CA2191562A1 - Fast dissolving dosage forms - Google Patents
Fast dissolving dosage formsInfo
- Publication number
- CA2191562A1 CA2191562A1 CA 2191562 CA2191562A CA2191562A1 CA 2191562 A1 CA2191562 A1 CA 2191562A1 CA 2191562 CA2191562 CA 2191562 CA 2191562 A CA2191562 A CA 2191562A CA 2191562 A1 CA2191562 A1 CA 2191562A1
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- CA
- Canada
- Prior art keywords
- pharmaceutical composition
- agent
- group
- mixtures
- agents
- 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.)
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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
- A61K9/0007—Effervescent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
Abstract
A nonrupturable, fast dissolving, taste masking composition providing immediate release of pharmaceutically acceptable active ingredients.
Description
wogs/334462~ 62 r~ o~
FAST DISSOLVING DQSAfiF FORM~
TECHNICAL FIELD
SThe present invention relates to a good tasting, nulu ul~Lul al~lc, fast dissolving, taste masking ~ that provide immediate release of l,l,~ "~, acceptable active ingredients.
BACKGROUND OF THE INVENTION
A topic of which many physicians and ~ are keenly aware concerns 10 the notion of patient compli~n( e The concern focuses on how to maintain or increase compliance with prescribed regimens. A major obstacle with regard to medication compliance relates to the patient's Ull~ , or inability to swallow traditional solid dosage forms. l~ecogni~ing the problem, r ' Cl~ strive to introduce novel ~...., ~l-l;...,~ geared at reVol~l6c~ ;"g solid dosage forrn technology and meeting this common need.
One approach has focused on taste masking technology. Taste masking of l ' "~, active ingredients is easily effected by creating structural matrices with or covering such products with various types of "taste masking" agents. Prior art examples include Polymeric poly~,a~l~u~-yl~ (U.S. Patent 4.971.791), clay silicates (U.S. Patent 3.140.978) and natural or pol~G.,.,,.~"idc gums (U.S. Patent s.2ss.sQ0!
One other approach pursued by a number of l l, ~ to improve patient compliance concerns the use of "quick dissolving" technology.
Several methods of a ~ l ,: g this form of technology have been disclosed in, for example, U.S. Patent 4.642.903. U.S. Patent 4.946.684. U.S. Patent 4.305.502. U S
Patent 4.371.516. U.S. Patent 5 188.825. U.S. Patent 5.215.756 and U.S. Patent 5.298.Z61. The use of effervescent cu 1 ~ is a paltil,uLly well known means of ~ rapid carrier dissolution. E~ ., ..t ~ u~ ~ l u - ~ are prepared by admixing active ingredients together with an a~ ul ' ' err~ t system. The .,~e-~ ,c~L system will usually comprise an acidifying agent and a carbonate containing material which upon addhion of an aqueous liquid bursts into a vigorous enel~ .e. Errel~ technology is further described in chapter 6 of ~
maceutical Dosaee Forms: Tablets. Vol. I, 2nd ed., A Lieberman ed., 1989, MarcelDekker, Inc. which is herein h~.,u~u~aled by reference. Examples of such errel~ uu~ l o, l;o ~ include U.S. Patent 3.882.228 to Boncey et al., which discloses preparing wettable aspirin particles. The aspirin particles are coated in a spray drying process with a mixture of a water soluble coating material, a wetting w09s/33446 2191~62 PCT/USgS/06855 agent, and/or a water soluble film forming agent. The coated aspirin particles are .then hlcu~yùldlcd into efiervescent tablets. See also U.S Patent 4.687.662 to Schobel, which discloses a therapeutic fast dissolving effervescent ~.o.~ ;n.l The is prepared by admixing~a granulated therapeutic agent having a 5 plcJ~,Iclll ncd particle size to an~effervescent system having roughly the same particle size. ''~
Effervescent cl,",l,.,~:l.-",~ providing a controlled release include U.S. Patent 4.94û.588 to Sparks et al., which discloses a controlled release powder which comprises discreet ~llk,luyal~i~,les ("yhdllllaaullle~") composed of an ~ "~ g,~lû active and at least one nontoxic polymer in the fomm of a nu~uu...GLIh~, and also U.S.
Patent 5.û55.306 to Barry et al., which discloses a sustained release cIrc.~w.,c..l ~.. ,1,l~; I;nu The ~ of Barry et al. is prepared by UUIllyl~ ;llg granules coated with a water insoluble, yet water swellable acrylic polymer and a water soluble hydroxylated cellulose derivative together with an effervescent system to 15 fomm CIrCl~,S~.CII~ tablets. Both Sparks et al. and Barry et al. describe their cu~ as resisting breakage (i.e., nOlUUylUldl'lC) U.S. Patent 5.178.878. to Wehling et al.7 discloses eIrcl~.,c.lt dosage fomms comprising llfi~,luyà.t;~ . The ~u I .~ I;u is composed of ~niwuyàl~i~,L,~ substan-tially ., O"~ and, or in the altemative, fommed into a matrjx with a protective 20 polymer. The polymeric substances of the invention added to enhance the taste-masking properties of the effervescent system. The Illil lupalLI,l.,i are described as "lUytUldbk." as opposed to the "lluluuytulcbl~," particles of Sparks et al. and Barry et al.
While the prior art discloses various ~,~ '' ''11~'' 1 ;1~ 7 useful in masking taste and 25 facilitating the dissolution of carriers containing phal. '~ , active com-pounds, there is still a need for improved, rapidly dissolving, immediate release, taste masked 1'1 ', . - ~~ l un .e Prior art disclosures in this field which relate to immediate release ~ . ~pu~;l;u~ have not directed their attention to forming a ~- -- l l rl~lc matrix between the taste masking agent and the, '. ".~, 30 active cnmpolln~le L~,o~yuldlillg such a matrix provides reliable taste masking since it is not easily ruptured (e.g. by chewing) so as to free the bitter tasting actives from the matrix. Moreover, the yhalllla.,culi.,al r~- yo~;fil~ maintain their immediate release profile. It is therefore an object of the present invention to provide a good-tasting, immediate release ~.u., .I.u~ I;l.u It is a further object of the present invention 35 to provide a nullluytuldlJle, rapidly dissolving cu ~1.l~:1;..l~, ill.~UIyUIdlillg phamma-ceutical actives. Still a further object is to provide a method of making a goodtasting, rapidly dissolving .,1. J: - Y .I containing }; 1 -- ", -- ~ actives.
.. . . . .....
w09s/33446 2191S6~ r~uO ~ s~s~
These objectives and additional objectives will become readily apparent from the detailed description which follows.
SUMMARY OF THE INVENTION
The present invention relates to an oral ~h~IUa-~CUL;~ ,ul~ a;Lion ~ 6 (a) a nulhu~,luldl,lc drug matrix ~u. ~lld~
i) a taste masking agent; and ii) a safe and effective amount of a ph~ ,culic~.lly active in-gredient; and (b) an orally acceptable ~L-I~ ;UL;UGI carrier wherein said pl,, l~, acceptable carrier is rapidly 1;~ 6.~-led in aqueoussolution without the need for .1 ~ and wherein said c~ ,l,o~ provides an immediate release of the phdl l"_~,cufi~ lly active ingredient.
The present invention further relates to methods of treating symptoms of 15 respiratory illnesses such as those associated with the cough, cold, cold-like, allergy and/or flu symptoms as well as ~5_aLIuhll~,Olillal disorders, comprising the administra-tion of a safe and effective amount of the ~ .lOaiLiu..O of the present invention.
All ~ .lt..,5_o and ratios herein are by weight unhess otherwise specified.
Additionally, all l..__o,,lClll~,llL~ are made at 25~C unless otherwise specified.
By "safe and effective amount," as used herein, is an amount that is effective to mitigate and/or treat the symptoms for which the active ingredient is indicated in a human without undue adverse side effects . dLe with a reasonable risk/benefit ratio.
By "llulh u~tul dl,l~ as used herein, means an ability to withstand those forcescommonly associated with the chewing process (i.e. direct co.~ ,OO;ull forces ranging from about above 4 Kilograms to about 5.6 Kilograms).
~ By "immediate release" as used herein, is meant that at least about 75 % of said j ' ' ingredient is released within 45 minutes after By "rapidly ~' ~, "" is meant that the shaped particles are d ~ ~ ' in water within 30 seconds. Preferably the shaped particle d;~ lc~ t~o (dissolves or disperses) within 10 seconds or less. Procedures for measuring d;~ c~dliu~ time are described in U.S. Patent 4.371.516 to Gregory et al. which is herein ;..~,ull~olalcd by reference.
DETAII,ED DESCRIPTION OF THE INVENTION
The ~.. 1,.-~;l;.. of the present invention contain essential ~o~ l u l~ as well as various ~ t;-~ ~ U~ - ~ ' as indicated below.
wo 9~/33446 21 91 5~ P~ S.'t~
ESSENTIA~ COMPONENTS
Taste M~ckinv Aeent. The first essential component of the present invention is a safe and effective amount of a taste masking agent. Taste masking agents suitable for the present invention include those substances effective at masking the untoward tzste(s) of comestible ççmpo~ln~ and which will form a nuluu~,luldblc matrix when combined with a uhalllla.,cul;~,al active. The taste masking agent may be ;ncu~.u~dLed to substantially encompass the IJhalllla~,~,uLically active ingredient.
The term " ' '1~, ~ .~"~ ," as used herein means that the tzste masking agent ' '1~ shields the p~ "~-~c ~l" ~lly active ingredient from contact with the .,.~ ullll.~,ul outside the active. Alternatively and/or ! ~ y, the ~JLal ~ active ingredient may be dispersed or dissolved within the taste masking agent to form the drug matrix u~ nC Suitable taste masking agents are described below.
Silicate clays are usefiul taste masking agents. Examples of such clays which include using magnesium trisiliczte zre describe in U.S. Patent 3.085.942 to Clifton et al., April 16, 1963; and U.S. Patents 4.581.232, April 8, 1966; 4.632.821, December 30, 1986;. 4.632.822. December 30, 1986; 4.623.823, December 30, 1986;
4.462.231. February 10~ 1987; 4.643.898. February 17, 1987; 4,643.892. February 17, 1987; 4.647.449, March 3, 1987; 4.647.450. March 3, 1987; 4.647.459, March 3, 1987; 4.649.û41. March 19, 1987; 4.650.663, March 17, 1987 to Peters et al. all of which are herein ;...,w~uldled by reference. Further exzmples using magnesiumaluminum silicates are described in U.S. Patent 4.761.274. August 2, 1988, to Denick, Jr. et al.; U.S. Patent 4.753.800, June 28, 1988, to Mozdz, and U.S. Patent 3.140.978. July 14, 1964 to Zentner; all of which are herein i~,o~u~dlcd by reference.
Additionally, acrylic polymer resins are usefiul taste masking agents and suitable for use in the present invention. The use acrylic polymer resins in this capacity hzs been disclosed in, for example, U.S. Patent 4.940.588. U.S. Patent 4.971,791~ U.S. Patent 5.055.306 and U.S. Pztent 5.178.878 and are herein incorpo-3û rzted by reference.
Natural gums such as gum karaya, gum arabic, and gum tragacanth znd poly~a.,.,l,àlide gums such as xanthan gum may also be used as the tzste maskingagent of the present invention. Gums useful to the present invention are furtherdescribed in U.S. Patent 5.288.S00 herein ;ncul~Juldlcd by reference.
Wzxes suitable for use zs tzste masking agents in the present invention include mono- or di b'~,,cl,id~s, carnauba wzx and paraffm wzx. A particularly WOg5t33446 ~l~I 562 PCTIUS9~/068~
useful example of such taste masking waxes appears in the ~ f-.~, "micro-sponge" technology marketed by Particle Dynamics under the tradename Descote3.
Pha~ d~ acceptable actives. Pl.A.-..a.,euLiL~lly acceptable actives useful in the present invention may be selected from among the various groups of5 chemical compounds or materials suitable for oral A l~ :.. and having a phA~qrnlf~gjfAl action. These l,I,A.."ac.,.~Li.,.-lly acceptable active .,., I)u ..1~ or materials should be compatible with the other essentiai ingredients and compatible in cfmh~ ion with other included active materials or l.U~ u.~ The IJh- 1"- ,~.;;
cally acceptable active ' U"'I'U""'I~ or materials are present at a level from about IJ 0.01% to about 90%, preferably from about 0.1% to about 75%, more preferablyfrom about 1.0% to about 50% and most preferably from about 1.0% to about 25%.
Useful pt~ Ally acceptable active materiais or f u~ may include, but are not limited to~ n.,~, anorexiants, A..l;~ ... c, nutritional supple-ments (such as vitamins, minerals, fatty acids, amino acids, and the like), iaxatives, 15 analgesics, antacids, H2-receptor antArgf--ictc~ h~is, ~ cng~ , anti-tussives, ,~,a;----~ ILi~ lui~;~b, antifungals, antivirals, eAIJ.,_lu.. ~L~, anti-; n~ ~ "~ agents, ~ ylcliu~, their ~hallllac.~lli.,fll~ acceptabie salts and mixtures thereo~
The term "~JL.llllldccllliu~dly acceptable salts" refers to saits prepared from 20 ~ acceptable non-toxic bases including, but not limited to: inorganic bases and organic bases. Salts derived from inorganic bases include sodium, potassium, lithium, ammonia, calcium, " ~ ferrous, zinc, aluminum, ferric, manganic salts and the like. Salts derived from çh "~, acceptable organic non-toxic bases include salts of primary, secondary, tertiary and 25 quaternary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as L i_,l.~' , Ll;~JIU~ , 2~ ' ~ ' 1, 2- i;~ll-, ' 1, Iysine, arginine, histidine, caffeine, procaine, N_CLLYI~ .' ' 9, choline, betaine, cLh~ Lll , methyl~, e, Lh_ub~u..lh~f." purines, piperazine, 30 piperidine, polyamine resins and the like.
Examples of ~ u~ useful in the ,.,.,,I...~:~;f,~.c of the present inven-tion include 1~ ;, ph~,.,yl~"u~ 1 ---, I,h'~,JI~ I,I;,,e and ephedrine, their ~ acceptable salts, and miAtures thereof.
Examples of ~ useful in the ~- I u~ of the present invention include d.,ALi U.. I~LIIU~ ¦ IJ~ I, ~.r.. IJ ¦ , I . . . noscapine, i;,,h_.lL,d._ ~, codeine, h~d~u~,odu~"~ u"~u~l~hv~" their pL.. "~, ac-ceptable salts, and mixtures thereof WO ss/33446 2 1 9 1 5 6 2 ' P .~
Examples of ~AL)~ OIGllL~ (also known as mucolytic agents) useful in the pre-sent invention include: ~nl~if~nr cin, terpin hydrate, ammonium chloride, N-acetyh,y~Lc;..c, and ambroxol, their phGIlllG~,cuLicGlly acceptable salts, and mixtures thereof 5Examples of analgesics useful in the present invention include; morphine, co- L
deine, mrreri~in~, p 1~ e, propoxyphene, a"eLG...;..u~L~.... allopurinol, acetyl-salicylic acid, choline salicylate, ketoprofen, magnesium silicate, fenoprofen, ibupro-fen, i~ r,. ~ ." naproxen, and many others and their phGllllG~CUli~,ally acceptable salts and mixtures thereof.
10Examples of A"l;ll;J~.";". c useful in the present invention include; brom-L ~ ' , UIIU~ clemastine, d.,Achlu~ r, di~Jh.,..hyL
doxylamine, ~J,...,.. IIA~ I~, terfenadine, triprolidine and many others and their phar-IIIG~CUL;~GIIY acceptable salts and mixtures thereo~
Analgesics, .Ir~ g~ .n t~ It'~ and antitussives, as well as their acceptable dosage ranges are described in U.S. Patent 4.783.465 to Sun-shine et al., issued November 8, 1988, and U.S. p~tPnt 4.619.934 to Sunshine et al., issued October 28, 1986, which are iu~,u~u~dLeJ by reference herein.
Examples of ga~LIu;"Lc~lhlàl agents suitable for use in the present invention include ' ' ~;;",, including atropine, clidinium and ~ ,y~' antacids, in-cluding aluminum hydroxide, bismuth ~ub: Gl;C~IGtC, calcium carbonate and GtC, H2-receptor antagonists including: cimetidine, famotidine, nizatidine and ranitidine; laxatives, including~ ' ' ' and casanthrol; and including: d;lJL~IluA~/lGLc and lor~r~mi~le Further examples of suitable analgesics, r~ ~ ~ L~ , antitussives, expecto-rants and ' as well as b.~ ' "' , anorexiants, laxatives, antiemet-ics, .~t;llli~lUbiG15, S, antifungals, anti '' y agents, antivirals, ~ 'i".cL;~,~, nutritional ~ ,a, antacids, H2-receptor antago-nists, G.-L;.liG.Ih~,Gls and other " ~G~Ll~ eomr ~ and their ac-ceptable dosage ranges are described in Remin~tûn's PLc,.. - n; ~1 Sri~nrrc pp 30 734-789, 791-799, 861-868, 907-945, 875-888, 1002-1034, 1098-1121, 1124-1131,1173-1224, 1232-1241, (Alfonso R.Gennaro, editor) (18th ed. 1990), herein incor-porated by reference.
NONESSENTIAL COMPONENTS
Persons skilled in the art will quickly realize many other ingredients will be 35 suitable for inclusion into the present invention. N"1 ~ "~r ..1~ include, but are not limited to: coloring agents; flavoring agents, including: vanilla, cherry, grape, orange, p~rperm;~ spearmint, anise, blueberry raspberry, banana, chocolate, WO gs/33446 21 g 1 5 6 2 P~ 6 caramel, strawberry, lemon, lime, menthol and ProsweetTM MM50 (a ..l.~ ;on of natural and artifcial flavors and propylene glycol, available from Virginia DareExtract Co., Inc., Brooklyn, NY); sweeteners, including saccharin, dextrose, levulose, sucrose, cyclamate, mannitol and aspartate, along with many others;
J 5 suspending agents, including xanthum gum, acacia gum, call,u~yul~Lll~Lellulo~
starch and .,..,lI,~ ,lL,lose; preservatives; releasing agents, including pol~u~; 80, sodium lauryl sulfate, vegetable oils and magnesium stearate; and water.
Another preferred n~nPcc,~nti~l component of the present invention is a cool-ing agent or a ~ ;l,n of cooling agents. Suitable cooling agents are those des-cribed in U.S. Patent 4,136.163. January 23, 1979, to Watson et al., U.S. Patent~ 4.230.688, October 28, 1980, to Rowsell et al. and U.S. Patent 4.032.661. to Rowsell et al., all of which are herein ;ncull,uldltd by reference. Pal~;~,ulally pre-ferred cooling agents include N-ethyl-p-menthane-3-calbu,~al";Je (WS-3 supplied by Sterling Organics) taught by the above hl~,ullJulaLcd U.S. Patent 4,136,163 and N~2~3-trimethyl-2-isopropylbut~ nirie which is ~/uuull~.~;.. l'y available as WS-23 from Wilkinson Sword Limited and taught by the above ill~,ull~olaLtd U.S. Patent4,230.688. Another particularly preferred cooling agent is 3-1-~ ,.lfllu~ lu~Ja~le 1,2-diol (TK-10 supplied by Takasago Perfumery Co., Ltd., Tokyo, Japan). This material is described in detail in U.S. Patent 4.459.425. July 10, 1984 to Amano et al.
20 and i~,Ol lJUl al~J herein by reference.
Good tasting l,l. -- -- - l; -I adsorbate ~ . of the present invention are prepared using art-recognized principles and ' ' ' 1~, in mixing the ingre-dients together and in choosing the type of mixing equipment to be used.
When using certain taste masking agents such as magnesium aluminum silicate, there is a potential for adverse hlltla~,l;UII:~ between the agent and various multiply charged cationic drugs (e.g. .,I,lu-l ll . .: -) - resulting in poor drug dis-solution, it is critical that certain measures be followed to insure effective drug dissolution. Such a situation is described in McGinty, J.W. and Lacb~ J.L., In Vitro ~C~ tion of Various Phall .-~vli~-35 to M~ullnu~i"c ~. Jour. of Pharrn. Sci., 65, 896-902 (1976) and is herein hlcull~ùlaLed by reference. By "multiply charged cationic drugs" as used herein, means cu..,l,uu..Js containing more than one posi-tively charged substituent. The crucial steps involve g the pH in a range equal to that of the pKa of the multiply charged cationic drug(s) and, "' "y, reserving the addition of said multiply charged cationic drug(s) until after the addition 35 of at least one other cationic compound.
Good tasting, IJLal ' ç..~..l,o~.l;..,.~ ill.,wlJulalillg alternative taste masking agents are similarly prepared using art-recognized principles and method-2191~62 g ologies A more detaiied description of these ~. t~lo.l aiiull processes are &sclûsed inthe examples listed below After the matrix of the present invention is forrned, it is hlcol~Jùlaled into an oraily acceptable ~ .1;. l carrier which rapidly d;...~c~aleD in aqueous 5 solutions Suitable carriers can ulcùllJùlale crrcl~.,s~.,~ or other water-dispersible substances and dried into dosage forms that rapidly r~ ' ~eL~ upon coming into contact with an aqueous iiquid. Suitable .,~cl..,s~,clll technology is described in Chapter 6 of Pl . ~ ,dl Dosage Forms Tablets. Voi I, 2nd ed., A Lieberman ed, 1989, Marcel Dekker, Inc herein ulcul~lùl~Led by reference. The above men-10 tioned .,..".~ ;-. may be formed by using any of a muititude of solid dosage forming techniques and equjpment Methods of soiid dosage rululu;aLioù are weii icnown in the art and any a~JInupl;a~. method may be utiiized. Further; ~...." ~;.~.~
regarding solid dosage ru----ulaLull can be found in ~ n's Pl~ SC;~
ences. pp 163}-1664, (Aifonso R Gennaro, editor~ (18th ed. 199û) Aiternatively, the e~.. l.. ,~;l;.~ .~ of the present invention nnay be achieved by iul,ul~ulaLillg the matrix into a freeze dried form. Freeze-drying or Iyu~.l.;l 1;~,~
facilitates ~ .. of the a~ by forming the dried ~ ~~ into an open matrix network. In most cases, this resuits jn rapid permeation by the aqueous media, promoting timely delivery of the product's actjve ingredients Suitable meth-20 ods of freeze drying are weii known jn the art and commoniy employed. Any surtable cul~ tiondi method of freeze-drying may be utiiized. A preferable method of freezing and drying is to fast freeze the c r ' and then dry the ~ 1;.... toa finai moisture content of about 2% to about 5% Suitable methods of freeze-drying and production are taught by U S p.t.-nt 4.642.903. February 17, 1987, to Davies, U S p_t.~nf 4.946.684. August 7, 1990, to Blank et ai, U S p_t~ntr 4.305.502 and4.371.516 . issued December 15, 1981 and February 1, 1983 lcDt~L;~ , to Gregory et ai., and U S p--t~nt 5.188.825. February 23,1993, to Iies et ai; which are aii in-corporated herein by reference Similarly, the c~ l o~ of the present invention may be vacuum dried Vacuum drying mvolves at least the partiai drying of c~ at Lelll~ aLu above the ~ o~:l;u ~' coiiapse Le--l~.aLul~, Freeze drying, on the other hand, involves the drying of ~ ~ at Lell~ uu~ beiow the uu ~ coiiapse clu~.,.a~ulc Any suitable method of vacuum drying may be used Suitable vacuum drying processes are described in U S p~t~? 5.298.261. to Pebley et ai, issued March 29, 1994, herein i.. cu-~,o-aled by reference.
One other form of fast dissolving technology that may be appiicable to the present invention is a iiquid/iiquid extract developed by Janssen Fh~ ..l;. A Inc ~MENDE5 SHE~
2191~62 ~ W O 95133446 ' PCT~US95/06855 and is identified by the trade name QuicksolvTM. This technology is fully described in U.S. Patent 5.215.756 herein ;,lcu.l,u,dL~d by reference.
~ EXAMPLES
The foilowing examples further describe and d.,.llullaLl ale ~ o~
5 within the scope of the present invention. The examples are given solely for the pur-pose of illustration and are not to be construed as limitations of the present invention, as many variations are possible without departing from the spirit and scope of the in-vention.
EXAMPLE I
Invredients W/W%
magnesium stearate 0.50000 sorbitol, ~,u",~ ,illc 44.17000 silicone dioxidel 0.10000 citricacid, anhydrous 6.25000 sodium bi~,albullat~" ~JleLltat~,J718.75000 .,llo~ .,.. ;. alll;ll~, maleate 0.80000 pl,~ "" -' - HCI . 5.00000 xanthum gum 24.00000 orange flavor 0.40000 cream flavor 0.30000 IAvailable as Cab-o-sil from Cabot Corporation, Tuscola, Illinois 7Ple~ is performed by heating overnight in a forced air oven (Despatch, Model # LDB-1-23) at 66 ~C.
In an . y~/lu~"ial.;lJ sized container, with LightninTM mixer (model #TS2010 (or a high shear 1~ - . set at 30 to 50 RPM)) mixing at du~JII ' Iy 250 to 1000 RPM, add the following agents allowing each to dissolve before adding the next: water (add a sufficient amount of water to thoroughly wet clllu~l~l.. i .;..
maieate and xanthum gum for mixing; water will be driven off via drying), "llc.. ~ ' ~ maieate, xanthum gum. Mix vigorously (250 to 1000 RPM) for 45 30 minutes. Dry mixture in 45 ~C oven for 12 hours or until mixture is dry and water is driven off. CTrind dry mixture to a particle size suitable for cu.,.~
In a separate, a~J~Jlu~lidlel~ sized container, following the same procedure, combine ph~ u~ . HCI with xanthum gum.
Next, dry blend via ~,u~ iundl blending methods (e.g., V- blender) the 35 above xanthum gum pre-complexes with magnesium stearate, . . ,,;,,il,le sorbitol, Silicone dioxide, citric acid anhydrous, pretreated sodium b;ua~ ale and orange and cream flavors.
WO 95/33446 ~ i 2 P~ .J,.. '.'C' -' ~
l ' I O
Using a conventional tablet press in a humidity controlled room (< 25 ~/0 RH), press tablets to a tablet weight of 500 mg. Protect tablets from moisture by sealing in glass jars or in foil pouches or blisters. Ad~ l;a~ L;on of two tablets is the normal and customary dosage.
EXAMPLE II
In~redients W/W~/Q
magnesium stearate o.soooo sorbitol, ~,UIII~JI caaiblc 56.76000 silicone dioxidel 0.10000 citric acid anhydrous 6.250ûO
sodium b;~ali , pretreated2 18.750ûO
d~Allull~Lllul~l'àn HBr 4.00000 methyl methacrylic copolymer3 13.34000 lemon/iime flavor 0.30000 15 IAvailable as Cab-o-sil from Cabot Corporation, Tuscoia, Illinois.
2PIcLl~aLillg is performed by heating overnight in a forced air oven (Despatch, Model # LDB-1-23) at 66 ~C. .
3Available as Eudragit~)L30D from Rohm and Haas.
In an appropriately sized container, with LightninTM mixer (model #TS2010 (or a high shear h.. ".aC,. 5,. . set at 30 to 50 RPM)) mixing at G~ lu~dllldt~,ly 250 to 1000 RP~4 add the following agents allowing each to dissolve before adding the next: water (add a sufficient amount of water to thoroughiy wet d~Llull~Lllul~ àn Br and methyl methacrylic copolymer for mixing; water will be driven off via drying), d~".L~um.,Lllul~ iBr, methyl lll~,Lha~lyl;c copolymer. Mix vigorously (250 to 1000 RPM) for 45 minutes. Dry mixture in 45 ~C oven for 12 hours or until mixture iâ dry and water is driven off. Grind dry mixture to a particle size suitable for Cu~ a;ll~,.
Dry blend via l,ùll.~"~Liul~al blending methods (e.g., V- blender) the dextrome-thorphan Br and methyl methacrylic copolymer pre-complex with magnesium stearate" . ~,~aible sorbitol, silicone dioxide, citric acid anhydrous, pretreated sodium bicarbonate and lemon/iime flavor.
Using a cu~ ..L;u..al tablet press in a humidity controlled room (< 25 % RH), preSs tablets to a tablet weight of 500 mg. Protect tablets from moisture by sealing in giass jars or in foil pouches or blisters. ~ U~ n of two tablets is the normal 35 and customary dosage.
WO 9~/33446 2 1 9 1 5 6 2 F~
EXAMPLE III
In~redients WlW% _ citric acid, anhydrous, fine 6.25000 sodium bicarbonate, pretreatedl18.75000 magnesium aluminum silicate2 42.00000 p ~ ~do~ J i"eHCI 6.00000 cl~lOl~l.~,.l;~a~ c maleate 0 40000 methyl salicylate 0.20000 magnesium stearate 0.50000 menthol 0.50000 N-ethyl-p-menthane-3-.,~.l,u,.~,.. ;dc~ 0.08000 llll;~t~,4 0.06000 sodium saccharin 0.05000 silicone dioxide5 0.50000 vanilla creme 0.03000 mannitol 23.18000 IPretreating is performed by heating overnight in a forced air oven (Despatch, Model # LDB-1-23) at 66 ~C.
2Available as Veegum~) HS from R.T. Vanderbilt, Norwalk, CT.
20 3Available as WS-3 supplied by Sterling Organics.
4Available as l~q" .. .,tC~ 185 supplied by McAndrews & Forbes, Camden, NJ.
In an ~ Jlu~Jl;dtl,ly sized container, with LightninTM mixer (model #TS2010 (or a high shear l~ 5 ~- set at 30 to 50 RPM)) mixing at ~y~lu~ilu~tul~ 250 to1000 RPM, heat 800 ml purified water to 54~C. Add 43.75 g Veegum~) HS while 25 mr~ing. Continue mrbcing and heat solution to 71~C, reduce heat to a~lylu~ illld~l~ 38 ~C and mix for 2 hours. Add I . ~1u lJh r l. ;,.~. HCI slowly and heat to 66~C and add additional water if necessary. Mix an additional 2 hours. Pour the mixture into teflon or stainless steel pans and dry for 12 hours at 45~C or until mixture is dry.
Grind dry mixture to a particle size suitable for cu.,.~ ~;llg~
Dry blend via ~,u.. ~u.. liu.lal blending methods (e.g., V- blender) the Veegum~9 HS/Pse~ , ' ' i..c HCI pre-complex with ~ lu~l~L~ c maleate, citric acid (anhydrous), pretreated sodium b;c~bull~le, aspartame, methyl salicylate, magnesium stearate, mannitol, .,.. -.,.. ~.. l;.l.. ~Iy.,~lll~dt~" sodium saccharin, Silicone dioxide, N-ethyl-p-menthane-3-..~.bu~..-idc, menthol and vanilla cream flavors.
35Using a ~,u~ iu.-al tablet press in a humidity controlled room (< 25 ~/0 RH), press tablets to a tablet weight of 500 mg. Protect tablets from moisture by sealing in t ~
FAST DISSOLVING DQSAfiF FORM~
TECHNICAL FIELD
SThe present invention relates to a good tasting, nulu ul~Lul al~lc, fast dissolving, taste masking ~ that provide immediate release of l,l,~ "~, acceptable active ingredients.
BACKGROUND OF THE INVENTION
A topic of which many physicians and ~ are keenly aware concerns 10 the notion of patient compli~n( e The concern focuses on how to maintain or increase compliance with prescribed regimens. A major obstacle with regard to medication compliance relates to the patient's Ull~ , or inability to swallow traditional solid dosage forms. l~ecogni~ing the problem, r ' Cl~ strive to introduce novel ~...., ~l-l;...,~ geared at reVol~l6c~ ;"g solid dosage forrn technology and meeting this common need.
One approach has focused on taste masking technology. Taste masking of l ' "~, active ingredients is easily effected by creating structural matrices with or covering such products with various types of "taste masking" agents. Prior art examples include Polymeric poly~,a~l~u~-yl~ (U.S. Patent 4.971.791), clay silicates (U.S. Patent 3.140.978) and natural or pol~G.,.,,.~"idc gums (U.S. Patent s.2ss.sQ0!
One other approach pursued by a number of l l, ~ to improve patient compliance concerns the use of "quick dissolving" technology.
Several methods of a ~ l ,: g this form of technology have been disclosed in, for example, U.S. Patent 4.642.903. U.S. Patent 4.946.684. U.S. Patent 4.305.502. U S
Patent 4.371.516. U.S. Patent 5 188.825. U.S. Patent 5.215.756 and U.S. Patent 5.298.Z61. The use of effervescent cu 1 ~ is a paltil,uLly well known means of ~ rapid carrier dissolution. E~ ., ..t ~ u~ ~ l u - ~ are prepared by admixing active ingredients together with an a~ ul ' ' err~ t system. The .,~e-~ ,c~L system will usually comprise an acidifying agent and a carbonate containing material which upon addhion of an aqueous liquid bursts into a vigorous enel~ .e. Errel~ technology is further described in chapter 6 of ~
maceutical Dosaee Forms: Tablets. Vol. I, 2nd ed., A Lieberman ed., 1989, MarcelDekker, Inc. which is herein h~.,u~u~aled by reference. Examples of such errel~ uu~ l o, l;o ~ include U.S. Patent 3.882.228 to Boncey et al., which discloses preparing wettable aspirin particles. The aspirin particles are coated in a spray drying process with a mixture of a water soluble coating material, a wetting w09s/33446 2191~62 PCT/USgS/06855 agent, and/or a water soluble film forming agent. The coated aspirin particles are .then hlcu~yùldlcd into efiervescent tablets. See also U.S Patent 4.687.662 to Schobel, which discloses a therapeutic fast dissolving effervescent ~.o.~ ;n.l The is prepared by admixing~a granulated therapeutic agent having a 5 plcJ~,Iclll ncd particle size to an~effervescent system having roughly the same particle size. ''~
Effervescent cl,",l,.,~:l.-",~ providing a controlled release include U.S. Patent 4.94û.588 to Sparks et al., which discloses a controlled release powder which comprises discreet ~llk,luyal~i~,les ("yhdllllaaullle~") composed of an ~ "~ g,~lû active and at least one nontoxic polymer in the fomm of a nu~uu...GLIh~, and also U.S.
Patent 5.û55.306 to Barry et al., which discloses a sustained release cIrc.~w.,c..l ~.. ,1,l~; I;nu The ~ of Barry et al. is prepared by UUIllyl~ ;llg granules coated with a water insoluble, yet water swellable acrylic polymer and a water soluble hydroxylated cellulose derivative together with an effervescent system to 15 fomm CIrCl~,S~.CII~ tablets. Both Sparks et al. and Barry et al. describe their cu~ as resisting breakage (i.e., nOlUUylUldl'lC) U.S. Patent 5.178.878. to Wehling et al.7 discloses eIrcl~.,c.lt dosage fomms comprising llfi~,luyà.t;~ . The ~u I .~ I;u is composed of ~niwuyàl~i~,L,~ substan-tially ., O"~ and, or in the altemative, fommed into a matrjx with a protective 20 polymer. The polymeric substances of the invention added to enhance the taste-masking properties of the effervescent system. The Illil lupalLI,l.,i are described as "lUytUldbk." as opposed to the "lluluuytulcbl~," particles of Sparks et al. and Barry et al.
While the prior art discloses various ~,~ '' ''11~'' 1 ;1~ 7 useful in masking taste and 25 facilitating the dissolution of carriers containing phal. '~ , active com-pounds, there is still a need for improved, rapidly dissolving, immediate release, taste masked 1'1 ', . - ~~ l un .e Prior art disclosures in this field which relate to immediate release ~ . ~pu~;l;u~ have not directed their attention to forming a ~- -- l l rl~lc matrix between the taste masking agent and the, '. ".~, 30 active cnmpolln~le L~,o~yuldlillg such a matrix provides reliable taste masking since it is not easily ruptured (e.g. by chewing) so as to free the bitter tasting actives from the matrix. Moreover, the yhalllla.,culi.,al r~- yo~;fil~ maintain their immediate release profile. It is therefore an object of the present invention to provide a good-tasting, immediate release ~.u., .I.u~ I;l.u It is a further object of the present invention 35 to provide a nullluytuldlJle, rapidly dissolving cu ~1.l~:1;..l~, ill.~UIyUIdlillg phamma-ceutical actives. Still a further object is to provide a method of making a goodtasting, rapidly dissolving .,1. J: - Y .I containing }; 1 -- ", -- ~ actives.
.. . . . .....
w09s/33446 2191S6~ r~uO ~ s~s~
These objectives and additional objectives will become readily apparent from the detailed description which follows.
SUMMARY OF THE INVENTION
The present invention relates to an oral ~h~IUa-~CUL;~ ,ul~ a;Lion ~ 6 (a) a nulhu~,luldl,lc drug matrix ~u. ~lld~
i) a taste masking agent; and ii) a safe and effective amount of a ph~ ,culic~.lly active in-gredient; and (b) an orally acceptable ~L-I~ ;UL;UGI carrier wherein said pl,, l~, acceptable carrier is rapidly 1;~ 6.~-led in aqueoussolution without the need for .1 ~ and wherein said c~ ,l,o~ provides an immediate release of the phdl l"_~,cufi~ lly active ingredient.
The present invention further relates to methods of treating symptoms of 15 respiratory illnesses such as those associated with the cough, cold, cold-like, allergy and/or flu symptoms as well as ~5_aLIuhll~,Olillal disorders, comprising the administra-tion of a safe and effective amount of the ~ .lOaiLiu..O of the present invention.
All ~ .lt..,5_o and ratios herein are by weight unhess otherwise specified.
Additionally, all l..__o,,lClll~,llL~ are made at 25~C unless otherwise specified.
By "safe and effective amount," as used herein, is an amount that is effective to mitigate and/or treat the symptoms for which the active ingredient is indicated in a human without undue adverse side effects . dLe with a reasonable risk/benefit ratio.
By "llulh u~tul dl,l~ as used herein, means an ability to withstand those forcescommonly associated with the chewing process (i.e. direct co.~ ,OO;ull forces ranging from about above 4 Kilograms to about 5.6 Kilograms).
~ By "immediate release" as used herein, is meant that at least about 75 % of said j ' ' ingredient is released within 45 minutes after By "rapidly ~' ~, "" is meant that the shaped particles are d ~ ~ ' in water within 30 seconds. Preferably the shaped particle d;~ lc~ t~o (dissolves or disperses) within 10 seconds or less. Procedures for measuring d;~ c~dliu~ time are described in U.S. Patent 4.371.516 to Gregory et al. which is herein ;..~,ull~olalcd by reference.
DETAII,ED DESCRIPTION OF THE INVENTION
The ~.. 1,.-~;l;.. of the present invention contain essential ~o~ l u l~ as well as various ~ t;-~ ~ U~ - ~ ' as indicated below.
wo 9~/33446 21 91 5~ P~ S.'t~
ESSENTIA~ COMPONENTS
Taste M~ckinv Aeent. The first essential component of the present invention is a safe and effective amount of a taste masking agent. Taste masking agents suitable for the present invention include those substances effective at masking the untoward tzste(s) of comestible ççmpo~ln~ and which will form a nuluu~,luldblc matrix when combined with a uhalllla.,cul;~,al active. The taste masking agent may be ;ncu~.u~dLed to substantially encompass the IJhalllla~,~,uLically active ingredient.
The term " ' '1~, ~ .~"~ ," as used herein means that the tzste masking agent ' '1~ shields the p~ "~-~c ~l" ~lly active ingredient from contact with the .,.~ ullll.~,ul outside the active. Alternatively and/or ! ~ y, the ~JLal ~ active ingredient may be dispersed or dissolved within the taste masking agent to form the drug matrix u~ nC Suitable taste masking agents are described below.
Silicate clays are usefiul taste masking agents. Examples of such clays which include using magnesium trisiliczte zre describe in U.S. Patent 3.085.942 to Clifton et al., April 16, 1963; and U.S. Patents 4.581.232, April 8, 1966; 4.632.821, December 30, 1986;. 4.632.822. December 30, 1986; 4.623.823, December 30, 1986;
4.462.231. February 10~ 1987; 4.643.898. February 17, 1987; 4,643.892. February 17, 1987; 4.647.449, March 3, 1987; 4.647.450. March 3, 1987; 4.647.459, March 3, 1987; 4.649.û41. March 19, 1987; 4.650.663, March 17, 1987 to Peters et al. all of which are herein ;...,w~uldled by reference. Further exzmples using magnesiumaluminum silicates are described in U.S. Patent 4.761.274. August 2, 1988, to Denick, Jr. et al.; U.S. Patent 4.753.800, June 28, 1988, to Mozdz, and U.S. Patent 3.140.978. July 14, 1964 to Zentner; all of which are herein i~,o~u~dlcd by reference.
Additionally, acrylic polymer resins are usefiul taste masking agents and suitable for use in the present invention. The use acrylic polymer resins in this capacity hzs been disclosed in, for example, U.S. Patent 4.940.588. U.S. Patent 4.971,791~ U.S. Patent 5.055.306 and U.S. Pztent 5.178.878 and are herein incorpo-3û rzted by reference.
Natural gums such as gum karaya, gum arabic, and gum tragacanth znd poly~a.,.,l,àlide gums such as xanthan gum may also be used as the tzste maskingagent of the present invention. Gums useful to the present invention are furtherdescribed in U.S. Patent 5.288.S00 herein ;ncul~Juldlcd by reference.
Wzxes suitable for use zs tzste masking agents in the present invention include mono- or di b'~,,cl,id~s, carnauba wzx and paraffm wzx. A particularly WOg5t33446 ~l~I 562 PCTIUS9~/068~
useful example of such taste masking waxes appears in the ~ f-.~, "micro-sponge" technology marketed by Particle Dynamics under the tradename Descote3.
Pha~ d~ acceptable actives. Pl.A.-..a.,euLiL~lly acceptable actives useful in the present invention may be selected from among the various groups of5 chemical compounds or materials suitable for oral A l~ :.. and having a phA~qrnlf~gjfAl action. These l,I,A.."ac.,.~Li.,.-lly acceptable active .,., I)u ..1~ or materials should be compatible with the other essentiai ingredients and compatible in cfmh~ ion with other included active materials or l.U~ u.~ The IJh- 1"- ,~.;;
cally acceptable active ' U"'I'U""'I~ or materials are present at a level from about IJ 0.01% to about 90%, preferably from about 0.1% to about 75%, more preferablyfrom about 1.0% to about 50% and most preferably from about 1.0% to about 25%.
Useful pt~ Ally acceptable active materiais or f u~ may include, but are not limited to~ n.,~, anorexiants, A..l;~ ... c, nutritional supple-ments (such as vitamins, minerals, fatty acids, amino acids, and the like), iaxatives, 15 analgesics, antacids, H2-receptor antArgf--ictc~ h~is, ~ cng~ , anti-tussives, ,~,a;----~ ILi~ lui~;~b, antifungals, antivirals, eAIJ.,_lu.. ~L~, anti-; n~ ~ "~ agents, ~ ylcliu~, their ~hallllac.~lli.,fll~ acceptabie salts and mixtures thereo~
The term "~JL.llllldccllliu~dly acceptable salts" refers to saits prepared from 20 ~ acceptable non-toxic bases including, but not limited to: inorganic bases and organic bases. Salts derived from inorganic bases include sodium, potassium, lithium, ammonia, calcium, " ~ ferrous, zinc, aluminum, ferric, manganic salts and the like. Salts derived from çh "~, acceptable organic non-toxic bases include salts of primary, secondary, tertiary and 25 quaternary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as L i_,l.~' , Ll;~JIU~ , 2~ ' ~ ' 1, 2- i;~ll-, ' 1, Iysine, arginine, histidine, caffeine, procaine, N_CLLYI~ .' ' 9, choline, betaine, cLh~ Lll , methyl~, e, Lh_ub~u..lh~f." purines, piperazine, 30 piperidine, polyamine resins and the like.
Examples of ~ u~ useful in the ,.,.,,I...~:~;f,~.c of the present inven-tion include 1~ ;, ph~,.,yl~"u~ 1 ---, I,h'~,JI~ I,I;,,e and ephedrine, their ~ acceptable salts, and miAtures thereof.
Examples of ~ useful in the ~- I u~ of the present invention include d.,ALi U.. I~LIIU~ ¦ IJ~ I, ~.r.. IJ ¦ , I . . . noscapine, i;,,h_.lL,d._ ~, codeine, h~d~u~,odu~"~ u"~u~l~hv~" their pL.. "~, ac-ceptable salts, and mixtures thereof WO ss/33446 2 1 9 1 5 6 2 ' P .~
Examples of ~AL)~ OIGllL~ (also known as mucolytic agents) useful in the pre-sent invention include: ~nl~if~nr cin, terpin hydrate, ammonium chloride, N-acetyh,y~Lc;..c, and ambroxol, their phGIlllG~,cuLicGlly acceptable salts, and mixtures thereof 5Examples of analgesics useful in the present invention include; morphine, co- L
deine, mrreri~in~, p 1~ e, propoxyphene, a"eLG...;..u~L~.... allopurinol, acetyl-salicylic acid, choline salicylate, ketoprofen, magnesium silicate, fenoprofen, ibupro-fen, i~ r,. ~ ." naproxen, and many others and their phGllllG~CUli~,ally acceptable salts and mixtures thereof.
10Examples of A"l;ll;J~.";". c useful in the present invention include; brom-L ~ ' , UIIU~ clemastine, d.,Achlu~ r, di~Jh.,..hyL
doxylamine, ~J,...,.. IIA~ I~, terfenadine, triprolidine and many others and their phar-IIIG~CUL;~GIIY acceptable salts and mixtures thereo~
Analgesics, .Ir~ g~ .n t~ It'~ and antitussives, as well as their acceptable dosage ranges are described in U.S. Patent 4.783.465 to Sun-shine et al., issued November 8, 1988, and U.S. p~tPnt 4.619.934 to Sunshine et al., issued October 28, 1986, which are iu~,u~u~dLeJ by reference herein.
Examples of ga~LIu;"Lc~lhlàl agents suitable for use in the present invention include ' ' ~;;",, including atropine, clidinium and ~ ,y~' antacids, in-cluding aluminum hydroxide, bismuth ~ub: Gl;C~IGtC, calcium carbonate and GtC, H2-receptor antagonists including: cimetidine, famotidine, nizatidine and ranitidine; laxatives, including~ ' ' ' and casanthrol; and including: d;lJL~IluA~/lGLc and lor~r~mi~le Further examples of suitable analgesics, r~ ~ ~ L~ , antitussives, expecto-rants and ' as well as b.~ ' "' , anorexiants, laxatives, antiemet-ics, .~t;llli~lUbiG15, S, antifungals, anti '' y agents, antivirals, ~ 'i".cL;~,~, nutritional ~ ,a, antacids, H2-receptor antago-nists, G.-L;.liG.Ih~,Gls and other " ~G~Ll~ eomr ~ and their ac-ceptable dosage ranges are described in Remin~tûn's PLc,.. - n; ~1 Sri~nrrc pp 30 734-789, 791-799, 861-868, 907-945, 875-888, 1002-1034, 1098-1121, 1124-1131,1173-1224, 1232-1241, (Alfonso R.Gennaro, editor) (18th ed. 1990), herein incor-porated by reference.
NONESSENTIAL COMPONENTS
Persons skilled in the art will quickly realize many other ingredients will be 35 suitable for inclusion into the present invention. N"1 ~ "~r ..1~ include, but are not limited to: coloring agents; flavoring agents, including: vanilla, cherry, grape, orange, p~rperm;~ spearmint, anise, blueberry raspberry, banana, chocolate, WO gs/33446 21 g 1 5 6 2 P~ 6 caramel, strawberry, lemon, lime, menthol and ProsweetTM MM50 (a ..l.~ ;on of natural and artifcial flavors and propylene glycol, available from Virginia DareExtract Co., Inc., Brooklyn, NY); sweeteners, including saccharin, dextrose, levulose, sucrose, cyclamate, mannitol and aspartate, along with many others;
J 5 suspending agents, including xanthum gum, acacia gum, call,u~yul~Lll~Lellulo~
starch and .,..,lI,~ ,lL,lose; preservatives; releasing agents, including pol~u~; 80, sodium lauryl sulfate, vegetable oils and magnesium stearate; and water.
Another preferred n~nPcc,~nti~l component of the present invention is a cool-ing agent or a ~ ;l,n of cooling agents. Suitable cooling agents are those des-cribed in U.S. Patent 4,136.163. January 23, 1979, to Watson et al., U.S. Patent~ 4.230.688, October 28, 1980, to Rowsell et al. and U.S. Patent 4.032.661. to Rowsell et al., all of which are herein ;ncull,uldltd by reference. Pal~;~,ulally pre-ferred cooling agents include N-ethyl-p-menthane-3-calbu,~al";Je (WS-3 supplied by Sterling Organics) taught by the above hl~,ullJulaLcd U.S. Patent 4,136,163 and N~2~3-trimethyl-2-isopropylbut~ nirie which is ~/uuull~.~;.. l'y available as WS-23 from Wilkinson Sword Limited and taught by the above ill~,ull~olaLtd U.S. Patent4,230.688. Another particularly preferred cooling agent is 3-1-~ ,.lfllu~ lu~Ja~le 1,2-diol (TK-10 supplied by Takasago Perfumery Co., Ltd., Tokyo, Japan). This material is described in detail in U.S. Patent 4.459.425. July 10, 1984 to Amano et al.
20 and i~,Ol lJUl al~J herein by reference.
Good tasting l,l. -- -- - l; -I adsorbate ~ . of the present invention are prepared using art-recognized principles and ' ' ' 1~, in mixing the ingre-dients together and in choosing the type of mixing equipment to be used.
When using certain taste masking agents such as magnesium aluminum silicate, there is a potential for adverse hlltla~,l;UII:~ between the agent and various multiply charged cationic drugs (e.g. .,I,lu-l ll . .: -) - resulting in poor drug dis-solution, it is critical that certain measures be followed to insure effective drug dissolution. Such a situation is described in McGinty, J.W. and Lacb~ J.L., In Vitro ~C~ tion of Various Phall .-~vli~-35 to M~ullnu~i"c ~. Jour. of Pharrn. Sci., 65, 896-902 (1976) and is herein hlcull~ùlaLed by reference. By "multiply charged cationic drugs" as used herein, means cu..,l,uu..Js containing more than one posi-tively charged substituent. The crucial steps involve g the pH in a range equal to that of the pKa of the multiply charged cationic drug(s) and, "' "y, reserving the addition of said multiply charged cationic drug(s) until after the addition 35 of at least one other cationic compound.
Good tasting, IJLal ' ç..~..l,o~.l;..,.~ ill.,wlJulalillg alternative taste masking agents are similarly prepared using art-recognized principles and method-2191~62 g ologies A more detaiied description of these ~. t~lo.l aiiull processes are &sclûsed inthe examples listed below After the matrix of the present invention is forrned, it is hlcol~Jùlaled into an oraily acceptable ~ .1;. l carrier which rapidly d;...~c~aleD in aqueous 5 solutions Suitable carriers can ulcùllJùlale crrcl~.,s~.,~ or other water-dispersible substances and dried into dosage forms that rapidly r~ ' ~eL~ upon coming into contact with an aqueous iiquid. Suitable .,~cl..,s~,clll technology is described in Chapter 6 of Pl . ~ ,dl Dosage Forms Tablets. Voi I, 2nd ed., A Lieberman ed, 1989, Marcel Dekker, Inc herein ulcul~lùl~Led by reference. The above men-10 tioned .,..".~ ;-. may be formed by using any of a muititude of solid dosage forming techniques and equjpment Methods of soiid dosage rululu;aLioù are weii icnown in the art and any a~JInupl;a~. method may be utiiized. Further; ~...." ~;.~.~
regarding solid dosage ru----ulaLull can be found in ~ n's Pl~ SC;~
ences. pp 163}-1664, (Aifonso R Gennaro, editor~ (18th ed. 199û) Aiternatively, the e~.. l.. ,~;l;.~ .~ of the present invention nnay be achieved by iul,ul~ulaLillg the matrix into a freeze dried form. Freeze-drying or Iyu~.l.;l 1;~,~
facilitates ~ .. of the a~ by forming the dried ~ ~~ into an open matrix network. In most cases, this resuits jn rapid permeation by the aqueous media, promoting timely delivery of the product's actjve ingredients Suitable meth-20 ods of freeze drying are weii known jn the art and commoniy employed. Any surtable cul~ tiondi method of freeze-drying may be utiiized. A preferable method of freezing and drying is to fast freeze the c r ' and then dry the ~ 1;.... toa finai moisture content of about 2% to about 5% Suitable methods of freeze-drying and production are taught by U S p.t.-nt 4.642.903. February 17, 1987, to Davies, U S p_t.~nf 4.946.684. August 7, 1990, to Blank et ai, U S p_t~ntr 4.305.502 and4.371.516 . issued December 15, 1981 and February 1, 1983 lcDt~L;~ , to Gregory et ai., and U S p--t~nt 5.188.825. February 23,1993, to Iies et ai; which are aii in-corporated herein by reference Similarly, the c~ l o~ of the present invention may be vacuum dried Vacuum drying mvolves at least the partiai drying of c~ at Lelll~ aLu above the ~ o~:l;u ~' coiiapse Le--l~.aLul~, Freeze drying, on the other hand, involves the drying of ~ ~ at Lell~ uu~ beiow the uu ~ coiiapse clu~.,.a~ulc Any suitable method of vacuum drying may be used Suitable vacuum drying processes are described in U S p~t~? 5.298.261. to Pebley et ai, issued March 29, 1994, herein i.. cu-~,o-aled by reference.
One other form of fast dissolving technology that may be appiicable to the present invention is a iiquid/iiquid extract developed by Janssen Fh~ ..l;. A Inc ~MENDE5 SHE~
2191~62 ~ W O 95133446 ' PCT~US95/06855 and is identified by the trade name QuicksolvTM. This technology is fully described in U.S. Patent 5.215.756 herein ;,lcu.l,u,dL~d by reference.
~ EXAMPLES
The foilowing examples further describe and d.,.llullaLl ale ~ o~
5 within the scope of the present invention. The examples are given solely for the pur-pose of illustration and are not to be construed as limitations of the present invention, as many variations are possible without departing from the spirit and scope of the in-vention.
EXAMPLE I
Invredients W/W%
magnesium stearate 0.50000 sorbitol, ~,u",~ ,illc 44.17000 silicone dioxidel 0.10000 citricacid, anhydrous 6.25000 sodium bi~,albullat~" ~JleLltat~,J718.75000 .,llo~ .,.. ;. alll;ll~, maleate 0.80000 pl,~ "" -' - HCI . 5.00000 xanthum gum 24.00000 orange flavor 0.40000 cream flavor 0.30000 IAvailable as Cab-o-sil from Cabot Corporation, Tuscola, Illinois 7Ple~ is performed by heating overnight in a forced air oven (Despatch, Model # LDB-1-23) at 66 ~C.
In an . y~/lu~"ial.;lJ sized container, with LightninTM mixer (model #TS2010 (or a high shear 1~ - . set at 30 to 50 RPM)) mixing at du~JII ' Iy 250 to 1000 RPM, add the following agents allowing each to dissolve before adding the next: water (add a sufficient amount of water to thoroughly wet clllu~l~l.. i .;..
maieate and xanthum gum for mixing; water will be driven off via drying), "llc.. ~ ' ~ maieate, xanthum gum. Mix vigorously (250 to 1000 RPM) for 45 30 minutes. Dry mixture in 45 ~C oven for 12 hours or until mixture is dry and water is driven off. CTrind dry mixture to a particle size suitable for cu.,.~
In a separate, a~J~Jlu~lidlel~ sized container, following the same procedure, combine ph~ u~ . HCI with xanthum gum.
Next, dry blend via ~,u~ iundl blending methods (e.g., V- blender) the 35 above xanthum gum pre-complexes with magnesium stearate, . . ,,;,,il,le sorbitol, Silicone dioxide, citric acid anhydrous, pretreated sodium b;ua~ ale and orange and cream flavors.
WO 95/33446 ~ i 2 P~ .J,.. '.'C' -' ~
l ' I O
Using a conventional tablet press in a humidity controlled room (< 25 ~/0 RH), press tablets to a tablet weight of 500 mg. Protect tablets from moisture by sealing in glass jars or in foil pouches or blisters. Ad~ l;a~ L;on of two tablets is the normal and customary dosage.
EXAMPLE II
In~redients W/W~/Q
magnesium stearate o.soooo sorbitol, ~,UIII~JI caaiblc 56.76000 silicone dioxidel 0.10000 citric acid anhydrous 6.250ûO
sodium b;~ali , pretreated2 18.750ûO
d~Allull~Lllul~l'àn HBr 4.00000 methyl methacrylic copolymer3 13.34000 lemon/iime flavor 0.30000 15 IAvailable as Cab-o-sil from Cabot Corporation, Tuscoia, Illinois.
2PIcLl~aLillg is performed by heating overnight in a forced air oven (Despatch, Model # LDB-1-23) at 66 ~C. .
3Available as Eudragit~)L30D from Rohm and Haas.
In an appropriately sized container, with LightninTM mixer (model #TS2010 (or a high shear h.. ".aC,. 5,. . set at 30 to 50 RPM)) mixing at G~ lu~dllldt~,ly 250 to 1000 RP~4 add the following agents allowing each to dissolve before adding the next: water (add a sufficient amount of water to thoroughiy wet d~Llull~Lllul~ àn Br and methyl methacrylic copolymer for mixing; water will be driven off via drying), d~".L~um.,Lllul~ iBr, methyl lll~,Lha~lyl;c copolymer. Mix vigorously (250 to 1000 RPM) for 45 minutes. Dry mixture in 45 ~C oven for 12 hours or until mixture iâ dry and water is driven off. Grind dry mixture to a particle size suitable for Cu~ a;ll~,.
Dry blend via l,ùll.~"~Liul~al blending methods (e.g., V- blender) the dextrome-thorphan Br and methyl methacrylic copolymer pre-complex with magnesium stearate" . ~,~aible sorbitol, silicone dioxide, citric acid anhydrous, pretreated sodium bicarbonate and lemon/iime flavor.
Using a cu~ ..L;u..al tablet press in a humidity controlled room (< 25 % RH), preSs tablets to a tablet weight of 500 mg. Protect tablets from moisture by sealing in giass jars or in foil pouches or blisters. ~ U~ n of two tablets is the normal 35 and customary dosage.
WO 9~/33446 2 1 9 1 5 6 2 F~
EXAMPLE III
In~redients WlW% _ citric acid, anhydrous, fine 6.25000 sodium bicarbonate, pretreatedl18.75000 magnesium aluminum silicate2 42.00000 p ~ ~do~ J i"eHCI 6.00000 cl~lOl~l.~,.l;~a~ c maleate 0 40000 methyl salicylate 0.20000 magnesium stearate 0.50000 menthol 0.50000 N-ethyl-p-menthane-3-.,~.l,u,.~,.. ;dc~ 0.08000 llll;~t~,4 0.06000 sodium saccharin 0.05000 silicone dioxide5 0.50000 vanilla creme 0.03000 mannitol 23.18000 IPretreating is performed by heating overnight in a forced air oven (Despatch, Model # LDB-1-23) at 66 ~C.
2Available as Veegum~) HS from R.T. Vanderbilt, Norwalk, CT.
20 3Available as WS-3 supplied by Sterling Organics.
4Available as l~q" .. .,tC~ 185 supplied by McAndrews & Forbes, Camden, NJ.
In an ~ Jlu~Jl;dtl,ly sized container, with LightninTM mixer (model #TS2010 (or a high shear l~ 5 ~- set at 30 to 50 RPM)) mixing at ~y~lu~ilu~tul~ 250 to1000 RPM, heat 800 ml purified water to 54~C. Add 43.75 g Veegum~) HS while 25 mr~ing. Continue mrbcing and heat solution to 71~C, reduce heat to a~lylu~ illld~l~ 38 ~C and mix for 2 hours. Add I . ~1u lJh r l. ;,.~. HCI slowly and heat to 66~C and add additional water if necessary. Mix an additional 2 hours. Pour the mixture into teflon or stainless steel pans and dry for 12 hours at 45~C or until mixture is dry.
Grind dry mixture to a particle size suitable for cu.,.~ ~;llg~
Dry blend via ~,u.. ~u.. liu.lal blending methods (e.g., V- blender) the Veegum~9 HS/Pse~ , ' ' i..c HCI pre-complex with ~ lu~l~L~ c maleate, citric acid (anhydrous), pretreated sodium b;c~bull~le, aspartame, methyl salicylate, magnesium stearate, mannitol, .,.. -.,.. ~.. l;.l.. ~Iy.,~lll~dt~" sodium saccharin, Silicone dioxide, N-ethyl-p-menthane-3-..~.bu~..-idc, menthol and vanilla cream flavors.
35Using a ~,u~ iu.-al tablet press in a humidity controlled room (< 25 ~/0 RH), press tablets to a tablet weight of 500 mg. Protect tablets from moisture by sealing in t ~
2 1 9 1~6 2 12 PCTrUS95/06855 glass jars or in foil pouches or blisters. Auuliu;~LIdLiuu of two tablets is the normal and customary dosage.
EXAMPLE IV
In~redients WlV%
S magnesium aluminum silicate 8.48900 loperamide 2.44000 polysorbate 80 0.04000 sodium saccharin 0.05200 aspartame 0.05200 sucrose 14.00000 mannitol 12.25500 novagel RCN-151 1.60000 lemon flavor 0.47200 vanilla creme O.lS000 citric acid 0.45000 purified water q.s. to 100 EXA~LE V
~g~ WIV%
magnesium aluminum silicate 4.00000 bismuth subsalicylate 21.69930 polysorbate 80 0.03500 sodium saccharin 0.04550 aspartame l.00000 sucrose 2.00000 mannitol 4.15000 novagel RCN-ISl 1.40000 strawberry flavor 0.54600 vanilla creme 0.54990 citric acid 0.06690 ~ucel EF ?IF2 0.25200 antifoam AF3 0.21000 purified water q.s. to 100 EXAMPLE Vl w~o/o magnesium aluminum silicate 4.00000 ~ 3.50000 p,~ .; - 80 0.03500 wos~/33446 2~91~i~2 r_l/u,.,~
sodium saccharin 0.04550 aspartame 0.04550 sorbitol 0 70000 sucrose 8.25000 mannitol 16.29800 novagel RCN- 151 1.40000 cherry flavor 0.19460 vanilla creme 0.24780 citric acid 0.28320 antifoam AF3 0.21000 purified water q.s. to 100 I Supplied by FMC Corporation, Ph;lalel~ ;4 Pa.
2Supplied by AQUALON, Hopewell, Va.
3Supplied by Dow Coming, Midland, Mich.
Examples IV -VI are further examples of ~u ~used in treating the .
symptoms of y,.l~Llu;llL~aL;ll.ll illnesses in humans and are ~ luur~,Lu~;d in a manner substantially similar to Example III. Ad~ ;un of two tablets is the nommal and customary dosage.
EXAMPLE IV
In~redients WlV%
S magnesium aluminum silicate 8.48900 loperamide 2.44000 polysorbate 80 0.04000 sodium saccharin 0.05200 aspartame 0.05200 sucrose 14.00000 mannitol 12.25500 novagel RCN-151 1.60000 lemon flavor 0.47200 vanilla creme O.lS000 citric acid 0.45000 purified water q.s. to 100 EXA~LE V
~g~ WIV%
magnesium aluminum silicate 4.00000 bismuth subsalicylate 21.69930 polysorbate 80 0.03500 sodium saccharin 0.04550 aspartame l.00000 sucrose 2.00000 mannitol 4.15000 novagel RCN-ISl 1.40000 strawberry flavor 0.54600 vanilla creme 0.54990 citric acid 0.06690 ~ucel EF ?IF2 0.25200 antifoam AF3 0.21000 purified water q.s. to 100 EXAMPLE Vl w~o/o magnesium aluminum silicate 4.00000 ~ 3.50000 p,~ .; - 80 0.03500 wos~/33446 2~91~i~2 r_l/u,.,~
sodium saccharin 0.04550 aspartame 0.04550 sorbitol 0 70000 sucrose 8.25000 mannitol 16.29800 novagel RCN- 151 1.40000 cherry flavor 0.19460 vanilla creme 0.24780 citric acid 0.28320 antifoam AF3 0.21000 purified water q.s. to 100 I Supplied by FMC Corporation, Ph;lalel~ ;4 Pa.
2Supplied by AQUALON, Hopewell, Va.
3Supplied by Dow Coming, Midland, Mich.
Examples IV -VI are further examples of ~u ~used in treating the .
symptoms of y,.l~Llu;llL~aL;ll.ll illnesses in humans and are ~ luur~,Lu~;d in a manner substantially similar to Example III. Ad~ ;un of two tablets is the nommal and customary dosage.
Claims (8)
1. An oral pharmaceutical composition comprising:
(a) a nonrupturable drug matrix comprising:
i) a taste masking agent selected from the group consisting of silicate clays, acrylic polymer resins, natural gums, and waxes; and ii) a safe and effective amount of at least one pharmaceutically active ingredient; and (b) an orally acceptable pharmaceutically carrier wherein said pharmaceutically acceptable carrier is rapidly disintegrated in aqueous solution without the need for mastication and wherein said composition provides an immediate release of the pharmaceutically active ingredient.
(a) a nonrupturable drug matrix comprising:
i) a taste masking agent selected from the group consisting of silicate clays, acrylic polymer resins, natural gums, and waxes; and ii) a safe and effective amount of at least one pharmaceutically active ingredient; and (b) an orally acceptable pharmaceutically carrier wherein said pharmaceutically acceptable carrier is rapidly disintegrated in aqueous solution without the need for mastication and wherein said composition provides an immediate release of the pharmaceutically active ingredient.
2. A pharmaceutically according to Claim 1 wherein said carrier is a freeze-dried matrix, an effervescent system, or a liquid/liquid extract system.
3. A pharmaceutical composition according to any one of the preceding Claims wherein the composition additionally contains one or more flavoring agents wherein the flavoring agent is preferably selected from the group consisting of menthol,peppermint, spearmint, raspberry, cherry, orange, vanilla, anise, blueberry, banana, chocolate, caramel, strawberry, lemon, lime, grape and mixtures thereof.
4. A pharmaceutical composition according to any one of the preceding Claims wherein the composition additionally contains one or more sweetening agents wherein the sweetening agent is preferably selected from the group consisting ofsodium saccharin, aspartame, monoammonium glycyrrhizate, sucrose, mannitol and mixtures thereof.
5. A pharmaceutical composition according to any one of the preceding Claims wherein the composition additionally contains one or more releasing agents wherein the releasing agent is preferably selected from the group consisting of: polysorbate 80, sodium lauryl sulfate, magnesium stearate and mixtures thereof.
6. A pharmaceutical composition according to any one of the preceding Claims wherein the composition additionally contains one or more cooling agents whereinthe cooling agent is preferably selected from the group consisting of 3-1-methoxypropane 1,2-diol, N-ethyl-p-methane-3-carboxamide, N,2,3-trimethyl-2-isopropylbutanamide and mixtures thereof.
7. A pharmaceutical composition according to any one of the preceding Claimswherein the pharmaceutical active ingredient is a gastrointestinal agent.
8. A pharmaceutical composition according to any one of the preceding Claims wherein the pharmaceutical actives are selected from the group of pharmaceuticalactives consisting of acetaminophen, ibuprofen, dextromethorphan, HBr, doxylamine succinate, pseudoephedrine HCI, phenylpropanolamine HCI, chloropheniramine maleate, guaifenesin, triprolidene HCI, diphenhydramine HCI, and mixtures thereof, preferably pseudoephedrine HCI and chlorpheniramine maleate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US25389094A | 1994-06-03 | 1994-06-03 | |
| US253,890 | 1994-06-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2191562A1 true CA2191562A1 (en) | 1995-12-14 |
Family
ID=22962124
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2191562 Abandoned CA2191562A1 (en) | 1994-06-03 | 1995-05-31 | Fast dissolving dosage forms |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0762869A1 (en) |
| JP (1) | JPH10501235A (en) |
| BR (1) | BR9507909A (en) |
| CA (1) | CA2191562A1 (en) |
| WO (1) | WO1995033446A1 (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000290199A (en) * | 1999-03-31 | 2000-10-17 | Taisho Pharmaceut Co Ltd | Oral medicinal composition |
| SE518184C2 (en) | 2000-03-31 | 2002-09-03 | Perstorp Flooring Ab | Floor covering material comprising disc-shaped floor elements which are joined together by means of interconnecting means |
| WO2005013944A1 (en) * | 2003-08-11 | 2005-02-17 | Merck Frosst Canada Ltd. | Flavored taste-masked pharmaceutical formulation made using a one-step coating process |
| US7201920B2 (en) | 2003-11-26 | 2007-04-10 | Acura Pharmaceuticals, Inc. | Methods and compositions for deterring abuse of opioid containing dosage forms |
| ES2516693T3 (en) | 2006-03-16 | 2014-10-31 | Euro-Celtique S.A. | Pharmaceutical spheroids |
| WO2010017296A1 (en) * | 2008-08-05 | 2010-02-11 | Wyeth | Lyophilization above collapse |
| MX2011008671A (en) | 2009-04-01 | 2011-09-06 | Colgate Palmolive Co | Dentifrice compositions and methods for treating and preventing damage to tooth surfaces. |
| EP3064064A1 (en) | 2009-09-30 | 2016-09-07 | Acura Pharmaceuticals, Inc. | Methods and compositions for deterring abuse |
| EP3446685A1 (en) | 2012-11-30 | 2019-02-27 | Acura Pharmaceuticals, Inc. | Self-regulated release of active pharmaceutical ingredient |
| GB2537652A (en) | 2015-04-22 | 2016-10-26 | Cosmetic Warriors Ltd | Composition |
| US11103581B2 (en) | 2015-08-31 | 2021-08-31 | Acura Pharmaceuticals, Inc. | Methods and compositions for self-regulated release of active pharmaceutical ingredient |
| JP6907486B2 (en) * | 2015-09-10 | 2021-07-21 | 大正製薬株式会社 | Solid formulation |
| JP7077589B2 (en) * | 2016-11-29 | 2022-05-31 | 大正製薬株式会社 | Solid product |
| CN112972439A (en) * | 2019-12-16 | 2021-06-18 | 南京亿华药业有限公司 | Yumei effervescent tablet and preparation method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK0494972T3 (en) * | 1989-10-02 | 1997-05-12 | Cima Labs Inc | Shower dose form and method of administration thereof |
-
1995
- 1995-05-31 WO PCT/US1995/006855 patent/WO1995033446A1/en not_active Application Discontinuation
- 1995-05-31 BR BR9507909A patent/BR9507909A/en not_active Application Discontinuation
- 1995-05-31 JP JP8501157A patent/JPH10501235A/en not_active Ceased
- 1995-05-31 CA CA 2191562 patent/CA2191562A1/en not_active Abandoned
- 1995-05-31 EP EP95921526A patent/EP0762869A1/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| BR9507909A (en) | 1997-08-12 |
| EP0762869A1 (en) | 1997-03-19 |
| JPH10501235A (en) | 1998-02-03 |
| WO1995033446A1 (en) | 1995-12-14 |
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