Note: Descriptions are shown in the official language in which they were submitted.
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
R4
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.
:. :
-5A-
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.
EXAMPLE 3
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.
