymers can be suitably employed in the compositions of this invention, preferred embodi-ments utili~e the homopolymers an~. copolymers o~ hetaines with water-~oluble monomers. Particu7 arly preferred ~re hom~p~lymers of betaines having the formula I w~erein Rl is me~hyi, A is oxygen, R2 is ethylene~ and R3 and R4 are methyl. :
Tlle compositions of this inYention can be p~epared by various procedures. Thus, the polymer can be formed as a c~sting syrup in a monomer, mixed with the thexapeuticâlly active material and cured.
Alternately, the polymers can he dissolved or swelled in water or ~ K~0-339 ~(~5;~58~
watcr and a misci~le solvent, the therapeutically acti~re ma~erial added a~d the composition obtained bv precipi~ation or ~y ev~parz-tion of the solvent system. ~nother prep~ra~ive techn~ue com-prises mixing the appropriate monomers Wi~ he therap~utically actlve material in water or a solvent, polymerizin~ and ~hcn r~-rnoving the solvent by evaporation. The therap~utically active material can ~e encapsulated il~ the polym~r i31 another technique;
when the polymer swells, the active material dif~uses thro~gh it and interacts with the polymer to form the desired cornple~. The compositions of this invention are obtained in the form of a clear film, indicating compatibil~ty of the therapeutic compo~ition with he homopolymer or copolymer due to ionic interactions.
. .
The ccmpositions of this invention can be provided for oral administration, or ~or implantation subcutaneously, intrclmuscular-ly or in a body cavity. Irrespective of the method Q~ impl~nta-tion, the compositions function by swelling thereby gradually re-leasing the therapeutically active material.
There is an interrelationship in the compositions of this invention among the following factors: potency of the thera-peutica~ly active material; chemical natuxe of the thexapeuticallyactive material; the rate of release; the area of administration;
the hydrophilicity of the polymer; and the degree of cross-linkin~
in the polym~r. Accordingly, the size of the dofiage form and the ratio of polymer to therapeutically active material will be chosen with the aforementioned considerations in mind. However, generally the compositions can contain ~xom 10 mi.croyrams to 2 ~ O grams of therapeutical~y acti~e material.
~ he ~ollowing examples will serve to illustrate the prac-tic~ o~ this i~ention. In th~ examples, all tes~s for pha~ma-cological activity ~re conduc~ed on adult albino mzle mice -~ -5-1053~8~ KEO-939 ~Cha~ies Rive~ st~ai~); the dosage co~sisted ~ the active agent s~spended in 10% aq~lc~ous acacia. Analgesic activity was det~r~ined ~y the Hot Plate method, ~,hich is descri~ed in detail ~y Eddy, ~.B. and Leimbach, D., J. Phaxm~col. Exptl.
~herap. 107, 38S (1953): activity was indica~ed if the paws le~t the surface of the plate.
:. :
KEO-9 3~
lOS3S8~
~XAIP~E 1 The ~.mount o~ lO.Q g. o~ N-~.eth~cryloirlox~ethyl~N,~I-dimethyl-~,3-proryl-sulfobetaine, m.p. 280-300~C (dec), (prepared as des-cribed in U.S. Patent 3,671,5G2~ was mixed ~ h 10 ml. f I~2~
and 0.054 g. potassilm ~ers~lfat~ an~ 0.02 y. soaium b~sulfite added thereto. The resul~ing mixture was ~laced in a 13. 5 cm x 4.2 cm x 0.4 cm cavity formed in a 15~7 cm x 4.5 cm x 1.3 cm polytetrafloroethylene piece. The ca~it~ was ~overcd wit~ a vented polytetraflo~oethylene co~er. Nitrogen was passed o~ex the mixture ~or about t~o hours; polym~ri2ation occurred over- :
night.
- The homopolymer described in the preceding paragraph ~l.C g.) and sodium pheno~arbital (0.1 g.J were placed in a S dra~ vial.
Then 6 ml. of distilled wate~ was added and the mixture st~.rred magr.etic~lly until a uniform, tra~sp~rent ~iscous solution o~ed.
This solution was poured into a small culture dish ~nd the water was removed by evaporation at 70C in ~n oven, leaving a white solid, which was ground and stored in a vacuum dessicator contain-ing P2O5.
~0 Following the procedure described in the preceding paragraph, mixtures A, B and C were prepared: A contained 0.8 g. of hcmo-poly~er and 0.2 g. sodium pheno~arbital; B ~ontain~d 0.75 g. of homopolyTner al~d 0.35 g. sodium phenobarbital and C contained 0.5 g. homopolymer and 0.5 g. sodium phenobar~ital.
The homopo~ymer -10% sodium phenobar~ital complex was tested for hypnotic activity ~y administering oral?y to 10 mice 1800 mg/kg of the complex and administering orally ~o ~no~her group of 10 mice 1~0 mg/kg of so~iwn phenobarbital~ The latter dosa~e repre-sents 2 x the HD50 reporte~ in the literature for sodium pheno- -r barbital. Th~ dos~ge of the complex represents one containing ~EO-9 3 ~
~0S;~5~
an ~quiv~len'; a~ount o~ ~o~ium pllen~ba~bita1. ~he m~arl induc-tion ti~e for th~ ccr~pl~x was q~.5 min~te~ d ~ mean sleepi~g time 249 minutes (2/1~ mice fell asleep); for s~dium pheno~ar-bital the me~n ir.duction time ~las 34.6 mir.utes and t~le mean sleeping time 119.6 minutes (10/10 mice fell asleep). No aft~r-effects were noted in any of t~e mice 3 days later.
Complexes A, B arc~ C were tested and the results are listed below. ~aPB is sodium pllei~obarbital, and al1 dosages for A, B
and C are expressed as sodium plleno~arbital equivalents.
TABLE I
llean Mean Induction Sleeping ~D50* LD50~ Time Time Dru~ (m~/kg)(mg/kg) (mins ) (mins.) NaPB 100 270 46.7 102.0 ~72.5-138.0~216-337.5) ~ : -A (~0~ ~aPB) 10~ __~. 45 90 (approx. ) (approx. ) ~approx.
B t35~ NaPB) 172 ~ 200 24.3 > 217 ~approx~
C ~50~ NaPB) 150 320 54.3 179 tl21.9-184.5)(275.6-371.2) * Uumbers in parentheses are 95~ fidllcial limits ~p - 0.05).
EXA~LE 2 Ten grams o~ N-methacryloyloxyethyl-N,N-dimethyl-~l,2-ethyl carboxybetaine, m.p. 102-105C, (prepared as described in U.S. ~ :
Patent 3r671,502~ in lOml. of water ~as polymerized at 60C in a capped bottle employing t}-e initiator system an~ follcwing the pr~cedure ~escri~e~ in ~xample 1.
The resulting homopolymer was extPnsively dialyzed again~t distillea water for 7-10 days and then vacuum dried at room temperature.
lOS~S8i KE~-93~ ~
A comple,; contailling ~5% ~y ~ieight o~ acetyl ~alicylic acid was prepared ~ollowins tlle procedure of Ex~rnpl~
The complex was tested ~or anal~etic activity according to ~ -the l~c)t Plate metllod. It was intended to admin1ster a dose of 1428. S m~/ky, which corresponds to 5CO mg/~;g o aspirin; how-ever, it was not possible to get all the drug in~o suspension hence the dose actually administered was somewhat les~ than ~he amount intended. P`our out of 10 mice showed anal~esia after 1~2 hour, 2 out of 10 after 1 hour and 0 out of 10 after 2 hours.
Ten grams of N-m~thacryloyloxyethyl-N,N-dimethyl-N,2-ethyl carboxybetaine and 0.02 ml. sf ethylene glycol dimethylmethacrylate in 10 ml. of water was polymerized following the procedure ar.d employang the initiator of the previous examples.
A complex containing 20~ by weight sodium phenobarbi~al ~-~
was prepared as in the preceding examples.
The complex was tested for hypnotic activity by administer-ing orally to 15 mice 10,00 mg~kg, corresponding to 200 mg/kg o~
sodium phenobar~ital. For compaxison, sodium phenobarbita~ was given to a second group of 15 mice at a dose of 200 mg/kg. The results are listed below in Table II.
Fraction Induction Sleeping Drug Sleeping Time (mins.) Time (mins.) ~ ~-(mean ~alues) .. ... .. .. . __ :
Example 3 6/15 60.8 194.1 NaPB 8/15 59.1 173.8 ":
-8- ~
~QS35~3~
Although specific embodirments o~ the invention have been described herein, it is not intended t~ li~it the inven-tion solely thereto but to include all of the variations and modi fications which su~est themselves to one sXilled in the art within the spirit and scope of the ap~ended claims.
polymeric ~arrier.
Va~lou~ sustained release compositions are well kno~rn in the art. For example, U.S. P~tent 3,577,512 discloses hydro-philic acrylate and methacrylate p~lymers whi.ch can be use~ ~
in s~stained release dosage forms. While functional for th~ -intended use, such gels serve sclely as physical carriers pro- :~
viding no interaction with the medication. U.S. Patent 3,551,556 teachss tllat it is known to have drugs ~ound ~y ionic or coordi-nation bonds to a soluble linear polymeric drug carrier, while IJ,S. Patent 3,~0,563 discloses the entrapment of ~ru~s in wat~r-soluhle hydro~;yal~yl acrylate or methacrylate polymers. Sustained release salts formed by reacting pharmacologically active ~eaX base amines with li~htly cross linked carboxylic acid or anhydride polymers are de~cribed in U.S. Patent 3,121,0~3. ..
Wow it has been ~ound in accordance ~lith this inv~ntion that therapeutically active materials ca~ be complexeG to a ~ ~ `
water-swellable carrier to provide stable, homogeneo~s dosag~ .
compositions having good sust.ai.ned release properties. . ~
More in detail, the sustained release dosage compositions of : -this invention comprise a cor.~plex of a. a therapeutically active material in an amount ~u~fi~ient to provide the desired ac~ivity upon release from sai~. composition, an~
~. a water-swellable betaine polymer selected from the gr~ consistil~ of h~mopolymers !
i~ S 3 5 8 ~ ~0-939 o ~ betaina ha~.ing the foxmu~.a ~ 3 ~2C C CA-R~-N - (CH2) -X
wherein ~1 is l~ydroge~ or methyl; A is oxygen or -NH-; ~2 is ethylene, propylene, 2-hydroxy- ;
propylene or 2-acetoxypxopylene; P~3 and R4 are alkyl having 1 to 4 car~on atoms; n is 1 to 4 and X is SO3 or CO2 ; and copolymers of mono mers consisting essentially of about 5.0 to about 99.0 percent by weight of said betaine and about 1.0 to about 95.0 percent ~y weight `~
of a monomer copolym~rizable therewith to pro~
vid~ a water-swellable polymer. :. .
The therapeutically acti~e material can be an organic or inorga~ic acid, base or salt. Exemplary active materials include antibiotics such as penicillin G, penicillin G potassium, te~ra~
cycline, tetracycline llydrochloride, erythromycin and erythro~ycin ~ .
stearate; sedativ~s such as phenoharbital, phenobarbital sodium, : -mepho~rbi~al ~nd me~hobarbital sodium; hypertensive agents such as ephedrine, ephearine hydrochloride, ~or epinephrine ~nd ~or-epinephrine hydrochloride; vasodilators such as papaverine, papaverine hydrochloride, dioxyli~e phospha~e and nicotinyl tartrate; tranquilizers such as chlorodiazepoxide, chloro- ;~
diazepoxide hydrochlorlde and di~ze~am hydrochloride; drug~ :
for the treatment of glaucomo such as pilocarpine and pilocarpine hydroc~loride; an~iconvulsants ~uch as diphenylhyaantoin and ~ :
diphenylhydantoin sodium; analges.ics such as ca~cium ~
~ lO~S~ KEO-939 ac~tyls~lic~lat~, ac~ty?.~alicylic acid, sodium salicylate, .or~hine ~nd ~orp~.ir.~ sulfate; anticholir.er~Jic compounds suc~
as atropine and atropille sulfatc; antimalarial compounds s~ch as cl~loroquine and cihlol-vquir.e hydrochloride; lccal anest~ietics such as procaine anrl procaine hydrochloride; antitussive co~-pounds ~uch as codeine and co~eine phosphate; antihistamin~s such as diphenylllydramir.e, diphenylhydramine hydrochloride, pyrilamine an~ pyrilaminc maleate; etc. Salts are preferred for complexiny to pro~ide the compositions of this invention~
'~he carboxyDetaine and sulfobetaine hvmopolymer~ are known materials. Tllus, the sulfobetaine ho~.opolymers are described in U.S. ~atent 3,497,482, while U.S. Patent 2,777,872 descrioes ::
carboxybetaine homopolymer5. Certain betaine copolymers are disclosed in U.S. Patent ~,671,502, while other co~olymers can be prepared as described hereinafter. :
rrhus, the copolymers suitable for use in this inYention are provided by polymexizing the betaine monomer with any comono~.er p~lymerizable therewith; The comonomer may alter or moai~y th~
hydrophilicity of the betaine homopolymer, provided that the re~
sultant copolymer retains hydrophilic and water-swellable prop-erties. Suitable comonorners include water-insoluble and partially water-soluble monomers, for example, acrylic and me~hacrylic esters such as methyl methacrylate, ethyl methacrylate, methyl acrylate, ethyl acrylate, 2-ethylhexyl acrylate, chloroethyl acrylate, hydroxypropyl methacrylate, etc.; vinyl esters SUC21 as vinyl acetate, vinyl propiona~e, vinyl ~utyrate, vinyl laurate, vinyl stearate, etc.; acrylonitri7e; styrene~ etc.
Ex~mpli~icati~e water-soluble monomers i~clude acrylic acid and methacry~.ic acid; hydroxyal]cyl acrylates and methacrylates such as hydro~:yethyl acrylate, hydro~yethy]. ~ethac~ylate, .
,, . . , .. . . , . , - .- , . . . .
JIUV ~ J_~
ll~S~581 hydroxyp~opyl acrylat~, etc.; ~inyl ethers such as vinyl rlethyl eth~r, v~n~ ethyl ether, etc.: v.inyl pyrollidone: acrylamide and methacrylamide.
The copolymers c~n be readily prep~ed by polym~rizing the carbo~ybetaine or ~ulfo~etaine or m~xture~ thereof wit~. at least one appro~7ri~te ~cmonomer, the proportion of mon~mers being with-in the aforement~oned range . The polymer~ zation can be initiated by ultraviole~ irradiatio~, heat, redox systems, pexoxides, 2,~ -azobis-isobutyronitrile or other sui~a~le ~eans. Prefera~ly, the 10 pol~merization is carried out in aqueous or organic solv~nt solu-tions at a temperature of ~rom about room temperaiure to 100C.
The homopolymers and copolymers can ~e partially cross-lin~ed if desired. For example, up to 10.0 per cent by weight of the total monomer charge of an appropriate crosslinking agent can be utilized. Thus, ethylene glycol dil"ethacrylate, polyethylene oxide dimethacrylate, N-methylol ~crylamide, glycidyl methacrylate, etc. can be suita~ly emPloyed as cross-linking agents.
The ~etaine homopolymers and copolymers are water-swellable, that is they are capable of a~sorbing water to become gels, the resultarl~ gel ~eing water-insoluble.
Wllile ~ny o the previously disclosed polymers can be suitably employed in the compositions of this invention, preferred embodi-ments utili~e the homopolymers an~. copolymers o~ hetaines with water-~oluble monomers. Particu7 arly preferred ~re hom~p~lymers of betaines having the formula I w~erein Rl is me~hyi, A is oxygen, R2 is ethylene~ and R3 and R4 are methyl. :
Tlle compositions of this inYention can be p~epared by various procedures. Thus, the polymer can be formed as a c~sting syrup in a monomer, mixed with the thexapeuticâlly active material and cured.
Alternately, the polymers can he dissolved or swelled in water or ~ K~0-339 ~(~5;~58~
watcr and a misci~le solvent, the therapeutically acti~re ma~erial added a~d the composition obtained bv precipi~ation or ~y ev~parz-tion of the solvent system. ~nother prep~ra~ive techn~ue com-prises mixing the appropriate monomers Wi~ he therap~utically actlve material in water or a solvent, polymerizin~ and ~hcn r~-rnoving the solvent by evaporation. The therap~utically active material can ~e encapsulated il~ the polym~r i31 another technique;
when the polymer swells, the active material dif~uses thro~gh it and interacts with the polymer to form the desired cornple~. The compositions of this invention are obtained in the form of a clear film, indicating compatibil~ty of the therapeutic compo~ition with he homopolymer or copolymer due to ionic interactions.
. .
The ccmpositions of this invention can be provided for oral administration, or ~or implantation subcutaneously, intrclmuscular-ly or in a body cavity. Irrespective of the method Q~ impl~nta-tion, the compositions function by swelling thereby gradually re-leasing the therapeutically active material.
There is an interrelationship in the compositions of this invention among the following factors: potency of the thera-peutica~ly active material; chemical natuxe of the thexapeuticallyactive material; the rate of release; the area of administration;
the hydrophilicity of the polymer; and the degree of cross-linkin~
in the polym~r. Accordingly, the size of the dofiage form and the ratio of polymer to therapeutically active material will be chosen with the aforementioned considerations in mind. However, generally the compositions can contain ~xom 10 mi.croyrams to 2 ~ O grams of therapeutical~y acti~e material.
~ he ~ollowing examples will serve to illustrate the prac-tic~ o~ this i~ention. In th~ examples, all tes~s for pha~ma-cological activity ~re conduc~ed on adult albino mzle mice -~ -5-1053~8~ KEO-939 ~Cha~ies Rive~ st~ai~); the dosage co~sisted ~ the active agent s~spended in 10% aq~lc~ous acacia. Analgesic activity was det~r~ined ~y the Hot Plate method, ~,hich is descri~ed in detail ~y Eddy, ~.B. and Leimbach, D., J. Phaxm~col. Exptl.
~herap. 107, 38S (1953): activity was indica~ed if the paws le~t the surface of the plate.
:. :
KEO-9 3~
lOS3S8~
~XAIP~E 1 The ~.mount o~ lO.Q g. o~ N-~.eth~cryloirlox~ethyl~N,~I-dimethyl-~,3-proryl-sulfobetaine, m.p. 280-300~C (dec), (prepared as des-cribed in U.S. Patent 3,671,5G2~ was mixed ~ h 10 ml. f I~2~
and 0.054 g. potassilm ~ers~lfat~ an~ 0.02 y. soaium b~sulfite added thereto. The resul~ing mixture was ~laced in a 13. 5 cm x 4.2 cm x 0.4 cm cavity formed in a 15~7 cm x 4.5 cm x 1.3 cm polytetrafloroethylene piece. The ca~it~ was ~overcd wit~ a vented polytetraflo~oethylene co~er. Nitrogen was passed o~ex the mixture ~or about t~o hours; polym~ri2ation occurred over- :
night.
- The homopolymer described in the preceding paragraph ~l.C g.) and sodium pheno~arbital (0.1 g.J were placed in a S dra~ vial.
Then 6 ml. of distilled wate~ was added and the mixture st~.rred magr.etic~lly until a uniform, tra~sp~rent ~iscous solution o~ed.
This solution was poured into a small culture dish ~nd the water was removed by evaporation at 70C in ~n oven, leaving a white solid, which was ground and stored in a vacuum dessicator contain-ing P2O5.
~0 Following the procedure described in the preceding paragraph, mixtures A, B and C were prepared: A contained 0.8 g. of hcmo-poly~er and 0.2 g. sodium pheno~arbital; B ~ontain~d 0.75 g. of homopolyTner al~d 0.35 g. sodium phenobarbital and C contained 0.5 g. homopolymer and 0.5 g. sodium phenobar~ital.
The homopo~ymer -10% sodium phenobar~ital complex was tested for hypnotic activity ~y administering oral?y to 10 mice 1800 mg/kg of the complex and administering orally ~o ~no~her group of 10 mice 1~0 mg/kg of so~iwn phenobarbital~ The latter dosa~e repre-sents 2 x the HD50 reporte~ in the literature for sodium pheno- -r barbital. Th~ dos~ge of the complex represents one containing ~EO-9 3 ~
~0S;~5~
an ~quiv~len'; a~ount o~ ~o~ium pllen~ba~bita1. ~he m~arl induc-tion ti~e for th~ ccr~pl~x was q~.5 min~te~ d ~ mean sleepi~g time 249 minutes (2/1~ mice fell asleep); for s~dium pheno~ar-bital the me~n ir.duction time ~las 34.6 mir.utes and t~le mean sleeping time 119.6 minutes (10/10 mice fell asleep). No aft~r-effects were noted in any of t~e mice 3 days later.
Complexes A, B arc~ C were tested and the results are listed below. ~aPB is sodium pllei~obarbital, and al1 dosages for A, B
and C are expressed as sodium plleno~arbital equivalents.
TABLE I
llean Mean Induction Sleeping ~D50* LD50~ Time Time Dru~ (m~/kg)(mg/kg) (mins ) (mins.) NaPB 100 270 46.7 102.0 ~72.5-138.0~216-337.5) ~ : -A (~0~ ~aPB) 10~ __~. 45 90 (approx. ) (approx. ) ~approx.
B t35~ NaPB) 172 ~ 200 24.3 > 217 ~approx~
C ~50~ NaPB) 150 320 54.3 179 tl21.9-184.5)(275.6-371.2) * Uumbers in parentheses are 95~ fidllcial limits ~p - 0.05).
EXA~LE 2 Ten grams o~ N-methacryloyloxyethyl-N,N-dimethyl-~l,2-ethyl carboxybetaine, m.p. 102-105C, (prepared as described in U.S. ~ :
Patent 3r671,502~ in lOml. of water ~as polymerized at 60C in a capped bottle employing t}-e initiator system an~ follcwing the pr~cedure ~escri~e~ in ~xample 1.
The resulting homopolymer was extPnsively dialyzed again~t distillea water for 7-10 days and then vacuum dried at room temperature.
lOS~S8i KE~-93~ ~
A comple,; contailling ~5% ~y ~ieight o~ acetyl ~alicylic acid was prepared ~ollowins tlle procedure of Ex~rnpl~
The complex was tested ~or anal~etic activity according to ~ -the l~c)t Plate metllod. It was intended to admin1ster a dose of 1428. S m~/ky, which corresponds to 5CO mg/~;g o aspirin; how-ever, it was not possible to get all the drug in~o suspension hence the dose actually administered was somewhat les~ than ~he amount intended. P`our out of 10 mice showed anal~esia after 1~2 hour, 2 out of 10 after 1 hour and 0 out of 10 after 2 hours.
Ten grams of N-m~thacryloyloxyethyl-N,N-dimethyl-N,2-ethyl carboxybetaine and 0.02 ml. sf ethylene glycol dimethylmethacrylate in 10 ml. of water was polymerized following the procedure ar.d employang the initiator of the previous examples.
A complex containing 20~ by weight sodium phenobarbi~al ~-~
was prepared as in the preceding examples.
The complex was tested for hypnotic activity by administer-ing orally to 15 mice 10,00 mg~kg, corresponding to 200 mg/kg o~
sodium phenobar~ital. For compaxison, sodium phenobarbita~ was given to a second group of 15 mice at a dose of 200 mg/kg. The results are listed below in Table II.
Fraction Induction Sleeping Drug Sleeping Time (mins.) Time (mins.) ~ ~-(mean ~alues) .. ... .. .. . __ :
Example 3 6/15 60.8 194.1 NaPB 8/15 59.1 173.8 ":
-8- ~
~QS35~3~
Although specific embodirments o~ the invention have been described herein, it is not intended t~ li~it the inven-tion solely thereto but to include all of the variations and modi fications which su~est themselves to one sXilled in the art within the spirit and scope of the ap~ended claims.
Claims (16)
1. A process for producing a sustained release dosage form of a therapeutically active material which comprises pre-paring a water-swellable butaine polymer, selected from the group consisting of homopolymers of a betaine having the formula wherein R1 is hydrogen or methyl; A is oxygen or -NH-; R2 is ethylene, propylene, 2-hydroxypropylene or 2-acetoxypropylene;
R3 and R4 are alkyl having 1 to 4 carbon atoms; n is 1 to 4 and X is S03- or C02-; and copolymers of monomers consisting essentially of about 5.0 to about 99.0 percent by weight of said betaine and about 1.0 to about 95.0 percent by weight of a monomer copolymerizable therewith to provide a water-swellable polymer, and then mixing said polymer with water and the thera-peutically active material to form a homogeneous mass, whereby a complex of sustained release characteristics is formed.
R3 and R4 are alkyl having 1 to 4 carbon atoms; n is 1 to 4 and X is S03- or C02-; and copolymers of monomers consisting essentially of about 5.0 to about 99.0 percent by weight of said betaine and about 1.0 to about 95.0 percent by weight of a monomer copolymerizable therewith to provide a water-swellable polymer, and then mixing said polymer with water and the thera-peutically active material to form a homogeneous mass, whereby a complex of sustained release characteristics is formed.
2. The process of Claim 1 wherein said therapeutically active material is a salt.
3. The process of Claim 2 wherein the water-swellable butaine polymer is a homopolymer of said betaine wherein R1 is methyl, A is oxygen, R2 is ethylene and R3 and R4 are methyl.
4. The process of Claim 3 wherein X- is S03- and n is 3.
5. The process of Claim 3 wherein X- is C02- and n is 2.
6. The process of Claim 3 wherein the therapeutically active material is an analgetic.
7. The process of Claim 3 wherein the therapeutically active material is an anti-convulsant.
8. The process of Claim 4 wherein the therapeutically active material is the therapeutic reactive material sodium phenobarbital.
9. A sustained release dosage composition prepared according to the method of Claim 1 comprising an ionic com-plex of a therapeutically active organic or inorganic cold, base or salt material in an amount sufficient to provide the desired activity upon release from said composition, and a water-swellable butaine polymer selected from the group con-sisting of homopolymers of a betaine having the formula wherein R1 is hydrogen or methyl; A is oxygen or -NH-; R2 is ethylene, propylene, 2-hydroxypropylene or 2-acetoxypropylene;
R3 and R4 are alkyl having 1 to 4 carbon atoms; n is l to 4 and X is SO3 or CO2 ; and copolymers of monomers consisting essen-tially of about 5.0 to about 99.0 percent by weight of said betaine and about 1.0 to about 95.0 percent by weight of a monomer copolymerizable therewith to provide a water-swellable polymer, said monomer being selected from the group consisting of methyl methacrylate, ethyl methacrylate, methyl acrylate, ethyl acrylate, 2-ethylhexyl acrylate, chloroethyl acrylate, hydroxypropyl methacrylate, vinyl acetate, vinyl propionate, vinyl butyrate, vinyl laurte, vinyl stearate, acrylonitrile, styrene, hydroxyethyl acrylate, hydroxyethyl methacrylate, hydroxypropyl acrylate, vinyl methyl ether, vinyl ethyl ether, vinyl pyrollidone, acrylamide and methacrylamide.
R3 and R4 are alkyl having 1 to 4 carbon atoms; n is l to 4 and X is SO3 or CO2 ; and copolymers of monomers consisting essen-tially of about 5.0 to about 99.0 percent by weight of said betaine and about 1.0 to about 95.0 percent by weight of a monomer copolymerizable therewith to provide a water-swellable polymer, said monomer being selected from the group consisting of methyl methacrylate, ethyl methacrylate, methyl acrylate, ethyl acrylate, 2-ethylhexyl acrylate, chloroethyl acrylate, hydroxypropyl methacrylate, vinyl acetate, vinyl propionate, vinyl butyrate, vinyl laurte, vinyl stearate, acrylonitrile, styrene, hydroxyethyl acrylate, hydroxyethyl methacrylate, hydroxypropyl acrylate, vinyl methyl ether, vinyl ethyl ether, vinyl pyrollidone, acrylamide and methacrylamide.
10. The composition of Claim 9 wherein said therapeutic-ally active material is a salt.
11. The composition of Claim 10 wherein said water-swellable butaine polymer is a homopolymer of said betaine wherein R1 is methyl, A is oxygen, R2 is ethylene and R3 and R4 are methyl.
12. The composition of Claim 11 wherein X- is S03- and n is 3.
13. The composition of Claim 11 wherein X- is C02- and n is 2.
14. The composition of Claim 11 wherein the therapeutic-ally active material is an analgetic.
15. The composition of Clam 11 wherein the therapeutic-ally active material is an anti-convulsant.
16. The composition of Claim 12 wherein the therapeutic-ally active material Is the therapeutic reactive material sodium phenobarbital.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US28943772A | 1972-09-15 | 1972-09-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1053581A true CA1053581A (en) | 1979-05-01 |
Family
ID=23111531
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA180,693A Expired CA1053581A (en) | 1972-09-15 | 1973-09-06 | Sustained release compositions |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1053581A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6106940A (en) * | 1998-03-17 | 2000-08-22 | 3M Innovative Properties Company | Adhesive compositions with zwitterionic tackifiers and plasticizers |
| US6133391A (en) * | 1998-03-17 | 2000-10-17 | 3M Innovative Properties Company | Adhesive compositions and adhesive tapes comprising zwitterionic copolymers, and novel zwitterionic copolymers |
| US7037889B2 (en) | 2000-09-13 | 2006-05-02 | Praecis Pharmaceuticals Inc. | Pharmaceutical compositions for sustained drug delivery |
| CN112708075A (en) * | 2020-12-29 | 2021-04-27 | 浙江工业大学 | Anti-swelling and anti-adhesion hydrogel as well as preparation method and application thereof |
-
1973
- 1973-09-06 CA CA180,693A patent/CA1053581A/en not_active Expired
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6106940A (en) * | 1998-03-17 | 2000-08-22 | 3M Innovative Properties Company | Adhesive compositions with zwitterionic tackifiers and plasticizers |
| US6133391A (en) * | 1998-03-17 | 2000-10-17 | 3M Innovative Properties Company | Adhesive compositions and adhesive tapes comprising zwitterionic copolymers, and novel zwitterionic copolymers |
| US7037889B2 (en) | 2000-09-13 | 2006-05-02 | Praecis Pharmaceuticals Inc. | Pharmaceutical compositions for sustained drug delivery |
| US8084419B2 (en) | 2000-09-13 | 2011-12-27 | GlaxoSmithKline, LLC | Pharmaceutical compositions for sustained drug delivery |
| CN112708075A (en) * | 2020-12-29 | 2021-04-27 | 浙江工业大学 | Anti-swelling and anti-adhesion hydrogel as well as preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4931519A (en) | Copolymers from n-alkyl-3-alkenylene-2-pyrrolidone | |
| US4851545A (en) | N-substituted-3-alkylene-2-pyrrolidone compounds | |
| FI85106C (en) | Process for preparing a transdermal dosing system | |
| US3931123A (en) | Hydrophilic nitrite copolymers | |
| KR950031088A (en) | Cross-linked Anion Exchange Particles and Manufacturing Method Thereof | |
| RU2002107977A (en) | A gel-like aqueous composition comprising a block copolymer in which there is at least one water-soluble block and one hydrophobic block | |
| EP0263605B1 (en) | Wound dressing | |
| CA1053581A (en) | Sustained release compositions | |
| US5413776A (en) | Pharmaceutical preparation for percutaneous absorption | |
| US3758629A (en) | By reaction with a di-2-oxazoline cross linking of addition polymers containing combined free carboxyl | |
| ATE102486T1 (en) | BASIC, INGREDIENT-PERMEABLE ADHESIVE POLYMER MASS, PROCESS FOR THEIR PRODUCTION AND ITS USE. | |
| WO2015138566A1 (en) | Amino-bis-phosphonate-containing polymers via raft polymerization and based on linear polyethyleneimine | |
| CN112375191A (en) | Block copolymer, preparation method and application thereof | |
| JP3121660B2 (en) | Thermoreversible hydrogel material | |
| Bae et al. | Heterogeneous interpenetrating polymer networks for drug delivery | |
| JPH0655876B2 (en) | Acrylamide-acrylic acid IPN | |
| US3728314A (en) | Chemical composition for viscosity control and film forming materials | |
| GB1097054A (en) | Acid-soluble veterinary medicaments | |
| Ramirez et al. | Polymer-drug grafts for iron chelation | |
| CN114099705B (en) | Nanometer medicine based on hydralazine for improving tumor microenvironment and preparation and application thereof | |
| US4374206A (en) | Synthesis of base-stable aliphatic anion exchange polymers | |
| JPH0560499B2 (en) | ||
| DE102008028146A1 (en) | Hydrolytically-degradable polyionic copolymers from cyclic ketene acetals and methacrylic acid derivatives with ionic groups, used e.g. for production of nano-particles and in adhesives or drug-release applications | |
| Hassanzadeh et al. | Effect of synthesis method and buffer composition on the LCST of a smart copolymer of N‐isopropylacrylamide and acrylic acid | |
| Ouchi et al. | Vinyl polymerization. 410. Polymerizations of vinyl monomers initiated by poly (styrene‐co‐sodium acrylate) or poly (methyl methacrylate‐co‐sodium methacrylate). A verification of the concept of hard and soft hydrophobic areas and monomers |