CA1268710A - Drug in bead form and process for preparing same - Google Patents

Abstract

ABSTRACT

A bead of a drug such as ASA or acetaminophen formed from a small spheriodal seed particle of the drug or of an inert material coated with an adhesive and layers of drug particles likewise adhered by said adhesive, is provided. The beads may be rendered suitable for time release by coating a plurality of said beads. An 8-12% polyvinylpyrrolidone (PVP) solution may be used as the adhesive, the PVP complexing with ASA and acetaminophen to reduce irritation of the user. Additionally, a method for manu-facturing a drug in small beads having time release properties is also provided.

Description

~26~71~ 1 " DRUG IN ~EAD FORM AND PROCESS FOR PREPARING SAME

~ACKGROUND OF THE INVENTION

ThL~ Inventlon relates to ~ m~thod or ~nU~cturlng a drug, especially acetylsalicylic acid ~hereinafter called "ASA"), acetaminophen, or the like, ln smail b~s to be placed in a capsuLe and to th~ drug tnu~ produced. In j . partlcular, the method lnvolves prcparatlon of a drug uslng a !

coating, such as ~n ~queous polymerlc coat~ng, on at le~st a portfon j of the bead~, whlch results ln sustained re1ea~e when tr~vellng through the digestive system.

Tlme release cap~ules contalnlng a drug are made by elther microencapsulation or by coating a seed, referred to ~5 the Nupareil seed coating process. In both the encapsulation process and the .

. Nupareil seed coating process~ however, it is aot feaslble to obtain i ¦¦6S0 mg of the active lngredient in bead orm to be enclosed in a zero ¦sized capsule. In a microencapsulation process, nearly 25~ of the l¦capsule is sugar, starch and moisture with the remainder being the 11 jlactive ingredient. Consequently, only ~50-S00 mg of active in- !

jlgredient may be contained in a zero sized capsule. In the Nupareil jseed coating process, seeds are relatively large, commonly 20-40 ¦mesh and, thus, coated seeds do not permit more than S00-S50 mg to I be encapsulated in bead form in a zero sized capsule.
An additional procesg involves granulation, in which the . drug used is combined with a starch and other materials, including i an adhesive, and the material is then forced through a screen. This process, however, also limits the amount of drug that can be 1 encapsulated to less than 550 mg.
I In U.S. patent 3,524,910 to Holiday et al., granules of ¦¦aspirln are encapsulated in a gelatin capgule. Additionally, the . .

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¦patent dlscloses sustained r~le~se of a portion oS the actlve ¦ingredlent-over an extended Rerlod of time by co~tlng some of the ¦qranules wLth ethylcellulose ln order to provlde an analgeslc effect ¦of prolonged duratlon. However, the ~ollday et al. delayed release ¦aspirln compound capsule has dlsadvantages Ln that a zero sized ¦capsule would not be sufficlently large ~n volume for holdlng the compound. AddltLonally, ~ngestLon of the ASA compound may produce undeslred g~trlc lrrltatlon.
I~ Accordingly, lt ls deslrable to provlde an improved metho~
i~ for manu~acturing sustalned release ASA ln a capsule.

SUMMARY OF T~E INVENTION

Generally speaking, in ~ccordance with the present inven-! tion, a bead of a drug is provided formed from a small spheroidal seed l particle of the drug coated with an adhesive and layers of particles i of the drug likewise adhered by said adhe~ive. The bead may be rendered suitable for time release by a suitable coatlng and a plurality of said beads, both coated and uncoated, may be provided in a capsule for dosage control. The drug is preferably ASA
acetaminophen, or the like. The adheslve is preferably poly-vinylpyrrolidone (PVP). In the case where the drug is ASA or acetaminophen, the adhesive is selected to complex with the ASA
or acetaminophen. The core is preferably essentially spheroidal and of 60-80 mesh size. In the case of ASA acetaminophen or like product, the core may be an essentially spheroidal seed particle formed from a pharmacologically suitable material such as potassium hloride or microcrystalline cellulose. The resultant drug beads onsist of at least 50~ by weight of the drug and preferably in excess f 90~ by weight.

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Further, ln accord~nce ~ith thc present Inventlon, a method ¦for manufacturlng 6 drug Ln small be~ds to b~ pl~c~d In a capsule ls provlded, preferably ln a tlme release form. In ~Ccordance wlth the Imethod, small, essentlnlly spheroldal seed partlcle3 of a pharma-¦cologlcally sultable m~terlal such as potQsslum chlorlde or mlcro-¦cry~talllne cellulose, are coated by ASA acet~mfnophen, orother dru~ p~rtlcles by placlng the partlcles ln a rotatlng coatlng , pan contalnlng baffles. AlternatlVely, sm~ll es~entlally spher-oldal cores of actlve drug lng~edlent are coated by placlng them ~n . a rotatlng coatlng pan contalnlng baffles. ~he baffles rotate the partlcles for a unlform coatlng.

! A solutlon of a sultable adhe~lve, preferably a solutlon of i polyvinylpyrrolldone (PVP) ln lsopropyl alcohol, ls added to the l coating pan ln order to uet the partlcles' surfaces. Following the i addltlon of the adheslve, a small amount of the active ingredfent in particulate form is entered into the coating pan and adheres to the coated spheroidal particles. The particles are then dried and the i process is repeated untll small beads are formed, comprlsing ap-! proxlmately S0-98~ of actlve ingredient.
Afterwards, a portion of the beads may be coated with an I aqueous polymeric coatlng in order to prevent immediate dissolution in the digestive tract. All the beads are then placed in a capsule, such as a zero or A sized capsule, for later medicinal use.
~f the active ingredient is ASA, it is found that a PVP-ASA complex is formed which reduces gastic irritatlon. SimiLarcomplexing is found in the case of acetaminophen.
Accordingly, it is an object of the invention to provide an iml:roved method of manufacturing a drug.

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!l Yet another object of the invention ls to provlde an ¦lmproved method of manufacturing a drug ln small beads to be placed ¦in ~ capsule.
It is still a further object of the lnventlon to peovlde an lmproved method for manufacturing a drug for enclosure of 650 mg in a zero or A slzed capsule.
St~ll another object o the lnven~ion is to provlde an lmproved method for manufacturing a drug for efectlve time release. ' It ls a further ob~ect of the lnvention to produce ~ bead ;
form of drug suitable for time release coating ~nd consl8t~ng o~ at i least 503 by weight and preferably in excess of 90~ by weight of the ¦
drug.
It is still another object of the lnventlon to produce a i bead form of ASA , acetaminophen or the like.
Still other objects and advantages of the inventlon wlll, i ¦in part be obvious and will in part be apparent from the speci- !
l fication.
¦ The invention accordingly comprises the several steps and !
the relatlon of one or more of such steps with respect to each of the i others, and the composition possessing the features, properties, and I
the relation of components, which are exemplified in the following ¦
detalled disclosure, and the scope of the invention will be indicated ¦
in the claims.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In a first embodiment of the invention, essentially spher- i oidal core particles of active inqredient ranging from 60 to 80 mesh I
are placed in a conventional coating pan having a baffle system ¦
attached thereto. The coating pan rotates about an axis defining an 12~ '3,Q

acute angle with the horizontal plane, with particles tending to remain at the lower region thereof. The inwardly projecting, ¦V-shaped baffle~ help the particles rotate during the coating opera-¦tlon. The baffle system extends essentially parallel to the axis of ¦rotatlon of the coating pan, the walls of the baffle~ defining a0-45 angle with respect to said axis of rotation, and preferably a lS angle.
A solution of polyvinylpyrrolidone ~PVP) in isopropyl alcohol is added to the coating pan and poured over the core material to sufficiently weteach particle'ssurface. The PVP solution serves as an adhesive and may range from 8 to 12~, but preferbaly is a 10~
solution. The amount of PVP solution is selected to be sufficient to wet the surface of the drug particles. An excess of PVP should be avoided to aid in avolding agglomeration. optionally, a small , amount of talc or other suitable lubricant, such as magnesium stearate, is added to minimize particle agglomeration. Manual or mechanical agitation may also aid in preventing the beads from ¦ sticking to each other.
Following the addition of PVP adhesive, the active in-gredient in powder form, 60-80 mesh, is sprinkled into the coating l pan, thereby sticking to the coated spheroidal cores. This process i is then repeated from four to eight times, preferably five times, with the addition of PVP solution at each repetition.
! The particles are then dried by means of a warm-air blower, l until completely dried. The particular drying mechanism should i provide fast drying and thus, a warm-air flow between the temperature ranges of 40oC. to 60C. is preferable.
i After drying, the process of adding active ingredient and ¦PVP adhesive is repeated between 10-S0 times, preferably 30-40 _5_ ~26~
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times. It 13 to be noted thatno more talc is added atthls partlcular ¦stage. Once the process of addlng the actlve lngredlent and PVP
¦solutlon i~ completed, the rotating coating p~n will contaln es-~entially spheroidal beads comprislng approxl~ately 503-98~ active l ingredlent, preferably 90~-9St. These bead8 ~e drled on a tray i dryer for a perlod of 6-8 hours, ln order to remove traces of , lsopropyl alcohol. rhe tray dryer ~houid be at a temperhture between 40-450C.
The next step consists of coating 25-75t, preferably 50~, , of the beads with an aqueous polymerlc solutlon. The aqueous polymer : is preferbaly ethylcellulose ~pseudolatex~ (~old under the trade-mark A~UACOAT~ having a solutlon concentration between about 3.5~-20.0~, but may also be an anionlc polymer syntheslzed from a ~Imethacrylic acid and methacryllc acid methylester ~sold under the !~ trademark EUDRAGIT L). ~he coating is applied in order to prevent immediate dissolution in the stomach so that the product has time ¦release properties.
In accordance with the invention, the aqueous polymeric solution is coated on the ~eads by use of an air-suspension coating device, such as an Aeromatic Strea-l, made by the Aeromatic Company.
In this process, beads are suspended in a column which is supplied with warm, compressed air while the solution is cprayed into the column. The liquid spray is coated on the beads and immedlately dried in warm air. Due to evaporation, surface temperature drops, thus minimizing the decomposition of ASA . After the first coat is dry, water can no longer attack the ASA. All the beads are then put into a zero sized or ~ sized capsule for packag~ng in a medicinal container.
In a further embodiment of the invention, coating of various pH sensitive acrylic polymer3 may be placed on the beads not 37~g coated with an aqueous acrylic polymer. Roughly one-half of the uncoated beads are coated with a polymer which is pH 6 sensitive while the other one-half are coated uith a polymer which is pH 7 sensitive. These various coatings promote dissolution along various points in the alimentary canal.
In an alternative method the drug is manufactured by first using small, spheroidal seed particles, ranging from 60 to 80 mesh such as potassium chloride or microcrystalline cellulose.
These particles are placed in a rotating coating pan having baffle system attached thereto. A solution of PVP in isopropyl alcohol is added to the coating pan to serve as an adhesive. Optionally, talc may be added. Following the addition of the PVP adhesive, powdered active ingredient, 60-89 mesh, is sprinkled into the coating pan, thereby sticking to the coated seed particle. The process continues in the same manner as discussed previously.
Depending on the active ingredient used in the starter core or the composition used in the seed particle, if may be necessary to first round off the core or seed before placement in the coating pan. Such is the case when potassium chloride is used as seed particles or aspirin is used for starter core particles.
Consequently, 60-80 mesh seed or core particles are first placed in a ~obart mixer. By simultaneously mixing the particles and adding a small amount of alcohol or hydroalcoholic solution, the individual particles are rounded-off and become spheroidal in shape.

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In the specific case where aspirin or acetaminophen is the active ingredient, the ASA or acetaminophen forms a molecular complex with the polyvinylpyrrolidone. In testing, it uas found that the ASA product in accordance with the invention was characterized by reduced gastric irritation. Similarly, it is expected that the acetaminophen product would be characterised by reduced gastric irritation. This is due to a layered complex in the product -7a-'7~e slnce e~ch PVP co~ted I~yer dissolvcs aspiriO or ~cet~minophen In successive stages within the stomach These complexe3 are simllar to a PVP-iodine complex whlch eliminates irrlt~tlon of iodine when a PVP-lodine product 1s placed on abraded ~kin. These co~plexes are shown to be present by the conventional equlllbrlum dlalysis tech-nlque.
The following examples are intended to 111ustrate th~ I
¦lnventLon and should not be construed as limiting the lnvention ¦
: thereto.
Example 1 100 grams of microcrystalline cellulose particle~, 60 to 80 mesh, were placed lnto a 16 inch pear-shaped conveDtional coating pan. The pan had a triangular baffle system attached at a 15 angle to the axis of rotation to the pan. After the pan was turned on, 10~

! polyvlnylpyrrolldone solution in isopropyl alcohol was poured over the microcrystalline cellulose particles in order to wet the par-i ticles' surfaces. ASA powder, 60 to 80 mesh, was then sprinkledinto the pan. A small amount of talc was also added to prevent ¦ particle agglomeration. The steps of adding PVP solution, sprink-i ling ASA powder and adding talc were repeated five times. The resulting particles were then dried by means of a warm air blower at a temPerature of about 50 C. After drying, the steps of sprinkling ASA powder and adding PVP solution were repeated 40 times until small beads were formed comprising 90 to 95~ ASA The beads were ithen separated into equal parts. One part was coated with a 5 ethylcellulose "pseudolatex~ solution (sold under the trademar~
AQUACOAT) which included 1~ dibutylphthalate as plasticizer and purified water as solvent. The solution was coated on the beads by use of an air suspension-coating device wherein the beads were suspended in a column supplied with warm, compressed air onto which lZ6~i71~

¦~the solution was sprayed. After coatlng the beads, the beads were IImmedlately dried in warm ~ir. Follo~lng coating, each bead had a jwelght gain of 1.5~ ethylcellulose ~pseudolatex~ and 1~ dibu-i tylphthalate. Two equal part~ of coated and uncoated beads having I a diameter ranglng from about 1.8-3.0 mm were then mlxcd ln order to ~
¦get a weight equlvalent of 650mg of ASA The beads were placed j into ~n A sLzed ~old under the trademar~ CONI SNAP SUPR0) qelatin capsule.
Ex~mple 2 Using the pro~uct of Example 1 1Q comparison with that o Bayer's tlme released Aspirin*dlssolut~on o~ the drugs using the . United States Pharmacopla test was compared. ~fter choosing ~ive ,¦healthy volunteers, a randomized crossover design study was per-ilformed to compare the ~in vlvo~ release o each analgeaic. Each I subject ingested the product of Example 1 And Bayer's time released ¦tablet. 80th contained 650 mg o aspirin. The amount of analgesic excreted in the urine was then measured at various time intervals.
¦The results showed that the encapsulated ASA of Example 1 '¦compared well with Bayer's commerical product with regard to release ! pattern. Additionally, the subjects reported substantially lesser ¦irritation when using the composition in accordance with the in-i vention.
1 Example 3 ! 300 grams of potassium chloride, 60 to 80 mesh, were placed in a Hobart mixing bowl having a 2 Iiter capacity. The mixer was set at speed of 4S0 rpm and then turned on. A small amount of 70~ ethyl alcohol in water was added to the bowl in order to help round off the potassium chloride crystals. After 5 minutes of mixing, the potas-¦sium chloride particles were air dried on a tray. 100 grams of ~* trademark 7;~3 ~ potassium chloride particles were then placed into a 16 inch pear-i shaped conventional coating pan. The pan had a triangular baffle system attached at a 15 angle of rotation to the pan. After the pan was turned on, 10~ PVP solution in isopropyl alcohol was psured over the potassium chloride particles in order to wet their surfaces.
ASA powder, 60 to 80 mesh, was then sprin~led into the pan. A
small amount of talc was also added to prevent particle agglomera-l tion. The steps of adding PVP solution, sprinkling ASA and ~ ladding talc were repeated five times. After drying, the steps of sprinkling AS~ powder and adding PVP solution were repeated 40 times, as in Example 1, until small beads were formed comprising approximately 90 to 95~ ASA The beads were then separated into jthree groups of 50~, 25& and 25& by weight. The 50& group was leftunchanged. The second group (25~) was coated with an aqueous anionic polymer solution synthesized from methacrylic acid and methacrylic acid methylester ~sold under the trademark EUDRAGIT L). The beads were coated using the air suspension coating method of Example 1.
' Following coating, each bead had a weight gain of 15~ anionic I polymer. The third group (25&) was coated with a 20& alcoholic anionic polymer solution in a similar manner as the second group l except that the anionic polymer was dissolved in isopropyl alcohol i rather than water. The solution also contained 15~ dibutylphthalate as plasticizer. Each bead of the third group had a weight gain of 15~ anionic polymer and 15~ dibutylphthalate. Thereafter, the three groups of beads having a diameter ranging from about 1.8 - 3.0 mm were mixed in order to get a weight equivalent of 650mg of ASA. The beads were placed in an A sized gelatin capsule.

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Example 4 l 300 grams of ASA , 60 to 80 mesh, were placed in a Hobart ,¦mixing bowl having a 2 liter capacity. The mixer was set at speed o 450 rpm and then turned on. A small amount of pure isopropyl alcohol was added in order to help round off the ASA particles.
¦After 5 minutes of mixing, the particles were air dried on a tray.
100 grams of ASA particles were then placed into a 16 inch Icoating pan. The pan had a triangular baffle system. The baffle ¦system was placed at a 15 angle of rotation to the pan. After turning on the pan, 10~ PVP solution in isopropyl alcohol was poured over the ASA particles in order to wet their surfaces. ASA
powder, 60 to 80 mesh, was then sprinkled into the pan. A small iamount of talc was also added to prevent particle agglomeration. The ,Iprocess was then continued as in Example 1. A weight equivalent of 650mg of ASA in bead form were placed in a zero sized gelatin ~capsule.
~I Example S

il 300 grams of spheroidal particles containing acetaminophen and chlorpheniramine maleate in the ratio of 325 to 2 by weight jlsold under the trademark COMPAP-CPM), were placed into a 16 inch l coating pan. The pan had a triangular baffle system attached at a i 15 angle to the axis of rotation to the pan. After the pan was turned ! on, 10~ PVP solution in isopropyl alcohol was poured over the ! particles in order to wet the particles' surfaces. Acetaminophen ¦powder, 60 to 80 mesh, was then sprinkled into the pan. A small ¦amount of talc was also added to prevent particle agglomeration. The ',steps of adding PVP solution, sprinkling acetaminophen and adding ,¦talc were repeated five times. The resulting particles were then 'Idried by means of a warm air blower at a temperature of ap-l¦proximately 50 C. The steps of sprinkling acetaminophen powder and ~ 1 ~26~

adding PVP solution were repeated 35 times until small beads were ¦formed, comprising 90 to 95~ acetaminophen. The beads were then ¦coated with an aqueous polymeric solution in accordance with the ¦procedure set forth in Example 1 in order to get a weight equivalent l ¦of 650mg of acetaminophen in beads. The beads were placed in a zero i ¦sized gelatin capsule.
il Example6 The method of Example 1 was followed except that 3.5~ ethyl cellulose ~pseudolatex~ solution ~sold under the trademark AQUA-COAT) including 1~ dibutylphthalate as plasticizer was used to coat 1, the beads. Following coating, each bead had a weight gain of 1.0%

, ethylcellulose "pseudoLatexU and 10~ dibutylphthalate. Two equalparts of coated and uncoated beads ranging from about 1.8 - 3.0 mm were then mixed to get a weight equivalent of 650 mg of ASA. The ll beads were placed into an A sized gelatin capsule.
I
t, !, Example 7 i The method of Example 1 was followed except that 20.0 ethylcellulose "pseudolatex~ including 1~ dibutylphthalate as plas- ~
ticizer was used to coat the beads. ~ollowing coating, each bead had ;
a weight gain of 6.0~ ethyl cellulose "pseudolatex" and 1~ di- !
butylphthalate, Two equal parts of coated and uncoated beads ranging , from about 1.8 - 3.0 mm were then mixed to get a weight equivalent j llof 650 mg of -~SA. The beads were placed in a zero sized gelatin ! capsule.

Example 3 The method of Example 1 was followed except that 8.0~ PvP
! solution in isopropyl alcohol was used as adhesive. Small beads were ,¦ formed comprising 90-95~ ~S~ which were then coated with an 1 '~2 l l I
aqueous polymeric coating as Example 1 states. Two equal parts of coated and-uncoated beads ranging from about 1.~ - 3.0 mm were then mixed to get a weight equivalent of 6S0 mg of ~SA. The beads were placed in a zero si~ed gelatin capsule.
l Example 9 ! The method of Example 1 was used except that 12.0~ PVP
solution in isopropyl alcohol was used as an adhesive. Small beads were formed comprising 90-95~ ASA which were then coated with an aqueous polymeric coating as Example 1 states. Two equal parts of coated and uncoated beads ranging from about 1.8 - 3.0 mm were then mixed to get a weight equivalent of 650 mg of AS~. The beads were placed in an A sized gelatin capsule.
The final ASA products in Examples 1-4 and 6-9 were tested for free salicylic acid content according to U.S. pharmacopia procedure. The ASA products were found to be within U.S.
I Pharmacopia specification.
Although polyvinylpyrrolidone (PVPJ in isopropyl alcohol is the adhesive composition disclosed in the examples, any suitable adhesive material w~ich is non-toxic and non-allergenic, preferably a natural or synthetic polymer, and preferably a complexing agent, may be used for coating the seed particles and adhering layers of i drug particles.
Additionally, although aqueous and alcohol-based polymeric coatings are the coatings ~or preventing immediate dissolution of the drug in the digestive tract disclosed in the examples, it is understood that any suitable coating which results in sustained release when travelling through the digestive tract may be used.
While microcrystilline cellulose and potassium chloride particles are used as seeds in the examples, any suitable pharma-coloqic-lly inert ma~erial cap~ble of formation t~ith small sized r~
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spheroidal material may be used as seeds in addition to particles of ¦
the drug ltself.
Although a conventional coating pan having a baffle system 1, l attached thereto is used in the examples, commercial high-speed j I rotation granulators may also be used for formation of beads from i spheroidal seed particles. I
, Furthermore, although ASA and acetaminophen are the j i drugs disclosed in the examples the method of manufacture of bead forms of drugs in accordance with the invention ls suitable for any , drug available in powered form.
It will thus be seen that the objects set forth, among those ¦
made apparent from the preceding description, are efficiently ob-i tained and, since certain changes may be made in carrying out the i above method and in the composition set forth without departing from I the spirit and scope of the invention, it is intended that all matter ~
contained in the above description shall be interpreted as il- I
, lustrative and not in a limiting sense.
l It is also to be understood that the following claims are I intended to cover all the ger.eric and specific features of the invention herein described and all statements of the scope of the , invention which, as a matter of language, might be said to fall i therebetween.

i Particularly, it is to be understood that in said claims, ! ingredients or compounds recited in the singular are intended to include compatible mixtures of such ingredients wherever the sense permits.

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Claims (61)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. An ASA product comprising a bead formed of a central seed having a mesh size between about 60 and 80 and successive layers of powdered ASA added to the seed or to the preceding layer by an adhesive comprising between about an 8 and 12% solution of polyvinylpyrrolidone in alcohol, the bead in-cluding at least 50% by weight of ASA.

2. The ASA product as recited in claim 1, wherein the adhesive has formed a complex with the ASA to reduce user irritation.

3. The ASA product of claim 1, wherein the seed is formed of pharmacologically inert material formed into an essen-tially spheroidal particle.

4. The ASA product of claim 3, wherein the seed material is selected from the group including potassium chloride and microcrystalline cellulose.

5. The ASA product of claim 1, wherein the seed is formed of a particle of ASA.

6. The ASA product of claim 5, wherein the seed particle of ASA is essentially spheroidal in shape.

7. The ASA product as recited in claim 1, wherein the bead is coated with a suitable time release material.

8. The ASA product as recited in claim 7, wherein the time release material includes a material selected from the group including ethylcellulose "pseudolatex", an aqueous anionic polymer and an alcoholic anionic polymer.

9. The ASA product as recited in claim 1, wherein the bead includes at least 90% by weight of ASA.

10. The ASA product as recited in claim 1, and including a plurality of said beads encapsulated in a capsule.

11. The ASA product as recited in claim 10, wherein the capsule is selected from the group including zero and A sized capsules.

12. The ASA product as recited in claim 11, wherein at least a portion of the beads are coated with a suitable time release material.

13. An acetaminophen product comprising a bead formed of a central seed and successive layers of powered acetaminophen added to the seed or to the preceding layer by an adhesive, the bead including at least 50% by weight of acetaminophen.

14. The acetaminophen product as recited in claim 13, wherein the adhesive has formed a complex with the acetaminophen.

15. The acetaminophen product as recited in claim 14, wherein the adhesive is polyvinylpyrrolidone.

16. The acetaminophen product as recited in claim 14, wherein the adhesive is A non-toxic, non-allergic polymer.

17. The acetaminophen product as recited in claim 13, wherein the seed is 60-80 mesh in size.

18. The acetaminophen product of claim 17, wherein the seed is formed of pharmacologically inert material formed into an essentially spheroidal particle.

19. The acetaminophen product of claim 18, wherein the seed material is selected from the group including potassium chloride and microcrystalline cellulose.

20. The acetaminophen product of claims 13, wherein the seed is formed of a particle of acetaminophen.

21. The acetaminophen product of claim 20, wherein the seed particle of acetaminophen is 60-80 mesh in size.

22. The acetaminophen product of claim 21, wherein the seed particle of acetaminophen is essentially spheroidal in shape.

23. The acetaminophen product as recited in claim 13, wherein the bead is coated with a suitable time release material.

24. The acetaminophen product as recited in claim 23, wherein the time release material includes a material selected from the group including ethylcellulose "pseudolatex", an aque-ous anionic polymer and an alcoholic anionic polymer.

25. The acetaminophen product as recited in claim 13, wherein the bead includes at least 90% by weight of acetaminophen.

26. The acetaminophen product as recited in claim 13, and including a plurality of said beads encapsulated in a capsule.

27. The acetaminophen product as recited in claim 26, wherein the capsule is selected from the group including zero and A sized capsules.

28. The acetaminophen product as recited in claim 27, wherein at least a portion of the beads are coated with a suitable time release material.

29. A drug product in bead form comprising a central seed having a mesh size between about 60 and 80 formed from an essentially spheroidal particle of the drug material and layers of granules of said material adhered to the seed or to the preceding layer by an adhesive comprising between about an 8 and 12% solution of polyvinylpyrrolidone in alcohol.

30. A drug product as recited in claim 29, wherein the bead includes at least 50% of weight of the drug.

31. A drug product as recited in claim 30, wherein the bead includes at least 90% by weight of the drug.

32. A drug product as recited in claim 29 and including a plurality of said beads, at least a portion of said beads including a time release coating.

33. A method for manufacturing a drug in bead form incorporating ASA or acetaminophen as the principal active ingredient comprising:
successively coating small sized seeds with layers of active ingredient using an adhesive, the resultant beads including at least 50% by weight of the active ingredient.

34. The method of claim 33, wherein the beads include at least 90% by weight of the active ingredient.

35. The method of claim 33, wherein the adhesive is selected to complex with the active ingredient for reducing user irritation.

36. The method of claim 35, wherein the adhesive is polyvinylpyrrolidone (PVP).

37. The method of claim 35, wherein the adhesive is a non-toxic, non-allergic polymer.

38. The method of claim 33, wherein the seeds are about 60-80 mesh in size.

39. The method of claim 33, wherein the seeds are formed of a pharmacologically inert material formed into an essentially spheroidal particle.

40. The method of claim 39, wherein the seed material is selected from the group including potassium chloride and micro-crystalline.

41. The method of claim 33, wherein the seeds are formed of particles of the active ingredient.

42. The method of claim 41, wherein the seed particle of active ingredient is 60-80 mesh in size.

43. The method of claim 42, including making the seed particles of the active ingredient essentially spheroidal in shape.

44. The method of claim 43, wherein the spheroidization of the active ingredient seed particles is by subjecting parti-cles of the active ingredient to a rolling motion in the presence of a solvent.

45. The method of claim 39, including makin the seed particles essentially spheroidal in shape.

46. The method of claim 45, wherein the spheroidization of the seed particles is by subjecting said particles to a rolling motion in the presence of a solvent.

47. The method of claim 36, wherein said coating further comprises:
adding a sufficient quantity of PVP in solution for coating the seeds and adhering added particles of the active ingredient to the seeds;
adding a sufficient quantity of particles of the active ingredient to form a layer on the seeds;

successively adding PVP solution and particles of the active ingredient to define a total of five to nine layers of active ingredient; and drying the resultant intermediate beads.

48. The method of claim 47, wherein said coating further comprises successively adding additional PVP and particle of active ingredient to define a total of an additional ten to forty layers to form the bead.

49. The method of claim 48, wherein the coating step further comprises drying the beads.

50. The method of claim 49, wherein the step of drying the beads at a temperature of about 40°C - 45°C for a period of 6 to 8 hours.

51. The method of claim 47, wherein the step of drying the intermediate beads is by a warm air blower at a temperature of about 40°C to 60°C.

52. The method of claim 47, including adding talc to the adhesive and particles of the active ingredient during the formation of the intermediate beads.

53. The method of claim 48, including adding talc to the adhesive and particles of its active ingredient during formation of the intermediate beads, the formation of the final bead from the intermediate bead being without additional talc.

54. The method of claim 36, wherein the adhesive is an 8-12% PVP solution in isopropyl alcohol.

55. The method of claim 54, wherein the PVP solution is about 10%.

56. The method of claim 33, wherein the coating is performed in a rotating coating pan having baffles extending essentially parallel to the axis of rotation of said coating pan.

57. The method of claim 33, further including coating at least a portion of the beads with a sustained release coating material.

58. The method of claim 57, wherein said time release coating material is a material selected from the group including an aqueous anionic polymer, an alcoholic anionic polymer and ethylcellulose "pseudolatex".

59. The method of claim 33, and further comprising encapsulating a plurality of said beads in a capsule.

60. The method of claim 59, wherein said capsule is selected from the group including zero and a sized capsules.

61. A drug in bead form incorporating ASA or aceta-minophen produced by the process of claim 36.